RESUMO
The tyrosine kinase inhibitor lenvatinib has been confirmed as an effective treatment option for patients with unresectable thyroid carcinoma. We conducted a retrospective analysis of the significance of the effect of continued lenvatinib treatment for the longest duration possible at a reasonable daily dose and with a minimum discontinuation period in 42 patients with unresectable thyroid carcinoma treated with lenvatinib between 2015 and 2020. A Cox proportional hazard model-based analysis revealed that the overall survival of the patients treated with a <8 mg/day mean dose of lenvatinib was significantly better than that of the patients treated with 8-24 mg/day (hazard ratio [HR] 0.38 for 1.14-4.54 mg/day, and HR 0.01 for 4.56-7.97 mg/day) adjusted for various factors (e.g., sex, age, drug interruption period). The cumulative dose of lenvatinib administered tended to be higher in the patients treated with low doses (< 8 mg/day) than in the patients treated with relatively high doses (8-24 mg/day). Considering its adverse events, the continuation of lenvatinib treatment with an adequate daily dose and drug interruption may help prolong the survival of patients with unresectable thyroid carcinoma.
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Antineoplásicos , Carcinoma , Quinolinas , Neoplasias da Glândula Tireoide , Humanos , Estudos Retrospectivos , Antineoplásicos/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Compostos de Fenilureia/uso terapêuticoRESUMO
Although the lung is the most common site of distant metastases from head and neck squamous cell carcinoma (HNSCC), the number of reports about the effects of pulmonary metastasectomy for the treatment of lung metastasis from HNSCC is limited. Metachronous pulmonary metastases were detected in 45 HNSCC patients at Kumamoto University Hospital from 1998 to 2018. Twenty-two patients underwent an operative resection (Ope group) and 23 underwent chemotherapy (Chemo group). The 3-year overall survival (OS) rate and median OS were evaluated. The effects of adjuvant chemotherapy after pulmonary metastasectomy and of new drugs (cetuximab and nivolumab), in the chemo group were also assessed. The 3-year OS rates and median OS were: Ope, 66.1% and 31.5 months; Chemo, 39.7% and 18 months, respectively. In the Ope group, addi-tional recurrences were significantly fewer in the patients who underwent adjuvant chemotherapy post-surgery versus the patients who underwent surgery alone (p = 0.013). In the Chemo group, the 3-year OS rate of the patients who received new drugs was significantly better than that of the patients who did not (p = 0.021). Adjuvant chemotherapy after pulmonary metastasectomy may be a preferable treatment option for preventing recurrences. Cetuximab and nivolumab have a potential to improve OS.
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Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Pulmonares/secundário , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/mortalidade , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Metastasectomia/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapiaRESUMO
PURPOSE: Immune checkpoint proteins programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important therapeutic targets for head and neck cancer. This large-scale case study aimed to analyze tongue squamous cell carcinomas (SCCs) and evaluate the correlation between PD-L1 expression and clinical prognosis. So far, this study is the largest case study on PD-L1 expression in tongue SCCs. METHODS: This is a case-control study that analyzed 121 tongue SCCs. Paraffin-embedded sections and clinical data were obtained retrospectively and immunohistochemistry with PD-L1 was performed. RESULTS: 11.6% contained ≥ 50% of PD-L1-positive cells, 57.1% of these cases had a poor prognosis with nodal metastasis. Among cases of T1/2 primary lesions with nodal metastasis, cases of high PD-L1 expression had a significantly shorter disease-free survival than cases of no PD-L1 expression (p = 0.018). The hazard ratio for high PD-L1 expression was 3.21 (95 per cent CI, 1.26-8.72) compared with no PD-L1 expression after adjusting for other factors. CONCLUSIONS: These data indicate that PD-L1 upregulation in tongue SCCs is associated with a more advanced stage and shorter disease-free survival. PD-1/PD-L1 inhibitors might hence constitute potential adjuvant therapy for tongue SCCs with PD-L1 upregulation.
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Antígeno B7-H1/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Neoplasias da Língua/mortalidade , Língua/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Antígeno B7-H1/antagonistas & inibidores , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Língua/cirurgia , Neoplasias da Língua/diagnóstico , Neoplasias da Língua/imunologia , Neoplasias da Língua/terapia , Regulação para Cima/imunologia , Adulto JovemRESUMO
BACKGROUND: Differentiated thyroid carcinoma (DTC) can invade the surrounding aerodigestive tract. Radical surgery for locally advanced DTC will require resection of the trachea, recurrent laryngeal nerve (RLN), inferior pharyngeal constrictor muscles (IPCMs), or a part of the esophagus. The purpose of this study was to demonstrate the effect of resection of these surrounding tissues combined with total thyroidectomy and neck dissection on swallowing function following surgery. METHODS: We performed total thyroidectomy combined with neck dissection and resection of the RLN in 24 patients with DTC with extrathyroidal invasion (19 unilateral, 1 bilateral), IPCMs (n = 5), or muscle layers of esophagus (n = 9). Nine patients received a tracheostomy placement due to a window resection of the trachea for tumor invasion (n = 6) and necessary upper airway management (n = 3). We used the duration of nasogastric tube feeding to evaluate swallowing function following surgery. RESULTS: Patients who underwent tracheostomy or IPCM resection showed significantly longer periods of tube feeding (p = 0.0057 and 0.0017, respectively). In contrast, resection of the unilateral RLN or esophageal muscle layer showed no difference in tube feeding duration. Multiple regression analysis indicated that tracheostomy and IPCM resection were significant independent predictors of longer periods of tube feeding (p = 0.04583 and 0.00087, respectively). CONCLUSION: These results indicate that tracheostomy placement and resection of the IPCMs, together with total thyroidectomy, extends the tube feeding duration in the postoperative period.
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Transtornos de Deglutição/etiologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Deglutição , Nutrição Enteral , Feminino , Humanos , Nervos Laríngeos/cirurgia , Masculino , Pessoa de Meia-Idade , Esvaziamento Cervical/efeitos adversos , Complicações Pós-Operatórias/etiologia , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia/métodos , Traqueia/cirurgia , Traqueostomia/efeitos adversosRESUMO
Intubation laryngeal granulomas (ILGs) are a well-known complication of endotracheal intubation. Cases other than ILGs can be categorized as unspecified laryngeal granulomas (ULGs) since their etiologies are often difficult to confirm. We intended to clarify clinical features of both ILGs and ULGs and that anticoagulant medication could cause the formation and delayed healing of ILGs in terms of wound-healing delay. We compared the results of our treatment of ILGs (n = 16) and ULGs (n = 47) treated between 1998 and 2009 to characterize these patients. The clinical course, treatment (medical vs. surgical), indications for surgical resection, treatment outcome, and use of anticoagulants for preexisting disease were reviewed and compared between these two groups. The resolution rate was significantly better in ILGs (p < .05). Five ILGs and seven ULGs were surgically resected. The main reason for resection was airway obstruction and the need for histological assessment, respectively. The use of anticoagulants was significantly higher in ILGs than ULGs (8/16 vs. 4/47, p < .01). The resolution period was significantly longer in the ILGs patients with anticoagulant medication compared to that in the ILGs patients without anticoagulant medication (152 ± 101 days vs. 76 ± 44 days, p < .05). ILGs may have different clinical course from ULGs, especially in terms of the resolution period. Moreover, administration of anticoagulants may deter healing of small injury due to intubation. Patients taking anticoagulants should be managed carefully during the perioperative period to prevent the occurrence of ILGs.
Assuntos
Granuloma Laríngeo/diagnóstico , Intubação Intratraqueal/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Obstrução das Vias Respiratórias/induzido quimicamente , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/patologia , Obstrução das Vias Respiratórias/cirurgia , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Feminino , Granuloma Laríngeo/induzido quimicamente , Granuloma Laríngeo/patologia , Granuloma Laríngeo/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Cicatrização/efeitos dos fármacos , Adulto JovemRESUMO
OBJECTIVES: We established an animal model of recurrent laryngeal nerve reinnervation with persistent vocal fold immobility following recurrent laryngeal nerve injury. METHODS: In 36 rats, the left recurrent laryngeal nerve was transected and the stumps were abutted in a silicone tube with a 1-mm interspace, facilitating regeneration. The mobility of the vocal folds was examined endoscopically 5, 10, and 15 weeks later. Electromyography of the thyroarytenoid muscle was performed. Reinnervation was assessed by means of a quantitative immunohistologic evaluation with anti-neurofilament antibody in the nerve both proximal and distal to the silicone tube. The atrophy of the thyroarytenoid muscle was assessed histologically. RESULTS: We observed that all animals had a fixed left vocal fold throughout the study. The average neurofilament expression in the nerve both distal and proximal to the silicone tube, the muscle area, and the amplitude of the compound muscle action potential recorded from the thyroarytenoid muscle on the treated side increased significantly (p < 0.05) over time, demonstrating regeneration through the silicone tube. CONCLUSIONS: Recurrent laryngeal nerve regeneration through a silicone tube produced reinnervation without vocal fold mobility in rats. The efficacy of new laryngeal reinnervation treatments can be assessed with this model.
Assuntos
Regeneração Tecidual Guiada/instrumentação , Regeneração Nervosa/fisiologia , Traumatismos do Nervo Laríngeo Recorrente/terapia , Nervo Laríngeo Recorrente/fisiologia , Silicones , Paralisia das Pregas Vocais/terapia , Prega Vocal/inervação , Animais , Modelos Animais de Doenças , Eletromiografia , Desenho de Equipamento , Feminino , Músculos Laríngeos/inervação , Ratos , Ratos Wistar , Traumatismos do Nervo Laríngeo Recorrente/complicações , Traumatismos do Nervo Laríngeo Recorrente/fisiopatologia , Paralisia das Pregas Vocais/etiologia , Paralisia das Pregas Vocais/fisiopatologiaRESUMO
BACKGROUND: Early detection of head and neck cancer recurrence after curative treatment is crucial for effective salvage treatment. OBJECTIVE: We aimed to examine the timing and method that allowed early detection of recurrence in each primary and recurrence site. MATERIALS AND METHODS: We enrolled 440 patients with head and neck squamous cell carcinoma (HNSCC) in the oral cavity, oropharynx, hypopharynx, or larynx who underwent curative treatment focusing on surgery at our hospital between 2009 and 2018. We examined the timing and diagnostic method (clinical examination, patient symptoms, or imaging examination) for HNSCC recurrence according to the primary and recurrence sites. RESULTS: Recurrence was observed in 133 patients. In all primary sites, regional recurrence occurred significantly earlier than local and distant recurrences. Local recurrence occurred later in the larynx than in other primary sites. Furthermore, the clinical examination had a higher ratio of detection of local recurrence in the larynx than in the other primary site. Regardless of the primary site, more than half of the regional recurrences and most of the distant recurrences were detected by imaging examination. CONCLUSIONS AND SIGNIFICANCE: Imaging examination is preferable for achieving early detection of regional and distant recurrences.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Detecção Precoce de Câncer , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/cirurgia , Resultado do Tratamento , Recidiva Local de Neoplasia/patologia , Estudos RetrospectivosRESUMO
Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a recently described sinonasal tract tumor that is associated with high-risk HPV subtype infection. Despite histological features that are suggestive of a high-grade malignant tumor, the prognosis of HMSC is relatively good; however, the clinical features of this tumor are poorly understood. Here, we describe two patients with HMSC. The first was initially diagnosed with adenoid cystic carcinoma of the right nasal cavity; the tumor was extirpated via endoscopic endonasal surgery. Seventy-four months later, the tumor recurred in the right inferior turbinate and was diagnosed as HMSC after biopsy, whereupon it was resected en block via endoscopic endonasal surgery. No adjuvant therapy was administered during either episode; moreover, no recurrences have occurred during the 44 months since the second operation. The second patient was diagnosed with HMSC based on the biopsy of the tumor occupying the left nasal cavity. The tumor was completely resected under endoscopic endonasal surgery, and no adjuvant therapy was administered. There has been no recurrence for 15 months after the operation. Herein, we also review the clinical features of this tumor type based on 69 previously reported cases as well as our patients.
Assuntos
Carcinoma Adenoide Cístico , Carcinoma , Infecções por Papillomavirus , Neoplasias dos Seios Paranasais , Humanos , Papillomavirus Humano , Neoplasias dos Seios Paranasais/diagnóstico por imagem , Neoplasias dos Seios Paranasais/cirurgia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Carcinoma/patologia , Carcinoma Adenoide Cístico/diagnóstico por imagem , Carcinoma Adenoide Cístico/cirurgia , Conchas Nasais/patologiaRESUMO
OBJECTIVE: To evaluate the impact of aging on vocal function following laryngeal reinnervation combined with arytenoid adduction (AA) in the treatment of paralytic dysphonia. METHODS: Sixty-eight patients with unilateral vocal fold paralysis who underwent refined nerve-muscle pedicle flap (NMP) implantation and AA were classified into four groups according to age: under 50 years (-50), in their 50s, 60s, and 70 years and older (70+). These groups consisted of 15, 14, 22, and 17 patients, respectively. Their vocal function was followed periodically for 24 months after surgery. RESULTS: Vocal function in all groups showed significant improvement after surgery. Significant improvements in vocal function were observed during a 24-month follow-up period: maximum phonation time in the -50 and 50 seconds groups; pitch range and voice handicap index-10 in the -50, 50s, and 60s groups; "Grade" in the -50, 50s, and 70+ groups; and "Breathiness" and voice-related quality of life in all groups. There were no significant differences in vocal function among the four groups, except for pitch range, at the 24-month postoperative assessment. CONCLUSIONS: Although the younger groups tended to exhibit better vocal function compared to the older groups 24 months postoperatively, the refined NMP+AA proved effective in the treatment of breathy dysphonia resulting from unilateral vocal fold paralysis, not only in the younger population but also in the older population.
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PURPOSE: Children with medical complexity frequently experience difficulty breathing and swallowing and occasionally develop aspiration pneumonia. Long-term intubation may cause fatal trachea-innominate artery fistula (TIF). In the present study, we retrospectively evaluated the efficacy of laryngeal closure and laryngostomy in children with medical complexity. MATERIALS AND METHODS: Laryngeal closure and laryngostomy were performed in eight children with severe neuromuscular disorders who were incapable of oral ingestion and verbal communication. The laryngostoma was placed at a higher position compared to that in conventional tracheostomies for easier management of the airway and to prevent TIF. RESULTS: Aspiration was successfully prevented postoperatively in all cases. Laryngocutaneous fistula formation was not observed. Two patients successfully achieved oral ingestion capability and tracheal cannulas were removed in two patients. Among the six patients who needed a mechanical ventilator before surgery, two patients were weaned from mechanical ventilation. Five patients were successfully discharged from the hospital. Although two patients died because of their primary condition, pneumonia exacerbation was not observed in any of the patients. CONCLUSION: Compared to the conventional tracheostomy, our procedure improved airway management and function in children with medical complexity and reduced the risk of TIF.
Assuntos
Fístula , Pneumonia Aspirativa , Doenças da Traqueia , Tronco Braquiocefálico/cirurgia , Criança , Fístula/cirurgia , Humanos , Pneumonia Aspirativa/etiologia , Estudos Retrospectivos , Doenças da Traqueia/cirurgia , Traqueostomia/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND/AIM: We retrospectively evaluated the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) for T3 N0 glottic carcinoma without vocal cord fixation. PATIENTS AND METHODS: Twenty-five patients underwent TPF-CCRT without elective nodal irradiaion (ENI). After the RT of 40 Gy, five patients (20%) without tumor regression underwent surgery. Others underwent RT with a median total dose of 66 Gy. RESULTS: Of the five patients who underwent surgery after the RT of 40 Gy, two showed residual carcinoma pathologically and the other three were confirmed to have complete pathological response to the treatment. The 5-year local control rate was 87%. No patients exhibited regional failure. No acute toxicities of grade 5 or late toxicities ≥grade 3 were observed. CONCLUSION: TPF-CCRT provides excellent tumor control with acceptable toxicities. CCRT while omitting ENI is a reasonable approach for T3 N0 glottic carcinoma without vocal cord fixation.
Assuntos
Carcinoma/tratamento farmacológico , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Prega Vocal/efeitos dos fármacos , Adulto , Idoso , Carcinoma/patologia , Carcinoma/radioterapia , Carcinoma/cirurgia , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/cirurgia , Estadiamento de Neoplasias , Prega Vocal/efeitos da radiação , Prega Vocal/cirurgiaRESUMO
We aimed to determine the optimal management of recurrent laryngeal nerve (RLN) involvement in thyroid cancer. We enrolled 80 patients with unilateral RLN involvement in thyroid cancer between 2000 and 2016. Eleven patients with preoperatively functional vocal folds (VFs) underwent sharp tumor resection to preserve the RLN (shaving group). Thirty-three patients underwent RLN reconstruction with RLN resection (reconstruction group). We divided the reconstruction group into two subgroups based on preoperative VF mobility (normal-reconstruction and paralyzed-reconstruction subgroups). In the cases where RLN reconstruction was difficult, phonosurgeries including arytenoid adduction (AA), with or without thyroplasty type I, or nerve muscle pedicle implantation with AA were performed later (phonosurgery group). We evaluated and compared vocal function among the evaluated periods and different groups. Postoperative vocal function in the shaving and normal-reconstruction subgroups was favorable. There were no significant differences between the two groups. In the paralyzed-reconstruction and phonosurgery groups, postoperative vocal function was significantly improved, and vocal function in the paralyzed-reconstruction subgroup was significantly better than that in the phonosurgery group. For optimal management of unilateral RLN involvement in thyroid cancer, first, sharp dissection should be performed, and if this is impossible, a simultaneous RLN reconstruction procedure should be adopted whenever possible.
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OBJECTIVES: This study examined the antifibrotic effect of pirfenidone (PFD), which has received regulatory approval in the United States and Japan for treatment of idiopathic pulmonary fibrosis, on the scarred ferret vocal fold (VF) in vivo. METHODS: Eight male ferrets were divided into two groups: saline and PFD. All animals underwent unilateral scarring under anesthesia. The right VF was electrocauterized with ablation of the entire lamina propria. PFD (1.0 mg/mL) or saline injections into right-side scarred VFs were performed (under an operating microscope) 4 weeks later. After an additional 4 weeks, the larynges were harvested for histological analysis. Prior to harvesting, the ferrets were re-anesthetized, and the VFs were observed and recorded using a rigid video laryngoscope. We immunohistochemically evaluated the expression of collagen types I and III, alpha-smooth muscle actin (α-SMA), and fibronectin in the entire lamina propria. We compared the affected areas (calculated using ImageJ software) between the treated (right) and untreated (left) sides within the same animals and between groups. RESULTS: Collagen type I (P = 0.0021) and α-SMA (P = 0.0021) expression levels were lower in the PFD group, but the collagen type III and fibronectin levels did not differ significantly between the two groups. CONCLUSION: PFD injection into the scarred VF is a potentially promising novel antifibrotic treatment. LEVEL OF EVIDENCE: NA Laryngoscope, 130:726-731, 2020.
Assuntos
Cicatriz/tratamento farmacológico , Doenças da Laringe/tratamento farmacológico , Piridonas/administração & dosagem , Prega Vocal , Animais , Furões , Injeções Intralesionais , MasculinoRESUMO
OBJECTIVE: Extrahepatic vitamin A is housed within organ-specific stellate cells that support local tissue function. These cells have been reported in the vocal fold mucosa (VFM) of the larynx; however, it is unknown how vitamin A reaches and is disseminated among VFM target cells, how VFM storage and utilization vary as a function of total body stores, and how these parameters change in the context of pathology. Therefore, in this study, we investigated fundamental VFM vitamin A uptake and metabolism. METHODS: Using cadaveric tissue and serum from human donors representing the full continuum of clinical vitamin A status, we established a concentration range and analyzed the impact of biologic and clinical covariates on VFM vitamin A. We additionally conducted immunodetection of vitamin A-associated markers and pharmacokinetic profiling of orally dosed α-retinyl ester (a chylomicron tracer) in rats. RESULTS: Serum vitamin A was a significant predictor of human VFM concentrations, suggesting that VFM stores may be rapidly metabolized in situ and replenished from the circulatory pool. On a vitamin A-sufficient background, dosed α-vitamin A was detected in rat VFM in both ester and alcohol forms, showing that, in addition to plasma retinol and local stellate cell stores, VFM can access and process postprandial retinyl esters from circulating chylomicra. Both α forms were rapidly depleted, confirming the high metabolic demand for vitamin A within VFM. CONCLUSION: This thorough physiological analysis validates VFM as an extrahepatic vitamin A repository and characterizes its unique uptake, storage, and utilization phenotype.
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Células Estreladas do Fígado/metabolismo , Vitamina A/metabolismo , Prega Vocal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Mucosa/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Vitamina A/análise , Vitamina A/sangueRESUMO
Fibrocytes (FCs) are hematopoietic lineage cells that migrate to sites of injury, transition to a mesenchymal phenotype, and help to mediate wound repair. Despite their relevance to human fibrotic disorders, there are few data characterizing basic FC biology. Herein, using proteomic, bioenergetic, and bioengineering techniques, we conducted deep phenotypic characterization of differentiating and mature FCs. Differentiation was associated with metabolic reprogramming that favored oxidative phosphorylation. Mature FCs had distinct proteomes compared to classic mesenchymal cells, formed functional stromae that supported epithelial maturation during in vitro organotypic culture, and exhibited in vivo survival and self-tolerance as connective tissue isografts. In an in vitro scratch assay, FCs promoted fibroblast migration and wound closure by paracrine signaling via the chemokine CXCL8 (interleukin-8). These findings characterize important aspects of FC differentiation and show that, in addition to their role in wound healing, FCs hold potential as an easily isolated autologous cell source for regenerative medicine.
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Leucócitos Mononucleares/citologia , Medicina Regenerativa , Animais , Antígeno CD11b/metabolismo , Diferenciação Celular , Movimento Celular , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Interleucina-8/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/transplante , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Comunicação Parácrina , Fenótipo , Proteoma , Ratos , Ratos Endogâmicos LewRESUMO
OBJECTIVES/HYPOTHESIS: Pirfenidone (PFD) is a strong antifibrotic agent that has been clinically approved in Japan for idiopathic pulmonary fibrosis. We examined the antifibrotic effects of PFD on fibroblasts isolated from scarred vocal folds (VFs) of ferrets in vitro. STUDY DESIGN: Prospective animal experiments with controls. METHODS: Scar fibroblasts (SFs) were isolated from scarred VFs that had been electrocauterized 2 weeks before harvesting (N = 4). Normal fibroblasts (NFs) were isolated from intact VFs (N = 4). SFs and NFs were incubated in the presence of 10 ng/mL transforming growth factor ß1 (TGF-ß1), with or without PFD. After the 48-hour incubation, mRNA expression levels of α smooth muscle actin (αSMA), TGF-ß1, collagen type I, and hyaluronan synthase 2 (HAS2) were examined by real-time polymerase chain reaction. Immunohistochemistry with anti-αSMA anti-collagen type I and phosphorylated Smad (p-Smad)2/3 antibodies in SFs with or without PFD was performed. SFs and NFs were cultured in collagen gel with or without PFD for 48 hours, and the extent of gel contraction was examined quantitatively. RESULTS: PFD treatment significantly (P < .05) decreased mRNA expression of collagen type I, significantly increased mRNA expression of TGF-ß1 and HAS2, and significantly suppressed collagen gel contraction. However, it did not have a significant effect on the expression of αSMA. The expression of p-Smad2/3 in the nucleus was faded with PFD, possibly demonstrating the suppression of translocation of p-Smad2/3 from cytoplasm to nucleus with PFD. CONCLUSIONS: This is the first report to demonstrate the in vitro antifibrotic effects of PFD on fibroblasts isolated from scarred VFs of ferrets. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E171-E177, 2018.
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Cicatriz/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Piridonas/farmacologia , Prega Vocal/citologia , Prega Vocal/lesões , Actinas/metabolismo , Animais , Células Cultivadas , Cicatriz/patologia , Colágeno Tipo I/metabolismo , Furões , Hialuronan Sintases/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVES: To develop a vocal fold (VF) scarring procedure in the ferret, characterize the scars histologically, and test the injectability of the lamina propria (LP). Secondarily, to compare laryngeal anatomy of the ferret with rat and rabbit. MATERIALS AND METHODS: The larynges of 18 male ferrets were prepared by unilateral scarring, and normal larynges from 6 female Wistar rats and 5 male albino rabbits were used for comparative purposes. For scarring, the right VF were electrocauterized, ablating the entire LP. Prior to harvesting the larynges at 4 and 16 weeks, each ferret was re-anesthetized, and in 3 animals, India ink was injected into the LPs of both normal and scarred VFs. RESULTS: Laryngoscopic methods and instrumentation for precise visualization, scarring, and injection were developed. The scarred VFs had reduced hyaluronic acid and increased collagen type I, III, and fibronectin compared with normal VFs. The 2 timepoints (4 and 16 weeks) differed significantly only in collagen type III level (levels were higher at 4 weeks). Injected ink migrated from scarred LP to muscle layer just beneath the scarred tissue 3 hours after injection. CONCLUSION: The ferret is a promising species for creation and experimental treatment of vocal fold scar.
Assuntos
Cicatriz , Eletrocoagulação/métodos , Laringoscopia , Mucosa , Prega Vocal/cirurgia , Animais , Cicatriz/etiologia , Cicatriz/metabolismo , Cicatriz/patologia , Colágeno Tipo I/análise , Colágeno Tipo III/análise , Feminino , Furões , Fibronectinas/análise , Laringoscopia/instrumentação , Laringoscopia/métodos , Modelos Anatômicos , Mucosa/patologia , Mucosa/cirurgia , Coelhos , Ratos , Prega Vocal/patologiaRESUMO
Background: Minimal human data exist on liver vitamin A (VA) compared with serum biomarkers. Cutoffs of 5% and 10% total serum VA as retinyl esters (REs) suggest a VA intoxication diagnosis. Objectives: We compared total liver VA reserves (TLRs) with the percentage of total serum VA as REs to evaluate hypervitaminosis with the use of US adult autopsy samples. Secondary objectives evaluated serum retinol sensitivity, TLRs among lobes, and hepatic α-retinol concentrations, an α-carotene cleavage product. Design: Matched serum and liver samples were procured from cadavers (n = 27; mean ± SD age: 70.7 ± 14.9 y; range: 49-101 y). TLRs and α-REs were quantified by ultra-performance liquid chromatography. Pearson correlations showed liver and serum associations. Sensitivity and specificity were calculated for >5%, 7.5%, and 10% total serum VA as REs to predict TLRs and for serum retinol <0.7 and 1 µmol/L to predict deficiency. Results: Serum RE concentrations were correlated with TLRs (r = 0.497, P < 0.001). Nine subjects (33%) had hypervitaminosis A (≥1.0 µmol VA/g liver), 2 of whom had >7.5% total serum VA as REs; histologic indicators corroborated toxicity at 3 µmol/g liver. No subject had >10% total serum VA as REs. Serum retinol sensitivity to determine deficiency (TLRs <0.1 µmol VA/g) was 83% at 0.7 and 1 µmol/L. Hepatic α-retinol was positively correlated with age (P = 0.047), but removing an outlier nullified significance. Conclusions: This study evaluated serum REs as a biomarker of VA status against TLRs (gold standard), and abnormal histology suggested that 7.5% total serum VA as REs is diagnostic for toxicity at the individual level in adults. The long-term impact of VA supplements and fortificants on VA status is currently unknown. Considering the high prevalence of hypervitaminotic TLRs in this cohort, and given that many countries are adding preformed VA to processed products, population biomarkers diagnosing hypervitaminosis before toxicity are urgently needed. This trial was registered at clinicaltrials.govas NCT03305042.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Hipervitaminose A/diagnóstico , Fígado/metabolismo , Deficiência de Vitamina A/metabolismo , Vitamina A/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Carotenoides/metabolismo , Estudos de Coortes , Suplementos Nutricionais/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/mortalidade , Ésteres/sangue , Feminino , Alimentos Fortificados/efeitos adversos , Humanos , Hipervitaminose A/sangue , Hipervitaminose A/metabolismo , Hipervitaminose A/mortalidade , Masculino , Pessoa de Meia-Idade , Vitamina A/efeitos adversos , Vitamina A/sangue , Vitamina A/uso terapêutico , Deficiência de Vitamina A/tratamento farmacológicoRESUMO
We report a rare case of black thyroid accompanied by papillary carcinoma in a patient with an extended history of minocycline treatment. A 78-year-old man was referred to our outpatient clinic with swelling in his neck. He had been taking minocycline for the previous 2 years and 7 months to treat chronic perianal pyoderma. Neck ultrasonography and computed tomography demonstrated a 3.5 × 3.7 × 5.0-cm nodule in the left thyroid lobe, and fine-needle aspiration cytology identified it as a papillary carcinoma. The patient underwent a total thyroidectomy and neck dissection. During the procedure, a distinct black discoloration of the thyroid parenchyma was observed. Histopathology confirmed both the black thyroid and the papillary carcinoma. Based on the thyroid gland's discoloration and the history of minocycline use, the patient was diagnosed with minocycline-induced black thyroid. He was symptom-free 20 months after surgery.