RESUMO
OBJECTIVES: To analyse operating time, intraoperative blood loss, postoperative bleeding rate and pain when using the relatively new BiZact™ tonsillectomy device compared to the commonly used cold steel dissection technique with bipolar cautery in adults. DESIGN: Retrospective case control study. Parameters analysed for significant association with technique were operating time, intraoperative blood loss, wound pain on postoperative days 1-4 and rate of post-tonsillectomy bleeding (PTB). SETTING: Monocentric study at a department of otolaryngology and head and neck surgery at a tertiary centre in Germany. PARTICIPANTS: A total of 183 patients who underwent a bilateral tonsillectomy with either the BiZact™ tonsillectomy device or the cold dissection technique with bipolar cautery for haemostasis. MAIN OUTCOME MEASURES: Operating time, intraoperative blood loss, postoperative pain on the first to fourth postoperative day (numeric rating scale: 0-10) (PTB, primary bleeding ≤24 h, secondary bleeding >24 h postoperative; Stammberger scale). RESULTS AND CONCLUSION: The BiZact™ tonsillectomy device leads to a significant shorter operating time with less intraoperative blood loss compared to cold steel dissection with bipolar haemostasis. No benefits with regards to PTB or postoperative pain could be observed. The use of the BiZact™ device provides major benefits in clinical routine and stands up to conventional tonsillectomy techniques.
Assuntos
Perda Sanguínea Cirúrgica , Tonsilectomia , Adulto , Humanos , Tonsilectomia/métodos , Estudos de Casos e Controles , Estudos Retrospectivos , Estudos Prospectivos , Hemorragia Pós-Operatória/epidemiologia , Hemorragia Pós-Operatória/etiologia , Dor Pós-Operatória/etiologia , Eletrocoagulação/métodosRESUMO
Signal transduction via protein kinases is of central importance in cancer biology and treatment. However, the clinical success of kinase inhibitors is often hampered by a lack of robust predictive biomarkers, which is also caused by the discrepancy between kinase expression and activity. Therefore, there is a need for functional tests to identify aberrantly activated kinases in individual patients. Here we present a systematic analysis of the tyrosine kinases in head and neck cancer using such a test-functional kinome profiling. We detected increased tyrosine kinase activity in tumors compared with their corresponding normal tissue. Moreover, we identified members of the family of Src kinases (Src family kinases [SFK]) to be aberrantly activated in the majority of the tumors, which was confirmed by additional methods. We could also show that SFK hyperphosphorylation is associated with poor prognosis, while inhibition of SFK impaired cell proliferation, especially in cells with hyperactive SFK. In summary, functional kinome profiling identified SFK to be frequently hyperactivated in head and neck squamous cell carcinoma. SFK may therefore be potential therapeutic targets. These results furthermore demonstrate how functional tests help to increase our understanding of cancer biology and support the expansion of precision oncology.
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Biomarcadores Tumorais/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Quinases da Família src/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Fosforilação , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Estudos Retrospectivos , Taxa de Sobrevida , Análise Serial de Tecidos , Células Tumorais Cultivadas , Quinases da Família src/antagonistas & inibidoresRESUMO
INTRODUCTION: Iatrogenic cervical esophageal perforations (CEP) and postoperative salivary fistulas (PSF) are some of the complications requiring treatment in head and neck surgery. Conservative, surgical and endoscopic therapeutic techniques are used. Both CEP and PSF are potentially life-threatening complications and require intensive treatment. Endoscopic negative pressure therapy (ENPT) is an innovative endoscopic surgical procedure for the treatment of transmural intestinal defects throughout the gastrointestinal tract (GIT). In this retrospective study, we demonstrate its application in head and neck surgery. MATERIALS AND METHODS: In ENPT, open-pore drains are placed endoscopically in the wound area. The drains can be inserted in an intraluminal position spanning the length of the defect (intraluminal ENPT), or through the defect into the extraluminal wound cavity (intracavitary ENPT). An electronic suction pump applies and maintains a continuous negative pressure of - 125 mmHg over a period of several days. The endoscopic drains are changed at regular intervals every few days until stable intracorporeal wound healing by secondary intention or defect closure is achieved. Between 06/2008 and 05/2019 ten patients (f = 3, m = 7; 46-78 years old) were treated with ENPT for CEP or PSF. Five patients had postoperative wound defects with consecutive PSF after total laryngectomy or floor of mouth resection. In five patients iatrogenic CEP was found following endoscopic procedures. RESULTS: In all patients treated with ENPT, healing of the perforation defect or fistula was achieved (cure rate 100%). The median treatment duration was 13.7 days (range 4-42 days). No relevant treatment-associated complications were observed. CONCLUSION: ENPT is a new, minimally invasive method for treating PSF and CEP.
Assuntos
Perfuração Esofágica , Fístula , Idoso , Endoscopia , Perfuração Esofágica/etiologia , Perfuração Esofágica/cirurgia , Humanos , Pessoa de Meia-Idade , Pescoço , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: Strong expression of survivin is associated with worse survival in many different tumours, and in cell culture, a correlation between radiation resistance and survivin expression can be seen. The potential of survivin expression as a prognostic/predictive marker or therapeutic target has not been examined in head and neck squamous cell carcinomas (HNSCC) yet. MATERIAL AND METHODS: Retrospective study of 452 tissue samples and clinical data from patients with squamous cell carcinomas of the larynx/hypopharynx (LSCC), oral cavity (OSCC) and oropharynx (OPSCC) treated in the University Medical Centre Hamburg-Eppendorf between 2002 and 2006. The expression patterns were detected by tissue microarray technique and correlated with clinical parameters (sex, age, tumour location, TNM 7th edition, grading, recurrence-free and overall survival). RESULTS: 222 OSCC, 126 OPSCC and 105 LSCC tumours of 118 females and 335 males with a mean follow-up of 41.3 months were examined. Survivin expression correlates with pN, cM, pT and overall survival. CONCLUSION AND CLINICAL RELEVANCE: The potential of survivin as a prognostic/predictive marker is very high. The findings have to be confirmed in a larger cohort of HNSCC esp. in those tumours treated primarily with radio/radiochemotherapy.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Survivina/metabolismo , Feminino , Humanos , Masculino , Gradação de Tumores , Valor Preditivo dos Testes , Prognóstico , 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/terapia , Taxa de Sobrevida , Análise Serial de Tecidos , Resultado do TratamentoRESUMO
This study is a retrospective analysis of clinico-pathological data to investigate survival rates of patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with different modalities in a single academic head and neck cancer center in different time intervals. Altogether, 287 patients with OPSCC were included in this comparison. Patients were analysed during two different treatment periods: Group 1 included patients treated mainly with primary surgery ± adjuvant radio(chemo)therapy between 2002 and 2007, while Group 2 included patients treated with organ/function-preservation protocols if indicated. Main outcome measures were overall survival (OS) and recurrence-free survival (RFS). Between 2002 and 2007, early-stage OPSCC showed a 5-year OS of 75% compared to that of 86% between 2008 and 2013. Locally advanced OPSCC showed a 5-year OS of 66% between 2002 and 2007 compared to that of 74% between 2008 and 2013. RFS in early-stage OPSCC was 48% between 2002 and 2007 in contrast to that of 77% between 2008 and 2013. With locally advanced OPSCC, RFS was 55% between 2002 and 2007 compared to that of 56% between 2008 and 2013. These differences were statistically not significant. The OS and RFS remained generally unchanged over the analysed time period. There was no significant difference in the outcomes with regards to HPV status and to their treatment modality.
Assuntos
Carcinoma de Células Escamosas , Quimiorradioterapia Adjuvante , Tratamento Conservador , Recidiva Local de Neoplasia , Neoplasias Orofaríngeas , Procedimentos Cirúrgicos Otorrinolaringológicos , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia Adjuvante/métodos , Quimiorradioterapia Adjuvante/estatística & dados numéricos , Tratamento Conservador/métodos , Tratamento Conservador/estatística & dados numéricos , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Preservação de Órgãos/métodos , Preservação de Órgãos/estatística & dados numéricos , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/terapia , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Procedimentos Cirúrgicos Otorrinolaringológicos/estatística & dados numéricos , Avaliação de Processos e Resultados em Cuidados de Saúde , Estudos Retrospectivos , Taxa de Sobrevida , Tempo para o TratamentoRESUMO
OBJECTIVES: CD151 is a plasma membrane protein belonging to the tetraspanin family. CD151 represents a putative therapeutic target and has been suggested as a prognostic marker in several cancer types. The present study aims to investigate the prognostic relevance of immunohistochemical CD151 expression in head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Tissue microarray (TMA) sections containing samples from 667 cancers of oral cavity, oro- and hypopharynx and larynx, for which follow-up data were available, were analyzed for CD151 expression by immunohistochemistry. RESULTS: Membranous CD151 immunostaining was recorded in 269 (60.3 %) of 446 analyzable cases. Staining was considered weak in 129 (28.9 %), moderate in 98 (22.0 %), and strong in 42 (9.4 %) of cancers. CD151 expression was unrelated to histological grade, tumor stage, nodal status, or surgical margin. There was a tendency towards a somewhat lower prevalence of CD151 expression in tumors of the oral cavity (52.9 % positive) as compared to cancers of the oro-hypopharynx (62.1 %) and larynx (63.3 %; p = 0.0100). CD151 expression had no impact on patient survival. CLINICAL RELEVANCE: In summary, immunohistochemical analysis of CD151 lacks prognostic utility in HNSCC. The high prevalence of CD151 expression in HNSCC emphasizes its putative relevance as a therapeutic target for further development of anti-CD151 drugs.
Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Tetraspanina 24/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Análise Serial de TecidosRESUMO
BACKGROUND AND OBJECTIVE: As a result of wound healing the original tissue is replaced by dysfunctional scar tissue. Reduced tissue damage during surgical procedures beneficially affects the size of the resulting scar and overall healing time. Thus the choice of a particular surgical instrument can have a significant influence on the postoperative wound healing. To overcome these problems of wound healing we applied a novel picosecond infrared laser (PIRL) system to surgical incisions. Previous studies indicated that negligible thermal, acoustic, or ionization stress effects to the surrounding tissue results in a superior wound healing. STUDY DESIGN/MATERIALS AND METHODS: Using the PIRL system as a surgical scalpel, we performed a prospective wound healing study on rat skin and assessed its final impact on scar formation compared to the electrosurgical device and cold steel. As for the incisions, 6 full-thickness, 1-cm long-linear skin wounds were created on the dorsum of four rats using the PIRL, an electrosurgical device, and a conventional surgical scalpel, respectively. Rats were euthanized after 21 days of wound healing. The thickness of the subepithelial fibrosis, the depth and the transverse section of the total scar area of each wound were analyzed histologically. RESULTS: After 21 days of wound healing the incisions made by PIRL showed minor scar tissue formation as compared to the electrosurgical device and the scalpel. Highly significant differences (P < 0.001) were noted by comparing the electrosurgical device with PIRL and scalpel. The transverse section of the scar area also showed significant differences (P = 0.043) when comparing PIRL (mean: 141.46 mm2; 95% CI: 105.8-189.0 mm2) with scalpel incisions (mean: 206.82 mm2; 95% CI: 154.8-276.32 mm2). The subepithelial width of the scars that resulted from using the scalpel were 1.3 times larger than those obtained by using the PIRL (95% CI: 1.0-1.6) though the difference was not significant (P < 0.083). CONCLUSIONS: The hypothesis that PIRL results in minimal scar formation with improved cosmetic outcomes was positively verified. In particular the resection of skin tumors or pathological scars, such as hypertrophic scars or keloids, are promising future fields of PIRL application.
Assuntos
Cicatriz/prevenção & controle , Procedimentos Cirúrgicos Dermatológicos/instrumentação , Raios Infravermelhos/uso terapêutico , Terapia a Laser/instrumentação , Lasers , Complicações Pós-Operatórias/prevenção & controle , Cicatrização , Animais , Cicatriz/etiologia , Eletrocirurgia/instrumentação , Feminino , Ratos , Resultado do TratamentoRESUMO
BACKGROUND: To date, this prospective cohort study is the largest of its kind from a single European academic tertiary care center to report 2-year survival outcomes for head and neck squamous cell carcinoma treated primarily with transoral robotic-assisted resection. PATIENTS AND METHODS: Fifty consecutive, appropriately staged patients were enrolled prospectively, and underwent transoral robotic surgery (TORS) between September 2011 and August 2013. Overall, 24 patients had a T1 primary tumor, 23 had a T2 primary tumor, 2 had a T3 primary tumor, and 1 had a T4a primary tumor. Eighteen patients had overall stage I-II disease, and 32 patients had stage III-IV disease. Following transoral robotic resection of their primaries and appropriate neck dissection(s) as indicated, adjuvant treatment could be spared for 20 patients; another 5 patients refused the recommended adjuvant treatment. Seventeen patients received 60 Gy adjuvant radiotherapy and 8 patients underwent 66 Gy adjuvant chemoradiotherapy. RESULTS: At the time of the last follow-up visit (median 27 months), overall survival was 94 %, with two disease-specific deaths and one unrelated death (heart attack). The 2-year disease-free and recurrence-free survival rates were 88 and 80 %, respectively; however, the local recurrence rate was only 10 % after 2 years. CONCLUSION: Using TORS as their primary modality, 40 % of patients did not need adjuvant treatment and showed similar survival rates to that of conventional surgery or primary chemoradiotherapy. In another 34 % of patients, adjuvant chemotherapy could be spared and adjuvant radiotherapy could be reduced by 10 Gy compared with primary chemoradiotherapy of 70 Gy. Further studies are warranted with respect to long-term survival.
Assuntos
Carcinoma de Células Escamosas/mortalidade , Neoplasias de Cabeça e Pescoço/mortalidade , Esvaziamento Cervical/mortalidade , Procedimentos Cirúrgicos Otorrinolaringológicos/mortalidade , Procedimentos Cirúrgicos Robóticos/mortalidade , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
PURPOSE: Patients with locally advanced head and neck cancer (LAHNC) undergo life-changing treatments that can seriously affect quality of life (QoL). This prospective study examined the key QoL domains during the first year after intensity-modulated radiotherapy (IMRT) and identified predictors of these changes in order to improve patient outcomes. PATIENTS AND METHODS: A consecutive series of patients with LAHNC completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core module (QLQ-C30) and the HNC-specific QLQ-HN35 before (t0) and at the end (t1) of definitive or adjuvant IMRT, then at 6-8 weeks (t2), 6 months (t3), and 1 year (t4) after IMRT. RESULTS: Patients (n = 111) completing questionnaires at all five time points were included (baseline response rate: 99%; dropout rate between t0 and t4: 5%). QoL deteriorated in all domains during IMRT and improved slowly during the first year thereafter. Many domains recovered to baseline values after 1 year but problems with smelling and tasting, dry mouth, and sticky saliva remained issues at this time. Increases in problems with sticky saliva were greater after 1 year in patients with definitive versus adjuvant IMRT (F = 3.5, P = 0.05). CONCLUSION: QoL in patients with LAHNC receiving IMRT takes approximately 1 year to return to baseline; some domains remain compromised after 1 year. Although IMRT aims to maintain function and QoL, patients experience long-term dry mouth and sticky saliva, particularly following definitive IMRT. Patients should be counseled at the start of therapy to reduce disappointment with the pace of recovery.
Assuntos
Neoplasias de Cabeça e Pescoço/psicologia , Neoplasias de Cabeça e Pescoço/radioterapia , Qualidade de Vida/psicologia , Lesões por Radiação/psicologia , Radioterapia Conformacional/psicologia , Distúrbios do Paladar/psicologia , Xerostomia/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Psicometria/métodos , Lesões por Radiação/etiologia , Radioterapia Conformacional/efeitos adversos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Inquéritos e Questionários , Distúrbios do Paladar/etiologia , Resultado do Tratamento , Xerostomia/etiologiaRESUMO
We discuss the clinical effectiveness and predictive value of routine panendoscopy for surveillance and follow-up of head and neck squamous cell carcinoma (HNSCC). Retrospective comparative study. Department of Otolaryngology-Head and Neck Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Two hundred and four HNSCC patients (follow-up between 2004 and 2007) were retrospectively evaluated. During follow-up, panendoscopy was performed routinely once a year. To avoid unnecessary procedures, we evaluated the value of radiological and clinical parameters in follow-up. On comparing normal-computerized tomography (CT) vs. abnormal CT results, a 13-fold higher frequency of recurrence (odds ratio 12.74; 95% CI 4.22, 38.48; p < 0.001) was found. Additionally, patient medical history, clinical investigation, and recurrence pattern were significant parameters when detecting a possible recurrence. Panendoscopy could have been avoided in 40% of patients with HNSCC (173/432). A follow-up schedule avoiding routine panendoscopy in HNSCC follow-up when the combination of diagnostic parameters is satisfactory does not influence the sensitivity or specificity of the test.
Assuntos
Carcinoma de Células Escamosas , Endoscopia/métodos , Neoplasias de Cabeça e Pescoço , Recidiva Local de Neoplasia/diagnóstico , Idoso , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Gerenciamento Clínico , Feminino , Seguimentos , Alemanha/epidemiologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Sensibilidade e Especificidade , Carcinoma de Células Escamosas de Cabeça e Pescoço , Tomografia Computadorizada por Raios X/métodosRESUMO
The carbon dioxide (CO2) laser is routinely used in glottic microsurgery for the treatment of benign and malignant disease, despite significant collateral thermal damage secondary to photothermal vaporization without thermal confinement. Subsequent tissue response to thermal injury involves excess collagen deposition resulting in scarring and functional impairment. To minimize collateral thermal injury, short-pulse laser systems such as the microsecond pulsed erbium:yttrium-aluminium-garnet (Er:YAG) laser and picosecond infrared laser (PIRL) have been developed. This study compares incisions made in ex vivo human laryngeal tissues by CO2 and Er:YAG lasers versus PIRL using light microscopy, environmental scanning electron microscopy (ESEM), and infrared thermography (IRT). In comparison to the CO2 and Er:YAG lasers, PIRL incisions showed significantly decreased mean epithelial (59.70 µm) and subepithelial (22.15 µm) damage zones (p < 0.05). Cutting gaps were significantly narrower for PIRL (133.70 µm) compared to Er:YAG and CO2 lasers (p < 0.05), which were more than 5 times larger. ESEM revealed intact collagen fibers along PIRL cutting edges without obvious carbonization, in comparison to diffuse carbonization and tissue melting seen for CO2 and Er:YAG laser incisions. IRT demonstrated median temperature rise of 4.1 K in PIRL vocal fold incisions, significantly less than for Er:YAG laser cuts (171.85 K; p < 0.001). This study has shown increased cutting precision and reduced lateral thermal damage zones for PIRL ablation in comparison to conventional CO2 and Er:YAG lasers in human glottis and supraglottic tissues.
Assuntos
Cicatriz/prevenção & controle , Terapia a Laser/métodos , Lasers de Estado Sólido/uso terapêutico , Microcirurgia/métodos , Prega Vocal/cirurgia , Cadáver , Cicatriz/patologia , Humanos , Microscopia Eletrônica de Varredura , Prega Vocal/ultraestruturaRESUMO
Despite causing significant thermocoagulative insult, use of the carbon dioxide (CO2) laser is considered gold standard in surgery for early stage larynx carcinoma. Limited attention has been paid to the use of the erbium:yttrium-aluminium-garnet (Er:YAG) laser in laryngeal surgery as a means to reduce thermal tissue injury. The objective of this study is to compare the extent of thermal injury and precision of vocal fold incisions made using microsecond Er:YAG and superpulsed CO2 lasers. In the optics laboratory ex vivo porcine vocal folds were incised using Er:YAG and CO2 lasers. Lateral epithelial and subepithelial thermal damage zones and cutting gap widths were histologically determined. Environmental scanning electron microscopy (ESEM) images were examined for signs of carbonization. Temperature rise during Er:YAG laser incisions was determined using infrared thermography (IRT). In comparison to the CO2 laser, Er:YAG laser incisions showed significantly decreased epithelial (236.44 µm) and subepithelial (72.91 µm) damage zones (p < 0.001). Cutting gaps were significantly narrower for CO2 (878.72 µm) compared to Er:YAG (1090.78 µm; p = 0.027) laser. ESEM revealed intact collagen fibres along Er:YAG laser cutting edges without obvious carbonization, in comparison to diffuse carbonization and tissue melting seen for CO2 laser incisions. IRT demonstrated absolute temperature rise below 70 °C for Er:YAG laser incisions. This study has demonstrated significantly reduced lateral thermal damage zones with wider basal cutting gaps for vocal fold incisions made using Er:YAG laser in comparison to those made using CO2 laser.
Assuntos
Neoplasias Laríngeas/cirurgia , Lasers de Gás/uso terapêutico , Lasers de Estado Sólido/uso terapêutico , Prega Vocal/cirurgia , Animais , Técnicas In Vitro , Mucosa Laríngea/lesões , Mucosa Laríngea/patologia , Neoplasias Laríngeas/patologia , Microscopia Eletrônica de Varredura , Suínos , Prega Vocal/patologiaRESUMO
BACKGROUND: Salivary gland tumors constitute 3-6% of all head and neck neoplasms in adults. Because of limited advances made in the treatment of metastatic disease, the more important is the role of new therapeutic strategies, including molecular therapy. The mammalian target of rapamycin (mTOR) has recently been established as a therapeutic target for several drugs. MATERIAL: Evaluation of phospho-mTOR as a possible therapy target by patients with salivary gland tumors. Immunohistochemical semi-quantitative analyses of the expression of phospho-mTOR(Ser2448) were processed on a tissue microarray containing samples from more than 900 patients. For statistical analysis, contingency table and chi-squared test (likelihood) were used. RESULTS: We observed at least weak phospho-mTOR expression in 25.6-41.2% of all 4 histological adenoma and in 36.8-61.6% of all 11 histological carcinoma subtypes analyzed. No association was seen between phospho-mTOR expression and tumor grade in mucoepidermoid carcinomas. CONCLUSION: In conjunction with literature data providing the evidence for a functional role of mTOR in salivary gland tumors, we conclude that treatment with mTOR-antagonists might potentially also be efficient in wide variety of salivary gland carcinomas.
Assuntos
Neoplasias das Glândulas Salivares/enzimologia , Serina-Treonina Quinases TOR/análise , Adenoma/classificação , Adenoma/enzimologia , Adulto , Carcinoma/classificação , Carcinoma/enzimologia , Carcinoma Mucoepidermoide/enzimologia , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Masculino , Terapia de Alvo Molecular , Neoplasias Parotídeas/enzimologia , Fosforilação , Glândulas Salivares Menores/enzimologia , Serina , Serina-Treonina Quinases TOR/antagonistas & inibidores , Análise Serial de TecidosRESUMO
PURPOSE: Immune checkpoint inhibition is a therapeutic option in many cancer entities. In head and neck squamous cell carcinoma (HNSCC) targeting of the PD-1/PD-L1 (B7-H1) axis is approved in recurrent/metastatic disease and is being explored in the curative setting. Here, we evaluated two related members of the B7 family, B7-H3 & B7-H4, for their prognostic impact under standard treatment. METHODS: A tissue microarray (TMA) of a single center HNSCC cohort was stained for B7-H3 and B7-H4. Staining intensity and the number of tumor cells stained were assessed, and the expression was scored according to an established algorithm. Staining scores were correlated with clinicopathological parameters and associated with patient survival. mRNA levels of both proteins were associated with patient outcome using the TCGA dataset. RESULTS: mRNA levels of B7-H3 and B7-H4 were not significantly associated with patient survival. TMA analysis revealed interpretable protein staining in 408 samples. Strong staining was the most frequent category for B7-H3 and no staining for B7-H4. In patients with p16-negative oropharyngeal SCC (OPSCC) and in a pooled cohort consisting of p16-negative OPSCC, laryngeal, hypopharyngeal and oral cavity SCC, strong B7-H3 expression was associated with better overall survival. For the latter cohort, this was in part due to reduced lymph node involvement. B7-H3 expression in p16-positive OPSCC and B7-H4 expression were not associated with outcome. CONCLUSION: Despite a possible role in tumor immune escape, B7-H3 was associated with favorable prognosis in HPV-negative HNSCC in our cohort. The underlying mechanisms and a potential impact for B7-H3 targeting remain to be elucidated.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Prognóstico , Antígeno B7-H1/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/genética , RNA Mensageiro , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análiseRESUMO
The receptor tyrosine kinase Axl is described to promote migration, metastasis and resistance against molecular targeting, radiotherapy, and chemotherapy in various tumor entities, including head and neck squamous cell carcinoma (HNSCC). Since clinical data on Axl and its ligand Gas6 in HNSCC are sparse, we assessed the association of Axl and Gas6 expression with patient survival in a single center retrospective cohort in a tissue microarray format. Expression was evaluated manually using an established algorithm and correlated with clinicopathological parameters and patient survival. A number of 362 samples yielded interpretable staining, which did not correlate with T- and N-stage. Protein expression levels were not associated with the survival of patients with p16-positive oropharyngeal SCC. In HPV-negative tumors, Axl expression did not impact patients treated with primary or adjuvant radio(chemo)therapy, but was significantly associated with inferior overall and recurrence-free survival in patients treated with surgery alone. Gas6 was a positive predictor of survival in patients whose treatment included radiotherapy. Associations remained significant in multivariable analysis. Our data question a meaningful contribution of the Axl/Gas6 pathway to radio-resistance in HNSCC and instead suggest that strong Axl expression identifies tumors requiring adjuvant radio(chemo)therapy after surgery.
RESUMO
BACKGROUND/AIMS: Thyroid hormones (THs) regulate many developmental processes, including the developmental onset of cochlear differentiation and function. TH action is mediated mostly by triiodothyronine (T3) bound to thyroid hormone nuclear receptors (TRs). At positive regulated genes and in the absence of THs, nuclear co-repressors are bound to TRs and decrease basal transcription rate. Ligand (T(3)) binding results in the dissociation of co-repressors and the recruitment of co-activators to the complex, which results in full transcriptional activation. METHODS: We measured cochlear function in two knock-in mouse models: TRß(E457A/E457A), with the TRß co-activator binding surface (AF-2) disrupted to prevent co-activator binding; and TRß(Δ337T/Δ337T), which is unable to bind T(3). Cochlear morphology and function were analyzed in 10-week-old normal and mutated mice. Cochlear function was determined by measuring auditory brainstem responses, cochlear tuning and compound action potential (CAP) thresholds. RESULTS: All TRß(Δ337T/Δ337T) and 85% of the TRß(E457A/E457A) mice presented elevated CAP thresholds (P < 0.05 or less). Five percent of the TRß(E457A/E457A) mice presented normal CAP thresholds with broadened cochlear tuning. TRß(E457A/E457A) and TRß(Δ337T/Δ337T) presented developmental defects that led to a decreased width (P < 0.01) and an increased thickness (P<0.01) of the tectorial membrane. In addition, TRß(Δ337T/Δ337T) animals showed an increased tectorial membrane area (P<0.01). CONCLUSION: Both mutations were deleterious to tectorial membrane development and led to important alterations in cochlear morphology and loss of cochlear function.
Assuntos
Cóclea , Receptores beta dos Hormônios Tireóideos/metabolismo , Substituição de Aminoácidos , Animais , Limiar Auditivo , Cóclea/anatomia & histologia , Cóclea/fisiologia , Técnicas de Introdução de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Mutação , Ligação Proteica , Receptores beta dos Hormônios Tireóideos/genética , Tri-Iodotironina/metabolismoRESUMO
PURPOSE: Controversies exist in regard to surgical neck management in total laryngectomies (TL). International guidelines do not sufficiently discriminate neck sides and sublevels, or minimal neck-dissection nodal yield (NY). METHODS: Thirty-seven consecutive primary TL cases from 2009 to 2019 were retrospectively analyzed in terms of local tumor growth using a previously established imaging scheme, metastatic neck involvement, and NY impact on survival. RESULTS: There was no case of level IIB involvement on any side. For type A and B tumor midline involvement, no positive contralateral lymph nodes were found. Craniocaudal tumor extension correlated with contralateral neck involvement (OR: 1.098, p = 0.0493) and showed increased involvement when extending 33 mm (p = 0.0134). Using a bilateral NY of ≥ 24 for 5-year overall survival (OS) and ≥ 26 for 5-year disease-free survival (DFS) gave significantly increased rate advantages of 64 and 56%, respectively (both p < 0.0001). CONCLUSIONS: This work sheds light on regional metastatic distribution pattern and its influence on TL cases. An NY of n ≥ 26 can be considered a desirable benchmark for bilateral selective neck dissections as it leads to improved OS and DFS. Therefore, an omission of distinct neck levels cannot be promoted at this time.
Assuntos
Neoplasias Laríngeas/cirurgia , Laringectomia/métodos , Esvaziamento Cervical/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
Aneuploidy is a consequence of chromosomal instability (CIN) that affects prognosis. Gene expression levels associated with aneuploidy provide insight into the molecular mechanisms underlying CIN. Based on the gene signature whose expression was consistent with functional aneuploidy, the CIN70 score was established. We observed an association of CIN70 score and survival in 519 HNSCC patients in the TCGA dataset; the 15% patients with the lowest CIN70 score showed better survival (p = 0.11), but association was statistically non-significant. This correlated with the expression of 39 proteins of the major repair complexes. A positive association with survival was observed for MSH2, XRCC1, MRE11A, BRCA1, BRCA2, LIG1, DNA2, POLD1, MCM2, RAD54B, claspin, a negative for ERCC1, all related with replication. We hypothesized that expression of these factors leads to protection of replication through efficient repair and determines survival and resistance to therapy. Protein expression differences in HNSCC cell lines did not correlate with cellular sensitivity after treatment. Rather, it was observed that the stability of the DNA replication fork determined resistance, which was dependent on the ATR/CHK1-mediated S-phase signaling cascade. This suggests that it is not the expression of individual DNA repair proteins that causes therapy resistance, but rather a balanced expression and coordinated activation of corresponding signaling cascades.
RESUMO
OBJECTIVES: The use of primary tumor tissue in experimental and pre-clinical cancer research is becoming increasingly important. Especially the use of tissue slice cultures of tumor specimen, so called ex vivo cultures or tumor explants, promises functional analysis under approximate physiological conditions. This includes screening and testing of targeted therapeutics directed against deregulated protein kinases. However, it is unclear if ex vivo cultures indeed represent the in situ situation especially with respect to very sensitive and transient molecular processes such as kinase dependent signaling. We now asked here, if and to what extent ex vivo culturing affects kinase activity. MATERIALS AND METHODS: We analyzed the activity of protein tyrosine kinases (PTK) using functional kinome profiling of either snap frozen or ex vivo-cultured tumor tissue samples of head and neck cancer patients. RESULTS: Although we observed a quantitative decline in overall kinase activity after 24 h or 48 h of ex vivo cultivation, we most importantly noticed that the signaling characteristics were conserved in most samples; approximately two thirds of all ex vivo-cultured samples displayed a signaling pattern which was qualitatively comparable to the parental tumor. We could also demonstrate kinase inhibition by treatment of ex vivo slice cultures with the multi-kinase inhibitor staurosporine, although higher concentrations were needed compared to cell cultures. CONCLUSION: We here demonstrate that the tyrosine kinase dependent signaling is conserved under exvivo culturing conditions in the majority of samples, which highlights the power of this method in experimental and pre-clinical cancer research.
Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Antineoplásicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina QuinasesRESUMO
Squamous cell carcinoma of the head and neck (HNSCC) consist of two distinct biological entities. While the numbers of classical, tobacco-induced HNSCC are declining, tumors caused by human papillomavirus (HPV) infection are increasing in many countries. HPV-positive HNSCC mostly arise in the oropharynx and are characterized by an enhanced sensitivity towards radiotherapy and a favorable prognosis. To identify molecular differences between both entities on the protein level, we conducted a mass spectrometric comparison of eight HPV-positive and nine HPV-negative oropharyngeal tumors (OPSCC). Overall, we identified 2051 proteins, of which 31 were found to be differentially expressed. Seventeen of these can be assorted to three functional groups, namely DNA replication, nuclear architecture and cytoskeleton regulation, with the differences in the last group potentially reflecting an enhanced migratory and invasive capacity. Furthermore, a number of identified proteins have been described to directly impact on DNA double-strand break repair or radiation sensitivity (e.g., SLC3A2, cortactin, RBBP4, Numa1), offering explanations for the differential prognosis. The unequal expression of three proteins (SLC3A2, MCM2 and lamin B1) was confirmed by immunohistochemical staining using a tissue microarray containing 205 OPSCC samples. The expression levels of SLC3A2 and lamin B1 were found be of prognostic relevance in patients with HPV-positive and HPV-negative OPSCC, respectively.