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BACKGROUND: Treatment options are limited, and the prognosis is poor for patients with platinum-resistant recurrent metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy and safety of a paclitaxel and ifosfamide (TI) regimen in patients with R/M HNSCC whose disease had progressed following platinum-based therapy. PATIENTS AND METHODS: In this retrospective study, we included 53 patients with R/M HNSCC who underwent at least one cycle of TI-based therapy, post platinum failure, between February 2020 and August 2023. Some patients received the TI regimen in combination with immunotherapy and/or cetuximab. Key metrics assessed included the objective response rate (ORR), disease control rate, and progression-free as well as overall survival. RESULTS: The study observed an ORR of 15.8% and a disease control rate of 36.8%. The median progression-free survival for the entire cohort was 3.3 months, and the median overall survival was 9.6 months. Notably, the combination of TI with immunotherapy yielded a higher ORR of 30.8%, compared to 14.3% with TI alone. The most prevalent grade 1-2 adverse events were anemia (81%), weight loss (68%) and hypernatremia (55%). CONCLUSION: The TI-based regimen demonstrated favorable efficacy and safety profile in treating R/M HNSCC. Enhanced outcomes may be attainable when combining it with immunotherapy. This study suggests that TI-based therapy could serve as a potential salvage option for this specific patient group.
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Protocolos de Quimioterapia Combinada Antineoplásica , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço , Ifosfamida , Recidiva Local de Neoplasia , Paclitaxel , Terapia de Salvação , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/mortalidade , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto , Ifosfamida/uso terapêutico , Ifosfamida/administração & dosagem , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Platina/uso terapêutico , Metástase Neoplásica , Idoso de 80 Anos ou mais , Resultado do TratamentoRESUMO
Intratumoral hypoxia not only promotes angiogenesis and invasiveness of cancer cells, but also creates an immunosuppressive microenvironment that facilitates tumor progression. However, the mechanisms by which hypoxic tumor cells disseminate immunosuppressive signals remain unclear. In this study, we demonstrate that a hypoxia-induced long non-coding RNA (lncRNA) HIF1A Antisense RNA 2 (HIF1A-AS2) is upregulated in both hypoxic tumor cells and hypoxic tumor-derived exosomes (TEXs) in head and neck squamous cell carcinoma (HNSCC). Hypoxia-inducible factor 1 alpha 1 (HIF-1α) was found to directly bind to the regulatory region of HIF1A-AS2 to enhance its expression. HIF1A-AS2 reduced the protein stability of major histocompatibility complex class I (MHC-I) by promoting the interaction between the autophagy cargo receptor Neighbor of BRCA1 gene 1 protein (NBR1) and MHC-I, thereby increasing the autophagic degradation of MHC-I. In HNSCC samples, the expression of HIF1A-AS2 was found to correlate with hypoxic signatures and advanced clinical stages. Patients with high HIF-1α and low HLA-ABC expression showed reduced infiltration of CD8+ T cells. These findings define a mechanism of hypoxia-mediated immune evasion in HNSCC through downregulation of antigen-presenting machinery via intracellular or externalized hypoxia-induced lncRNA.
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BACKGROUND: The presence of p16 and neck disease is important predictors of prognosis for oropharyngeal squamous cell carcinoma (OPSCC). Patients who are p16-negative and have clinically node-positive (cN+) disease generally have worse oncologic outcomes. This study aimed to investigate whether upfront neck dissection (UFND) could provide potential benefits for patients with cN+ p16-negative OPSCC. METHODS: Through this retrospective study, 76 patients with cN+ p16-negative OPSCC were analyzed, those who received either definite concurrent chemoradiotherapy (CCRT group) or UFND followed by chemoradiotherapy (UFND group). The primary endpoints were regional recurrence-free survival (RRFS), disease-specific survival (DSS), and overall survival (OS). Factors associated with survival were evaluated by univariate and multivariate analysis. Survival between the two groups was compared by propensity score-matched analysis. RESULTS: Matched 23 patients in each group through propensity analysis, the UFND group showed a significantly better 5-year RRFS (94.1% vs 61.0%, p = 0.011) compared to the CCRT group. Univariate analysis revealed that UFND was the sole factor associated with regional control (hazard ratio [HR] = 0.110; 95% CI, 0.014-0.879; p = 0.037). Furthermore, the study found that the CCRT group was associated with a higher dose of radiotherapy and exhibited a significantly higher risk of mortality due to pneumonia. CONCLUSION: The study indicated that UFND followed by CCRT may be a potential treatment option for patients with cN+ p16-negative OPSCC, as it can reduce the risk of regional recurrence. Additionally, the study highlights that definite CCRT is connected to a larger dose of radiotherapy and a higher risk of fatal pneumonia. These findings could be beneficial in informing clinical decision-making and improving treatment outcomes for patients with OPSCC.
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Quimiorradioterapia , Inibidor p16 de Quinase Dependente de Ciclina , Esvaziamento Cervical , Neoplasias Orofaríngeas , Feminino , Humanos , Masculino , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/mortalidade , Pontuação de Propensão , Estudos RetrospectivosRESUMO
BACKGROUND: Esophageal squamous cell neoplasms (ESCNs) are common second primary tumors in patients with head and neck cancer. Image-enhanced endoscopy (IEE) with Lugol chromoendoscopy or magnifying narrow-band imaging both increase the detection of early ESCNs. No evidence-based ESCN surveillance program for head and neck cancer patients without a history of synchronous ESCNs exists. We aimed to evaluate the performance of an IEE surveillance program with magnifying narrow-band imaging endoscopy and Lugol chromoendoscopy. METHODS: From April 2016, we routinely used IEE with magnifying narrow-band imaging and Lugol chromoendoscopy to evaluate patients with head and neck cancer history. All patients who were negative for ESCNs at the first surveillance endoscopy and received at least 2 IEEs through December 2019 were included. Demographic profiles, clinical data, cancer characteristics, IEE results and pathology reports were analyzed. RESULTS: A total of 178 patients were included. Only 4 patients (2.2%) developed metachronous ESCNs during follow-up, all of whom received curative resection treatment. The interval for the development of metachronous ESCNs was 477 to 717 days. In multivariate Firth logistic regression and KaplanâMeier survival curve analysis, Lugol's voiding lesion type C had an increased risk of esophageal cancer development (adjusted odds ratio = 15.71; 95% confidence interval, 1.33-185.87, p = 0.029). Eight patients died during the study period, and none of them had metachronous ESCNs. CONCLUSIONS: IEE with magnifying narrow-band imaging and Lugol chromoendoscopy is an effective surveillance program in head and neck cancer patients without a history of ESCNs. Annual surveillance can timely detect early ESCNs with low ESCN-related mortality.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Neoplasias de Cabeça e Pescoço , Segunda Neoplasia Primária , Humanos , Segunda Neoplasia Primária/diagnóstico , Esofagoscopia/métodos , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologiaRESUMO
Most studies for comprehensive molecular profiling of papillary thyroid carcinoma (PTC) have been performed before the 2017 World Health Organization (WHO) classification, in which the diagnostic criteria of follicular variants of PTC have been modified and noninvasive follicular thyroid neoplasm with papillary-like nuclear features has been introduced. This study aims to investigate the shift in the incidence of BRAF V600E mutations in PTCs following the 2017 WHO classification and to further characterize the histologic subtypes and molecular drivers in BRAF-negative cases. The study cohort consisted of 554 consecutive PTCs larger than 0.5 cm between January 2019 and May 2022. Immunohistochemistry for BRAF VE1 was performed for all cases. Compared with a historical cohort of 509 PTCs from November 2013 to April 2018, the incidence of BRAF V600E mutations was significantly higher in the study cohort (86.8% vs 78.8%, P = .0006). Targeted RNA-based next-generation sequencing using a FusionPlex Pan Solid Tumor v2 panel (ArcherDX) was performed for BRAF-negative PTCs from the study cohort. Eight cribriform-morular thyroid carcinomas and 3 cases with suboptimal RNA quality were excluded from next-generation sequencing. A total of 62 BRAF-negative PTCs were successfully sequenced, including 19 classic follicular predominant PTCs, 16 classic PTCs, 14 infiltrative follicular PTCs, 7 encapsulated follicular PTCs, 3 diffuse sclerosing PTCs, 1 tall cell PTC, 1 solid PTC, and 1 diffuse follicular PTC. Among them, RET fusions were identified in 25 cases, NTRK3 fusions in 13 cases, BRAF fusions in 5 cases including a novel TNS1::BRAF fusion, NRAS Q61R mutations in 3 cases, KRAS Q61K mutations in 2 cases, NTRK1 fusions in 2 cases, an ALK fusion in 1 case, an FGFR1 fusion in 1 case, and an HRAS Q61R mutation in 1 case. No genetic variants, from our commercially employed assay, were detected in the remaining 9 cases. In summary, the incidence of BRAF V600E mutations in PTCs significantly increased from 78.8% to 86.8% in our post-2017 WHO classification cohort. RAS mutations accounted for only 1.1% of the cases. Driver gene fusions were identified in 8.5% of PTCs and were clinically relevant given the emerging targeted kinase inhibitor therapy. Of the 1.6% of cases for which no driver alteration was detected, the specificity of drivers tested and tumor classification require further investigation.
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Carcinoma Papilar , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Proteínas Proto-Oncogênicas B-raf/genética , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Neoplasias da Glândula Tireoide/patologia , MutaçãoRESUMO
As a type of immunogenic cell death, ferroptosis participates in the creation of immunoactive tumor microenvironments. However, knowledge of spatial location of tumor cells with ferroptosis signature in tumor environments and the role of ferroptotic stress in inducing the expression of immune-related molecules in cancer cells is limited. Here the spatial association of the transcriptomic signatures is demonstrated for ferroptosis and inflammation/immune activation located in the invasive front of head and neck squamous cell carcinoma (HNSCC). The association between ferroptosis signature and inflammation/immune activation is more prominent in HPV-negative HNSCC compared to HPV-positive ones. Ferroptotic stress induces PD-L1 expression through reactive oxygen species (ROS)-elicited NF-κB signaling pathway and calcium influx. Priming murine HNSCC with the ferroptosis inducer sensitizes tumors to anti-PD-L1 antibody treatment. A positive correlation between the ferroptosis signature and the active immune cell profile is shown in the HNSCC samples. This study reveals a subgroup of ferroptotic HNSCC with immune-active signatures and indicates the potential of priming HNSCC with ferroptosis inducers to increase the antitumor efficacy of immune checkpoint inhibitors.
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Ferroptose , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Animais , Camundongos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Microambiente TumoralRESUMO
Objective: We investigated the effects of different treatment modalities and clinical stage for hypopharyngeal carcinoma (HPC) patients. Methods: Between February 2004 and December 2012, 167 HPC patients were reviewed. We calculated overall survival (OS), progression-free survival (PFS), local failure-free survival (LFFS), regional failure-free survival (RFFS), and distant metastasis failure-free survival (DMFFS) using the Kaplan-Meier method and compared various survival outcomes between definitive chemoradiotherapy (CRT) and surgery-based therapy (SBT). Results: There were no significant differences in baseline characteristics between SBT (n = 102) and definitive CRT (n = 65) groups. The 5-year rates of OS (59.7% vs. 24.0%, p < 0.0001) and PFS (49.9% vs. 22.6%, p = 0.0002) were significantly better in patients who received SBT than in those who received definitive CRT. The SBT group also obtained better LFFS (p < 0.0001), RFFS (p = 0.0479), and DMFFS (p = 0.0110). We did similar analyses by different T-classification (T1-2, T3, and T4) and found that SBT had better OS (p < 0.0001 and p = 0.0020), PFS (p < 0.0001 and p = 0.0513), LFFS (p = 0.0002 and p = 0.0075), RFFS (p = 0.1949 and p = 0.0826), and DMFFS (p = 0.0248 and p = 0.0436) in the T4 and T1-2 subgroups but similar OS (p = 0.9598), PFS (p = 0.5052), RFFS (p = 0.9648), and DMFFS (p = 0.8239) in T3 patients. Analyses by different overall stages revealed no differences between definitive CRT and SBT for stage III patients but significantly better results for stage IV patients who received SBT. Conclusions: SBT can obtain significant survival benefits when compared with definitive CRT for the whole cohort of patients. Definitive CRT has similar survival outcomes compared with SBT only for T3 tumors or overall stage III disease.
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BACKGROUND: Recurrent/ metastatic squamous cell carcinoma of head and neck (R/M SCCNH) is still a difficult-to-treat disease with poor clinical outcomes and limited treatment choices. In view of locoregional recurrent versus distant metastatic SCCHN, the therapeutic efficacy of cetuximab-containing regimen and relevant prognostic factors for these two groups may be different. Thus, the aim of this study was to explore the treatment outcomes of cetuximab-containing regimen in locoregional recurrent and distant metastatic SCCHN groups, and to identify clinical factors correlated with better survival outcomes. METHODS: From 2016 to 2020, patients with R/M SCCHN who received cetuximab-containing regimen in our institute were enrolled in this study. Clinical outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated in both locoregional recurrence and distant metastasis groups. Exploratory analysis were conducted to investigate major clinical features associated with better outcomes. RESULTS: A total of 107 patients with locoregional recurrent SCCHN (N = 66) and distant metastatic SCCNH (N = 41) who received cetuximab-containing regimen were enrolled in this retrospective study. Patients with oral cavity cancer and patients with disease recurrence within 6 months after radiation therapy were significantly increased in locoregional recurrence group. The median OS (15.6 vs. 9.7 months, P = 0.004) and PFS (5.8 months vs. 4.2 months, P = 0.008) were longer in locoregional recurrence group than in distant metastasis group. In multivariate analysis of clinical features, locoregional recurrence was still an important risk factor associated with better OS (Hazzard ratio (HR) 0.64, p = 0.06) and PFS (HR 0.67, p = 0.075). In addition, a trend of favorable disease control rate (DCR; 62.5% vs. 45.0%, p = 0.056) was noted in locoregional recurrence group. In locoregional recurrence group, prior salvage surgery was associated with longer OS (HR = 0.24, P = 0.008) and PFS (HR = 0.30, P = 0.005). CONCLUSION: SCCHN with locoregional recurrence is associated with better disease control and survival outcomes comparing to distant metastatic SCCHN when treated with cetuximab-containing regimen. Salvage surgery for locoregional recurrence may further improves clinical outcome.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Cetuximab/uso terapêutico , Carcinoma de Células Escamosas/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia , Resultado do Tratamento , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/etiologia , Doença Crônica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Fine-needle aspiration biopsy (FNAB) is a routine diagnostic test for thyroid nodules. The use of local anesthesia (LA) before the procedure is still controversial. This prospective study aimed to evaluate the degree of pain and specimen adequacy in liquid-based cytology (LBC) for FNAB of thyroid nodules with and without LA. A total of 100 consecutive patients with thyroid nodules who underwent FNAB with and without LA between January and December 2020 were included. Patients who received LA had a significantly lower immediate pain scale score (P = 0.01). Multivariate analysis demonstrated that no use of LA (odds ratio [OR] = 3.48, 95% confidence interval [CI] = 1.50-8.10, P = 0.004) and lesion abutting the trachea (OR = 6.14, 95% CI = 1.56-24.12, P = 0.009) were independently and significantly associated with pain degree immediately after FNAB. A higher proportion of patients who previously underwent FNAB thought that LA was helpful and should be performed prior to FNAB. However, the use of LA did not improve the specimen adequacy (P = 0.075). The results showed that administration of LA with a proper technique before ultrasound-guided FNAB might reduce immediate pain after the procedure, and patients may experience more pain when the aspirated nodules abut the trachea.
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Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Humanos , Nódulo da Glândula Tireoide/patologia , Biópsia por Agulha Fina/métodos , Anestesia Local , Estudos Prospectivos , Dor/etiologia , Neoplasias da Glândula Tireoide/patologia , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Compared with the precise targeting of drug-resistant mutant cancer cells, strategies for eliminating non-genetic adaptation-mediated resistance are limited. The pros and cons of the existence of inflammasomes in cancer have been reported. Nevertheless, the dynamic response of inflammasomes to therapies should be addressed. METHODS: Tumor-derived exosomes were purified by differential ultracentrifugation and validated by nanoparticle tracking analysis and transmission electron microscopy. A proximity ligation assay and interleukin-1ß (IL-1ß) level were used for detecting activation of NLRP3 inflammasomes. RNA sequencing was used to analyze the exosomal RNAs. MIR21 knocked out human monocytic THP cells and mir21 knocked out murine oral cancer MTCQ1 cells were generated for confirming the exosomal delivery of microRNA (miR)-21. Syngeneic murine models for head and neck cancer (C57BLJ/6J), breast cancer (BALB/C) and lung cancer (C57BL/6J) were applied for examining the impact of Snail-miR21 axis on inflammasome activation in vivo. Single-cell RNA sequencing was used for analyzing the tumor-infiltrated immune cells. Head and neck patient samples were used for validating the findings in clinical samples. RESULTS: We demonstrated that in cancer cells undergoing Snail-induced epithelial-mesenchymal transition (EMT), tumor cells suppress NLRP3 inflammasome activities of tumor-associated macrophages (TAMs) in response to chemotherapy through the delivery of exosomal miR-21. Mechanistically, miR-21 represses PTEN and BRCC3 to facilitate NLRP3 phosphorylation and lysine-63 ubiquitination, inhibiting NLRP3 inflammasome assembly. Furthermore, the Snail-miR-21 axis shapes the post-chemotherapy tumor microenvironment (TME) by repopulating TAMs and by activating CD8+ T cells. In patients with head and neck cancer, the Snail-high cases lacked post-chemotherapy IL-1ß surge and were correlated with a worse response. CONCLUSIONS: This finding reveals the mechanism of EMT-mediated resistance beyond cancer stemness through modulation of post-treatment inflammasome activity. It also highlights the dynamic remodeling of the TME throughout metastatic evolution.
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Neoplasias de Cabeça e Pescoço , MicroRNAs , Fatores de Transcrição da Família Snail/metabolismo , Animais , Linfócitos T CD8-Positivos , Cisplatino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Inflamassomos , Camundongos , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Microambiente TumoralRESUMO
BACKGROUND: The antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab and immune checkpoint inhibitors (ICIs) are the current front-line treatment for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, understanding of the efficacy of cetuximab-containing regimens in patients who fail ICI treatments is limited. In this study, we present the efficacy of cetuximab-based regimens in heavily pretreated R/M HNSCC patients after progression to ICIs. METHODS: This was a retrospective study that analyzed patients diagnosed with R/M HNSCC who progressed after ICIs and then received their first-time cetuximab-based regimens at Taipei Veterans General Hospital from January 2017 to December 2020. The response rate, overall survival, and progression-free survival were measured. RESULTS: A total of 28 patients were included in this study. Most patients had received pembrolizumab as an ICI. The median duration of cetuximab-based regimens prescribed was 4.5 months. The objective response rate (ORR) was 32.1% (95% confidence interval [CI], 17.9%-50.6%), and the disease control rate (DCR) was 53.6% (95% CI, 42.4%-76.4%). The median overall survival and median progression-free survival were 9.1 months (95% CI, 1.3-16.8) and 2.9 months (95% CI, 2.2-3.5), respectively. The incidence of cetuximab-related adverse events was reported as 39.2%. CONCLUSION: A cetuximab-based regimen is still an effective and tolerable treatment for R/M HNSCC after progression on ICIs. Future prospective studies are needed to identify better treatments for previously ICI-treated or heavily treated R/M HNSCC patients.
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Neoplasias de Cabeça e Pescoço , Inibidores de Checkpoint Imunológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológicoRESUMO
BACKGROUND: To assess the feasibility of tongue conservation treatment with induction chemotherapy (ICT), tongue conservation surgery, and risk-adapted postoperative adjuvant therapy in oral tongue squamous cell carcinoma (OTSCC). METHODS: Patients with newly diagnosed OTSCC cT2-4 N0-2 M0 were recruited. The ICT with a regimen of docetaxel, cisplatin, and oral tegafur/uracil (DCU) was administrated every 21 days. After the first cycle of ICT (DCU1), patients with a more than 30% decrease in the longest diameter of primary tumor underwent a second cycle of ICT (DCU2). Tongue conservation surgery was performed after ICT, and risk-adapted adjuvant therapy was organized based on pathological features. RESULTS: From July 2011 to December 2015, a total of 23 patients were enrolled, 87% of whom were classified as stage III-IV. Clinical responders to DCU1 and DCU2 were determined in 90.5% (19/21) and 88.2% (15/17) of patients. Tongue conservation surgery was performed in 16 responders to ICT. Only one patient had a positive margin (6.3%), and a complete pathologic response was achieved in eight patients (50%). Only one patient developed local recurrence after a median follow-up of 58.6 months (range, 7.9-105.2). The 5-year overall survival (0% vs. 87.5%, P = 0.001) and disease-specific survival (0% vs. 93.3%, P = 0.000) were significantly different between the DCU1 nonresponders and responders. CONCLUSION: Tongue conservation treatment with ICT, followed by conservation surgery and risk-adapted adjuvant therapy, is feasible for patients with OTSCC who are good responders to ICT. However, the outcomes of nonresponders are dismal. Further study in a larger patient population is warranted.
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Carcinoma de Células Escamosas/terapia , Neoplasias da Língua/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia Adjuvante , Feminino , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Procedimentos Cirúrgicos Bucais , Taxa de Sobrevida , Neoplasias da Língua/patologiaRESUMO
Postoperative adjuvant therapy has been indicated by advanced T classification for T3-4 oral squamous cell carcinoma (OSCC) and the significance of perineural invasion (PNI) and lymphovascular invasion (LVI) in treatment for T3-4 OSCC remains unclear. Ninety-eight cumulative patients with T3-4 OSCC who underwent curative surgery between Jan 2002 and Dec 2010 were recruited and analyzed. Twenty-seven (27.6%) patients were PNI/LVI double positive. PNI/LVI double positive demonstrated independent predictive values for higher neck metastasis (LN+), higher distant metastasis (DM) and low 5-year disease-specific survival (DSS) rates (p < 0.001, p = 0.017, and p < 0.001, respectively) after controlling for other pathologic features of the primary tumors. A high DM rate of 33.3% was noted in PNI/LVI double-positive patients. Among the PNI/LVI double negative, single positive to double positive subgroups, increasing LN+, DM rates and decreasing DSS rate were observed. Among the 44 LN+ patients, PNI/LVI double positive remained associated with a markedly high DM rate of 42.9% and a poor 5-year DSS of 27.7%. PNI/LVI double positive plays important roles in prognostication and potential clinical application for T3-4 OSCC by independently predicting LN+, DM, and poor DSS, and can be used as a good marker to select DM high-risk patients for novel adjuvant therapy trials.
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Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/terapia , Análise Multivariada , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Vigilância em Saúde Pública , Análise de SobrevidaRESUMO
BACKGROUND: Esophageal second primary neoplasms (ESPNs) are common in hypopharyngeal squamous cell carcinoma (HPSCC) patients and are associated with poor prognoses. The effectiveness of image-enhanced endoscopy (IEE) has not been well established. METHODS: We reviewed the patients between April 2016 and April 2018 with HPSCC receiving ESPNs screening via white-light imaging, narrow-band imaging, and Lugol chromoendoscopy. RESULTS: Of 99 eligible patients, ESPNs prevalence was 31%. Of the 69 patients assigned to the follow-up group, 23 with positive findings showed significantly increased previous histories of second primary malignancies in the upper aerodigestive tract. Among them, patients without symptoms at the time of IEE screening showed less advanced T stages and higher percentages of receiving minimal invasive therapy. CONCLUSION: The present study represented the clinical utility of routine IEE screening in HPSCC patients and proposed routine surveillance may help identify and properly manage early-stage ESPN.
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Neoplasias Esofágicas/patologia , Esofagoscopia/métodos , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/fisiopatologia , Prevalência , Fatores de RiscoRESUMO
BACKGROUND: Angiopoietin-Tie2 and nitric oxide pathway is crucial in tumor angiogenesis and closely correlates with tumor development, growth, and metastasis. This study aimed to investigate the angiopoietin-Tie2 and nitric oxide signaling of the erythrocyte membrane in response to surgical trauma in head and neck cancer. METHODS: We prospectively enrolled the patients with histology-proven head and neck squamous cell carcinoma undergoing surgical resection of primary tumors at the medical center between August and November 2019. We measured the preoperative and postoperative levels of angiopoietin-1, angiopoietin-2 in plasma using enzyme-linked immunosorbent assays, nitric oxide in plasma using nitrate/nitrite colorimetric assays, and Tie2 phosphorylation in erythrocyte membrane using Western blotting. RESULTS: The plasma angiopoietin-1 was downregulated from the median 971.3 pg/mL (interquartile range [IQR] 532.1-1569.3) to 417.9 (IQR 270.5-597.3) after tumor resection (p = 0.0020). Conversely, the plasma angiopoietin-2 was enhanced from 1173.6 pg/mL (IQR 977.7-1450.2) to 2353.7 (IQR 1352.4-2954.3) after surgery (p = 0.0021), with a concomitant increase in plasma nitric oxide level from 7.73 µM (IQR 5.39-10.06) to 10.50 (IQR 7.65-14.18) after surgical resection (p = 0.0093). Subgroup analyses further showed the angiopoietin-Tie2 and nitric oxide signaling was significant only in stage III and IV cancer. CONCLUSIONS: The dynamic change of angiopoietin-Tie2 signaling in the erythrocyte membrane along with the enhanced nitric oxide in plasma after tumor resection suggests erythrocytes play a significant role in modulating surgery-induced angiogenesis, which may provide a novel marker for cancer surveillance and control.
Assuntos
Neoplasias de Cabeça e Pescoço , Receptor TIE-2 , Angiopoietina-1 , Angiopoietina-2 , Angiopoietinas , Eritrócitos , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Óxido Nítrico , PrognósticoRESUMO
Early enzyme replacement therapy (ERT) improve long-term outcomes in patients with infantile-onset Pompe disease (IOPD). Our cohort of patients with IOPD at Taipei Veterans General Hospital (TVGH) joined Taiwan Pompe newborn screening program from 2008, testing more than one million newborns until 2018. By 2010, we had established rapid diagnostic strategies. Now, the average age of ERT initiation starts at an average age of <10 days-old, the earliest group in the world. However, they still presented some airway problems. We present a retrospective study focused on airway abnormalities in these patients along 8 years of observation. Fifteen patients with IOPD, who received very early treatment at a mean age of 8.94 ± 3.75 days, underwent flexible bronchoscopy (FB) for dynamic assessment of the whole airway. Long-term clinical outcomes and relevant symptoms of the upper airway were assessed. All patients in the study had varying degrees of severity of upper airway abnormalities and speech disorders. The three oldest children (Age 94, 93, and 88 months, respectively) had poor movement of the vocal cords with reduced abduction and adduction and had silent aspiration of saliva through the glottis during respiration. This is the largest cohort study presented to date about airway abnormalities in very early treated patients with IOPD patients by FB. Despite very early treatment, we observed upper airway abnormalities in these IOPD patients. In IOPD, upper airway abnormalities seem inevitable over time. We suggest early and continuous monitoring for all IOPD patients, even with early and regular treatment.
Assuntos
Broncoscopia/métodos , Doença de Depósito de Glicogênio Tipo II/complicações , Anormalidades do Sistema Respiratório/patologia , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Anormalidades do Sistema Respiratório/etiologia , Anormalidades do Sistema Respiratório/terapia , Estudos RetrospectivosRESUMO
OBJECTIVES: Perineural invasion (PNI) is a poor prognostic pathologic feature of oral squamous cell carcinoma (OSCC). The mechanisms of PNI remain poorly understood, and nerve-tumour interactions have been implicated for its pathogenesis. DESIGN AND SETTING: Systematic investigation of nerve-tumour interactions was performed using fresh human peripheral nerve. In vitro and in vivo models were used to determine the ability of human peripheral nerves to enhance OSCC migration/invasion. Retrospective cohort study was also carried out in one medical centre from 2001 to 2009. PARTICIPANTS: 314 T1-2 OSCC patients. MAIN OUTCOME MEASURES: In the transwell migration/invasion assay, the cells in five representative fields were counted. In the nerve implantation model, tumour size was estimated. PNI quantification by PNI focus number was carried out in the OSCC patients to correlate with cervical lymph node metastasis and oncologic outcomes. RESULTS: The transwell migration/invasion assay demonstrated that human peripheral nerves, compared with subcutaneous soft tissue, significantly enhanced the migration/invasion abilities of OSCC. Moreover, the enhanced migration was dose-dependent with increased length or number of peripheral nerve segments. The nerve implantation model showed that human peripheral nerve also enhanced OSCC growth in vivo. Finally, increased PNI focus number was found dose-dependently associated with increased cervical lymph node metastasis and decreased 5-year disease-specific survival rates. CONCLUSIONS: These results clearly indicated the presence of nerve-tumour interaction that involved paracrine influences leading to aggressiveness of OSCC. Further investigations are required to explore key cell types and molecules involved in nerve-tumour interactions for future therapeutic targeting of PNI in OSCC.
Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Invasividade Neoplásica/patologia , Nervos Periféricos/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Humanos , Metástase Linfática/patologia , Camundongos Nus , Prognóstico , Estudos RetrospectivosRESUMO
Epithelial-mesenchymal transition (EMT) is a pivotal mechanism for cancer dissemination. However, EMT-regulated individual cancer cell invasion is difficult to detect in clinical samples. Emerging evidence implies that EMT is correlated to collective cell migration and invasion with unknown mechanisms. We show that the EMT transcription factor Snail elicits collective migration in squamous cell carcinoma by inducing the expression of a tight junctional protein, claudin-11. Mechanistically, tyrosine-phosphorylated claudin-11 activates Src, which suppresses RhoA activity at intercellular junctions through p190RhoGAP, maintaining stable cell-cell contacts. In head and neck cancer patients, the Snail-claudin-11 axis prompts the formation of circulating tumour cell clusters, which correlate with tumour progression. Overexpression of snail correlates with increased claudin-11, and both are associated with a worse outcome. This finding extends the current understanding of EMT-mediated cellular migration via a non-individual type of movement to prompt cancer progression.
Assuntos
Movimento Celular/genética , Claudinas/genética , Neoplasias/genética , Fatores de Transcrição da Família Snail/genética , Animais , Células CACO-2 , Linhagem Celular Tumoral , Células Cultivadas , Claudinas/metabolismo , Transição Epitelial-Mesenquimal/genética , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Fatores de Transcrição da Família Snail/metabolismo , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
OBJECTIVE: Perineural invasion (PNI) has been an established poor prognostic feature for T1-T2 oral squamous cell carcinoma (OSCC). Different presentations and amounts of PNI are commonly observed, but PNI is currently recorded as being present or absent. This study asked whether the quantification of PNI provides additional information for early OSCC. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral medical center. SUBJECTS AND METHODS: Pathologic reevaluations were performed for 314 patients with T1-T2 OSCC who underwent curative surgery from June 2001 to August 2009. A novel parameter, PNI focus number, was defined for PNI quantification. With 5 PNI foci as the cutoff, patients were categorized into 3 groups: no PNI (0 PNI foci), low PNI (PNI foci, 1-5), and high PNI (PNI foci >5). Rate of cervical lymph node metastasis (LN+), 5-year disease-specific survival (DSS), and 5-year overall survival (OS) were analyzed among these groups. RESULTS: PNI focus number independently predicted for LN+, poor DSS, and poor OS in multivariate analysis after controlling for T classification, lymphovascular invasion, differentiation, margin, and tumor thickness. The 5-year DSS demonstrated a dose-dependent decrease among the 3 groups (no PNI, 88.6%; low PNI, 75.2%; high PNI, 33.8%; P < .001). Moreover, the 5-year DSS of the high PNI group was significantly worse than that of the low PNI group. CONCLUSION: PNI focus number can be a novel parameter for PNI quantification in early OSCC. Although optimal quantification methods still require further investigation, this study offers clear clinical support for the nerve-tumor interaction hypothesis and advocates further mechanistic research for the exploration of PNI-related treatment concepts for OSCC.
Assuntos
Carcinoma de Células Escamosas/secundário , Neoplasias Bucais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Bucais/terapia , Invasividade Neoplásica , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic sites, TAMs secrete interleukin-35 (IL-35) to facilitate metastatic colonization through activation of JAK2-STAT6-GATA3 signaling to reverse epithelial-mesenchymal transition (EMT) in cancer cells. In primary tumors, inflammation-induced EMT upregulates IL12Rß2, a subunit of the IL-35 receptor, in cancer cells to help them respond to IL-35 during metastasis. Neutralization of IL-35 or knockout of IL-35 in macrophages reduces metastatic colonization. These results indicate the distinct TMEs of primary and metastatic tumors and provide potential targets for intercepting metastasis.