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BACKGROUND: Lactate dehydrogenase (LDH) is involved in the Warburg effect. Elevated serum LDH is a prognostic marker for metastatic solid cancer. AIM: To investigate the prognostic impact of serum LDH in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: This retrospective study included 129 patients treated with ICIs between 2017 and 2023. The effects of pretreatment LDH, LDH at 3 months, and change in LDH during the first 3 months (ΔLDH) on overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and Cox regression model. RESULTS: The 1-year PFS and OS rates for high and low groups were 6.0% and 30.1% for pretreatment LDH (p = 0.044), 25.7% and 38.3% for on-treatment LDH (p = 0.079), and 14.3% and 38.7% for ΔLDH (p = 0.008), as well as 42.1% and 60.9% for pretreatment LDH (p = 0.109), 56.0% and 80.5% (p < 0.001) for on-treatment LDH, and 31.0% and 81.0% for ΔLDH (p < 0.001), respectively. ΔLDH was an independent prognostic factor for both PFS and OS. CONCLUSIONS AND SIGNIFICANCE: ΔLDH can be used to predict ICI treatment outcomes and as a marker in deciding to continue ICI therapy.
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Objectives We aimed to examine the effectiveness of platinum-based triplet induction chemotherapy in metastatic squamous cell carcinoma of the head and neck (HNSCC) at diagnosis in terms of tumor human papillomavirus (HPV) status and the clinical relevance of circulating tumor HPV DNA (ctHPVDNA) during induction chemotherapy. Methods Twenty-one patients were included. ctHPVDNA was longitudinally quantified using optimized digital PCR in a subset of patients. Results HPV-related HNSCC patients (N=7) had a significantly better response to induction chemotherapy than HPV-unrelated HNSCC patients (N=14) (complete or partial response rate, 100% vs. 36%, P = 0.007). Following induction chemotherapy, more HPV-related HNSCC patients than HPV-unrelated patients received radiotherapy (86% vs. 36%, P = 0.06). With a median follow-up of 26 months in surviving patients, the two-year overall survival was 86% in HPV-related HNSCC patients and 43% in HPV-unrelated HNSCC patients (P = 0.04). In two patients, ctHPVDNA levels drastically decreased after the first cycle of induction chemotherapy but turned to continuous increase after the second cycle, suggesting the acquisition of drug resistance by the end of the second cycle. Radiographic imaging after induction chemotherapy failed to identify the drug resistance. In one patient, ctHPVDNA decreased gradually but remained detectable after induction chemotherapy despite no radiographic residual disease. ctHPVDNA became undetectable during radiotherapy. Conclusion HPV-related HNSCC patients with distant metastasis at diagnosis should be treated definitively. The ctHPVDNA level reflects real-time disease activity. ctHPVDNA monitoring during induction chemotherapy could help the decision-making of the therapeutic strategy.
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Purpose: Radiation therapy is widely used to treat head and neck squamous cell carcinoma (HNSCC). This study evaluated the association between circulating plasma programmed death-ligand 1 (PD-L1) and the outcomes of patients with HNSCC after radiation therapy. Methods and Materials: In this retrospective observational study, plasma samples of 76 patients with HNSCC who underwent radiation therapy from June 2019 to August 2021 were analyzed. These plasma samples were obtained before radiation therapy. The median follow-up was 32.5 months. Total and exosomal PD-L1 was measured by enzyme-linked immunosorbent assay and retrospectively analyzed for association with overall survival (OS), progression-free survival (PFS), and local control (LC). Prognostic factors among patients' characteristics and circulating PD-L1 in plasma were evaluated by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses. Results: The median concentration of total PD-L1 in plasma was 115.1 pg/mL (95% CI, 114.7-137.9 pg/mL), and the median concentration of exosomal PD-L1 was 2.8 pg/mL (95% CI, 6.0-13.0 pg/mL). Univariate and multivariate analyses showed exosomal PD-L1 as a prognostic factor for PFS and LC. Patients with high exosomal PD-L1 in plasma had poor PFS and LC compared with those with low exosomal PD-L1, indicating that 1-year PFS was 79.2% versus 33.3% (P < .001) and 1-year LC was 87.3% versus 50.0% (P < .001) in patients with high and low exosomal PD-L1, respectively. However, exosomal PD-L1 in plasma had no significant effect on OS. Total PD-L1 in plasma did not correlate with PFS, LC, and OS. Conclusions: The pretreatment circulating exosomal PD-L1 in plasma of patients with HNSCC was a prognostic factor after radiation therapy.
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Circulating tumor DNA (ctDNA), which circulates in the blood after being shed from cancer cells in the body, has recently gained attention as an excellent tumor marker. The purpose of this study was to evaluate whether ct human papillomavirus (HPV) 16 DNA (ctHPV16DNA) levels were associated with quantitative PET parameters in patients with HPV-positive head and neck (HN) squamous cell carcinoma (SCC). Fifty patients with oropharyngeal SCC (OPSCC) and 5 with SCC of unknown primary (SCCUP) before treatment were included. They all underwent blood sampling to test ctHPV16DNA levels and FDG PET-CT examinations. Quantitative PET parameters included SUVmax, metabolic tumor volume (MTV), MTV of whole-body lesions (wbMTV), and 56 texture features. ctHPV16DNA levels were compared to texture features of primary tumors in OPSCC patients (Group A) or the largest primary or metastatic lymph node lesions in OPSCC and SCCUP patients (Group B) and to other PET parameters. Spearman rank correlation test and multiple regression analysis were used to confirm the associations between ctHPV16DNA levels and PET parameters. ctHPV16DNA levels moderately correlated with wbMTV, but not with SUVmax or MTV in Groups A and B. ctHPV16DNA levels exhibited a weak negative correlation with low gray-level zone emphasis in Groups A and B. Multiple regression analysis revealed that wbMTV and high gray-level zone emphasis were the significant factors for ctHPV16DNA levels in Group B. These results were not observed in Group A. This study demonstrated that ctHPV16DNA levels correlated with the whole-body tumor burden and tumor heterogeneity visualized on FDG PET-CT in patients with HPV-positive HNSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18/metabolismo , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , RadiofármacosRESUMEN
BACKGROUND: Although patients with head and neck squamous cell cancer (HNSCC) often show malnutrition, its effects on immune checkpoint inhibitor (ICI) treatment outcomes in these patients are unclear. OBJECTIVES: To investigate the prognostic influence of nutritional indices in patients with HNSCC treated with ICIs and determine the optimal indices. METHODS: This retrospective study included 106 patients with HNSCC treated with ICIs between 2017 and 2022. The prognostic influences of body mass index (BMI), geriatric nutritional risk index (GNRI), and prognostic nutritional index (PNI) on overall survival (OS) and progression-free survival (PFS) were analysed using the Kaplan-Meier method and Cox-regression models. RESULTS: The 1-year PFS rates in the groups with high and low BMI, GNRI, and PNI were, respectively, 24.2% and 28.4% (p = .731), 29.7% and 14.4% (p = .024), and 30.3% and 13.9% (p = .015). PNI was an independent prognostic factor for both PFS (hazard ratio (HR) = 1.89; 95% confidence interval (CI), 1.08-3.29) and OS (HR = 3.26; 95% CI, 1.66-6.40). CONCLUSIONS: PNI can predict ICI outcomes and should be assessed when ICI treatment is considered.
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Neoplasias de Cabeza y Cuello , Evaluación Nutricional , Humanos , Anciano , Pronóstico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
PURPOSE: This study aimed to examine whether circulating tumor human papillomavirus type 16 (HPV16) DNA (ctHPV16DNA) can help identify patients with locally advanced HPV16-related oropharyngeal squamous cell carcinoma who may benefit from deintensified treatment. MATERIALS AND METHODS: We serially collected blood samples before, during, and after treatment from 22 patients who received 70 Gy radiotherapy alone and longitudinally quantified ctHPV16DNA using droplet digital polymerase chain reaction. We correlated the clearance profile of ctHPV16DNA with clinical outcomes. RESULTS: The percentage of patients with detectable ctHPV16DNA decreased after every 10 Gy of radiotherapy. By contrast, the percentage of patients who later developed treatment failure among patients with detectable ctHPV16DNA gradually increased as radiotherapy proceeded, reaching 100% after 60 Gy of radiotherapy. We defined patients with and without detectable ctHPV16DNA after receiving 40 Gy as having slow and rapid clearance profiles, respectively. All 12 patients with a rapid clearance profile remained disease-free after radiotherapy. Of the 10 patients with a slow clearance profile, three had persistent or progressive disease at response evaluation after radiotherapy and one developed distant metastasis during follow-up (ie, four patients experienced treatment failure). The median follow-up for surviving patients was 38.6 months, and the 3-year failure-free survival rates of patients with rapid and slow clearance profiles were 100% and 58%, respectively (P = .02). Neither baseline ctHPV16DNA levels nor metabolic tumor volume was an independent predictor of the pattern of the clearance profile. CONCLUSION: In patients with HPV16-related oropharyngeal squamous cell carcinoma receiving radiotherapy, a slow ctHPV16DNA clearance profile could prelude unfavorable outcomes. Monitoring ctHPV16DNA is essential for determining the clearance profile, which might help optimize treatment intensity individually.
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Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Virus del Papiloma Humano , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Neoplasias Orofaríngeas/radioterapia , Neoplasias Orofaríngeas/patología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/radioterapia , Infecciones por Papillomavirus/patología , ADN/uso terapéuticoRESUMEN
Objective: Basal information of head and neck small-cell carcinoma (HNSmCC) including epidemiology, primary site, treatment, and prognosis remains sparse due to its rarity. We report here a multicenter retrospective study on the diagnosis, treatment, and outcomes of patients with HNSmCC. Materials and methods: This study involved 47 patients with HNSmCC from 10 participating institutions. Eight patients were excluded for whom no pathological specimens were available (n = 2) and for discrepant central pathological judgements (n = 6). The remaining 39 patients were processed for data analysis. Results: As pretreatment examinations, computed tomography (CT) was performed for the brain (n = 8), neck (n = 39), and chest (n = 32), magnetic resonance imaging (MRI) for the brain (n = 4) and neck (n = 23), positron emission tomography-CT (PET-CT) in 23 patients, bone scintigraphy in 4, neck ultrasonography in 9, and tumor markers in 25. Primary sites were oral cavity (n = 1), nasal cavity/paranasal sinuses (n = 16), nasopharynx (n = 2), oropharynx (n = 4), hypopharynx (n = 2), larynx (n = 6), salivary gland (n = 3), thyroid (n = 2), and others (n = 3). Stages were II/III/IV-A/IV-B/IV-C/Not determined = 3/5/16/6/5/4; stage IV comprised 69%. No patient had brain metastases. First-line treatments were divided into 3 groups: the chemoradiotherapy (CRT) group (n = 27), non-CRT group (n = 8), and best supportive care group (n = 4). The CRT group included concurrent CRT (CCRT) (n = 17), chemotherapy (Chemo) followed by radiotherapy (RT) (n = 5), and surgery (Surg) followed by CCRT (n = 5). The non-CRT group included Surg followed by RT (n = 2), Surg followed by Chemo (n = 1), RT alone (n = 2), and Chemo alone (n = 3). The 1-year/2-year overall survival (OS) of all 39 patients was 65.3/53.3%. The 1-year OS of the CRT group (77.6%) was significantly better compared with the non-CRT group (31.3%). There were no significant differences in adverse events between the CCRT group (n = 22) and the Chemo without concurrent RT group (n = 9). Conclusion: Neck and chest CT, neck MRI, and PET-CT would be necessary and sufficient examinations in the diagnostic set up for HNSmCC. CCRT may be recommended as the first-line treatment. The 1-year/2-year OS was 65.3%/53.3%. This study would provide basal data for a proposing the diagnostic and treatment algorithms for HNSmCC.
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A biomarker that is useful for the detection of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) and cancer of unknown primary (CUP) is indispensable. We evaluated the diagnostic performance of HPV DNA and mRNA in oral gargle samples and circulating tumor HPV16 DNA (ctHPV16DNA) in blood samples. Oral HPV DNA and mRNA were analyzed using commercially available HPV assays of the GENOSEARCH HPV31 and Aptima, respectively. ctHPV16DNA was analyzed using in-house droplet digital polymerase chain reaction. Seventy-four patients with OPC and eight patients with CUP were included. The sensitivity and specificity of oral HPV DNA, oral HPV mRNA, and ctHPV16DNA were 82% (95% confidence interval [CI] = 66-92) and 100% (95% CI = 88-100), 85% (95% CI = 69-94) and 94% (95% CI = 73-100), and 93% (95% CI = 81-99) and 97% (95% CI = 84-100), respectively, for HPV16-related OPC, while those were 20% (95% CI = 1-72) and 100% (95% CI = 3-100), 0% (95% CI = 0-52) and 100% (95% CI = 3-100), and 100% (95% CI = 54-100) and 100% (95% CI = 16-100), respectively, for HPV16-related CUP. The sensitivity of ctHPV16DNA for HPV16-related OPC was higher than that of oral biomarkers, though the difference was not statistically significant. ctHPV16DNA remarkably correlated with the anatomic extent of disease, total metabolic tumor volume and HPV16 copy number per tumor genome in patients with HPV16-related OPC/CUP, whereas oral biomarkers did not. In conclusion, ctHPV16DNA is a potentially promising biomarker for HPV16-related OPC, while further studies are required for HPV16-related CUP.
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Alphapapillomavirus/genética , ADN Tumoral Circulante/genética , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Orofaríngeas/diagnóstico , Infecciones por Papillomavirus/complicaciones , ARN Mensajero/genética , Adulto , Anciano , Anciano de 80 o más Años , Alphapapillomavirus/aislamiento & purificación , ADN Viral/sangre , ADN Viral/genética , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Primarias Desconocidas/sangre , Neoplasias Primarias Desconocidas/epidemiología , Neoplasias Primarias Desconocidas/virología , Neoplasias Orofaríngeas/sangre , Neoplasias Orofaríngeas/epidemiología , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/virología , Pronóstico , Estudios Prospectivos , ARN Mensajero/sangre , ARN Viral/sangre , ARN Viral/genéticaRESUMEN
Positron emission tomography and computed tomography (PET-CT) is widely used to assess the response to radiotherapy. However, the ability of PET-CT to predict treatment failure in human papillomavirus (HPV)-related squamous cell carcinoma of the head and neck (HNSCC) is unsatisfactory. We quantified circulating tumor HPV type16 DNA (ctHPV16DNA) using optimized droplet digital PCR in 35 patients with HPV16-related HNSCC, who received radiotherapy with or without chemotherapy, and prospectively correlated ctHPV16DNA and metabolic response with treatment failure. After a median follow-up of 21 months, ctHPV16DNA and PET-CT had similar negative predictive values (89.7% vs 84.0%), whereas the positive predictive value was much higher in ctHPV16DNA than in PET-CT (100% vs 50.0%). Notably, six patients who had detectable posttreatment ctHPV16DNA all had treatment failure irrespective of metabolic response, whereas none of five patients who had partial metabolic response without detectable posttreatment ctHPV16DNA had treatment failure. The risk of treatment failure was high in patients who had incomplete metabolic response with detectable posttreatment ctHPV16DNA (hazard ratio [HR], 138.8; 95% confidence interval [CI], 15.5-3366.4; P < .0001) and intermediate in patients who had discordant results between metabolic response and posttreatment ctHPV16DNA (HR, 4.7; 95% CI, 0.8-36.2, P = .09) as compared with patients who had complete metabolic response without detectable posttreatment ctHPV16DNA. One-year event-free survival rates of each risk group were 0%, 88% (95% CI, 46-98) and 95% (95% CI, 72-99), respectively (P < .0001). In conclusion, posttreatment ctHPV16DNA complements PET-CT and helps guide decisions managing patients with HPV16-related HNSCC after radiotherapy.
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Carcinoma de Células Escamosas/genética , ADN Tumoral Circulante/genética , Neoplasias de Cabeza y Cuello/genética , Papillomavirus Humano 16/genética , Infecciones por Papillomavirus/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , ADN Tumoral Circulante/sangre , Femenino , Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/terapia , Papillomavirus Humano 16/fisiología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Infecciones por Papillomavirus/diagnóstico por imagen , Infecciones por Papillomavirus/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodosRESUMEN
OBJECTIVES/HYPOTHESIS: Meniere's disease (MD) patients can show normal head impulses despite poor caloric test results. This study aimed to investigate the discrepancy in the vestibulo-ocular reflex (VOR) in MD patients and whether endolymphatic hydrops (EH) influence the VOR. STUDY DESIGN: Prospective, cross-sectional observational study. METHODS: Ninety MD patients were enrolled. Neuro-otological testing, including a video head impulse test (vHIT) of all semicircular canals (SCs), and gadolinium-enhanced inner ear magnetic resonance imaging were performed. The vestibular EH volume was quantitatively evaluated by processing magnetic resonance images. RESULTS: Abnormal vHIT results in MD patients were found most frequently in the posterior (44.4%) SCs, followed by the horizontal (13.3%) and anterior (10%) SCs. Canal paresis (CP) was assessed using the vHIT and the caloric test, and results were not significant when vHIT responses were assessed as CP only using the horizontal SC. The difference in the vestibular EH between the presence and absence of CP was not significant if assessed using the vHIT (P = .5591), but it was statistically different if assessed using the caloric test (P = .0467). CONCLUSIONS: The contradictory reaction of VOR in MD patients may result from the high specificity but low sensitivity of CP in the horizontal vHIT. EH volume in the vestibule affects the caloric response but does not affect the vHIT response. LEVEL OF EVIDENCE: 2b Laryngoscope, 129:1660-1666, 2019.