Efficacy of ionizing radiation (I/R) was compared with phototoxic effects of photodynamic therapy (PDT) in vitro using two cell lines derived from patients with head and neck squamous cell carcinoma ...(HNSCC). A cell line derived from a donor with a human papilloma virus (HPV) infection was more responsive to I/R but significantly less responsive to PDT than a cell line derived from an HPV‐free patient. Cell death after I/R in the HPV(+) cell line was associated with increased DEVDase activity, a hallmark of apoptosis. The HPV(−) line was considerably less responsive to I/R, with DEVDase activity greatly reduced, suggesting an impaired apoptotic program. In contrast, the HPV(−) cells were readily killed by PDT when the ER was among the targets for photodamage. While DEVDase activity was enhanced, the death pathway appears to involve paraptosis until the degree of photodamage reached the LD99 range. These data suggest that PDT‐induced paraptosis can be a death pathway for cells with an impaired apoptotic program.
This image demonstrates the ability of photodynamic therapy (PDT) directed at ER/mitochondria to eradicate a head & neck cancer cell line (WSU12) from a patient with a human papilloma virus infection. These cells were relatively unresponsive to ionizing radiation, typical of HPV (+) tumors. In contrast, cells from an HPV (−) patient (UP154) were responsive to ionizing radiation but not to PDT.
The aim of this study is to understand the mechanism of EGFR overexpression in head and neck squamous cell carcinoma (HNSCC). For this reason, expression/mutation of EGFR were analyzed in 30 ...dysplastic head and neck lesions and 148 HNSCC samples of Indian patients along with 3 HNSCC cell lines. In addition, deletion/methylation/mutation/expression of SH3GL2 (associated with EGFR degradation) and CDC25A (associated with dephosphorylation of EGFR) were analyzed in the same set of samples. Our study revealed high frequency of EGFR overexpression (66-84%), low frequency of gene amplification (10-32.5%) and absence of functional mutation in the dysplastic lesions and HNSCC samples. No correlation was found between protein overexpression and mRNA expression/gene amplification status of EGFR. On the other hand, frequent alterations (deletion/methylation) of SH3GL2 (63-77%) and CDC25A (37-64%) were seen in the dysplastic and HNSCC samples. Two novel single nucleotide polymorphism (SNPs) were found in the promoter region of SH3GL2. Reduced expression of these genes showed concordance with their alterations. Overexpression of EGFR and p-EGFR were significantly associated with reduced expression and alterations of SH3GL2 and CDC25A respectively. In-vitro demethylation experiment by 5-aza-2'-deoxycytidine (5-aza-dC) showed upregulation of SH3GL2 and CDC25A and downregulation of EGFR expression in Hep2 cell line. Poor patient outcome was predicted in the cases with alterations of SH3GL2 and CDC25A in presence of human papilloma virus (HPV) infection. Also, low SH3GL2 and high EGFR expression was a predictor of poor patient survival. Thus, our data suggests that overexpression of EGFR due to its reduced degradation and dephosphorylation is needed for development of HNSCC.
Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (HNSCC). Predictive biomarkers have not been established and patient stratification based on molecular ...tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment. From our patient‐derived xenograft platform of HNSCC, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid‐clustering with previously published gene expression data by Keck et al. The models were treated in groups of 5–6 animals with docetaxel, cetuximab, everolimus, cis‐ or carboplatin and 5‐fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after 3 weeks of treatment (RTV). Tumors distributed over the 3 signature‐defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs. BA 0.78 (MS vs. BA, unpaired t‐test, p 0.0002). Cetuximab responders were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the subtypes. In conclusion basal subtype was associated with response to EGFR directed therapy in head and neck squamous cell cancer patient‐derived xenografts.
What's new?
Head and neck squamous cell carcinoma (HNSCC) has multiple subtypes, including basal and classical subtypes, which exhibit elevated expression of epidermal growth factor receptor (EGFR) pathway members. EGFR inhibition is the central action of cetuximab, the only targeted treatment approved for HNSCC. Whether EGFR expression predicts cetuximab response, however, is unclear. In our study, analysis of whole gene expression in patient‐derived xenografts revealed a positive association between the basal subtype of HNSCC and cetuximab response. By contrast, mesenchymal subtype tumors were associated with cetuximab resistance. Functional analyses revealed an enrichment in EGFR pathway gene expression in the basal subtype.
Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck ...cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other.
We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer MACH-NC) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck MARCH). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies).
115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0–9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 95% CI 0·51–0·77 compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66–1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%).
The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer.
French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.
Opinion statement
Human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (OPSCC) incidence has been increasing in recent decades. Treatment of the locally advanced HPV-related OPSCC ...includes a multidisciplinary approach. Immunotherapy with immune checkpoint inhibitors is used in the treatment of patients with recurrent/metastatic head and neck squamous cell carcinomas (HNSCC), including HPV-related OPSCC patients. There is increasing knowledge of the role of HPV in the tumor immune microenvironment. Therefore, HPV status of OPSCC plays an essential role in the design of immunotherapy clinical trials in both curative intent and metastatic settings. Moreover, HPV has become a potential therapeutic target, with vaccines and adoptive T-cell therapies being developed against HPV for the treatment of OPSCC. Several novel studies are designed to target HPV in combination with immune checkpoint inhibitors. Thus, HPV-related OPSCC remains a unique subgroup in the immunotherapy era.
Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 ...(PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial.
Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated.
Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ≥2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8–45.8 months). Median progression-free survival was 2.6 months (range 0.5–48.4 months), and median overall survival was 6.0 months (range 0.5–51.6+ months). Responses showed no association with HPV status or PD-L1 expression level.
In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC.
ClinicalTrials.gov number: NCT01375842.
Despite the wide use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in bone defect, its application in treating osteonecrosis of femoral head (ONFH) is yet to be elucidated. The ...heterotopic ossification (HO) after rhBMP-2 usage in some orthopedic surgeries has been reported previously; however, only a few studies describe this complication in the treatment of ONFH.The present study investigated whether the rhBMP-2 application would increase the risk of HO formation in selected ONFH patients with nonvascularized bone grafting surgery and enhance the surgical results of nonvascularized bone grafting as compared to patients who did not receive intraoperative rhBMP-2.A retrospective analysis was performed on 94 patients (141 hips) who, with Association Research Circulation Osseous (ARCO) stages IIb, IIc, and IIIa ONFH, underwent nonvascularized bone grafting surgery. The first 46 patients (66 hips) received intraoperative rhBMP-2. The postoperative radiographic results (X-ray and CT scan) and Harris hip score (HHS) were reviewed in each patient to record the incidence of HO formation and evaluate the clinical efficacy of rhBMP-2, respectively.HO formation frequently occurred in patients receiving intraoperative rhBMP-2 (8/66 hips) than those not receiving the protein (1/75 hips) (P = .02). HHS improved from preoperatively at the final follow-up (P < .01) in the BMP-positive group, with a survival rate of 83.3%. In the BMP-negative group, the HHS improved from preoperatively at the end of the follow-up (P < .01), and the survival rate was 72.0%.rhBMP-2 has osteoinductive property and might serve as an adjuvant therapy in the surgical treatment of ONFH. However, the incidence of HO formation might increase when used in high doses.
Head and neck tumors are malignant tumors that appear in the head and neck. Although much progress has been made in the treatment of head and neck tumors, many challenges remain. The prognosis of ...some advanced cases remains poor and survival and quality of life after treatment face certain limitations. Therefore, further research into the pathogenesis and treatment options for head and neck tumors is important in order to improve the prognosis and quality of life of patients. The Protein Arginine Methyltransferase (PRMT) family is a class of enzymes that are responsible for adding methyl groups to arginine residues in proteins. PRMT family members play important roles in regulating many cellular processes, such as transcriptional regulation, signaling, and cell cycle regulation. Recent studies have shown that the PRMT family also plays an important function in tumorigenesis and development. Here, we found that PRMT family members are significantly overexpressed in head and neck tumors and that PRMT5 may serve as an independent prognostic factor in head and neck tumors. We found that PRMT5-regulated differential genes were significantly enriched in tumor-associated signaling pathways such as IL-17 and p53. And we also found that the expression of PRMT5 in head and neck tumors was significantly correlated with immune cell infiltration, m6A as well as the expression of ferroptosis-related genes, and drug sensitivity. These results suggest that PRMT may play an important role in the development of head and neck tumors.
Oral squamous cell carcinoma (OSCC) is characterized by rapid local migration and invasion. This study was aimed at clarifying the effect of miR-654-5p on progression of OSCC. miR-654-5p promoted ...proliferation, metastasis, and chemoresistance of OSCC in vitro and in vivo. Consistently, miR-654-5p was upregulated in late-stage OSCC and was correlated with poor prognosis of OSCC patients. Furthermore, miR-654-5p was mechanistically verified to target Grb-2-related adaptor protein (GRAP), accompanied by the activation of Ras/MAPK signaling and the facilitation of epithelial-mesenchymal transition in OSCC cells. GRAP was downregulated in T1-2 stage versus T3-4 stage head and neck squamous cell carcinoma (HNSC) and was negatively correlated with tumor-node-metastases (TNM) stage in HNSC patients based on The Cancer Genome Atlas (TCGA) analysis. In addition, GRAP was positively correlated with good prognosis in HNSC patients. Our findings suggest that the miR-654-5p/GRAP/Ras/Erk signaling pathway in OSCC cells might contribute to the underlying mechanism through which miR-654-5p participates in the regulation of OSCC progression. miR-654-5p, as a potential biomarker for the clinical diagnosis and prognosis of OSCC, may be an effective anticancer target for the treatment of OSCC.
Objectives/Hypothesis
Poor nutritional status in patients with head and neck squamous cell carcinoma (HNSCC) is associated with tumor progression and survival. This study examined the prognostic ...value of nutritional and hematological markers in patients with HNSCC who received definitive treatments.
Study Design
A prospective observational cohort study.
Methods
This study included 338 consecutive patients who underwent surgery and/or radiotherapy/chemoradiotherapy for treatment‐naïve HNSCC. Body weight and nutritional and hematological parameters were regularly measured before and after treatment. Univariate and multivariate analyses using Cox proportional hazards models were performed to identify factors associated with disease‐free survival (DFS), cancer‐specific survival (CSS), and overall survival (OS).
Results
Body weight, serum total protein and albumin levels, and hematological variables significantly decreased after treatment. Univariate analyses illustrated that age, tumor site, T and N classifications, overall stage, pretreatment serum albumin (<3.5 g/dL) and hemoglobin (<12 g/dL) levels, and neutrophil‐lymphocyte ratio were significantly associated with DFS, CSS, and OS (all P < .05). Multivariate analyses identified age, tumor site, N classification, and pretreatment albumin levels as independent predictors of DFS, CSS, and OS (all P < .05). Patients with low serum albumin levels prior to treatment experienced approximately sixfold increases in the risks of tumor progression and cancer‐specific and overall mortality compared to the findings in their counterparts.
Conclusions
Our results suggest that pretreatment serum albumin levels predict DFS, CSS, and OS in patients who received definitive treatment for HNSCC. These findings might help to predict treatment outcome and guide nutritional intervention in patients with HNSCC.
Level of Evidence
2b. Laryngoscope, 127:E437–E442, 2017
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