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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.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.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%.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.

Purpose: We investigated the mechanism and clinical significance of the epithelial-mesenchymal transition (EMT)-induced chemoresistance in head and neck squamous cell carcinoma (HNSCC).Experimental Design: The correlation between the expression of different EMT regulators and chemoresistance genes, such as excision repair cross complementation group 1 (ERCC1), was evaluated in cancer cell lines from the NCI-60 database and four human HNSCC cell lines. Ectopic expression of Snail or short-interference RNA-mediated repression of Snail or ERCC1 was done in HNSCC cell lines. Cell viability was examined for cells after cisplatin treatment. A luciferase reporter assay and chromatin immunoprecipitation were used to identify the transcriptional regulation of ERCC1 by Snail. Immunohistochemical analysis of Snail, Twist1, ERCC1, hypoxia inducible factor-1 α (HIF-1α), and NBS1 were done in samples from 72 HNSCC patients receiving cisplatin-based chemotherapy.Results: The correlation between the expression of Snail and ERCC1 was confirmed in different cell lines, including HNSCC cells. In HNSCC cell lines, overexpression of Snail in the low endogenous Snail/ERCC1 cell lines FaDu or CAL-27 increased ERCC1 expression, and hypoxia or overexpression of NBS1 also upregulated ERCC1. Knockdown of Snail in the high endogenous Snail/ERCC1 cell line OECM-1 downregulated ERCC1 expression and attenuated cisplatin resistance. Furthermore, suppression of ERCC1 in Snail- or NBS1-overexpressing HNSCC cells enhanced sensitivity to cisplatin. Snail directly regulated ERCC1 transcription. In patients with HNSCC, coexpression of Snail and ERCC1 correlated with cisplatin resistance and a poor prognosis.Conclusions: Activation of ERCC1 by Snail is critical in the generation of cisplatin resistance of HNSCC cells. Clin Cancer Res; 16(18); 4561–71. ©2010 AACR.

Activation of EGFR and the NF-κB pathway in cetuximab-resistant cells

Supplementary Figures S1-S8 and Supplementary Tables S1-S8.

S1A: S1A: Gene expression profile of OECM1-CtxR cells (1.5 folds, 1955 identities); S1B: Cetuximab resistance signature (170 identities); S1C:Gene expression profiles in FaDu-Snail cells (2.5 folds with FPKM>1, 477 genes)

Purpose: In head and neck squamous cell carcinoma (HNSCC), the incidence of RAS mutation, which is the major cause of cetuximab resistance, is relatively rare compared with the other types of cancers, and the mechanism mediating acquired resistance is unclear compared with the driver gene mutation–mediated de novo resistance. Here, we investigated the driver gene mutation–independent mechanism for cetuximab resistance in HNSCC.Experimental Design: We used the in vitro-selected and in vivo-selected cetuximab-resistant sublines of HNSCC cell lines for investigating the mechanism of acquired resistance to cetuximab. Zebrafish model was applied for evaluating the synergistic effect of combinatory drugs for overcoming cetuximab resistance.Results: The cetuximab-resistant HNSCC cells undergo a Snail-induced epithelial–mesenchymal transition. Mechanistically, Snail induces the expression of lymphotoxin-β (LTβ), a TNF superfamily protein that activates NF-κB, and protein arginine methyltransferase 1 (PRMT1), an arginine methyltransferase that methylates EGFR. LTβ interacts with methylated EGFR to promote its ligand-binding ability and dimerization. Furthermore, LTβ activates the NF-κB pathway through a LTβ receptor–independent mechanism. Combination of an EGFR tyrosine kinase inhibitor and a NF-κB inhibitor effectively suppressed cetuximab-resistant HNSCC and interfering with the EGFR–LTβ interaction reverses resistance.Conclusions: Our findings elucidate the mechanism of driver gene mutations–independent mechanism of acquired resistance to cetuximab in HNSCC and also provide potential strategies for combating cetuximab resistance. Clin Cancer Res; 23(15); 4388–401. ©2017 AACR.

Includes legends to 5 supplementary figures, supplementary methods, and supplementary references

PDF file - 104KB

PDF file - 95KB, Sequence of the oligonucleotides for shRNA construct-making, reverse transcription, real-time PCR, and ChIP assay (S1); List of proteins tested by antibodies and characteristics of the corresponding antibodies (S2); Expression profile of microRNAs in FaDu-Bmi1 versus FaDu-cDNA3 (S3)

PDF file - 541K, Expression of CTGF among HNSCC cell lines, and CTGF does not have significant impact on HNSCC cells proliferation (S1); CTGF enriches stem-like population of SAS cells (S2); CTGF promotes stem-like properties of FaDu cells (S3); Exogenous CTGF promotes stem-like properties of HNSCC cells (S4); The impact of CTGF on pluripotency genes expression in HNSCC cells (S5); CTGF induces the expression of pluripotency genes in a dose and time-dependent manner (S6); c-Jun and ESR1 are critical for CTGF-induced pluripotency genes expression (S7); CTGF activates POU5F1/NANOG/SOX2 transcription through ESR1 (S8).

PDF file - 93K, The Supplemental Methods file includes additional information regarding Sample Collection and analysis, Reverse Transcription and Quantitative PCR analysis, Western Blot and Flow Cytometry analysis, Immunohistochemistry data, and Immunofluorescent staining.

Chromosomal instability (CIN) is widely considered a hallmark of cancer, but its precise roles in cancer stem cells (CSC) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin-modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial–mesenchymal transition (EMT) that promotes invasion, metastasis, and poor prognosis. Here, we report that BMI1 mediates its diverse effects through upregulation of the mitotic kinase Aurora A, which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exerts several effects, including centrosomal amplification and aneuploidy, antiapoptosis, and cell-cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting Aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT, and CIN through the BMI1–AURKA axis and suggest therapeutic use from inhibiting Aurora A in head and neck cancers, which overexpress BMI1. Cancer Res; 73(2); 953–66. ©2012 AACR.

PDF file -810KB, Twist1 upregulates Bmi1 and aurora kinase A expression, and co-amplification of BMI1 and AURKA in CD44+ HNSCC cells (S1); Akt pathway and let-7i repression are two independent mechanisms induced by Bmi1 to regulate aurora kinase A expression (S2); Suppression of Bmi1 or aurora kinase A reduces centrosomal amplification, aneuploidy, reduces p53 serine 315 phosphorylation and stabilizes p53 in OECM-1 cells (S3); Knockdown of aurora kinase A represses EMT, and overexpression of aurora kinase A is sufficient to induce EMT (S4); The influence of aurora kinase A on the expression of different EMT regulators (S5); Aurora kinase A increases GSK-3� phosphorylation and interacts with GSK-3� in HNSCC cell lines (S6)

PDF file - 111K, Sequence of the oligonucleotides for siRNA construct-making, reverse transcription, real-time PCR, and qChIP assay (S1); List of proteins tested by antibodies and characteristics of the corresponding antibodies (S2); Clinical characteristics of 78 HNSCC cases (S3).

Compared to 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. Here, we have 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 microRNA (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 head and neck cancer patients, the Snail-high cases lacked post-chemotherapy IL-1β surge and were correlated with a worse response. 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.

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.

Objective: To determine the role of upfront neck dissection (ND) in patient survival and regional control of p16-negative oropharyngeal squamous cell carcinoma (OPSCC) with neck metastases. Design: Retrospective study. Participants: Patients with p16-negative OPSCC with neck metastases, diagnosed between January 1, 2011 and December 31, 2017, and treated with upfront ND followed by chemoradiotherapy (ND + CCRT) or primary chemoradiotherapy (CCRT). Main outcome measures: Recurrence and survival rates were analysed using the Kaplan-Meier method. Results: Data of 67 patients with p16-negative cN+ OPSCC were analysed. Of them, 23 (34.3%) received ND + CCRT and 44 (65.7%) received primary CCRT. At a median follow-up of 37.9 months, the 3-year neck recurrence rate was significantly lower in the ND + CCRT group than in the CCRT group (0% vs. 19%, p=0.031). This trend was more obvious in patients with neck metastases ≥3 cm (0% vs. 32.1%, p=0.045). Survival outcomes were comparable between the groups; notably, the ND + CCRT group received a significantly lower dose of radiotherapy (3-year disease-specific survival: 77.3% and 75.3%, p=0.968, respectively; 3-year disease-free survival: 77.3% and 70.1%, p=0.457, respectively; 3-year overall survival: 62% and 61.8%, p=0.771, respectively between the ND + CCRT and CCRT groups). Conclusion: Upfront ND was significantly beneficial for regional control and resulted in comparable oncological outcomes with a significantly reduced radiation dose. These results findings can help guide the development of a standardised treatment plan for p16-negative OPSCC. Additional prospective studies with larger sample sizes are warranted.

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.

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.Retrospective cohort study.Tertiary referral medical center.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 foci5). Rate of cervical lymph node metastasis (LN+), 5-year disease-specific survival (DSS), and 5-year overall survival (OS) were analyzed among these groups.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.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.

Epithelial-mesenchymal transition (EMT) is a major event during cancer progression and metastasis; however, the definitive role of EMT in remodeling tumor microenvironments (TMEs) is unclear. Tumor-associated macrophages (TAMs) are a major type of host immune cells in TMEs, and they perform a wide range of functions to regulate tumor colonization and progression by regulating tumor invasiveness, local tumor immunity, and angiogenesis. TAMs are considered to have an M2-like, i.e., alternatively activated, phenotype; however, how these EMT-undergoing cancer cells promote M2 polarization of TAMs as a crucial tumor-host interplay during cancer progression is unclear. In this study, we investigated the mechanism of EMT-mediated TAM activation. Here, we demonstrate that the EMT transcriptional factor Snail directly activates the transcription of MIR21 to produce miR-21-abundant tumor-derived exosomes (TEXs). The miR-21-containing exosomes were engulfed by CD14+ human monocytes, suppressing the expression of M1 markers and increasing that of M2 markers. Knockdown of miR-21 in Snail-expressing human head and neck cancer cells attenuated the Snail-induced M2 polarization, angiogenesis, and tumor growth. In head and neck cancer samples, a high expression of miR-21 was correlated with a higher level of SNAI1 and the M2 marker MRC1. This study elucidates the mechanism of EMT-mediated M2 polarization through delivery of the miR-21-abundant exosomes, which may serve as a candidate biomarker of tumor progression and provide a potential target for intercepting EMT-mediated TME remodeling.

Overexpression of ALDH is associated with cancer stem-like features and poor cancer prognosis. High ALDH activity has been observed in cancer stem-like cells. There are a total of 19 human ALDH isoforms, all of which are associated with reducing oxidative stress and protecting cells from damage. However, it is unknown whether all ALDHs are associated with poor cancer prognosis and which ones play a significant role in cancer progression. In this study, we used RNA sequencing data from The Cancer Genome Atlas (TCGA) to evaluate the differential expression of 19 ALDH isoforms in 5 common human cancers. The 19 ALDH genes were analyzed with an integrating meta-analysis of cancer prognosis. Genotyping and next-generation RNA sequencing for 30 pairwise samples of head and neck squamous cell carcinoma were performed and compared with the TCGA cohort. The analysis showed that each ALDH isoform had a specific differential expression pattern, most of which were related to prognosis in human cancer. A lower expression of ALDH2 in the tumor was observed, which was independent from the ALDH2 rs671 SNP variant and the expression of other mitochondria-associated protein coding genes. This study provides new insight into the association between ALDH expression and cancer prognosis.

Background To evaluate the failure pattern and identify predictors of locoregional control in lateralized buccogingival cancer after postoperative radiotherapy (RT) at a single institution. Methods We retrospectively reviewed the clinical data of 150 patients with lateralized oral squamous cell carcinoma, including carcinoma of the buccal mucosa, gingiva and retromolar trigone. All patients underwent radical surgery followed by postoperative RT with or without concurrent chemotherapy. We registered planning computer tomography images with images obtained at recurrence and categorized the failure pattern as in-field, marginal, or out-field recurrence. Results The median follow-up duration was 47 months (range, 2–131 months). Twenty-eight patients (19%) experienced locoregional failure, including 20 local failure, 5 regional failure and 3 with both. Among the 24 patients who had image studies at recurrence, 15 patients had in-field recurrence, 5 were marginal recurrence and 4 were out-field recurrence. Seven patients (5%) had contralateral neck failure. Four of 5 patients with marginal failure had recurrent tumors in the infratemporal fossa. In multivariate analysis, extracapsular spread and positive or close surgical margin were associated with poor locoregional control. Conclusion Local in-field recurrence is the most common failure pattern in lateralized buccogingival cancer after postoperative RT. The infratemporal fossa is a risk area for marginal failure and should be encompassed adequately in the postoperative RT field. Extracapsular spread and positive or close margin are predictors of locoregional control for lateralized oral cancer. Patients exhibiting such adverse features require more aggressive treatment.

Background Inoperable oral cavity squamous cell carcinoma (SCC) is a highly invasive disease associated with the extensive destruction of locoregional tissues and a dismal prognosis. Management strategies for these patients are limited. Methods This study was a single arm, prospective, open-label phase II trial. A regimen consisting of cetuximab-docetaxel, cisplatin, and fluorouracil (C-TPF) followed by bio-chemoradiotherapy (bio-CRT) with cisplatin and cetuximab was administered to patients who responded to induction chemotherapy. The objective response rate to C-TPF was the primary endpoint. Results Forty-three patients were enrolled in this study. The objective response rate of C-TPF was 88.4%; 88.9% (32/36) of the responders completed the full bio-CRT course, and the objective response rate of bio-CRT was 64.7%. The most common grade 3/4 adverse events for induction chemotherapy were leucopenia (32.6%) and febrile neutropenia (14.0%). The 1-year progression-free survival (PFS) and overall survival (OS) rates were 43% and 68%, respectively. Conclusion C-TPF is an effective and tolerable induction chemotherapy regimen for inoperable oral cavity SCC.

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

Objective This paper aims to comprehensively document a rare case of thyroid carcinoma with rhabdoid phenotype and literature review of this disease. Methods A 59-year-old man presented with a rapidly enlarging, painful left lateral cervical mass. CT scan revealed a tumor over the left the thyroid gland with multiple left cervical lymphadenopathy over left level II–IV and level VI. Fine-needle aspiration cytology reported carcinoma, type undetermined. Total thyroidectomy with central compartment and left neck dissection was performed. Results Pathology report showed rhabdoid phenotype of thyroid carcinoma. Final staging was pT4N1M1. Conclusions Although WHO classification of thyroid tumor histology does not define this disease entity, few cases were reported. In the last 20 years, English literature review revealed only 12 cases about thyroid carcinoma with rhabdoid phenotype. Major treatment of thyroid carcinoma with rhabdoid phenotype is surgery, and the benefit of adjuvant therapies as radiotherapy or systemic chemotherapy is not clear. The prognosis of thyroid carcinoma with rhabdoid phenotype is extremely poor, with mean survival of only 6 months.

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.

SummaryLet-7 is crucial for both stem cell differentiation and tumor suppression. Here, we demonstrate a chromatin-dependent mechanism of let-7 in regulating target gene expression in cancer cells. Let-7 directly represses the expression of AT-rich interacting domain 3B (ARID3B), ARID3A, and importin-9. In the absence of let-7, importin-9 facilitates the nuclear import of ARID3A, which then forms a complex with ARID3B. The nuclear ARID3B complex recruits histone demethylase 4C to reduce histone 3 lysine 9 trimethylation and promotes the transcription of stemness factors. Functionally, expression of ARID3B is critical for the tumor initiation in let-7-depleted cancer cells. An inverse association between let-7 and ARID3A/ARID3B and prognostic significance is demonstrated in head and neck cancer patients. These results highlight a chromatin-dependent mechanism where let-7 regulates cancer stemness through ARID3B.

Conventional wisdom holds that methylation of RTKs should be restricted to intracellular sites. Alterations--such as deletion, mutation, and proteolytic cleavage events--to the extracellular ligand binding and dimer interface domains of the EGFR can induce EGFR dimer formation, leading to aberrant receptor activation and oncogenic activity. Recently, the extracellular domain of EGFR was also shown to be methylated, suggesting that posttranslational protein methylation events directed to the extracellular dimer interface provide another mechanism to regulate the EGFR activation state by modulating receptor dimerization. Critically, these methylation events abrogate response to conformation-specific therapeutic antibodies such as cetuximab. In this issue of the JCI, Liao et al. investigate the role of protein arginine methyltransferase I (PRMT1) in regulating EGFR function in colorectal cancer. The authors provide evidence that methylation of R198 and R200 within the dimer interface enhances growth factor ligand binding and cetuximab resistance through induction and stabilization of the active EGFR dimer conformation. Delineation of these and other subtleties involved in oncogenic RTK activation and their response to targeted therapies should facilitate the development of improved antibody-based treatments.

PD-L1 expression is critical in helping tumor cells evade the immune system. However, the level of PD-L1 expression in non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC) and its association with patient prognosis remains unclear. A retrospective clinicopathological analysis was performed on 106 patients with non-OPHNSCC diagnosed between 2007 and 2014. In the current study, tissue arrays from paraffin-embedded non-OPHNSCC samples obtained from patients were constructed, and PD-L1 and p16INK4A expression were determined using immunohistochemistry. Systemic inflammatory factors, including C-reactive protein, serum white blood cell, neutrophil, monocyte and lymphocyte counts were also analyzed. The current study demonstrated that PD-L1 was overexpressed in 32.1% (34/106) and p16INK4A in 20.8% (22/106) of patients. The expression of PD-L1 was associated with p16INK4A expression (P

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 IL12Rβ2, 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.

The aim of this study is to introduce pterygomandibular suspension suture as a simple modification of uvulopalatopharyngoplasty for severe obstructive sleep apnea in dealing with lateral pharyngeal wall and retropalatal space collapse. This retrospective study was conducted at Taipei Veterans General Hospital, Taiwan. Ten adult patients underwent modified uvulopalatopharyngoplasty with pterygomandibular suspension suture according to following inclusion criteria: severe obstructive sleep apnea (apnea–hypopnea index [AHI] > 30 events/h), type I Fujita with lateral pharyngeal wall collapse, and failure for continuous positive airway pressure (CPAP) therapy. The philosophy of this modification technique is to create a firm anterolateral suspension of the lateral pharyngeal wall and soft palate by sutures. The mean operative time of modified uvulopalatopharyngoplasty with pterygomandibular suspension suture was 60 min. The mean AHI decreased significantly from 77.2 ± 25.0 preoperatively to 28.7 ± 18.8 postoperatively (P = 0.005) and the lowest oxygen saturation increased from 69.9 ± 11.4 to 81.1 ± 7.19% (P = 0.005). No major perioperative complication such as massive bleeding or respiratory distress was noted. No patient experienced a swallowing disturbance, taste change, or voice change 6 months postoperatively. The mean period for resuming a normal diet was 15 days. Modified uvulopalatopharyngoplasty with pterygomandibular suspension suture is a simplified and effective surgical approach with satisfactory functional recovery for selective patients with severe obstructive sleep apnea.

// Yi-Fen Wang 1,2 , Chun-Ju Chang 3 , Jen-Hwey Chiu 4 , Chin-Ping Lin 5 , Wing-Yin Li 2,6 , Shyue-Yih Chang 1 , Pen-Yuan Chu 1,2 , Shyh-Kuan Tai 1,2 , Yu-Jen Chen 4,5,7 1 Department of Otorhinolaryngology and Head and Neck Surgery, Taipei Veterans General Hospital, Taipei, Taiwan 2 Department of Medicine, National Yang Ming University, Taipei, Taiwan 3 Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan 4 Institute of Traditional Medicine, National Yang Ming University, Taipei, Taiwan 5 Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan 6 Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan 7 Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan Correspondence: Chun-Ju Chang, email: // Yu-Jen Chen,, email: // Keywords : Head and neck squamous cell carcinoma (HNSCC); NM23-H1; Metastasis; Cisplatin; Prognosis Received : February 20, 2014 Accepted : April 16, 2014 Published : April 18, 2014 Abstract We recently reported that low NM23-H1 expression of head and neck squamous cell carcinoma (HNSCC) correlated with poor patients’ prognosis. Growing evidence has indicated that high tumor NM23-H1 expression contributes to a good response to chemotherapy. Therefore, we investigated the role of NM23-H1 in susceptibility of HNSCC cells to cisplatin and its clinical significance, as well as the in vitro study for validation was performed. Using immunohistochemistry, we analyzed NM23-H1 expression in surgical specimens from 46 HNSCC patients with cervical metastases receiving surgery and adjuvant chemoradiotherapy. Low tumor NM23-H1 expression correlated with locoregional recurrence of HNSCC following postoperative cisplatin-based therapy (p = 0.056) and poor patient prognosis (p = 0.001). To validate the clinical observation and the effect of NM23-H1 on cisplatin cytotoxicity, we established several stable clones derived from a human HNSCC cell line (SAS) by knockdown and overexpression. Knockdown of NM23-H1 attenuated the chemosensitivity of SAS cells to cisplatin, which was associated with reduced cisplatin-induced S-phase accumulation and downregulation of cyclin E1 and A. Overexpression of NM23-H1 reversed these results, indicating the essential role of NM23-H1 in treatment response to cisplatin. NM23-H1 may participate in HNSCC cell responses to cisplatin and be considered a potential therapeutic target.

In the version of Supplementary Fig. 3c originally published with this Article, the authors mistakenly duplicated a blot from Supplementary Fig. 3b. The correct versions of these figures are shown below. In addition, two independent repeats of the experiments presented in Supplementary Figs. 3b and 3c, showing results consistent with those originally reported, have been deposited in Figshare ( 10.6084/m9.figshare.7545263 ).