Publications by authors named "Mizuo Ando"

62 Publications

[Ⅳ. Towards Precision Medicine for Head and Neck Cancer].

Authors:
Mizuo Ando

Gan To Kagaku Ryoho 2021 Jul;48(7):903-906

Dept. of Otolaryngology-Head and Neck Surgery, Okayama University, Academic Field of Medicine, Dentistry and Pharmaceutical Sciences.

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July 2021

Apocrine Hidrocystoma of the External Auditory Canal in a Child.

Otol Neurotol 2021 Jun 11. Epub 2021 Jun 11.

Department of Otolaryngology, Japanese Red Cross Society Himeji Hospital, Himeji Department of Radiological Technology, Okayama University Graduate School of Health Sciences, Okayama Departments of Pathology, Japanese Red Cross Society Himeji Hospital, Himeji Department of Otolaryngology Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

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http://dx.doi.org/10.1097/MAO.0000000000003220DOI Listing
June 2021

Transoral surgery for superficial head and neck cancer: National Multi-Center Survey in Japan.

Cancer Med 2021 Jun 15;10(12):3848-3861. Epub 2021 May 15.

Department of Gastroenterology, Kobe City Medical Center General Hospital, Kobe, Japan.

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.
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http://dx.doi.org/10.1002/cam4.3927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209601PMC
June 2021

A retrospective analysis of radiotherapy in the treatment of external auditory canal carcinoma.

Mol Clin Oncol 2021 Mar 13;14(3):45. Epub 2021 Jan 13.

Department of Radiology, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan.

External auditory canal carcinoma (EACC) is a rare disease. The current study aimed to evaluate the clinical outcomes of patients treated with external beam radiotherapy (EBRT) for EACC. The present study retrospectively reviewed 34 consecutive patients treated for EACC with EBRT between February 2001 and January 2019 at the University of Tokyo Hospital. Clinical staging was performed according to the modified Pittsburgh classification. Of all the included patients, seven patients were in the early stages (I or II) and 27 in the advanced stages (III or IV) of EACC. A total of 16 patients underwent EBRT and surgery (S+RT) pre- and/or postoperatively, while 18 patients underwent definitive radiotherapy (dRT). The median prescribed doses for the S+RT and dRT groups were 66 and 70 Gy, respectively. The median follow-up period for all patients was 22.4 months (range, 2-205 months). The 5-year overall survival rates of the S+RT and dRT groups were 66.7 and 45.1%, respectively. The progression-free survival rate at 5-year was 55.6% (95% confidence interval: 36.5-71.1%) for the entire cohort. A total of 14 patients experienced disease relapse after treatment, consisting of 11 locoregional recurrences and three distant metastases. The current study revealed the clinical outcomes of EBRT for EACC.
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http://dx.doi.org/10.3892/mco.2021.2207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818098PMC
March 2021

Reciprocal activation of HEY1 and NOTCH4 under SOX2 control promotes EMT in head and neck squamous cell carcinoma.

Int J Oncol 2021 02 10;58(2):226-237. Epub 2020 Dec 10.

Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.

Several comprehensive studies have demonstrated that the NOTCH pathway is altered in a bimodal manner in head and neck squamous cell carcinoma (HNSCC). In a previous study, it was found that the NOTCH4/HEY1 pathway was specifically upregulated in HNSCC and promoted epithelial‑mesenchymal transition (EMT), and that HEY1 activation supported SOX2 expression. However, the interactions in this pathway have not yet been fully elucidated. The present study investigated the NOTCH4/HEY1/SOX2 axis in HNSCC using in vitro models and the Cancer Genome Atlas (TCGA) database. To explore the association, reporter and ChIP RT‑qPCR assays using SOX2‑overexpressing (SOX2‑OE) cells were performed. The association between NOTCH4 and HEY1 was examined in the same manner using HEY1‑overexpressing (HEY1‑OE) cells. The results of the in vitro experiments indicated that HEY1 promoted EMT in the HNSCC cells. Furthermore, the overexpression of HEY1 also promoted sphere formation and increased murine xenograft tumorigenicity. Reporter assays and ChIP RT‑qPCR experiments indicated that SOX2 regulated HEY1 expression via direct binding of the HEY1 promoter. HEY1 expression significantly correlated with SOX2 expression in primary lung SCC and other SCCs using the TCGA database. HEY1 also regulated NOTCH4 expression to create a positive reciprocal feedback loop. On the whole, the present study demonstrates that HEY1 expression in HNSCC is regulated via the promotion of SOX2 and promotes EMT. The NOTCH4/HEY1 pathway is specifically upregulated via a positive reciprocal feedback loop mediated by the HEY1‑medaited regulation of NOTCH4 transcription, and SOX2 correlates with HEY1 expression in SCC from other primary sites.
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http://dx.doi.org/10.3892/ijo.2020.5156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864008PMC
February 2021

Full-coverage TP53 deep sequencing of recurrent head and neck squamous cell carcinoma facilitates prognostic assessment after recurrence.

Oral Oncol 2021 02 26;113:105091. Epub 2020 Nov 26.

Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan. Electronic address:

Objectives: This study aims to evaluate whether the accumulation of TP53 mutations is associated with clinical outcome by comparing full-coverage TP53 deep sequencing of the initial and recurrent head and neck squamous cell carcinoma (HNSCC).

Materials And Methods: Medical records and surgical specimens of 400 patients with HNSCC surgically treated with curative intent, of which 95 patients developed local or locoregional recurrence, were reviewed. Of these patients, 63 were eligible for genomic analysis. Full-coverage TP53 deep sequencing of 126 paired initial and recurrent tumor samples was examined using next-generation sequencing (NGS). Temporal changes in the mutation status, molecular characterization, and clinical outcome were compared. Fisher's exact test, Kaplan-Meier method, log-rank test, and Cox regression models were used for statistical analysis.

Results: Of the recurrent tumors, 22% harbored accumulation of TP53 mutations, and 16% lost the original mutation. The accumulation of TP53 mutations was significantly more frequent in oral cancer than in pharyngeal or laryngeal cancer (33% vs. 7%, p = 0.016). Two-year post-recurrence survival (PRS) was associated with TP53 status for recurrent tumors, but not for initial tumors. The TP53 status for recurrent tumors was an independent risk factor in multivariate analysis (hazard ratio, 5.76; 95% confidence interval, 1.86-17.8; p = 0.0023).

Conclusion: Approximately one-third of the recurrent HNSCC cases showed a different TP53 status from the initial tumor. Temporal changes in the mutation status differed by primary site. Full-coverage TP53 deep sequencing of recurrent tumors was useful in predicting post-recurrence prognosis.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105091DOI Listing
February 2021

HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers.

Oncogene 2020 10 26;39(40):6327-6339. Epub 2020 Aug 26.

Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.

The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.
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http://dx.doi.org/10.1038/s41388-020-01431-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529583PMC
October 2020

Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing.

PLoS One 2020 21;15(5):e0233380. Epub 2020 May 21.

Moores Cancer Center, University of California San Diego, San Diego, California, United States of America.

Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype. We identified 319 spliceosome genes and employed a discovery pipeline to identify 13 candidate spliceosome genes altered in HNSCC using The Cancer Genome Atlas (TCGA) HNSCC data. Phenotypic screens identified amplified and overexpressed CPSF1 as a target gene alteration that was validated in proliferation, colony formation, and apoptosis assays in cell line and xenograft systems as well as in primary HNSCC. We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models. Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233380PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241804PMC
August 2020

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma.

Virchows Arch 2020 Aug 26;477(2):291-299. Epub 2020 Feb 26.

Department of Otorhinolaryngology/Head & Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Salivary duct carcinoma (SDC) is an aggressive, uncommon tumor histologically comparable to high-grade mammary ductal carcinoma. SDCs are usually androgen receptor (AR)-positive and often HER2-positive. Recently, therapies targeting these molecules for SDC have attracted attention. Lipid metabolism changes have been described in association with biological behavior in various cancers, although no such relationship has yet been reported for SDC. We therefore analyzed the clinicopathological relevance of the immunohistochemical expression of adipophilin (ADP) and fatty acid synthase (FASN), representative lipid metabolism-related proteins, in 147 SDCs. ADP and FASN were variably immunoreactive in most SDCs (both 99.3%), and the ADP and FASN expression was negatively correlated (P = 0.014). ADP-positive (≥ 5%) SDCs more frequently exhibited a prominent nuclear pleomorphism and high-Ki-67 labeling index than those ADP-negative (P = 0.013 and 0.011, respectively). In contrast, a high FASN score, calculated by the staining proportion and intensity, (≥ 120) was correlated with the high expression of AR and FOXA1 (P < 0.001 and = 0.003, respectively). The ADP and FASN expression differed significantly among the subtypes based on biomarker immunoprofiling, as assessed by the AR, HER2, and Ki-67 status (P = 0.017 and 0.003, respectively). A multivariate analysis showed that ADP-positive expression was associated with a shorter overall and progression-free survival (P = 0.018 and 0.003, respectively). ADP was associated with an aggressive histopathology and unfavorable prognosis, and FASN may biologically interact with the AR signaling pathway in SDC. ADP may, therefore, be a new prognostic indicator and therapeutic target in SDC.
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http://dx.doi.org/10.1007/s00428-020-02777-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371671PMC
August 2020

Cannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation.

Clin Cancer Res 2020 06 13;26(11):2693-2703. Epub 2020 Jan 13.

Moores Cancer Center, University of California San Diego, La Jolla, California.

Purpose: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV-positive HNSCC.

Experimental Design: The expression of cannabinoid receptors and was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs, or shRNA-based models to explore the roles of and in HPV-positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single-sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS).

Results: In TCGA cohort, the expression of and was elevated in HPV-positive HNSCC compared with HPV-negative HNSCC, and knockdown of / expression inhibited proliferation in HPV-positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as nonselective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration and induced apoptosis. Using whole-genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure.

Conclusions: Cannabinoids can promote progression of HPV-positive HNSCC through p38 MAPK pathway activation.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538010PMC
June 2020

Spinal solitary fibrous tumor of the neck: Next-generation sequencing-based analysis of genomic aberrations.

Auris Nasus Larynx 2020 Dec 24;47(6):1058-1063. Epub 2019 Dec 24.

Department of Otolaryngology-Head and Neck Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo 113-8655, Japan.

A solitary fibrous tumor (SFT) is a rare neoplasm with recurrent NAB2-STAT6 gene fusion. An SFT may develop almost anywhere throughout the body, including the head and neck region, and is characterized by a broad spectrum of malignancy. Here we present a case involving a 57-year-old male with a dumbbell-shaped SFT in the cervical spine that mimicked schwannoma. Repeated fine-needle aspiration cytology failed to establish a definitive diagnosis. Given that the tumor size increased significantly over a 10-month period, open biopsy was then performed. Though the biopsy result was inconclusive, a nonepithelial tumor, including sclerosing epithelioid fibrosarcoma or ossifying fibromyxoid tumor, was suspected. The tumor was then completely removed together with adjacent parts of C2 and C3 vertebrae and left vertebral artery via combined anterior and posterior approaches. Histologically, the tumor consisted of round cells with prominent stromal hyalinization and was immunohistochemically positive for STAT6, CD34, and cytokeratin. Finally, Todai OncoPanel, a next-generation sequencing-based molecular profiling system using formalin-fixed paraffin-embedded samples, demonstrated fusion transcript in which NAB2 exon 6 was fused to STAT6 exon 16 supporting the diagnosis of SFT, while whole-exome sequencing analysis detected no somatic mutations which were known to be oncogenic.
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http://dx.doi.org/10.1016/j.anl.2019.12.001DOI Listing
December 2020

Rational genomic optimization of DNA detection for human papillomavirus type 16 in head and neck squamous cell carcinoma.

Head Neck 2020 04 18;42(4):688-697. Epub 2019 Dec 18.

Moores Cancer Center, University of California San Diego, San Diego, California.

Background: We aimed to use genomic data for optimizing polymerase chain reaction (PCR) primer/probe sets for detection of human papillomavirus (HPV)-16 in body fluids of patients with HPV-related head and neck squamous cell carcinoma (HPV-HNSCC).

Methods: We used genomic HPV-HNSCC sequencing data from a single institutional and a TCGA cohort. Optimized primer/probe sets were designed and tested for analytical performance in CaSki HPV-16 genome and confirmed in salivary rinse samples from patients with HPV-HNSCC.

Results: The highest read density was observed between E5 and L2 regions. The E1 region contained a region that was universally present. Among candidate PCR primer/probe sets created, six reliably detected 30 HPV-16 copy number. In a CLIA certified laboratory setting, the combination of two novel primer/probe with E7 sets improved performance in salivary rinse samples with a sensitivity of 96% and specificity of 100%.

Conclusions: PCR-based detection of HPV-16 DNA in HPV-HNSCC can be improved using rational genomic design.
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http://dx.doi.org/10.1002/hed.26041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699136PMC
April 2020

Prognostic Implication of Histopathologic Indicators in Salivary Duct Carcinoma: Proposal of a Novel Histologic Risk Stratification Model.

Am J Surg Pathol 2020 04;44(4):526-535

Departments of Anatomic Pathology.

Salivary duct carcinoma (SDC) is a rare, aggressive malignancy that histologically resembles high-grade mammary duct carcinoma. Because of the rarity of this entity, data verifying the association between histologic features and patient survival are limited. We conducted a comprehensive histologic review of 151 SDC cases and performed an analysis of the association between various histomorphologic parameters and the clinical outcome with the aim of developing a histologic risk stratification model that predicts the prognosis of SDC patients. A multivariate analysis revealed that prominent nuclear pleomorphism (overall survival [OS]: P=0.013; progression-free survival [PFS]: P=0.019), ≥30 mitoses/10 HPF (PFS: P=0.013), high tumor budding (OS: P=0.011; PFS: P<0.001), and high poorly differentiated clusters (OS: P<0.001; PFS: P<0.001) were independent prognostic factors. Patients with vascular invasion demonstrated a marginally significant association with shorter PFS (P=0.064) in a multivariate analysis. We proposed a 3-tier histologic risk stratification model based on the total number of positive factors among 4 prognostically relevant parameters (prominent nuclear pleomorphism, ≥30 mitoses/10 HPF, vascular invasion, and high poorly differentiated clusters). The OS and PFS of patients with low-risk (0 to 1 point) (23% of cases), intermediate-risk (2 to 3 points) (54% of cases), and high-risk (4 points) (23% of cases) tumors progressively deteriorated in this order (hazard ratio, 2.13 and 2.28, and 4.99 and 4.50, respectively; Ptrend<0.001). Our histologic risk stratification model could effectively predict patient survival and may be a useful aid to guide clinical decision-making in relation to the management of patients with SDC.
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http://dx.doi.org/10.1097/PAS.0000000000001413DOI Listing
April 2020

A novel splice variant of LOXL2 promotes progression of human papillomavirus-negative head and neck squamous cell carcinoma.

Cancer 2020 02 13;126(4):737-748. Epub 2019 Nov 13.

Moores Cancer Center, University of California at San Diego, San Diego, California.

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers worldwide. LOXL2 demonstrates alternative splicing events in patients with human papillomavirus (HPV)-negative HNSCC. The current study explored the role of a dominant LOXL2 variant in HPV-negative HNSCC.

Methods: Expression of the LOXL2 variant was analyzed using The Cancer Genome Atlas cohorts and validated using quantitative reverse transcriptase-polymerase chain reaction in a separate primary tumor set. The authors defined the effect of LOXL2 splice variants in assays for cell proliferation using a cell viability assay and colony formation assay. Cell migration and invasion were examined using a cell scratch assay and transwell cell migration and invasion assay in LOXL2 splice variant gain and loss of expression cells. Western blot analysis and gene set enrichment analysis were used to explore the potential mechanism of the LOXL2 splice variant in HPV-negative HNSCC.

Results: Expression of a novel LOXL2 variant was found to be upregulated in The Cancer Genome Atlas HPV-negative HNSCC, and confirmed in the separate primary tumor validation set. Analyses of loss and gain of function demonstrated that this LOXL2 variant enhanced proliferation, migration, and invasion in HPV-negative HNSCC cells and activated the FAK/AKT pathway. A total of 837 upregulated and 820 downregulated genes and 526 upregulated and 124 downregulated pathways associated with LOXL2 variant expression were identified using gene set enrichment analysis, which helped in developing a better understanding of the networks activated by this LOXL2 variant in patients with HPV-negative HNSCC.

Conclusions: The novel LOXL2 variant can promote the progression of HPV-negative HNSCC, in part through FAK/AKT pathway activation, which may provide a new potential therapeutic target among patients with HPV-negative HNSCC.
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http://dx.doi.org/10.1002/cncr.32610DOI Listing
February 2020

Use of intensity-modulated radiation therapy for nasopharyngeal cancer in Japan: analysis using a national database.

Jpn J Clin Oncol 2019 Jul;49(7):639-645

Division of Health Services Research, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan.

Background: Intensity-modulated radiation therapy (IMRT) yields better outcomes and fewer toxicities for radiation therapy (RT) of head and neck cancers (HNCs), including nasopharyngeal cancer (NPC). IMRT is the standard RT treatment and has been widely adopted in Western countries to treat HNCs. However, its uptake in clinical practice among NPC patients has never been studied.

Methods: We investigated the use of IMRT for NPC using data from a nationwide cancer registry to describe the use of IMRT among NPC patients in Japan. We analyzed the data of patients with HNC, including NPC, who underwent IMRT between 2012 and 2014, as recorded in the hospital-based cancer registries linked with insurance claims. We calculated the proportion of patients with NPC who underwent IMRT at each hospital. To evaluate the use of IMRT for NPC, the IMRT use for NPC was compared with the proportion of patients with prostate cancer who underwent IMRT.

Results: Among 508 patients with NPC who underwent RT at one of 87 hospitals, 348 (69%) underwent IMRT. This proportion gradually increased between 2012 and 2014 (62%, 64% and 77%). Meanwhile, 4790 patients with prostate cancer (90%) underwent IMRT. Although some hospitals where IMRT was performed treated many patients with NPC, the proportion of patients with NPC who were treated with IMRT was low.

Conclusions: IMRT has not been widely adopted in Japan for treating NPC. Barriers for adopting its use should be identified to close the gap between the standard and actual medical practice in Japan.
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http://dx.doi.org/10.1093/jjco/hyz042DOI Listing
July 2019

High CT attenuation values relative to the brainstem may predict squamous cell carcinoma arising from inverted papilloma.

Acta Otolaryngol 2019 Nov 9;139(11):1030-1037. Epub 2019 Sep 9.

Department of Otolaryngology, Graduate School of Medicine, University of Tokyo , Tokyo , Japan.

A diagnostic indicator for differentiating squamous cell carcinomas (SCCs) from inverted papillomas (IPs) has not been established. This study aimed to evaluate whether CT attenuation values relative to those of the brainstem (relative CT number) could be useful in differentiating IPs from SCCs. Consecutive patients who were pathologically diagnosed with IP or SCC between 2007 and 2017 were retrospectively identified. Relative CT numbers were compared between the two patient groups. The factors with predictive power for differentiating IPs from SCCs were identified by univariate and multivariate logistic regression analyses. Fifty-four sinonasal tumour cases were finally analysed (IP, 25 cases; SCC, 29 cases). Relative CT numbers were significantly higher in SCC than in IP ( < .001). The univariate logistic regression analysis showed BMI, relative CT number, and disease duration to have predictive value for differentiating IPs from SCCs. In the multivariate logistic regression analysis, only the relative CT number had predictive value for distinguishing IP from SCC (odds ratio, 1.97), with a relative CT number of ≥1.4 being significantly associated with SCC. High relative CT numbers could potentially be used to identify SCCs, and their measurement could provide a basis for differentiating IPs from SCCs.
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http://dx.doi.org/10.1080/00016489.2019.1659515DOI Listing
November 2019

Caloric restriction reduces basal cell proliferation and results in the deterioration of neuroepithelial regeneration following olfactotoxic mucosal damage in mouse olfactory mucosa.

Cell Tissue Res 2019 Nov 6;378(2):175-193. Epub 2019 Jun 6.

Department of Otolaryngology-Head and Neck Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

The effects of caloric restriction (CR) on cell dynamics and gene expression in the mouse olfactory neuroepithelium are evaluated. Eight-week-old male C57BL/6 mice were fed either control pellets (104 kcal/week) or CR pellets (67 kcal/week). The cytoarchitecture of the olfactory neuroepithelium in the uninjured condition and its regeneration after injury by an olfactotoxic chemical, methimazole, were compared between mice fed with the control and CR diets. In the uninjured condition, there were significantly fewer olfactory marker protein (OMP)-positive olfactory receptor neurons and Ki67-positive proliferating basal cells at 3 months in the CR group than in the control group. The number of Ki67-positive basal cells increased after methimazole-induced mucosal injury in both the control and the CR groups, but the increase was less robust in the CR group. The recovery of the neuroepithelium at 2 months after methimazole administration was less complete in the CR group than in the control group. These histological changes were region-specific. The decrease in the OMP-positive neurons was prominent in the anterior region of the olfactory mucosa. Gene expression analysis using a DNA microarray and quantitative real-time polymerase chain reaction demonstrated that the expression levels of two inflammatory cytokines, interleukin-6 and chemokine ligand 1, were elevated in the olfactory mucosa of the CR group compared with the control group. These findings suggest that CR may be disadvantageous to the maintenance of the olfactory neuroepithelium, especially when it is injured.
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http://dx.doi.org/10.1007/s00441-019-03047-1DOI Listing
November 2019

Publisher Correction: Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers.

Nat Commun 2019 May 29;10(1):2415. Epub 2019 May 29.

Moores Cancer Center, University of California San Diego, 3855 Health Sciences Dr, La Jolla, CA, 92093, USA.

The original version of this Article contained an error in the author affiliations. Trey Ideker was incorrectly associated with 'Department of Medicine (Oncology), Stanford University School of Medicine, 875 Blake Wilbur Dr, Palo Alto, CA 94304, USA.' This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-10557-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541594PMC
May 2019

Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers.

Nat Commun 2019 05 16;10(1):2188. Epub 2019 May 16.

Moores Cancer Center, University of California San Diego, 3855 Health Sciences Dr, La Jolla, CA, 92093, USA.

Although promoter-associated CpG islands have been established as targets of DNA methylation changes in cancer, previous studies suggest that epigenetic dysregulation outside the promoter region may be more closely associated with transcriptional changes. Here we examine DNA methylation, chromatin marks, and transcriptional alterations to define the relationship between transcriptional modulation and spatial changes in chromatin structure. Using human papillomavirus-related oropharyngeal carcinoma as a model, we show aberrant enrichment of repressive H3K9me3 at the transcriptional start site (TSS) with methylation-associated, tumor-specific gene silencing. Further analysis identifies a hypermethylated subtype which shows a functional convergence on MYC targets and association with CREBBP/EP300 mutation. The tumor-specific shift to transcriptional repression associated with DNA methylation at TSSs was confirmed in multiple tumor types. Our data may show a common underlying epigenetic dysregulation in cancer associated with broad enrichment of repressive chromatin marks and aberrant DNA hypermethylation at TSSs in combination with MYC network activation.
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http://dx.doi.org/10.1038/s41467-019-09937-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522544PMC
May 2019

Mutation of chromatin regulators and focal hotspot alterations characterize human papillomavirus-positive oropharyngeal squamous cell carcinoma.

Cancer 2019 07 1;125(14):2423-2434. Epub 2019 Apr 1.

Moores Cancer Center, University of California San Diego, La Jolla, California.

Background: Human papillomavirus (HPV)-associated oropharyngeal cancer is a disease clinically and biologically distinct from smoking-related head and neck squamous cell carcinoma (HNSCC). Despite its rapidly increasing incidence, the mutational landscape of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) remains understudied.

Methods: This article presents the first mutational analysis of the 46 HPV+ OPSCC tumors within the newly expanded cohort of 530 HNSCC tumors from The Cancer Genome Atlas. A separate exome sequencing analysis was also performed for 46 HPV+ OPSCCs matched to their normal lymphocyte controls from the Johns Hopkins University cohort.

Results: There was a strikingly high 33% frequency of mutations within genes associated with chromatin regulation, including mutations in lysine methyltransferase 2C (KMT2C), lysine methyltransferase 2D (KMT2D), nuclear receptor binding SET domain protein 1 (NSD1), CREB binding protein (CREBBP), E1A-associated protein p300 (EP300), and CCCTC-binding factor (CTCF). In addition, the commonly altered genes phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and fibroblast growth factor receptor 3 (FGFR3) showed distinct domain-specific hotspot mutations in comparison with their HPV- counterparts. PIK3CA showed a uniquely high rate of mutations within the helicase domain, and FGFR3 contained a predominance of hotspot S249C alterations that were not found in HPV- HNSCC.

Conclusions: This analysis represents one of the largest studies to date of HPV+ OPSCC and lends novel insight into the genetic landscape of this biologically distinct disease, including a high rate of mutations in histone- and chromatin-modifying genes, which may offer novel therapeutic targets.
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http://dx.doi.org/10.1002/cncr.32068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602825PMC
July 2019

All-Exon TP53 Sequencing and Protein Phenotype Analysis Accurately Predict Clinical Outcome after Surgical Treatment of Head and Neck Squamous Cell Carcinoma.

Ann Surg Oncol 2019 Jul 21;26(7):2294-2303. Epub 2019 Mar 21.

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: This study elucidates the clinical impact of surgical treatment of head and neck squamous cell carcinoma (HNSCC) based on a detailed search of all exons of the TP53 gene and p53 protein phenotypic analysis using formalin-fixed paraffin-embedded (FFPE) specimens.

Methods: Clinically well-annotated FFPE specimens from 317 patients with HNSCC treated by surgery were examined by all-exon TP53 sequencing using a next-generation sequencer and p53 protein phenotype by immunohistochemistry. After excluding human papillomavirus-associated oropharyngeal carcinomas, two risk categories were classified as "p53 adverse function" and "p53 favorable function" based on TP53 mutation status and p53 protein phenotype. Mutation in PIK3CA, AKT, and HRAS was also evaluated by target sequence. Cox proportional hazards regression models were used for statistical analysis of clinical outcomes. Receiver operating characteristic curve analysis was used to determine the optimal surgical margin cutoff for local recurrence. Local control rates were compared between the risk groups using Fisher's exact test.

Results: Multivariate analysis identified "p53 adverse function" as an independent poor predictor of overall survival, local control, and distant metastasis-free survival. In oral cavity cancer, the optimal surgical margin cutoff associated with local recurrence was 6 mm. In patients with surgical margin > 6 mm, the "p53 adverse function" group demonstrated significantly higher local recurrence rate than the "p53 favorable function" group. PIK3CA, AKT, or HRAS mutation did not correlate with improved overall survival.

Conclusions: All-exon TP53 sequencing and p53 protein phenotype analysis using FFPE specimens can accurately predict clinical outcomes.
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http://dx.doi.org/10.1245/s10434-019-07287-xDOI Listing
July 2019

4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer.

Cancer Res 2019 04 20;79(7):1438-1450. Epub 2019 Mar 20.

Moores Cancer Center, University of California, San Diego, La Jolla, California.

Aberrant activation of the PI3K-mTOR signaling pathway occurs in >80% of head and neck squamous cell carcinomas (HNSCC), and overreliance on this signaling circuit may in turn represent a cancer-specific vulnerability that can be exploited therapeutically. mTOR inhibitors (mTORi) promote tumor regression in genetically defined and chemically induced HNSCC animal models, and encouraging results have been recently reported. However, the mTOR-regulated targets contributing to the clinical response have not yet been identified. Here, we focused on (), a direct target of mTOR that serves as key effector for protein synthesis. A systematic analysis of genomic alterations in the -mTOR pathway in HNSCC revealed that is rarely mutated, but at least one gene copy is lost in over 35% of the patients with HNSCC, correlating with decreased 4E-BP1 protein expression. gene copy number loss correlated with poor disease-free and overall survival. Aligned with a tumor-suppressive role, knockout mice formed larger and more lesions in models of HNSCC carcinogenesis. mTORi treatment or conditional expression of a mutant 4E-BP1 that cannot be phosphorylated by mTOR was sufficient to disrupt the translation-initiation complex and prevent tumor growth. Furthermore, CRISPR/Cas9-targeted HNSCC cells resulted in reduced sensitivity to mTORi and . Overall, these findings indicate that in HNSCC, mTOR persistently restrains 4E-BP1 via phosphorylation and that mTORi can restore the tumor-suppressive function of 4E-BP1. Our findings also support 4E-BP1 expression and phosphorylation status as a mechanistic biomarker of mTORi sensitivity in patients with HNSCC. SIGNIFICANCE: These findings suggest that EIF4E-BP1 acts as a tumor suppressor in HNSCC and that 4E-BP1 dephosphorylation mediates the therapeutic response to mTORi, providing a mechanistic biomarker for future precision oncology trials.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445709PMC
April 2019

Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin-fixed paraffin-embedded specimens.

Cancer Sci 2019 Apr 5;110(4):1464-1479. Epub 2019 Mar 5.

Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Tumor molecular profiling is becoming a standard of care for patients with cancer, but the optimal platform for cancer sequencing remains undetermined. We established a comprehensive assay, the Todai OncoPanel (TOP), which consists of DNA and RNA hybridization capture-based next-generation sequencing panels. A novel method for target enrichment, named the junction capture method, was developed for the RNA panel to accurately and cost-effectively detect 365 fusion genes as well as aberrantly spliced transcripts. The TOP RNA panel can also measure the expression profiles of an additional 109 genes. The TOP DNA panel was developed to detect single nucleotide variants and insertions/deletions for 464 genes, to calculate tumor mutation burden and microsatellite instability status, and to infer chromosomal copy number. Clinically relevant somatic mutations were identified in 32.2% (59/183) of patients by prospective TOP testing, signifying the clinical utility of TOP for providing personalized medicine to cancer patients.
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http://dx.doi.org/10.1111/cas.13968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447855PMC
April 2019

Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma.

Int J Cancer 2018 11 21;143(10):2425-2436. Epub 2018 Sep 21.

Moores Cancer Center, University of California San Diego, La Jolla, CA.

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) exhibits a different composition of epigenetic alterations. In this study, we identified differentially methylated regions (DMRs) with potential utility in screening for HPV-positive OPSCC. Genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV-positive OPSCC tissues and 25 normal tissues. Fifty-one DMRs were defined with maximal methylation specificity to cancer samples. The Cancer Genome Atlas (TCGA) methylation array data was used to evaluate the performance of the proposed candidates. Supervised hierarchical clustering of 51 DMRs found that HPV-positive OPSCC had significantly higher DNA methylation levels compared to normal samples, and non-HPV-related head and neck squamous cell carcinoma (HNSCC). The methylation levels of all top 20 DNA methylation biomarkers in HPV-positive OPSCC were significantly higher than those in normal samples. Further confirmation using quantitative methylation specific PCR (QMSP) in an independent set of 24 HPV-related OPSCCs and 22 controls showed that 16 of the 20 candidates had significant higher methylation levels in HPV-positive OPSCC samples compared with controls. One candidate, OR6S1, had a sensitivity of 100%, while 17 candidates (KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, ELMO1, SFMBT2, C1QL3, MIR129-2, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P and ZNF773) had specificities of 100%. The prediction accuracy of the 20 candidates rang from 56.2% to 99.8% by receiver operating characteristic analysis. We have defined 20 highly specific DMRs in HPV-related OPSCC, which can potentially be applied to molecular-based detection tests and improve disease management.
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http://dx.doi.org/10.1002/ijc.31778DOI Listing
November 2018

Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant.

Clin Cancer Res 2018 10 26;24(20):5123-5132. Epub 2018 Jun 26.

Moores Cancer Center, University of California San Diego, San Diego, California.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide, and alternative splicing is considered to play important roles in tumor progression. Our study is designed to identify alternative splicing events (ASEs) in human papillomavirus (HPV)-negative HNSCC. RNA sequencing data of 407 HPV-negative HNSCC and 38 normal samples were obtained from The Cancer Genome Atlas (TCGA), and splice junctions were discovered using MapSplice. Outlier analysis was used to identify significant splicing junctions between HPV-negative HNSCC and normal samples. To explore the functional role of the identified DOCK5 variant, we checked its expression with qRT-PCR in a separate primary tumor validation set and performed proliferation, migration, and invasion assays. A total of 580 significant splicing events were identified in HPV-negative HNSCC, and the most common type of splicing events was an alternative start site (33.3%). The prevalence of a given individual ASE among the tumor cohort ranged from 9.8% and 64.4%. Within the 407 HPV-negative HNSCC samples in TCGA, the number of significant ASEs differentially expressed in each tumor ranged from 17 to 290. We identified a novel candidate oncogenic DOCK5 variant confirmed using qRT-PCR in a separate primary tumor validation set. Loss- and gain-of-function experiments indicated that DOCK5 variant promoted proliferation, migration, and invasion of HPV-negative HNSCC cells, and patients with higher expression of DOCK5 variant showed decreased overall survival. Analysis of ASEs in HPV-negative HNSCC identifies multiple alterations likely related to carcinogenesis, including an oncogenic DOCK5 variant. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440699PMC
October 2018

Radiotherapy alone and with concurrent chemotherapy for nasopharyngeal carcinoma: A retrospective study.

Medicine (Baltimore) 2018 May;97(18):e0502

Department of Radiology, University of Tokyo Hospital Department of Radiology, Japan Self Defense Force Central Hospital Department of Otolaryngology-Head and Neck Surgery, University of Tokyo Hospital, Tokyo, Japan.

We sought to evaluate clinical outcomes and toxicities of radiation therapy (RT) alone compared to RT with concurrent chemotherapy (CCT) for nasopharyngeal carcinoma (NPC) treatment.We conducted a retrospective review of consecutive patients with biopsy-proven nonmetastatic NPC who underwent RT at our institution. From May 2001 to April 2015; 62 newly diagnosed NPC patients were treated with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) with or without CCT. The patients were classified as follows: 8% stage I, 15% stage II, 32% stage III, and 45% stage IVA/IVB. A total of 76% of tumors were World Health Organization types II or III. Acute and late toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0. Overall survival (OS), progression-free survival (PFS), locoregional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS) were analyzed.The median follow-up period for living patients was 53 months. The median actual delivered dose was 70 Gy with a range of 28 to 70 Gy in fraction sizes of 2 Gy. The estimated 5-year OS, PFS, LRPFS, and DMFS rates were 72.7%, 59.8%, 77.9%, and 84.2%, respectively. The use of CCT was a predictive factor of significantly better OS and PFS, whereas stage IV was a significant predictor of poor OS and PFS. The most severe acute toxicities included Grade 3 mucositis in 56% and Grade 3 dermatitis in 8%. Subset analysis revealed that Grade 2 xerostomia was significantly lower in the IMRT (23%) group than in the 3D-CRT (52%) group (P = .02).RT yielded favorable outcomes. CCT was associated with longer PFS and OS than RT alone.
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http://dx.doi.org/10.1097/MD.0000000000010502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392595PMC
May 2018

Postoperative mechanical bowel obstruction after pharyngolaryngectomy for hypopharyngeal cancer: Retrospective analysis using a Japanese inpatient database.

Head Neck 2018 07 14;40(7):1548-1554. Epub 2018 Mar 14.

Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine, the University of Tokyo, Tokyo, Japan.

Background: Data have been limited on donor-site mechanical bowel obstruction after pharyngolaryngectomy with free jejunum graft reconstruction.

Methods: Using a nationwide Japanese inpatient database, we extracted data on patients who underwent pharyngolaryngectomy for hypopharyngeal cancer between July 2007 and March 2014. A Cox proportional hazard model was used to determine the association between background characteristics and the occurrence of mechanical bowel obstruction.

Results: Among the 3320 eligible patients from 332 hospitals, 108 patients (3.3%) developed mechanical bowel obstruction after a median 88 (interquartile range 26-217) postoperative days. Multivariable Cox regression analysis revealed that older age (≥60 years old) was independently associated with an increased risk of mechanical bowel obstruction, whereas sex, body mass index [BMI], smoking status, comorbidity at admission, blood transfusion, history of surgery, and hospital type were not.

Conclusion: In pharyngolaryngectomy, careful attention should be paid to the risk of abdominal complications and, thus, to the graft choice, especially in elderly patients.
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http://dx.doi.org/10.1002/hed.25139DOI Listing
July 2018

Prognostic and histogenetic roles of gene alteration and the expression of key potentially actionable targets in salivary duct carcinomas.

Oncotarget 2018 Jan 4;9(2):1852-1867. Epub 2017 Dec 4.

Department of Otorhinolaryngology, Showa University School of Medicine, Tokyo, Japan.

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: , 68%; , 18%; , 16%; , 4%; and , 1.5%. mutations were more common in SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. mutations were frequently detected in cases with the aberrant p53 expression, and missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.
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http://dx.doi.org/10.18632/oncotarget.22927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788604PMC
January 2018

The prognostic value of TP53 mutations in hypopharyngeal squamous cell carcinoma.

BMC Cancer 2017 12 28;17(1):898. Epub 2017 Dec 28.

Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: TP53 is the most frequently mutated gene in human cancers. Previous studies reported that TP53 mutations correlated with poor prognoses in patients with head and neck squamous cell carcinoma (HNSCC). However, the relationship between TP53 mutations and hypopharyngeal squamous cell carcinoma (HPSCC) is not known. The current study aimed to evaluate TP53 mutation status as a predictive biomarker in patients with HPSCC.

Methods: We retrospectively reviewed the clinical charts of 57 HPSCC patients treated with initial surgery between 2008 and 2014. TP53 mutation status was determined by Sanger sequencing, and patients were classified into wild-type, missense mutation, and truncating mutation groups. Additionally, p53 expression was determined using immunohistochemistry in surgical specimens.

Results: TP53 mutations were identified in 39 (68%) patients. The 3-year disease-specific survival (DSS) rate of wild-type, missense mutation, and truncating mutation group were 94%, 61%, and 43%, respectively. The TP53 mutation group displayed significantly worse DSS and overall survival rates than the wild-type group (P = 0.01 and P = 0.007, respectively). Multivariate analyses revealed that the presence of TP53 mutations and ≥4 metastatic lymph nodes were independent adverse prognostic factors for HPSCC. p53 immunopositivity was detected in 22 patients, including 5 (28%) and 17 (71%) patients in the wild-type and missense mutation groups, whereas none of the patients with truncating mutation exhibited p53 immunopositivity (P = 0.0001).

Conclusion: The TP53 mutation status correlated with poor prognosis in surgically treated HPSCC patients. Specifically, truncating mutations which were not detected by p53 immunohistochemistry were predictive of worst survival.
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http://dx.doi.org/10.1186/s12885-017-3913-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745778PMC
December 2017

The impact of elevated C-reactive protein level on the prognosis for oro-hypopharynx cancer patients treated with radiotherapy.

Sci Rep 2017 12 19;7(1):17805. Epub 2017 Dec 19.

Department of Radiology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

The purpose of this study was to investigate an association between the prognosis for oro-hypopharynx squamous cell carcinoma treated with radiation therapy and the pre-therapeutic level of C-reactive protein (CRP). Patient with oro-hypopharyngeal squamous cell carcinoma who underwent definitive radiotherapy in our institution from January 2002 to August 2016 were enrolled. The patient were divided into elevated CRP (over 0.3 mg/dl) group and normal CRP groups, according to pre-treatment serum levels. There were 276 evaluable patients, and the median follow up was 41 months, ranging from 2 to 171 months. The 3-year OS and CSS for all enrolled patients were 67.0% and 72.8%, respectively. The OS and CSS rates were significantly worse in the elevated CRP group than in the normal CRP group, according to Kaplan-Meier survival curves analysed by a Log-rank test (p = 0.005 and p < 0.001, respectively). Multivariate analyses indicated that serum CRP levels remained independent predictors for both OS (HR: 1.588, p = 0.022) and CSS (HR: 1.989, p = 0.005). The pre-treatment CRP level is an independent predictor of treatment prognosis in patients with oro-hypopharyngeal cancer who underwent definitive radiotherapy. Especially, it is curious that an elevated CRP serum level is a significant predictor of loco-regional recurrence.
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http://dx.doi.org/10.1038/s41598-017-18233-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736698PMC
December 2017
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