• Asian Pacific Journal of Cancer Prevention
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• v.15 no.19
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• pp.8351-8359
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• 2014

Background: Recent epidemiological data have implicated human papilloma virus (HPV) infection in the pathogenesis of head and neck cancers, especially oropharyngeal cancers. Although, HPV has been detected in varied amounts in persons with oral dysplasia, leukoplakias and malignancies, its involvement in oral tongue carcinogenesis remains ambiguous. Materials and Methods: HPV DNA prevalence was assessed by PCR with formalin fixed paraffin embedded sections (n=167) of oral tongue squamous cell carcinoma patients and the physical status of the HPV16 DNA was assessed by qPCR. Immunohistochemistry was conducted for p16 evaluation. Results: We found the HPV prevalence in tongue cancers to be 51.2%, HPV 16 being present in 85.2% of the positive cases. A notable finding was a very poor concordance between HPV 16 DNA and p16 IHC findings (kappa<0.2). Further molecular classification of patients based on HPV16 DNA prevalence and p16 overexpression showed that patients with tumours showing p16 overexpression had increased hazard of death (HR=2.395; p=0.005) and disease recurrence (HR=2.581; p=0.002) irrespective of their HPV 16 DNA status. Conclusions: Our study has brought out several key facets which can potentially redefine our understanding of tongue cancer tumorigenesis. It has emphatically shown p16 overexpression to be a single important prognostic variable in defining a high risk group and depicting a poorer prognosis, thus highlighting the need for its routine assessment in tongue cancers. Another significant finding was a very poor concordance between p16 expression and HPV infection suggesting that p16 expression should possibly not be used as a surrogate marker for HPV infection in tongue cancers. Interestingly, the prognostic significance of p16 overexpression is different from that reported in oropharyngeal cancers. The mechanism of HPV independent p16 over expression in oral tongue cancers is possibly a distinct entity and needs to be further studied.

• Radiation Oncology Journal
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• v.14 no.1
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• pp.9-15
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• 1996

Purpose: The traditional approach with surgery and/or radiotherapy(RT) for advanced head and neck cancer Provides anticipated cure rates of $10-65\%$ depending on stages and sites. Recently, combined modality with chemotherapy have been extensively investigated in attempts to improve survival and local control. We retrospectively analysed our experience of 31 patients with advanced head and neck cancer. Materials and Methods : November 1983 to October 1994. 31 Patients with Stage III and IV squamous cell head and neck cancer were treated with RT. Sixteen patients were treated with RT alone, and IS patients were treated with combined RT plus chemotherapy. All patients were treated with 4-MV LINAC and radiation dose ranged from 5000 cGy to 7760 cGy (median 7010 cGy). In combined group, 7 patients were treated with cisplatin plus 5-FU 2 patients were treated with methotrexate plus leucovorin plus 5-FU plus cisplatin or carboplatin, and 6 patients were treated with cisplatin as a radiosensitizer. Results : Median follow up period was 16 months (range 4-134 months). The major responses (CR+PR) were noted in 10 patient ($66.6\%$) of the RT alone group and 14 patient ($93.3\%$) of the chemoradiation group. There was no statistical difference in CR rate between the two groups The overall survival rates at 5 years were $23.4\%$ in the radiation alone group, $23.5\%$ in the chemoradiation group Disease-free survival rates at 3 years were $44.5\%$ in the radiation alone group, $40\%$ in the chemoradiation group. There was no statistical differences in overall survival rates and disease-free survival rates between the two groups. Local recurrences occurred in $71.5\%$ of the radiation alone group, $72.7\%$ of the chemoradiation group and distant metastasis occurred in $14.4\%$ of radiation alone group, $9.1\%$ of the chemoradiation group. The frequencies of complications were comparable in both groups except hematologic toxicity Conclusion : Total response rates in the combined chemotherapy and radiotherapy was relatively higher than radiotherapy alone. But our result failed to show any survival benefit of the combined chemotherapy and radiotherapy. The accrual of large number of patients and long term follow-un may be necessary to confirm the present result of combined chemotherapy and radiotherapy.

• Radiation Oncology Journal
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• v.10 no.1
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• pp.27-34
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• 1992

Cis-Platinum (DDP) was utilized as a radiosensitizer in a pilot study for stage III and IV squamous cell carcinoma between 1984-1987, and DDP 20 $mg/M^2$/day was administered for 4 days at 3 week interval with concurrent radiotherapy. This study consisted of three phases: cytoreduction phase, eradicative treatment phase and adjuvant phase. Total 59 patients were subjected to evaluate a tumor response and its toxicity. During the eradicative phase,27 patients underwent surgery (group I ), 29 patients were treated with radiotherapy only (group II) and 3 patients did not complete the second phase of therapy. At the cytoreduction phase, $95\%$ response rate with complete response (CR) $47.5\%$ and partial response (PR) $47.5\%$ was observed. Complete tumor clearance (CTC) rate following 2nd phase of therapy was $84\%$ (47/56) with 26/27($96\%$) in group I achieved CTC with surgery and 21/29 ($72\%$) patients In group II achieved CTC following 2nd phase. $67\%$ of primary lesions and $70\%$ of nodal diseases in group I showed no tumor in the surgical specimen. $34\%$ of patiets who achieved CTC at 2nd phase developed recurrence and median time to recur was 8 months. Actuarial disease free survival at 4 years was $59\%$ and $51\%$(24/27) of patients who achieved CTC at 2nd phase were alive without any evidence of disease at median follow-up 31 months (range, 10-48 months). There was no significant difference in overall and disease free survival between group I and II between CR and PR group following 1st Phase. Only significant Prognostic factor in this study was the complete tumor clearance following 2nd phase theapy. In general, toxicity was not excessive. Author concludes that this study confirmed the significant radiosensitizing effect of DDP with the acceptable toxicity and warrant the prospective study to determine optimum scheduling for DDP and radiotherapy which maximizes the therapeutic gain.

• Korean Journal of Head & Neck Oncology
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• v.17 no.1
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• pp.59-62
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• 2001

Objectives: We report an interim result of conformal radiotherapy in a patient with early stage cancer at the base of the tongue, which developed in a previously irradiated area. Materials and Methods: A 64-year-old male patient was diagnosed with T4N0M0 supraglottic cancer. He received 72Gy of radiation therapy from 21 November 1988 to 24 February 1989. He had local failure and underwent a salvage total laryngectomy on 28 August 1989. Subsequently, he did well. In early 1999, he suffered from throat pain. He had a 2.5cm ulcerative mass at the base of his tongue, in the area that had been irradiated previously. Biopsy showed squamous cell carcinoma. After workup, he was diagnosed with base of tongue cancer with T2N0M0. Surgery was not feasible because the morbidity was not acceptable. Since it was difficult to re-irradiate the area with a curable dose using conventional 2D radiation therapy with an acceptable morbidity, we decided to try conformal radiotherapy. We used 7 static beam ports with field sizes from $7x6.4\;to\;8x8cm^2$, using 6 and 10MV photons. The fractionation regimen was 1.8Gy, 5 times per week. He received 64.8Gy in 36 fractions from 9 April 1999 to 1 June 1999. Results: In the 21 months since radiotherapy, the patient has not experienced any acute or chronic complications, such as xerostomia. He experienced relief of pain shortly after the start of radiotherapy, showed a complete response, and is still doing well. Conclusion: Conformal radiotherapy can be used to treat cancer that develops within a previously irradiated field, with curative intent.

• Korean Journal of Head & Neck Oncology
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• v.23 no.1
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• pp.3-8
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• 2007

연구목적：국소적 진행성 편도암환자에서 수술적치료와 비수술적치료의 결과를 비교 분석하고자 하였다. 연구방법 : 수술 후 보조방사선요법을 시행한 군과 유도화학요법 시행 유무에 상관없이 근치적 방사선 치료 또는 항암화학-방사선 동시치료를 받은 비수술군의 임상결과를 후향적으로 분석하였다. 연구결과：52.4개월의 중앙 추적기간결과, 대상환자의 중앙 연령은 53세 이었다. 대상 환자 중 병기 Ⅲ, Ⅳ기 환자는 72명(82.8%)이었고, 49명(56.3%)이 수술적 치료를, 38명(43.7%)명이 비수술적 치료를 받았다. 방사선 조사량외에 양군간의 차이는 없었다 (수술군：60.4Gy, 비수술군：70.2Gy, p=0.02). 비수술군의 전체 생존율은 81.6%이었다. 수술군의 8명(16.3%), 비수술군의 6명 (15.8%)에서 재발이 발생하였다. 흥미로운 사실은 원격재발은 2명 모두 수술군에서 발생하였다. 병기 III, IV기의 5년 무병생존율과 전체생존율은 수술군이 각각 82.1%, 86.9%이고, 비수술군이 각각 83.3%, 83.1%이었다(p=0.96, p=0.96). 결론：수술적 치료에 비해 비수술적 치료가 활동능력이 불량한 환자에게 선호되었을 가능성이 있었음에도 불구하고, 치료성적은 비슷하였다. 편도암에서 수술적 치료와 비수술적 치료의 전향적 무작위 비교연구가 필요하다.

• Imaging Science in Dentistry
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• v.31 no.3
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• pp.135-143
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• 2001

Purpose : To evaluate the effect of all-trans-retinoic acid on radiosensitivity and radiation-induced apoptosis in NHOK, HEp-2 and FaDu cell lines. Material and Methods: We measured the changes in survival fraction at 2 Gy (SF2), α and β after treatment of retinoic acid (1μM) prior to irradiation with doses of 2, 4, 6 and 10 Gy and correlated the radiosensitizing effect of retinoic acid with them. Also, apoptosis induction was assayed with the flow cytometry on days 1,2, 3, 4 and 5 after irradiation (2, 10 and 20 Gy) combined with retinoic acid. Results and Conclusion: SF2 values for NHOK, HEp-2 and FaDu cell lines were 0.54, 0.64 and 0.41, respectively and the cell line of FaDu was the most radiosensitive. For cell lines of NHOK and HEp-2, pretreatment of cells with retinoic acid resulted in a significant decrease of the SF2 values. The α/β ratios of x-ray survival curve were 8.714 (NHOK), 4.098 (HEp-2) and 11.79 (FaDu). The α/β ratio for NHOK decreased on pretreatment with retinoic acid, whereas those for HEp-2 and FaDu increased. Radiation induced apoptosis in all cell lines but, retinoic acid did not affect the apoptosis.

• Radiation Oncology Journal
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• v.28 no.1
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• pp.9-15
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• 2010

Purpose: This study was performed to examine the neck failure patterns after a complete response (CR) to definitive radiotherapy for advanced head and neck cancer patients, as well as evaluate the clinical significance of the results of this study. Materials and Methods: Between 1987 and 2008, the clinical data of patients who had been treated with radical radiotherapy for primary squamous cell carcinomas and enlarged cervical lymph nodes was analyzed retrospectively. Ultimately, the cases that showed CR of the cervical lymph node lesions to full-dose radiotherapy were included in this study. The recurrent rate and sites in the cervical lymphatic area were evaluated periodically by radiologic imaging studies, along with some factors which might have affected the rate of recurrence. Results: A total of 73 patients who achieved CR in neck area after radiotherapy were included in this study. The rate of subsequent neck failure among those patients was 19.2%. There was only a 5.5% failure rate in the 55 patients who underwent radiotherapy in their primary site. Eighty percent of the recurrent cases were found within 3 years (median follow-up, 68 months). The majority of neck recurrent cases (47%) were accompanied with the failure of the primary lesions. The initial response of the primary site and the method of radiotherapy simulation were significant prognostic factors associated with the nodal recurrence rate. Conclusion: The recurrence rate of cervical nodes in patients with CR to radiotherapy in the primary site and neck area was about 5%. These patients could be followed up with close observation without a planned neck dissection.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.22 no.2
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• pp.164-173
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• 2000

The p16 protein is a cyclin dependent kinase inhibitor that inhibits cell cycle progression from $G_1$ phase to S phase in cell cycle. Many p16 gene mutations have been noted in many cancer-cell lines and in some primary cancers, and alterations of p16 gene function by DNA methylation have been noticed in various kinds of cancer tissues and cell-lines. There have been a large body of literature has accumulated indicating that abnormal patterns of DNA methylation (both hypomethylation and hypermethylation) occur in a wide variety of human neoplasma and that these aberrations of DNA methylation may play an important epigenetic role in the development and progression of neoplasia. DNA methylation is a part of the inheritable epigenetic system that influences expression or silencing of genes necessary for normal differentiation and proliferation. Gene activity may be silenced by methylation of up steream regulatory regions. Reactivation is associated with demethylation. Although evidence or a high incidence of p16 alterations in a variety of cell lines and primary tumors has been reported, that has been contested by other investigators. The precise mechanisms by which abnormal methylation might contribute to carcinogenesis are still not fully elucidated, but conceivably could involve the modulation of oncogene and other important regulatory gene expression, in addition to creating areas of genetic instability, thus predisposing to mutational events causing neoplasia. There have been many variable results of studies of head and neck squamous cell carcinoma(HNSCC). This investigation was studied on 13 primary HNSCC for p16 gene status by protein expression in immunohistochemistry, and DNA genetic/epigenetic analyzed to determine the incidence, the mechanisms, and the potential biological significance of its Inactivation. As methylation detection method of p16 gene, the methylation specific PCR(MSP) is sensitive and specific for methylation of any block of CpG sites in a CpG islands using bisulfite-modified DNA. The genomic DNA is modified by treatment with sodium bisulfate, which converts all unmethylated cytosines to uracil(thymidine). The primers designed for MSP were chosen for regions containing frequent cytosines (to distinguish unmodified from modified DNA), and CpG pairs near the 5' end of the primers (to provide maximal discrimination in the PCR between methylated and unmethylated DNA). The two strands of DNA are no longer complementary after bisulfite treatment, primers can be designed for either modified strand. In this study, 13 paraffin embedded block tissues were used, so the fragment of DNA to be amplified was intentionally small, to allow the assessment of methylation pattern in a limited region and to facilitate the application of this technique to samlples. In this 13 primary HNSCC tissues, there was no methylation of p16 promoter gene (detected by MSP and automatic sequencing). The p16 protein-specific immunohistochemical staining was performed on 13 paraffin embedded primary HNSCC tissue samples. Twelve cases among the 13 showed altered expression of p16 proteins (negative expression). In this study, The author suggested that low expression of p16 protein may play an important role in human HNSCC, and this study suggested that many kinds of genetic mechanisms including DNA methylation may play the role in carcinogenesis.

• Journal of Life Science
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• v.19 no.6
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• pp.770-780
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• 2009

A new photosensitizer, 9-Hydroxypheophorbide-a (9-HpbD-a), was derived from Spirulina platensis. We conducted a series of experiments, in vitro and in vivo, to evaluate the anticancer effect and mechanism of photodynamic therapy using 9-HpbD-a and 660 nm diode lasers on a squamous carcinoma cell line. We studied the cytotoxic effects of pheophytin-a, 9-HpbD-a, 9-HpbD-a red and 660 nm diode lasers in a human head and neck cancer cell line (SNU-1041). Cell growth inhibition was determined by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. The effects of 9-HpbD was higher than those of 9-HpbD-a red or pheophytin-a in PDT. We then tested the cytotoxic effects of 9-hydroxypheophorbide-a (9-HpbD-a) in vitro. The cultured SNU-I041 cells were treated with serial concentrations of 9-HpbD-a followed by various energy doses (0, 0.1, 0.5, 3.2 J/$cm^{2}$) and by various interval times (0, 3, 6, 9, 12 hr) until laser irradiation, then MTT assay was applied to measure the relative inhibitory effects of photodynamic therapy (PDT). Optimal laser irradiation time was 30 minutes and the cytotoxic effects according to incubation time after 9-HpbD-a treatment increased until 6 hours, after which it then showed no increase. To observe the cell death mechanism after PDT, SUN-I041 cells were stained by Hoechst 33342 and propidium iodide after PDT, and observed under transmission electron microscopy (TEM). The principal mechanism of PDT at a low dose of 9-HpbD-a was apoptosis, and at a high dose of 9-HpbD-a it was necrosis. PDT effects were also observed in a xenografted nude mouse model. Group I (no 9-HpbD-a, no laser irradiation) and Group II (9-HpbD-a injection only) showed no response (4/4, 100%), and Group III (laser irradiation only) showed recurrence (1/4,25%) or no response (3/4, 75 %). Group IV (9-HpbD-a + laser irradiation) showed complete response (10/16, 62.5%), recurrence (4/16, 25%) or no response (2/16, 12.5%). Group IV showed a significant remission rate compared to other groups (p<0.05). These results suggest that 9-HpbD-a is a promising photosensitizer for the future and that further studies on biodistribution, toxicity and mechanism of action would be needed to use 9-HpbD-a as a photosensitizer in the clinical setting.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5965-5972
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• 2013

PIN1 is one member of the parvulin PPIase family. By controlling Pro-directed phosphorylation, PIN1 plays an important role in cell transformation and oncogenesis. There are many polymorphisms in the PIN1 gene, including rs2233678 and rs2233679 affecting the PIN1 promoter. Recently, a number of case-control studies were conducted to investigate the association between PIN1 gene rs2233678 and rs2233679 polymorphism and cancer risk. However, published data are still conflicting. In this paper, we summarized data for 5,427 cancer cases and 5,469 controls from 9 studies and attempted to assess the susceptibility of PIN1 gene polymorphism to cancers by a synthetic meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the relationship. All analyses were performed using Stata software. Our results suggested that rs2233678 represented a protective factor in overall analysis (CC vs GG: OR= 0.697, 95%CI: 0.498-0.976; CG vs GG: OR=0.701, 95%CI: 0.572-0.858; Dominant model: OR= 0.707, 95%CI: 0.590-0.847; C allele vs G allele: OR=0.734, 95%CI: 0.623-0.867) and especially for squamous cell carcinoma of the head and neck, lung cancer and breast cancer in Asians and Caucasians. The rs2233679 polymorphism was significantly associated with decreased cancer risk in overall analysis (CT vs CC: OR=0.893, 95%CI=0.812-0.981; Dominant model: OR=0.893, 95%CI=0.816-0.976; T allele vs C allele; OR=0.947, 95%CI=0.896-1.000) and especially in Asians. In conclusion, our meta-analysis suggested that -842G>C (rs2233678) and -667C>T (rs2233679) may contribute to genetic susceptibility for cancer risks. Further prospective research with larger numbers of worldwide participants is warranted to draw comprehensive and firm conclusions.