CHEMOTHERAPY FOR ADVANCED NASOPHARYNGEAL CARCINOMA WITH METHOTREXATE, VINCRISTINE, CISPLATIN AND ADRIAMYCIN

Objective: To evaluate the efficacy and toxicity of M-VCA (methortrexate 30 mg/m2, vincristine 2 mg, cisplatin 70 mg/m2, adriamycin 30 mg/m2) combination chemotherapy for advanced nasopharyngeal carcinoma. Methods: Thirty-five patients with advanced nasopharyngeal carcinoma, including 11 patients with untreated local advanced nasopharyngeal carcinoma and 24 patients with local-regional recurrent or metastatic nasopharyngeal carcinoma, received the chemotherapy of M-VCA. The cycle was repeated on day 22 for two cycles. All patients completed the chemotherapy courses. Results: The overall response rate was 75%, with untreated local advanced nasopharyngeal carcinomas 11/11(100%), local-regional recurrent nasopharyngeal carcinomas 12/18(67%), lung metastases 8/9(89%), bone metastases 5/9(56%), and liver metastases 1/2(50%). The main side effects included mild to moderate degree alopecia, nausea/vomiting, and neutropenia. Conclusion: M-VCA is well tolerated and has good efficacy for advanced nasopharyngeal carcinoma and is worth investigating further.

THREE-DIMENSIONAL CONFORMAL RADIATION THERAPY FOR LOCALLY RECURRENT NASOPHARYNGEAL CARCINOMA

Objective: To investigate the safety and effectiveness of three-dimensional conformal radiation therapy (3-D CRT) for locally recurrent nasopharyngeal carcinoma (NPC). Methods: From April 1998 to March 2000, 34 patients who had undergone previous external beam radiation therapy were retreated with 3-D CRT for locally recurrent NPC (33 poorly differentiated squamous cell carcinomas, 1 adenoma). The patients were re-staged according to Huaqing staging system with the following distribution: T1N0M0 in 5 cases, T2N0M0 in 11 cases, T3N0M0 in 12 cases, T4N0M0 in 6 cases. The maximal dimension of the gross tumor volume (GTV) ranged from 1.0 cm to 5.0 cm (median: 2.9 cm). CT simulation and 3-D planning were used to ensure full and conformal coverage of the planning target volume (PTV) by treated volume, while minimizing the absorbed dose of the adjacent normal tissue. 5–7 static conformal coplanar or noncoplanar portals were delivered for each fraction irradiation. The total dose delivered ranged from 65–70 Gy, with 2.5 Gy per fractionation, one fractionation per day, 5 days a week. Median follow-up time from 3-D CRT was 25 months (range: 12–36 months). Results: Over the follow-up period, local recurrence was observed in 3 patients, regional failure in 3, distant metastasis in 3, and six patients died; 88.2% (30/34) of the patient maintained local control, 82.4% (28/34) survived, and 76.5% (26/34) survived with no evidence of tumor. Acute complications were minor and few. The overall incidence of late complication was 20.6% (7/34), and severe complication was 14.7% (5/34), after re-irradiation with 3-D CRT. Conclusion: 3-D CRT is safety and effectiveness for most of the patients with locally recurrent NPC. Our preliminary results indicate a high local control rate and a low complication rate. The long-term curative effect and sequelae await further study.

A PROPOPSAL CONCERNING THE HISTOLOGICAL TYPING OF PRIMARY NASOPHARYNGEAL CARCINOMA

A proposal concerning the histological typing of primary nasopharyngeal carcinoma is offered in order to coincide with pathologic terms used both by Chinese and foreign pathologists and reflect the achievements in the research field of NPC. This proposal was worked out mainly basing upon the authors’ diagnostic experience gained in the past 30 years and the international criteria for tumor classification. Primary nasopharyngeal carcinoma could be classified into four major types, namely, keratinizing squamous cell carcinoma (KSCC), non- keratinizing carcinoma (NKC), adenocarcinoma (AC) and carcinomain-situ (CIS). KSCC could be graded as being well, moderately and poorly differentiated according to the amount of keratinization and intercellular bridges presented in the biopsy slide. The NKC is the most frequent type seen in the high-incidence area of NPC, and could also be subdivided into differentiated and undifferentiated variants. Actually, three grades of KSCC and two variants of NKC are a reflection of different degrees of squamous differentiation. They are consistently associated with Epstein-Barr virus (EBV) infection. There are two major categories of nasopharyngeal AC, namely, traditional and salivary-gland type. As contrasted with KSCC and NKC, nasopharyngeal AC is rarely infected with EBV. There are two subtypes of CIS, namely, squamous- and columnar-cell type. The histological typing concerning the primary nasopharyngeal carcinoma offered above is really a practical proposal and also coincided with the international usage. This proposal can be mastered easily and the authors recommend its routine use in diagnostic pathology.

THE INTRACELLULAR FORM OF EPSTEIN-BARR VIRUS GENOME IN NASOPHARYNGEAL CARCINOMA

This work was supported by the National Natural Science Foundation of China (No. 39370766). Object: To study the existent form of EBV genome in nasopharyngeal carcinoma (NPC) biopsies, in a trans planted NPC tumor SUNT 1 and its corresponding epithelial cell line SUNE 1. Methods: By using polymerase chain reaction (PCR) amplification of Epstein Barr virus (EBV) BamHI W fragment, EBV DNA was detected in 20/20 biopsy specimens of poorly differentiated, as well as in a nude mouse xenografted NPC tumor (SUNT 1, from passage 1 to 34) and in the corresponding epithelial cell line (SUNE 1, from passage 1 to 62). The intracellular form of EBV genome was studied by analyzing the terminal structure using a LMP2A probe and an “ in situ lysing gel” technique. Results: A single EBV fused terminal DNA fragment was detected in 19 biopsy specimens, two hybridized bands were seen in one specimen. These results indicate that an episomal form of EBV genome is predominantly present in most NPC biopsy specimens, but insertion of the genome into the host chromosome could not be excluded. Conclusion: The finding suggests that EBV infection precedes clonal amplification of transformed cells, or in a rare case, that a single EBV infected clone is predominant in the development of NPC. Linear form of EBV DNA was detected in the 20th passage of SUNE 1; this may imply the in vitro activation of the productive cycle of EBV.

鼻咽部髓外浆细胞瘤1例

1临床资料患者,女,54岁,主因渐进性鼻塞1年余入院。患者夜间睡眠时张口呼吸伴打鼾,偶有头痛,无发热、血涕、耳鸣及听力下降。鼻内镜检查:右侧鼻咽部淡红色新生物,表面不光滑,质韧,堵塞全部右侧后鼻孔及大部分、左侧后鼻孔,基底位于右侧咽隐窝处(图1A)。耳内镜检查发现右耳鼓膜内陷,入院诊断为鼻咽部肿物。

新辅助化疗联合同期放化疗治疗局部晚期鼻咽癌的毒副反应及近期疗效(英文)

Background and Objective:Concurrent chemoradiation therapy(CCRT) is the standard treatment for patients with locally advanced nasopharyngeal carcinoma(NPC).The effect of neoadjuvant chemotherapy followed by CCRT has not been determined.Therefore,we conducted 2 phase Ⅱ studies to evaluate the efficacy and safety of neoadjuvant chemotherapy with a regimen of docetaxel,cisplatin,and 5-fluorouracil(5-Fu)(TPF) followed by radiotherapy and concurrent cisplatin in patients with stage-Ⅲ and -Ⅳ(A -B) NPC.This article is the preliminary report on treatment-related toxicities and response.Methods:Graded according to the 2002 American Joint Committee on Cancer(AJCC) staging criteria,only patients with stage-Ⅲ or -Ⅳ(A-B) poorly differentiated or undifferentiated NPC(World Health Organization type Ⅱ/Ⅲ) were included.We planned to recruit 52 patients with stage-Ⅲ disease and 64 patients with stage-Ⅳ(A-B) disease.All patients received neoadjuvant chemotherapy with TPF(docetaxel 75 mg/m2,day 1;cisplatin 75 mg/m2,day 1;5-Fu 500 mg/(m2·day),continuous intravenous infusion for 120 h),every 3 weeks for 3 cycles,followed by weekly cisplatin(40 mg/m2) concurrent with radiotherapy.Three-dimensional conformal radiotherapy(3D-CRT) and intensity-modulated radiotherapy(IMRT) were used.Gross disease planning target volume(PTV),high-risk and low-risk subclinical PTV doses were prescribed at 70-76 Gy,66-70 Gy,and 60-61.25 Gy at 1.75-2.0 Gy per fraction.The lower neck or supraclavicular fields may be treated with conventional AP/PA fields for a total of 54 Gy at 1.8 Gy per fraction.Patients were evaluated for tumor response after the completion of neoadjuvant chemotherapy,and at 3 months after radiation according to the Response Evaluation Criteria In Solid Tumors(RECIST).The latest version of the National Cancer Institute's Common Terminology Criteria for Adverse Events(NCI CTCAE 3.0) was used for grading all adverse events.Results:Fifty-nine patients were evaluable for treatment response.Thirty patients had stage-III disease and 29 patients had stage-IV(A-B).All patients completed RT to the prescribed dose and 2 cycles of neoadjuvant chemotherapy,with 51 patients(86.4%) completing 3 cycles.A total of 50(84.7%) and 39 patients(66.1%) completed 4 weeks and 5 weeks of cisplatin during CCRT,respectively.The overall response rate in the primary site and the neck region were 94.9% [complete response(CR) in 25.4%] and 100%(CR in 19.6%) after completing neoadjuvant chemotherapy.At 3 months after RT,the CR rates increased to 96.6% and 90.2%,respectively.After a median follow-up of 14.3 months,we observed 5 treatment failures and 2 deaths.The 1-year overall survival,distant metastasis-free survival,and locoregional relapse-free survival rates were 100%,95.7%,and 97.7%,respectively.The rates of grade 3/4 myelosuppression and anorexia/nausea/vomiting during neoadjuvant chemotherapy were 55.9% and 16.9%,respectively.The corresponding rates were 11.9% and 23.7% during CCRT.Grade 3/4 mucositis,skin desquamation,and xerostomia occurred in 6.8%,44.1%,and 27.1% of patients,respectively.There were no treatment-related deaths.Conclusions:Neoadjuvant chemotherapy with TPF followed by CCRT was well tolerated with a manageable toxicity profile.Preliminary results are encouraging and warrant further investigation.

RADIATION-INDUCED APOPTOSIS OF TWO NASOPHARANGEALCARCINOMA CELL LINES

Objective: To study apoptosis induced by radiation in two nasopharyngeal carcinoma (NPC) cell lines, CNE and CNE-2. Methods: Hoechst 33342 staining, immuno-histochemical staining, RT-PCR, DNA dot blotting and Southern blotting were used to identify apoptosis. Results: A single dose of X-irradiation resulted in apoptosis, the apoptotic index (AI) was time- and dose-dependent. Different apoptotic responses existed in the two cell lines. Immunohistochemical staining showed that bcl-2 protein was strongly positive in CNE but negative in CNE-2. However, RT-PCR revealed p53 mRNA in CNE-2 but not in CNE. P53 and bcl-2 genes were both present in the two cell lines as shown by DNA blotting, but the 2.8 kb fragment of the p53 gene was much lower than the 5.6 kb fragment on CNE which was clearly shown in Southern hybridization, suggestive of partial deletion of p53 gene in CNE. Conclusion: Apoptotic response to radiation is different in two NPC cell lines. CNE is more radioresistant than CNE-2. Overexpression of bcl-2 protein and partial deletion of p53 gene may explain their difference in radiosensitivity.

A comprehensive review and characterization of nasopharyngeal carcinoma clinical trials

Objective:Although standard of care for primary nasopharyngeal carcinoma(NPC)is chemoradiotherapy,there remains no consensus on management of recurrent or metastatic disease.We characterized recent clinical trials on NPC to assess trends in NPC treatment and establish promising areas for future research.Study Design:Retrospective database study.Setting:ClinicalTrials.gov database.Methods:Retrospective review of all NPC trials from November 1999 to June 2021.For each study,the following variables were extracted:study characteristics,intervention,outcome measures,and inclusion criteria.Secondary searches via PubMed and Google scholar determined trial publication status.Results:A total of 448 clinical trials were identified:72(16%)observational and 376(84%)interventional,of which there were 30(8%)Phase I,183(49%)Phase II,86 Phase III(23%),and 5(1%)Phase IV trials.Fifty-four percent of trials included only primary NPC while 111(25%)exclusively studied recurrent cancers.The most common interventions were cisplatin(n=64)and intensity modulated radiation therapy(n=54);there were 38 trials involving PD-1 monoclonal antibodies.Thirty-four studies examined quality of life measures,including xerostomia and mucositis.Of the completed studies,53.2%have published manuscripts.Poor patient accrual was the most common reason for premature study termination.Conclusions:Novel immunotherapies have been increasingly incorporated into NPC studies in recent years,however,chemotherapy and radiation,despite their numerous side effects,are still widely used due to their clinical effectiveness.Future trials are warranted to determine the optimal therapeutic regimens to decrease relapse rates and side effects.

Post-radiation CT changes and recurrent nasopharyngeal carcinoma

Background Nasopharyngeal carcinoma （NPC） is endemic in Southern Asia. Radiation therapy remains the mainstay of treatment strategies for NPC. Although approximately 19%-56% of patients develop a recurrent disease 5 years after their primary treatment, recognition of post-radiation changes and early detection of relapse are important in improving the outcome of NPC. Our aim was to analyze the post-radiation changes and recurrent diseases related to NPC using computed tomography （CT） scans and to investigate their relationship. Methods CT scans of 510 pathologically proven NPC patients who have been followed up for more than 2 years after radiation were reviewed. The tumor＇s response to the radiation therapy and its relevance to recurrence were evaluated. Results For patients who were followed up for more than 2 years, their CT scans-obtained within 3 months, during the 4th to the 6th month, and beyond 7 months after radiation therapy, showed a normal nasopharyngeal cavity with a slight thickening in the wall in 93.5%, 95.0% and 84.8% of the patients respectively. The degree of tumor regression had no significant relevance to the risk of recurrence within the initial 3 months （P=0.094）. During this term, the relapse rates in the cases in which the nasopharyngeal walls were displayed as normal, slightly or moderately thickening, or with obvious residual masses on CT scans were 7.1%, 11.7%, 23.5% and 23.1% respectively. The degree of tumor regression beyond 3 months after radiation therapy had a considerable reverse relevance to the risk of recurrence （P=-0.000）. The relapse rates were 13.2%, 14.1%, 10.2% and 2.1%, respectively, in the cases with a normal and a slightly thickening nasopharyngeal wall during the 4th to the 6th month, the 7th to the 12th month, the 13th to the 24th month, and beyond 25 months after radiation. In contrast, the percents in cases with moderate or more aggressive thickening walls in the corresponding periods were 62.5%, 88.9%, 100% and 100%. Within 6 months after radiation therapy, shown by CT scans the metastatic lymph nodes disappeared, markedly decreased, slightly decreased, or enlarged in 37.4%, 51.8%, 4.7%, and 0.4%, respectively, of the patients. During 6 to 12 months after radiation therapy, the proportions were 78.5%, 19.2%, 0.6% and 1.7% correspondingly. Beyond 12 months, the proportions were 83.7%, 7.9%, 0%, and 8.4%. The regression degree of the malignant nodes after radiation therapy showed a remarkable reverse relevance to the risk of recurrence in lymph nodes （P=0.000）. In the cases with disappearing, markedly decreased, slightly decreased, or enlarged malignant nodes within six months after radiation, the relapse rates were 2.9%, 4.5%, 12.5% and 100%, respectively. Conclusions If the nasopharyngeal walls are shown to remain moderately thick on a CT scan beyond 6 months after radiotherapy, the risk of relapse will increase. The baseline images taken within 3 months after radiotherapy and regular follow-uo studies are the kev to pick up the tumor recurrences in an earlier stage.

Distinct serumal proteomic patterns between ascending and descending types of loco-regionally advanced nasopharyngeal carcinoma assessed by surface enhanced laser desorption ionization and artificial neural network analyses

Nasopharyngeal carcinoma （NPC） is rare in most countries, especially in Europe and NorthAmerica （incidence rate below 1/100 000 people per year）. However, it has a high incidence in several southern areas in China, especially in the Cantonese region, including Guangzhou city, where the incidence rate is approximately 30-80/100 000 people per year. In the high incidence areas, more than 95% NPCs are poorly differentiated （WHO types 2 and 3）, which are sensitive to radiotherapy and chemotherapy. Besides its special epidemiological and pathological characteristics,

Macrophage migration inhibitory factor enhances neoplastic cell invasion by inducing the expression of matrix metalloproteinase 9 and interleukin-8 in nasopharyngeal carcinoma cell lines

Background Nasopharyngeal carcinoma (NPC) shows highly invasive and metastatic features. This study aims to investigate macrophage migration inhibitory factor (MIF)-induced invasion of NPC cells in vitro and the effects on matrix metalloproteinases (MMPs) and interleukin-8 (IL-8),and to study the mechanism of tumor cell invasion and metastasis in the early stage of NPC. Methods Two nasopharyngeal carcinoma cell lines,CNE-1 and CNE-2,were adopted in this study. The NPC cell invasion and migration were evaluated by microinvasion assay. The variation of expression percentages of MMP2- or MMP9-positive cells was detected by flow cytometry in two cell lines with or without MIF treatment. Western blotting and RT-PCR were used to assay the protein and mRNA expressions of MMP2 and MMP9. The IL-8 concentration secreted by NPC cells was compared with the cells with different treatments using ELISA. Results After treating with MIF for 48 hours,the cell numbers of CNE-1 and CNE-2 which went through the 8-μm filter membrane were increased. Compared with non-MIF treated NPC cells,significant difference could be found both in CNE-1( P =0.005) and CNE-2 cells ( P =0.001) . The percentages of MMP9-positive cells were significantly increased in both CNE-1 [from (28.5±2.5)% to (82.4±3.5)%, P =0.001] and CNE-2 [from (32.8±3.5)% to (86.1±1.6)%, P =0.002]. The relative intensity of MMP9 protein expression was also enhanced in both cell lines (CNE-1: from 83.1±6.0 to 242.9±22.9, P =0.002;CNE-2: from 84.4±4.3 to 278.9±29.7, P =0.003). Correspondingly,the increased MMP9 mRNA expression level was significantly detectable in both cell lines.The concentration of IL-8 in the supernatant of CNE-2 was higher [(1201.8±593.3) pg/ml] after treatment. It was also remarkably higher than that in the supernatant of CNE-2 without treatment ( P =0.026). However,there was no significant difference in the concentration variation of IL-8 in CNE-1 ( P =0.581), while the IL-8 mRNA level was only enhanced in CNE-2. Conclusions MIF can induce potent invasion of NPC cell lines in vitro , and the infiltrating lymphocytes in NPC might be responsible for the invasion and metastasis of tumor cells. MIF cytokine which is secreted by these infiltrating lymphocytes might contribute to the invasion as well as metastasis of NPC in the early stages by induction of MMP9 and IL-8 in an indirect pathway.