Kwok Seng Loh

The candidate tumor suppressor gene BLU , located at the commonly deleted region 3p21.3, is an E2F-regulated, stress-responsive gene and inactivated by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma

Loss of heterozygosity at 3p21 is common in various cancers including nasopharyngeal carcinoma (NPC). BLU is one of the candidate tumor suppressor genes (TSGs) in this region. Ectopic expression of BLU results in the inhibition of colony formation of cancer cells, suggesting that BLU is a tumor suppressor. We have identified a functional BLU promoter and found that it can be activated by environmental stresses such as heat shock, and is regulated by E2F. The promoter and first exon are located within a CpG island. BLU is highly expressed in testis and normal upper respiratory tract tissues including nasopharynx. However, in all seven NPC cell lines examined, BLU expression was downregulated and inversely correlated with promoter hypermethylation. Biallelic epigenetic inactivation of BLU was also observed in three cell lines. Hypermethylation was further detected in 19/29 (66%) of primary NPC tumors, but not in normal nasopharyngeal tissues. Treatment of NPC cell lines with 5-aza-2′-deoxycytidine activated BLU expression along with promoter demethylation. Although hypermethylation of RASSF1A, another TSG located immediately downstream of BLU, was detected in 20/27 (74%) of NPC tumors, no correlation between the hypermethylation of these two TSGs was observed (P=0.6334). In addition to methylation, homozygous deletion of BLU was found in 7/29 (24%) of tumors. Therefore, BLU is a stress-responsive gene, being disrupted in 83% (24/29) of NPC tumors by either epigenetic or genetic mechanisms. Our data are consistent with the interpretation that BLU is a TSG for NPC.

The genomic landscape of nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.

MUCOSAL MELANOMAS OF THE HEAD AND NECK: THE PRINCESS MARGARET HOSPITAL EXPERIENCE

The aim of this study was to identify the prognostic variables in mucosal melanoma of the head and neck.

Complications of Foreign Bodies in the Esophagus

Major complications of foreign bodies in the esophagus carry significant morbidity and mortality risks. A retrospective case control study was performed to assess the factors associated with major complications. In total, 273 patients seen within a 7-year period were divided into 2 groups; 253 had no or minor complications, and 20 had major complications. Age, sex, duration of the foreign body, total white cell count (TWC), and nature and site of the foreign body were analyzed in the 2 groups. The major complication rate was 7.3%. Duration of the foreign body and TWC were the only statistically significant factors associated with major complications. Six patients required open neck exploration, 1 had an open thoracotomy, and 13 were treated by endoscopic removal. There were 2 deaths. Given the significant morbidity and mortality risks, we conclude that patients with a prolonged history of a foreign body in the esophagus and a raised TWC should be treated urgently.

Epidermal growth factor receptor in undifferentiated carcinoma of the nasopharynx.

Objectives To determine the expression levels of epidermal growth factor receptor (EGFR) and its prognostic value in undifferentiated carcinoma (UC) of the nasopharynx.

Tuberculous and nontuberculous cervical lymphadenitis: a clinical review.

OBJECTIVES : The aim of the present study was to identify differences in clinical characteristics between patients with tuberculous cervical lymphadenitis and those with nontuberculous cervical lymphadenitis and to determine the diagnostic accuracy of fine needle aspiration (FNA) cytology. STUDY DESIGN AND SETTING : Seventy-two patients with inflammatory cervical lymphadenitis were studied retrospectively. They were divided into 2 groups: group 1 consisted of those with tuberculous lymphadenitis and group 2 consisted of those with non-tuberculous lymphadenitis. The demographic characteristics, clinical parameters, and hematological and cytological results of the 2 groups were compared. RESULTS : Other than there being a significantly higher proportion of foreign-born patients in group 1, there were no differences in clinical characteristics between the 2 groups. The sensitivity and specificity of FNA cytology in the diagnosis of tuberculous lymphadenitis were 88% and 96%, respectively. CONCLUSION : It is difficult to clinically differentiate tuberculous from nontuberculous lymphadenitis. FNA cytology is useful in the diagnosis of tuberculous lymphadenitis. SIGNIFICANCE : In regions where tuberculosis is endemic, treatment can be instituted without the need for excisional biopsy if the FNA results show characteristic caseating granuloma.

ROLE OF FINE-NEEDLE ASPIRATION CYTOLOGY IN THE EVALUATION OF PAROTID TUMOURS

Background:  The aim of this study was to evaluate the accuracy of fine‐needle aspiration cytology in the diagnosis of parotid tumours.

Tailoring distant metastatic imaging for patients with clinically localized undifferentiated nasopharyngeal carcinoma

PURPOSE The 2000 practice guidelines of the National Comprehensive Cancer Network recommend World Health Organization Type 2-3 nasopharyngeal carcinoma (NPC) be staged for distant disease using chest X-ray and bone scan. Our aim was to evaluate these modalities plus liver ultrasonography for American Joint Committee on Cancer/International Union Against Cancer 1997 clinical Stage I-IVB NPC. METHODS AND MATERIALS Between February 1999 and May 2002, all patients with clinical (examination plus CT/MRI of head and neck) Stage I-IVB undifferentiated NPC were prospectively evaluated for distant disease with chest X-ray, liver ultrasonography, and bone scan. Suspicious lesions underwent confirmatory investigation, and patients were reevaluated at 4 months. RESULTS In the 139 patients evaluated, the positive yield was 3.6% and prevalence was 5.8% (0.7% lung, 2.2% skeletal, and 2.9% liver metastases). The prevalence increased by N stage (p = 0.004) and overall stage (p = 0.05). Compared with N3 disease (odds ratio 1.0), the odds of metastases for N0, N1, and N2 disease was 0, 0.12, and 0.33, respectively. The positive yield was 0%, 1.8%, 4.8%, and 14.3% for N0, N1, N2, and N3 disease, respectively. CONCLUSION This is the first study to evaluate the use of distant staging investigations for American Joint Committee on Cancer/International Union Against Cancer 1997 staged NPC. We recommend alterations to the 2000 National Comprehensive Cancer Network guidelines as follows: high-risk (N3) disease should be fully staged with chest X-ray, bone scan, and liver ultrasonography; intermediate risk (N1 and N2) disease may be staged using all three modalities on an institutional basis. No evidence supports distant imaging for low-risk (N0 or Stage I) disease.

Increased production of interferon-γ by tumour infiltrating T lymphocytes in nasopharyngeal carcinoma: indicative of an activated status

Undifferentiated nasopharyngeal carcinomas (UNPC) are characterised by an association with Epstein-Barr virus and an abundant lymphoid stroma. We studied the functional status of the infiltrating T cells in ten UNPC biopsies using an immunohistochemical approach. Twelve non-NPC biopsies were included as controls. Tumour cells of UNPC were positive for HLA class I (10/10) and II (8/10), LMP1 (3/10), and CD86 (6/10). Tumour infiltrating T cells (TILs) were detected with antibodies directed at CD3, CD4, and CD8, and shown to be comparable to that in the control biopsies. Although expression of CD28 was shown to be decreased in TILs, expression of CD25 and IFN-gamma at a relatively high percentage could be consistently detected in the UNPC biopsies. These data suggest that TILs in UNPC are in an activated status, and this T cell response is possibly directed at the tumour cells.

Identification of a subpopulation of nasopharyngeal carcinoma cells with cancer stem-like cell properties by high aldehyde dehydrogenase activity

Cancer stem cells have been reported as a new therapeutic target in many cancers, but their existence in nasopharyngeal carcinoma (NPC) is largely unknown. This study was conducted to determine cancer stem‐like cells in NPC cell line.