放射線引起的惡性纖維組織細 胞瘤在第三和第十一對染色體之異合性喪失－病例報告

癌症的形成大都是一連串的基因變化所致，其中抑癌基因的不活化是癌細胞形成最常 見的現象，雖然抑癌基因的不活化有很多機轉，找出腫瘤細胞失去的染色體片段，再 從中找尋可能含有的抑癌基因是一種有效的方法。來自雙親的兩個同源染色體，若其 中之一有一段缺失，謂之有失異合性。部份頭頸部癌症在第3，9，11對染色體已被發 現有失異合性。頭頸部區域之放射線引起的惡性纖維組織細胞瘤，是一種惡性度極高 的肉瘤，和原發性的鎮一樣，前者非常罕見但生長極為快速，復發率高。為瞭解放射 線引起的惡性纖維組織細胞瘤在第3，9，11對染色體有無失異合性的情形，取1名惡 性纖維組織細胞癌病人的癌組織，及抽取周邊血液，分別萃取癌細胞及正常淋巴球之 去氧核榶醣核酸，然後以位於第3，9，11對染色體上特定位置的53個附有螢光物質的 微衛星多形標記引子，放入分別含有正常細胞或癌細胞去氧核醣核酸的反應液中，藉 助聚合酵素鏈反應複製60次，確定有產物後，便在Perkin-Elmer/Applied Biosystems(PE/ABI)的377去氧核醣核酸分析儀進行電泳，經雷射激發，蒐集訊息於 電腦，再以GeneScanTM軟體判讀。結果在染色體3p的D3S1300和3q的D3S1262、D3S 1311及染色體11p的D11S922有失異合性的情形。 Malignant transformation in tumor development results from a series of genetic changes and the inactivation of tumor suppressor genes is among the most common molecular events that contribute to tumorigenesis. Although a variety of mechanisms exsist for the inactivation of tumor suppressor genes, loss of chromosomal segments in tumor cells has proven common and useful in mapping regions containing putative tumor suppressor genes. Loss of one homologous chromosomal segment means loss of heterozygosity (LOH) (hemizygous deletion). Microsatellite polymorphic markers consist of CA dinucleotide repeats and often display extensive length polymorphism. LOH on the chromosomes 3, 9, 11 by means of microsatellite markers has been found in squamous cell carcinomas of the head and neck. The radiation-induced malignant fibrous histiocytoma in the head and neck region is rare and grows very rapidly with a poor prognosis. To detect LOH in this cancer, we analysed microsatellite polymorphism in the tumor tissue and peripheral lymphocytes of a patient with radiation-induced malignant fibrous histiocytoma. Fifty-three microsatellite polymorphic markers with corresponding pairs of primers labeled with fluorescent on chromosomes 3, 9 and 11 were used. The respective DNA’s of the cancer cells and normal lymphocytes were amplified with polymerase chain reaction (PCR). We analysed the PCR products on a Model 377 DNA Analysis System (Perkin-Elmer /Applied Biosystems Division) using the GeneScanTM software. LOH was found on one marker of chromosome arm 3p (D3S1300), two markers of chromosome arm 3 q (D3S1262, D3S1311), and one marker of chromosome arm 11p ( D11S922 )

Definition of Three Minimal Deleted Regions Comprehensive Allelotyping and Mutational of Fhit, P16(Ink4a), and P19(Arf) Genes in Nasopharyngeal Carcinoma

BACKGROUND. Recurrent deletion on a chromosomal location in tumor cells can be detected by frequent allelic loss and generally is considered to be an indication of the existence of a tumor suppressor gene (TSG) in the region. In the current study, using fluorescent-labeled, high-density microsatellite markers for allelotyping, the authors pinpointed three minimal deleted regions (MDRs) and screened mutations of putative TSGs on chromosomes 3, 9, and 11 in nasopharyngeal carcinoma (NPC) cases occurring in Taiwan. METHODS. A total of 133 informative microsatellite markers were used on chromosomes 3, 9, and 11 with an average marker density of 4 centimorgans (cM) for the allelotyping of genomic DNAs isolated from NPC tissues and their corresponding lymphocytes in 48 patients. The correlation between allelic loss and the clinicopathologic parameters of NPC tissues was examined. In addition, putative TSGs including FHIT, p16( INK4a), and p19(ARF) were selected for mutation screening to investigate their potential participation in NPC tumorigenesis. RESULTS. Of 3787 informative allelotyping data, 25 frequent allelic losses ( or loss of heterozygosity (LOH]) in 13 cytogenetic loci were identified based on a deletion frequency that was greater than the average of allelic loss on that particular chromosome. Several significant associations were determined after statistical analysis of the correlation between allelic loss and clinicopathologic parameters. The allelic losses by D9S318 and D 11S1304 were associated with N2/N3 (P= 0.035 and P = 0.005, respectively), and those by D9S905 and D11S1304 were associated with grouped American Joint Committee on Cancer (AJCC) Stage III/IV samples (P = 0.022 and P = 0 .017, respectively) of NPC tissues. In addition, three MDRs were revealed on 3p25.3-24.1 (< 19 cM), 3p23-21. 31 (< 9 cM), and 11q22.1-23.2 (< 8 cM). To examine somatic mutations in previously reported TSGs located near these frequent LOH loci, three candidate genes, p16(INK4a), p19' and FHIT, were analyzed. Point mutations in the coding region of FHIT and in the intron 1 splicing acceptor site of both p16(INK4a) and p19(ARF) were detected in NPC cell lines. Sequence analysis of both p16(INK4a) and p19( ARF) transcripts revealed that the point mutation resulted in skipping of exon 2 and the generation of shorter transcripts . CONCLUSIONS. High- density allelotyping permitted the discovery of 3 MDRs on 3p25.3-24.1 (< 19 cM), 3p23-21.31 (< 9 cM), and 11q22.1-23.2 (< 8 cM) and a correlation was determined between allelic loss and clinicopathologic parameters of NPC tissues. More important, one somatic mutation in NPC cell lines on the intron 1/exon 2 splicing acceptor site of the INK4a/ARF locus was found to result in exon 2 skipping both p16(INK4a) and p19(ARF) transcripts, which presumably inactivates the functions of both the p16( INK4a) and p19 (ARF) proteins

Herpes Zoster Oticus Treated with Acyclovir and Prednisolone: Clinical Manifestation and Analysis of Prognostic Factors

Herpes zoster oticus is a cranial polyneuropathy with facial nerve involvement as its main feature. The prognosis of the facial palsy is usually poor. Thirty patients with herpes zoster oticus suffering from facial palsy were admitted for parenteral acyclovir and oral prednisolone. Multiple regression analysis of improvement of facial palsy showed three significant covariates: age, multiple nerve palsies, and the initial grading of the palsy. The recovery of the facial palsy treated with acyclovir and prednisolone was good, and possibility of a good outcome was greater when the initial grade of the palsy was higher. Multiple nerve palsies and age had negative effects on the improvement

Endoscopic Nasopharyngectomy with Potassium-Titanyl-Phosphate (Ktp) Laser for Early Locally Recurrent Nasopharyngeal Carcinoma

Background. Although early recurrent nasopharyngeal carcinoma (NPC) can be treated with surgery alone, conventional nasopharyngectomy still results in serious complications.Endoscopic nasopharyngectomy has been introduced but the treatment outcome of this technique lacks . Methods. Between March 2004 to December 2007, 28 patients with rT1 or rT2a NPC underwent potassium-titanylphosphate( KTP) laser nasopharyngectomy by endoscopic techniques with curative intent. Results. Twenty-five patients received the operation alone. Only 3 patients received postoperative adjuvant therapy. The 2-year local disease-free and 2-year overall survival rates for the 12 patients with rT1 tumor and for the 16 patients with rT2a tumor were 100% and 41.7%( p=0.007); 90.9% and 38. 5% (p=0.03), respectively. Only 3 patients had obvious osteonecrosis at the nasopharynx and one patient developed hypoglossal nerve dysfuction. Conclusions. Endoscopic KTP laser nasopharyngectomy is a simple, safe, and successful procedure for treating rT1 NPC, though its benefits are less clear for rT2 a

Alternative Surgery for Low Grade Thyroid Malignancies

Traditional surgery for thyroid nodule is usually performed via anatomic localization of the recurrent laryngeal nerve (RLN), inferior thyroid artery and parathyroid glands (PTGs) initially. Due to the RLN constantly lying beneath the thyroid gland and low grade malignancy of well-differentiated thyroid cancer (WDTC), it is not necessary to find the nerve initially and impossible to make too deep resection. From May 1998 to July 2005, 33 patients with WDTC underwent total thyroidectomy along the capsule with or without modified radical neck dissection without identifying the RLN and PTGs initially. The isthmus, capsular vessels and Berry's ligament were cut from above and the RLN could be found lying in the surgical bed. The PTGs could be found when the thyroid was retracted medially and removed. The patients were followed-up until December 2007. The safety of the method, complications and clinical outcomes were evaluated. For the patients with WDTC, only one patient (3%) had transient vocal palsy. Incidental parathyroidectomy was found in six (18%) patients, resulting in two (6%) with temporary and two (6%) with permanent hypocalcemia. Only one 86-year-old woman died of disease recurrence; the other patients remained disease-free. Total thyroidectomy for WDTC without identifying the RLN and PTGs initially is an easy and safe alternative method

Identification of Oncogenic Point Mutations and Hyperphosphorylation of Anaplastic Lymphoma Kinase in Lung Cancer12

The oncogenic property of anaplastic lymphoma kinase (ALK) plays an essential role in the pathogenesis of various cancers and serves as an important therapeutic target. In this study, we identified frequent intragenic loss of heterozygosity and six novel driver mutations within ALK in lung adenocarcinomas. Overexpression of H694R or E1384K mutant ALK leads to hyperphosphorylation of ALK, and activation of its downstream mediators STAT3, AKT, and ERK resulted in enhanced cell proliferation, colony formation, cell migration, and tumor growth in xenograft models. Furthermore, the activated phospho-Y1604 ALK was increasingly detected in 13 human lung cancer cell lines and 263 lung cancer specimens regardless of tumor stages and types. Treatment of two different ALK inhibitors, WHI-P154 and NVP-TAE684, resulted in the down-regulation of aberrant ALK signaling, shrinkage of tumor, and suppression of metastasis and significantly improved survival of ALK mutant-bearing mice. Together, we identified that novel ALK point mutations possessed tumorigenic effects mainly through hyperphosphorylation of Y1604 and activation of downstream oncogenic signaling. The upregulated phospho-Y1604 ALK could serve as a diagnostic biomarker for lung cancer. Furthermore, targeting oncogenic mutant ALKs with inhibitors could be a promising strategy to improve the therapeutic efficacy of fatal lung cancers

Secondary Prevention of Esophageal Squamous Cell Carcinoma in Areas Where Smoking, Alcohol, and Betel Quid Chewing are Prevalent

Esophageal cancer is ranked as the sixth most common cause of cancer death worldwide and has a substantial effect on public health. In contrast to adenocarcinoma arising from Barrett's esophagus in Western countries, the major disease phenotype in the Asia-Pacific region is esophageal squamous cell carcinoma which is attributed to the prevalence of smoking, alcohol, and betel quid chewing. Despite a multidisciplinary approach to treating esophageal cancer, the outcome remains poor. Moreover, field cancerization reveals that esophageal squamous cell carcinoma is closely linked with the development of head and neck cancers that further sub-optimize the treatment of patients. Therefore, preventive strategies are of paramount importance to improve the prognosis of this dismal disease. Since obstacles exist for primary prevention via risk factor elimination, the current rationale for esophageal cancer prevention is to identify high-risk groups at earlier stages of the disease, and encourage them to get a confirmatory diagnosis, prompt treatment, and intensive surveillance for secondary prevention. Novel biomarkers for identifying specific at-risk populations are under extensive investigation. Advances in image-enhanced endoscopy do not just substantially improve our ability to identify small precancerous or cancerous foci, but can also accurately predict their invasiveness. Research input from the basic sciences should be translated into preventive measures in order to decrease the disease burden of esophageal cancer