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Hand, foot, and mouth disease (HFMD) and encephalomyelitis were two major clinical manifestations during the 1998 enterovirus 71 (EV71) epidemic in Taiwan. To investigate whether different clinical patterns were caused by alterations in EV71 genomes, the complete nucleotide sequences of four EV71 strains associated with HFMD or encephalomyelitis were compared. Among these viral strains, two or three nucleotide differences were found within the 5'-noncoding region, and two or four amino acid differences were found within the regions encoding viral polyproteins; however, none of these differences were correlated with either clinical manifestation. Because coxsackievirus A16 was another major causative agent of HFMD, a reverse transcription-polymerase chain reaction assay, with high sensitivity and specificity for identification of EV71 (both 100%) and coxsackievirus A16 (100 and 98.8%), was developed for the rapid differential identification of these two viruses in HFMD patients., (Copyright 2001 Wiley-Liss, Inc.)

Chronic suppurative otitis media, averaging 20 or more years of duration, has been associated with cancer in this region in 40%-80% of cases. Although human papillomaviruses (HPV) have been implicated in many human squamous-cell neoplasms, their role in the pathogenesis of middle-ear malignancies remains unexplored. In this study, we investigated the presence and subtypes of HPV in middle-ear carcinomas. Formalin-fixed and paraffin-embedded tumor tissues were sampled for DNA extraction. PCR was done with consensus primers, capable of detecting HPV 16, 18, 31, 33, 52b and 58. Typing of the products generated by consensus primers was performed with restriction enzyme digestion. It was found that a resulting 89% (8/9) of the middle-ear carcinomas contained HPV DNA. Coexistence of HPV 16 and 18 was detected in 3 squamous-cell carcinomas. HPV 16 was detected in 4 squamous-cell carcinomas and 1 adenocarcinoma. The high prevalence of high-risk-type HPV in carcinomas of the middle ear suggests that viral infection may be an important etiologic component in the carcinogenic process.

The Epstein-Barr virus (EBV) is prevalent in nasal and peripheral T-cell lymphoma (NPTL) in Taiwan, where nasopharyngeal carcinoma (NPC) is endemic. In order to understand the pathogenesis of these two malignancies in this endemic area, genomic analysis of EBV in NPTL with comparison to NPC is important. We investigated the EBV subtype (types A and B), BamH-I "f" variant, and the Xho-I site mutant of the latent membrane protein-1 (LMP-1) gene in 19 cases of EBV-associated NPTL and in 30 cases of NPC. EBV DNA from three patients with infectious mononucleosis (IM) was simultaneously studied as representative of normal healthy carriers. Similar to NPC and IM, the EBV in NPTL was found to belong to the type A strain in the majority (18 of 19) of cases by analyzing the 3' divergence of EBNA-2 genes. The extra restriction enzyme site in the BamHI-F region ("f" variant) of EBV DNA was frequently (15 of 30) demonstrated in NPC, but only rarely (1 of 19) was it detected in NPTL and IM (0 of 3). The Xho-I site mutant of the LMP-1 gene previously characterized in Chinese NPC also prevailed in NPTL and IM with an identical nucleotide sequence. No correlation exists between the EBV subtype and its variants. In conclusion, type A EBV is prevalent in Taiwanese NPTL, a finding much distinct from the dominance of type B virus in nonendemic European patients. The EBV genomes in NPTL are closely similar to those in IM or normal healthy carriers, but are distinct from NPC for the infrequency of the "f" variant. The prevalence of the LMP-1 mutant in this endemic region suggests that this EBV strain may confer a growth advantage role in the pathogenesis of these EBV-associated diseases. The rarity of the "f" variant in NPTL and its high frequency in NPC may explain the differential tumorigenesis of different EBV strains.

Human T-cell leukemia virus type I (HTLV-I) is etiologically associated with adult T-cell leukemia/lymphoma (ATL). We cloned and sequenced host DNA adjacent to the long terminal repeats of HTLV-I from uncultured leukemic cells of 4 ATL patients. The region flanking the provirus was generally A/T-rich (60-64% A/T), and a nucleotide composition bias was noticed when sequences within 25 bp on both sides of the integration target site were analyzed. In the 6-bp direct repeat, both end positions are preferentially occupied by G/C, whereas the middle positions are preferentially occupied by A/T. Furthermore, AA or TT dinucleotides are frequently present on each side adjacent to the center of the direct repeat. Our finding suggests preferential integration target sites of HTLV-I in the host genome. Further study is warranted to determine whether each of the target sequence preference is a general property of HTLV-I integration or may be associated with the leukemogenesis of ATL.

An EBV variant has been identified in NPC tissues in Taiwan. This EBV variant contains a point mutation in exon I of the LMP I gene. This mutation results in the loss of an XhoI site at nt 169,426, which is present in strain B95-8. In addition, this variant contains a 30-bp deletion in exon 3 of the gene. The recent demonstration of the prevalence of EBV-containing nasal and peripheral T-cell lymphoma in this region drove us to evaluate the presence of this NPC-EBV strain in 7 cases of T-cell lymphoma, as well as in 48 NPC tissues, 2 cases of Hodgkin's disease and I B-cell lymphoma. Four samples of normal lymph node tissue, 40 of normal nasopharynx tissue and 78 throat washings of healthy individuals were included for comparison. We used sequence-specific primers and the polymerase chain reaction (PCR) method to amplify LMP I gene fragments containing these variations. Mutations were then confirmed by restriction-enzyme digestion and the DNA sequencing analysis. Our results showed that 57 of 58 tumor-tissues samples were EBV-positive. Among them, 56, including 6 T-cell-lymphoma samples, belonged to the NPC strain. This strain of EBV was also present in 92% of EBV-positive normal nasopharynx tissues and in 84% of EBV-positive throat washings of the healthy individuals tested. These results suggest that the NPC-EBV strain is prominently present in Taiwan.

Peripheral T-cell lymphoma (PTL), which is characterized by hepatosplenic presentation and the gamma/delta T-cell receptor (TCR) phenotype on the malignant cells, is a rare but distinct subtype of non-Hodgkin's lymphomas. Little is known about the chromosomal changes in these lymphomas. We report the cytogenetic analysis of three patients who had neoplastic proliferation of T gamma/delta cells in the spleen, bone marrow, and liver, but not in lymph nodes or skin. Isochromosome 7q and trisomy 8 were observed in all three patients. Isochromosome 7q as the sole abnormality has been previously reported in one patient with similar clinicopathologic features. It is suggested that i(7q) is a primary, nonrandom chromosomal abnormality in hepatosplenic T gamma/delta PTL.

We encountered five children with peripheral T-cell lymphoma (PTL) at National Taiwan University Hospital (NTUH) from 1985-1989. The patients were four boys and one girl, aged between 5 and 13 years. The duration of prediagnostic symptoms varied from 1 month to 5 years. All had pyrexia and lymphadenopathy; one had a prolonged history of granulomatosis with repeated infection. Four had hepatosplenomegaly. One patient presented with diffuse pulmonary infiltration and impending respiratory failure. All patients were negative for human T-cell leukemia virus (HTLV)-I antibody, and positive for HBsAg. Four patients who had EBV-viral capsid antigen (VCA) IgG and who were IgM tested were positive for EBV-VCA IgG, but only two had evidence of active EBV infection. Tumor cell markers were examined and showed the following phenotypes: all patients were CD2, CD3, and CD7 positive but CD19 and CD20 negative; three patients were CD4 positive and CD8 negative; the other two patients were CD4 negative and CD8 positive. Four patients died 2-7 months after diagnosis. The remaining patient received allogeneic bone marrow transplantation and has survived free of disease for more than 22 months after transplant. Our five cases reconfirm the high frequency of diagnostic delay, the heterogenous immunophenotypes, high mortality, and poor responsiveness to conventional therapy for PTL. Bone marrow transplantation in the early stage might be a possible cure of this disease.

A serological survey of antibodies to the adult T-cell leukemia virus-associated antigen (HTLV-A) conducted in Taiwan revealed II seropositive individuals among 2,565 serum donors tested, which included 1,187 hospital or free clinic patients, 1,065 blood donors and 313 aborigines. The overall prevalence rate was 0.43% and was 0.90% (9/995) for adults aged 40 years or over, which was similar to the rates observed in the non-endemic areas in Japan. No highly prevalent area was demonstrated. The II seropositive individuals identified were 8 hospital or clinic patients, 1 blood donor and 2 aborigines. Among 108 various leukemia/lymphoma patients also studied, 7 were positive. These 7 anti-HTLV-A-positive patients also had clinicopathologic features of adult T-cell leukemia/lymphoma (ATL). Among 21 relatives of 3 seropositive individuals in the epidemiologic study, 2 were positive; and among 25 relatives of 5 ATL patients, 6 were positive. Our data support the contention that horizontal familial transmission of human T-cell leukemia virus (HTLV-I) is an important route and HTLV-I infection can occur on a different genetic background. Furthermore, the antibody titer did not correlate with the manifestation or the state of the disease.

We report a case of chronic myeloid leukemia with spontaneous splenic rupture as the initial presenting feature; there was a successful surgical outcome, but this case terminated in megakaryoblastic transformation. Results are reported based on morphological, immunological, cytochemical, ultrastructural, immunocytochemical studies, and in vitro liquid culture studies. The megakaryocytic nature of the blast cells was identified through the demonstration of platelet peroxidase activity by ultrastructural cytochemistry and the presence of platelet and megakaryocyte-specific antigen using monoclonal antibody, as well as the anti-factor VIII antibody by immunocytochemical technique.