Ih-Jen Su

Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology

A workshop jointly sponsored by the University of Hong Kong and the Society for Hematopathology explored the definition, differential diagnosis, and epidemiology of angiocentric lymphomas presenting in the nose and other extranodal sites. The participants concluded that nasal T/natural killer (NK) cell lymphoma is a distinct clinicopathologic entity highly associated with Epstein-Barr virus (EBV). In situ hybridization for EBV an be very valuable in early diagnosis, especially if tissue is sparse. The cytologic spectrum is broad, ranging from small or medium-sized cells to large transformed cells. Histologic progression often occurs with time. Necrosis is nearly always present, and angioinvasion by tumor cells is seen in most cases. Nasal T/NK cell lymphoma has a characteristic immunophenotype: CD2-positive, CD56-positive, but usually negative for surface CD3. Cytoplasmic CD3 can be detected in paraffin sections. Clonal T-cell receptor gene rearrangement is not found. Tumors with an identical phenotype and genotype occur in other extranodal sites, most commonly in the skin, subcutis, and gastrointestinal tract, and should be referred to as nasal-type T/NK cell lymphomas. The differential diagnosis includes lymphomatoid granulomatosis, blastic or monomorphic NK cell lymphoma/leukemia, CD56-positive peripheral T-cell lymphoma, and enteropathy-associated T-cell lymphoma.

Tumours of histiocytes and accessory dendritic cells: An immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases

Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases

Clinical and Histological Events Preceding Hepatitis B e Antigen Seroconversion in Chronic Type B Hepatitis

A 60-mo longitudinal study has been undertaken in 99 HBeAg-positive patients with clinicopathologically verified chronic hepatitis. Hepatitis B e antigen clearance occurred in 30 patients at a rate of approximately 17% per year. A phenomenon of abrupt elevation of serum glutamic pyruvic transaminase (greater than 300 IU/L) with histological changes compatible with chronic lobular hepatitis was observed in 13 of 20 patients (65%) preceding spontaneous HBeAg clearance. In contrast, 8 of 10 patients on immunosuppressive or antiviral therapy, or both, had uneventful HBeAg clearance. It was concluded that HBeAg clearance can occur in patients with varying immunologic status. The mechanism responsible for HBeAg clearance awaits further study.

A revisit of prophylactic lamivudine for chemotherapy‐associated hepatitis B reactivation in non‐Hodgkin's lymphoma: A randomized trial

Lamivudine is effective to control hepatitis B virus (HBV) reactivation in HBV‐carrying cancer patients who undergo chemotherapy, but the optimal treatment protocol remains undetermined. In this study, HBV carriers with newly diagnosed non‐Hodgkins lymphoma (NHL) who underwent chemotherapy were randomized to either prophylactic (P) or therapeutic (T) lamivudine treatment groups. Group P patients started lamivudine from day 1 of the first course of chemotherapy and continued treatment until 2 months after completion of chemotherapy. Group T patients received chemotherapy alone and started lamivudine treatment only if serum alanine aminotransferase (ALT) levels elevated to greater than 1.5‐fold of the upper normal limit (ULN). The primary endpoint was incidence of HBV reactivation during the 12 months after starting chemotherapy. During chemotherapy, fewer group P patients had HBV reactivation (11.5% versus 56%, P = 0.001), HBV‐related hepatitis (7.7% versus 48%, P = 0.001), or severe hepatitis (ALT more than 10‐fold ULN) (0 versus 36%, P < 0.001). No hepatitis‐related deaths occurred during protocol treatment. Prophylactic lamivudine use was the only independent predictor of HBV reactivation. After completion of chemotherapy, the incidence of HBV reactivation did not differ between the 2 groups. Two patients, both in group P, died of HBV reactivation–related hepatitis, 173 and 182 days, respectively, after completion of protocol treatment. When compared with an equivalent group of lamivudine‐naïve lymphoma patients who underwent chemotherapy, therapeutic use of lamivudine neither reduced the severity of HBV‐related hepatitis nor changed the patterns of HBV reactivation. Conclusion: Prophylactic lamivudine use, but not therapeutic use, reduces the incidence and severity of chemotherapy‐related HBV reactivation in NHL patients. (HEPATOLOGY 2008;47:844–853.)

Pathogenesis of Enterovirus 71 Brainstem Encephalitis in Pediatric Patients: Roles of Cytokines and Cellular Immune Activation in Patients with Pulmonary Edema

Taiwan experienced several epidemics of enterovirus 71 (EV71) infections, which were associated with brainstem encephalitis (BE) and pulmonary edema (PE). To elucidate the role of immune mechanisms in the pathogenesis of BE caused by EV71 and its fatal complication, PE, we analyzed the laboratory findings, cytokine, and immunophenotypes of 73 EV71-infected patients with BE. Patients were stratified by disease: PE (n=14), autonomic nervous system (ANS) dysregulation (n=25), and isolated BE (n=34). The mortality rate for PE was 64.3%. Leukocytosis and thrombocytosis were significantly more frequent among patients with PE. A significant elevation of plasma interleukin (IL)-10, IL-13, and interferon (IFN)-gamma levels observed in patients with PE. Patients with PE also had lower circulating CD4(+) T cells, CD8(+) T cells, and natural killer (NK) cells. An extensive peripheral and central nervous system inflammatory response with abnormal IL-10, IL-13, and IFN-gamma cytokine production and lymphocyte depletion appears to be responsible for the pathogenesis of EV71-associated PE.

Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle

ABSTRACT Mitochondrial dysfunction in skeletal muscle has been implicated in the development of insulin resistance and type 2 diabetes. Considering the importance of mitochondrial dynamics in mitochondrial and cellular functions, we hypothesized that obesity and excess energy intake shift the balance of mitochondrial dynamics, further contributing to mitochondrial dysfunction and metabolic deterioration in skeletal muscle. First, we revealed that excess palmitate (PA), but not hyperglycemia, hyperinsulinemia, or elevated tumor necrosis factor alpha, induced mitochondrial fragmentation and increased mitochondrion-associated Drp1 and Fis1 in differentiated C2C12 muscle cells. This fragmentation was associated with increased oxidative stress, mitochondrial depolarization, loss of ATP production, and reduced insulin-stimulated glucose uptake. Both genetic and pharmacological inhibition of Drp1 attenuated PA-induced mitochondrial fragmentation, mitochondrial depolarization, and insulin resistance in C2C12 cells. Furthermore, we found smaller and shorter mitochondria and increased mitochondrial fission machinery in the skeletal muscle of mice with genetic obesity and those with diet-induced obesity. Inhibition of mitochondrial fission improved the muscle insulin signaling and systemic insulin sensitivity of obese mice. Our findings indicated that aberrant mitochondrial fission is causally associated with mitochondrial dysfunction and insulin resistance in skeletal muscle. Thus, disruption of mitochondrial dynamics may underlie the pathogenesis of muscle insulin resistance in obesity and type 2 diabetes.

A Mouse-Adapted Enterovirus 71 Strain Causes Neurological Disease in Mice after Oral Infection

ABSTRACT A mouse-adapted enterovirus 71 (EV71) strain with increased virulence in mice, MP4, was generated after four serial passages of the parental EV71 strain 4643 in mice. Strain MP4 exhibited a larger plaque size, grew more rapidly, and was more cytotoxic in vitro than strain 4643. Although strains 4643 and MP4 both induced apoptosis of SK-N-SH human neuroblastoma cells, MP4 was more virulent than 4643 in 1-day-old mice (50% lethal doses, 102 and 104 PFU/mouse, respectively). Strain MP4 (5 × 106 PFU/mouse), but not 4643, could orally infect 7-day-old mice, resulting in rear-limb paralysis followed by death 5 to 9 days after inoculation with the virus. Histopathologically, neuronal loss and apoptosis were evident in the spinal cords as well as the brain stems of the infected mice. The limb muscles displayed massive necrosis. There was early and transient virus replication in the intestines, whereas the spinal cord, brain, and muscle became the sites of viral replication during the late phase of the infection. Virus transmission occurred among infected and noninfected cagemates, as demonstrated by the occurrence of seroconversion and the presence of viable viruses in the stool samples of the latter. Protection against EV71 challenge was demonstrated following administration of hyperimmune serum 1 day after inoculation with the virus. Nucleotide sequence analysis of the genome of EV71 strain MP4 revealed four nucleotide changes on the 5′ untranslated region, three on the VP2 region, and eight on the 2C region, resulting in one and four amino acid substitutions in the VP2 and 2C proteins, respectively.

Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis

Although hepatitis B virus (HBV) has been documented to cause hepatocellular carcinoma (HCC), the exact role of HBV in the development of HCC remains enigmatic. Several hypotheses have been proposed to explain the potential mechanism, including insertional mutagenesis of HBV genomes and transcriptional activators of HBV gene products such as hepatitis B x protein (HBx) and truncated middle S mutants. In the past few years, we have identified two types of large HBV surface antigens (LHBs) with deletions at the pre‐S1 (ΔS1‐LHBs) and pre‐S2 (ΔS2‐LHBs) regions in ground glass hepatocytes. The pre‐S mutant LHBs are retained in the endoplasmic reticulum (ER) and escape from immune attack. The pre‐S mutants, particularly ΔS2‐LHBs, are increasingly prevalent in patients with hepatitis B e antigen (HBeAg)‐positive chronic HBV infection, ranging from 6% before the 3rd decade to 35% in the 6th decade. In HCC patients, the two pre‐S mutants were detected in 60% of HCC patients, in the serum and in HCC tissues. Pre‐S mutant LHBs can initiate ER stress to induce oxidative DNA damage and genomic instability. Furthermore, pre‐S mutant LHBs can upregulate cyclooxygenase‐2 and cyclin A to induce cell cycle progression and proliferation of hepatocytes. In transgenic mice, the pre‐S mutants can induce dysplasia of hepatocytes and development of HCC. In a nested control study, the presence of pre‐S mutants carried a high risk of developing HCC in HBV carriers. In summary, the findings we describe in this review suggest a potential role for HBV pre‐S mutants in HBV‐related hepatocarcinogenesis, providing a model of viral carcinogenesis associated with ER stress. (Cancer Sci 2006; 97: 683–688)

An outbreak of enterovirus 71 infection in Taiwan, 1998: epidemiologic and clinical manifestations

BACKGROUND An outbreak of enterovirus infections occurred throughout Taiwan in 1998. The diseases were manifectated with hand, foot, and mouth disease (HFMD), some associated with meningitis, encephalitis, or acute flaccid paralysis (AFP). OBJECTIVES This study is aimed to characterize and analyze the epidermologic and clinical features during the outbreak. STUDY DESIGN The epidemiologic information was collected from the Ministry of Health on passive surveillance; clinical and virological investigations were carried out at National Cheng Kung University Medical Center. RESULTS Between April and December 1998, 405 children were hospitalized, and 78 patients died during this outbreak in Taiwan. There were 119 cases identified to be EV71 infection in Tainan and Chiayi areas; 105 cases by virus isolation and 14 by serological assay. The outbreak had a biphasic curve with peak in June and October, especially in the southern Taiwan. Seventy-two percent of patients were below 3 years of age. The spectrum of disease included HFMD in 54, HFMD with central nerve system (CNS) involvement in 37, herpangina in 12, aseptic meningitis in three, encephalitis/ meningoencephalitis in ten, acute flaccid paralysis in three. There was nine fatal cases complicated with neurogenic pulmonary edema. Myoclonus with sleep disturbance was the most important early sign of EV71 infection with CNS involvement. CONCLUSION Our experience demonstrated that the EV71 isolated in Taiwan had strong dermatotropic as well as neurotropic tendencies. Early detecting CNS involvement and commencing aggressive therapy may reduce the mortality.

Waning immunity to plasma-derived hepatitis B vaccine and the need for boosters 15 years after neonatal vaccination

Neonatal immunization with hepatitis B (HB) vaccine is highly effective; however, more needs to be learned about the duration of protection and indications for boosters. We measured antibody to HB core antigen (anti‐HBc), HB surface antigen (HBsAg), and pre‐ and postbooster titers of HBsAg antibody (anti‐HBs) 15 years after primary neonatal immunization with plasma‐derived HB vaccines in 2 cohorts of 15‐year‐old children. Group A consisted of 78 children who were born to HB e antigen–positive HBsAg carrier mothers and had developed protective levels of anti‐HBs antibodies (≥10 mIU/mL) following HB immunization. Group B consisted of 113 apparently healthy children whose anti‐HBs titers after vaccination were unknown. Anti‐HBs was undetectable (antibody titer <10 mIU/mL) in 29.9% in group A and 62.4% in group B (P < .001). Anti‐HBc was detected in 33.3 % in group A and 4.4 % in group B (P < .001). After a single booster dose of HB vaccine, 2.7% in group A and 3.3% in group B remained anti‐HBs–negative. A blunted serological response was noted in approximately 20% in both groups. One HBsAg carrier was detected in group A (1.3%) and 4 in group B (3.5%). Fifteen years after neonatal immunization with plasma‐derived HB vaccine, a large proportion of children exhibited waning immunity. This poses the risk of breakthrough infection. A single booster augmented the serological response to the vaccine in most but not all subjects. In conclusion, our findings suggest that one or more booster immunizations are needed in seronegative subjects by at least 15 years following neonatal immunization with plasma‐derived HB vaccine. (HEPATOLOGY 2004;40:1415–1420.)