Initial staging by positron emission tomography/computed tomography (PET/CT) scanning is recommended for patients with diffuse large B-cell lymphoma (DLBCL). Whether both PET/CT and bone marrow ...biopsy (BMB) are required remains unclear. This study examined whether staging by PET/CT is sufficient. Participants with untreated DLBCL assessed using both PET/CT and BMB were included. Patients received independent diagnostic assessments from a radiologist and a hematopathologist. Both hematoxylin–eosin staining and CD20 immunostaining were performed to determine the bone marrow involvement in BMB. A total of 84 patients were included. The number of patients with positive bone marrow involvement identified by PET/CT and BMB was 16 (19%) and 22 (26%), respectively. Eight (10%) patients showed positive results in both tests. When considering BMB as a reference, PET/CT showed 36% sensitivity and 87% specificity, with positive and negative predictive values of 50% and 79%, respectively. BMB-positive patients had shorter progression-free (PFS) and overall (OS) survival than their BMB-negative counterparts. Compared to PET/CT-negative patients, patients with positive results did not show any significant differences in PFS and OS. However, among 16 PET/CT-positive patients, poor PFS and OS were observed among patients who were also BMB positive. BMB remains a mandatory step in staging of untreated DLBCL patients.
Systemic chronic active Epstein-Barr virus disease (sCAEBV) is a rare and fatal neoplasm, involving clonally proliferating Epstein-Barr virus (EBV)-infected T cells or natural killer cells. Patients ...with sCAEBV have abnormal titers of anti-EBV antibodies in their peripheral blood, but their significance is unknown. We retrospectively investigated titers and their relationship with the clinical features of sCAEBV using the data collected by the Japanese nationwide survey. Eighty-four patients with sCAEBV were analyzed. The anti-EBV nuclear antigen (EBNA) antibody, targeting EBNA-expressing EBV-positive cells, was found in 87.5% of children (<15 years old), 73.7% of adolescents and young adults (15-39 years old), and 100% of adults (≥40 years old). Anti-EBNA antibody titers were significantly lower and anti-VCA-IgG antibody titers significantly higher in patients with sCAEBV than those in healthy controls (
< 0.0001). Patients with high anti-VCA-IgG and anti-early antigen-IgG antibody (antibodies against the viral particles) levels had significantly better 3-year overall survival rates than those with low titers, suggesting that patients with sCAEBV have a reduced immune response to EBV-infected cells.
Epstein-Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, ...systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.
Activation‐induced cell death (AICD) mediated by the Fas/Fas ligand (FasL) system plays a key role in regulating immune response. Although normal natural killer (NK) cells use this system for their ...homeostasis, malignant NK cells seem to disrupt the process. Extranodal NK/T‐cell lymphoma, nasal type (ENKL) is a rare but fatal disease, for which novel therapeutic targets need to be identified. We confirmed that ENKL‐derived NK cell lines NK‐YS and Hank1, and primary lymphoma cells expressed procaspase‐8/FADD‐like interleukin‐1β‐converting enzyme (FLICE) modulator and cellular FLICE‐inhibitory protein (c‐FLIP), along with Fas and FasL. Compared with Fas‐sensitive Jurkat cells, NK‐YS and Hank1 showed resistance to Fas‐mediated apoptosis in spite of the same expression levels of c‐FLIP and the death‐inducing signaling complex (DISC) formation. Unexpectedly, the long isoform of c‐FLIP (c‐FLIPL) was coimmunoprecipitated with Fas predominantly in both ENKL‐derived NK cell lines after Fas ligation. Indeed, c‐FLIPL was more sufficiently recruited to the DISC in both ENKL‐derived NK cell lines than in Jurkat cells after Fas ligation. Knockdown of c‐FLIPL per se enhanced autonomous cell death and restored the sensitivity to Fas in both NK‐YS and Hank1 cells. Although ENKL cells are primed for AICD, they constitutively express and efficiently utilize c‐FLIPL, which prevents their Fas‐mediated apoptosis. Our results show that c‐FLIPL could be a promising therapeutic target against ENKL.
Extranodal natural killer (NK)/T‐cell lymphoma, nasal type (ENKL)‐derived NK cells are primed for activation‐induced cell death (AICD) like activated normal NK cells. ENKL‐derived NK cells efficiently recruit the long isoform of c‐FLIP to the death‐inducing signaling complex and show resistance to AICD.
Background: Systemic chronic active Epstein-Barr virus infection (sCAEBV) is a rare and fatal lymphoid neoplasm characterized by sustained systemic inflammation and clonal proliferation of ...EBV-infected T or NK cells. Because the mechanisms responsible for the development of the disorder have not been elucidated to date, its optimal chemotherapy has not been established, and the prognosis of sCAEBV has remained very poor. We previously found and reported that simvastatin, an inhibitor of HMG-CoA reductase, inhibits prenylation of intracellular signal-mediating molecules in adult T-cell lymphoma/leukemia cells. On the basis of these findings, we hypothesized that simvastatin could also induce apoptosis in EBV-positive T or NK cells from sCAEBV.Methods: We examined two clinical samples of EBV-positive T-cell lines derived from sCAEBV, SNT8 and SNT15. The samples were obtained from six patients with sCAEBV. The in vitro effects of simvastatin on the cells were examined by XTT and Annexin V assay, and the in vivo effects of simvastatin on sCAEBV were examined in xenograft models of sCAEBV generated from NOD/Shi-scid/IL-2Rγnull mice.Results: Simvastatin suppressed proliferation and induced apoptosis in the cell lines in a dose-dependent manner. Simvastatin also suppressed proliferation and induced apoptosis of peripheral blood mononuclear cells derived from patients with sCAEBV with infected cell types of CD4 in 3 patients, CD8 in 2 patients, and CD56 in 1 patient. The presence of farnesyl pyrophosphate, one of the intermediates in the mevalonate pathway, restored the number of viable SNT8 and SNT15 cells treated with simvastatin. Furthermore, oral administration of simvastatin reduced EBV-DNA in the peripheral blood of sCAEBV xenograft models.Conclusions: Simvastatin may be an attractive reagent for sCAEBV.
We performed a retrospective analysis of patients with adult-onset chronic active Epstein–Barr virus infection (CAEBV). First, we analyzed five patients (aged 28–72) diagnosed at our hospitals with ...EBV-infected clonally proliferating T cells. Four patients were administered cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy, but no remarkable decrease of viral load was observed in three of the patients. The other patient died 19 days after initiation of CHOP treatment due to disease progression. Addition of high-dose cytarabine to the regimens of two of the patients was discontinued shortly after administration, due to the development of grade 4 pericardial effusion. Together, these regimens may be insufficient for treating adult-onset CAEBV. We next reviewed 23 adult-onset CAEBV patients, adding 18 previously reported patients to the five patients described in the present study. T cells were frequently infected (87%), whereas NK- and T-cell types are known to be almost equally prevalent in childhood-onset cases. The time duration from the onset of disease to initiation of treatment averaged 20 months. Reports showed that 12 patients died; seven patients died at an average of 8 months after initiation of treatment. Patients’ disease courses seemed to be rapidly progressive and more aggressive than those of childhood-onset cases. More cases must be studied to clarify clinical features and establish an optimal treatment strategy.
The effects of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) on systemic chronic active Epstein–Barr virus infection (sCAEBV) are yet to be analyzed in a large number of patients. ...Using the Japanese registry database, Transplant Registry Unification Management Program, we investigated the outcomes of 102 sCAEBV patients who underwent allo‐HSCT. The median age at HSCT was 21 years, and the three‐year overall survival (3‐year OS) rate was 72.5%. Of the 90 patients whose viral load after allo‐HSCT was evaluated, 56 (62.2%) achieved a virological complete response, defined by the complete resolution of disease activity with a significant decrease in EBV‐DNA in peripheral blood. The multivariate Cox proportional hazard model indicated that advanced age, in adolescents and young adults (AYA) (age, 15–39) and adults (age, ≥40 years) was a risk factor of poor OS. The hazard ratios (HRs) of the AYA and adult groups were 10.87 (95% confidence interval CI: 1.98–59.56, p = .006) and 15.93 (95% CI: 2.45–103.8, p = .004), respectively. Disease activity (HR 5.74), elevated soluble IL‐2 receptor (sIL‐2R) (≥ median, 691 U/mL) at HSCT (HR 6.93), and conditioning without radiotherapy (HR 3.53) were also independently associated with poor survival. Notably, 79% of radiotherapy doses were less than 6 Gy. Regardless of the presence of hemophagocytic lymphohistiocytosis, the group with a high sIL‐2R level (≥2000 U/mL) showed a poorer prognosis. Although allo‐HSCT is the only curative therapy for sCAEBV, treatment strategies need to be improved for high‐risk patients, especially those with high levels of sIL‐2R.
The combination of microvascular invasion and PSA levels before salvage radiation therapy (SRT) may provide a better way to stratify the risk of biochemical recurrence after SRT.
Abstract
Objectives
...The aim of this study was to identify risk factors to predict a biochemical recurrence (BCR) in patients treated with salvage radiation therapy (SRT) after radical prostatectomy (RP).
Methods
We retrospectively reviewed 122 Japanese patients who received SRT for BCR after RP. Using uni- and multivariate Cox proportional hazard models, we identified the predictive factors of BCR after SRT.
Results
With a median follow-up of 61.3 months, 45.9% of the patients showed BCR after SRT, with 61.5 and 41.8% of non-BCR rates at the second and fifth years. Univariate proportional hazards analysis demonstrated that extraprostatic disease (P = 0.029), seminal vesicle invasion (P = 0.005), microvascular invasion (P = 0.001), postoperative Gleason score (P = 0.008) and pre-SRT prostate-specific antigen (PSA) (P = 0.005) were significantly associated with BCR after SRT. However, only the presence of microvascular invasion and a higher pre-SRT PSA were significant predictors in the multivariate analysis. The non-BCR rate in the second year after SRT for 15 patients with microvascular invasion and pre-SRT PSA > 1.2 ng/ml was only 21% compared to 72.5% of 72 patients with negative microvascular invasion and a pre-SRT PSA of <1.2 ng/ml (P = 0.000031).
Conclusions
While SRT is the most important secondary treatment option for patients with BCR after RP, the effectiveness of SRT may not be uniform. The combination of risk factors such as microvascular invasion in RP specimens and pre-SRT PSA may provide a better way to stratify the risk of BCR after SRT.
Systemic chronic active Epstein-Barr virus infection (sCAEBV) is an EBV-positive T- or NK-cell neoplasm revealing persistent systemic inflammation. Twenty-five percent of sCAEBV patients accompany ...angiopathy. It is crucial to clarify the mechanisms of angiopathy development in sCAEBV because angiopathy is one of the main causes of death. Interleukin-1β (IL-1β) is reported to be involved in angiopathy onset. We investigated if IL-1β plays a role as the inducer of angiopathy of sCAEBV. We detected elevated IL-1β levels in four out of 17 sCAEBV patient's plasma. Interestingly, three out of the four had clinically associated angiopathy. None of the other patients with undetectable level of IL-1β had angiopathy. In all patients with high plasma levels of IL-1β and vascular lesions, EBV-infected cells were CD4-positive T cells. In one patient with high plasma IL-1β, the level of
mRNA of the monocytes was 17.2 times higher than the level of the same patient's EBV-infected cells in peripheral blood. In Ea.hy926 cells, which are the models of vascular endothelial cells, IL-1β inhibited the proliferation and induced the surface coagulation activity. IL-1β is a potent biomarker and a potent therapeutic target to treat sCAEBV accompanying angiopathy.
To report 2 cases of bilateral granulomatous panuveitis accompanied by chronic active Epstein-Barr virus infection (CAEBV).
Case 1 was a 38-year-old man who had a history of bilateral mild panuveitis ...who was diagnosed with CAEBV. Fifteen months later, a severe bilateral granulomatous panuveitis developed. White infiltrates covered the optic disc and all the retinal vessels of the right eye, and white nodules were seen along the retinal veins and arteries of the left eye. Case 2 was a 34-year-old man with bilateral panuveitis showing mutton-fat keratic precipitates and diffuse vitreous opacity in both eyes. A snow ball-like vitreous opacity was present in the right eye. Systemic investigations revealed the presence of CAEBV. In both cases, a comprehensive polymerase chain reaction (PCR) analyses of the aqueous humor detected significant copy numbers of EBV-DNA. The intraocular inflammation did not respond to steroid, methotrexate, and other immunosuppressive therapies, but was ameliorated after hematopoietic stem cell transplantation with preceding chemotherapy and low-dose total body irradiation in both cases.
Granulomatous panuveitis can develop in eyes with CAEBV as a primary symptom. Ophthalmologists should rule out CAEBV when EBV-DNA is positive in the intraocular fluids of steroid-resistant panuveitis.
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