Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors.

We investigated the possibility of using a pharmacologic agent to modulate viral gene expression to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [(125)I]2'-fluoro-2'-deoxy-beta-D-5-iodouracil-arabinofuranoside ([(125)I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [(131)I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK. With naturally infected EBV tumor cell lines (Burkitt's lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposi's sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.

KSHV- and EBV-associated germinotropic lymphoproliferative disorder.

Kaposi sarcoma-associated herpesvirus (KSHV) is known to be associated with 3 distinct lymphoproliferative disorders: primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and MCD-associated plasmablastic lymphoma. We report 3 cases of a previously undescribed KSHV-associated lymphoproliferative disorder. The disease presented as localized lymphadenopathy and showed a favorable response to chemotherapy or radiotherapy. Histologically, the lymphoproliferation is characterized by plasmablasts that preferentially involved germinal centers of the lymphoid follicles, forming confluent aggregates. They were negative for CD20, CD27, CD79a, CD138, BCL6, and CD10 but showed monotypic kappa or lambda light chain. Clusters of CD10(+)CD20(+) residual follicle center cells were identified in some of the follicles. The plasmablasts were positive for both KSHV and EBV, and most of them also expressed viral interleukin-6 (vIL-6). Unexpectedly, molecular analysis of whole tissue sections or microdissected KSHV-positive aggregates demonstrated a polyclonal or oligoclonal pattern of immunoglobulin (Ig) gene rearrangement. The plasmablasts showed somatic mutation and intraclonal variation in the rearranged Ig genes, and one case expressed switched Ig heavy chain (IgA), suggesting that they originated from germinal center B cells. We propose calling this distinctive entity "KSHV-associated germinotropic lymphoproliferative disorder."

[Highly malignant T-cell non-Hodgkin lymphoma (nasal type) of the hard palate]. / Hochmalignes T-Zell-Non-Hodgkin-Lymphom (nasal type) des harten Gaumens.

The monomorphic clinical aspect of destructive mid-face lesions is characterised by inflammation, induration and granulomatous transformation. This feature can be caused by various infections, toxical noxa, Wegener's Granulomatosis and different neoplasms. The case of a 19 year old patient with EBV associated nasal type T-cell lymphoma located at the hard palate is presented. The diagnostic approach and difficulties in diagnosing this entity assessing by using multiple biopsies, serological and molecularbiological detection of EBV association and immunohistochemistry for atypic T-cells are elucidated. In the presented case the treatment with chemotherapy and irradiation following a well-defined therapy concept leaded to a three year recurrence-free survival so far. The comparison of the key-histological findings and the major differential diagnoses is mandatory to establish the final diagnosis of lymphoma. This is the basement for treating this disease with combined chemotherapy and irradiation for optimizing survival.

Primary ocular Epstein-Barr virus-associated non-Hodgkin's lymphoma in a patient with AIDS: a clinicopathologic report.

OBJECTIVE: To report an unusual case of chronic multifocal chorioretinitis with vitritis in a patient with acquired immunodeficiency syndrome (AIDS) that was resistant to antiviral and antitoxoplasmic medication and required a retinal biopsy for definitive diagnosis. METHODS: Vitreous biopsy, pars plana vitrectomy, and retinal biopsy were performed. The vitreous biopsy material was sent for bacterial, fungal, and viral culture, and the vitreous cassette was sent for cytology. The retinal biopsy material was divided and sent for polymerase chain reaction testing for toxoplasmosis and virology and pathologic tissue analysis. RESULTS: Vitreous cytology showed a mixed population of lymphocytes and histiocytes, but all other microbiologic and virologic studies were negative. Tissue analysis revealed an infiltrate of atypical mononuclear cells extending from the inner limiting membrane through the outer plexiform layer characteristic of a B cell, non-Hodgkin's lymphoma of the central nervous system (NHL-CNS). In situ hybridization for the Epstein-Barr virus (EBV) was positive. An extensive systemic evaluation did not show evidence of extraocular tumor. CONCLUSION: Although rare, primary ocular NHL-CNS can be seen in patients with AIDS, and its clinical presentation often closely resembles other disorders. To our knowledge, this case represents the first ocular NHL in which EBV is shown to be associated.

Prognostic value of anti-Epstein-Barr virus antibodies in nasopharyngeal carcinoma (NPC).

INTRODUCTION: Epstein-Barr virus (EBV) is a ubiquitous human herpes virus with worldwide infection. It is associated with Burkitt's lymphoma in Africa and nasopharyngeal cancer (NPC) in Asian countries. EBV-coded DNA was found to be present in epithelial elements of NPC, and is usually associated with non-keratinizing (WHO type II) or undifferentiated carcinoma (WHO type III). Transcriptional analyses of EBV genome expression in NPC demonstrate an activated viral state in some of these tumors, leading to elevated levels of serum anti-viral capsid antigen (VCA) antibody in NPC patients. METHODS: Eighty patients with histological diagnoses of NPC according to the 1978 WHO classification were referred to the Department of Radiation Oncology at Chang-Hua Christian Hospital for curative radiotherapy from 1985 to 1995. The patients were staged according to the AJCC staging system. A mean dose of 7,020 cGy in 39 fractions was delivered to the primary tumor using a telecobalt-60 unit or 6-10 MV X-ray linear accelerator. Pre- and postradiotherapy serum levels of anti-EBV/VCA IgG and IgA were determined for all patients using the indirect immunoperoxidase assay (IPA). Multivariate analysis was done to determine which factors affected the patients' treatment outcome and survival. RESULTS: Five patients were excluded from this study due to incomplete radiotherapy, leaving 75 patients eligible for analysis. Overall local control was 77.3%, with a mean disease-free interval of 19.7 months. Factors affecting local control included radiation dose and pretreatment anti-EBV/VCA IgG titer. The overall 5-year actuarial survival for the 75 patients was 75%, with a median survival of 129.5 months. The 5-year actuarial survival rates for stage I + II, III, and IV patients were 90%, 40%, and 45%, respectively. Prognostic factors for survival included tumor histological type and pretreatment anti-EBV/VCA IgA titer, while prognostic factors for local control included total radiation dose received and pretreatment anti-EBV/VCA IgG titer. CONCLUSION: We found that there was a significant difference in the geometric mean titer of anti-EBV/VCA IgA antibodies before and after radiotherapy. Prognostic factors affecting NPC patients' actuarial survival included tumor histology and pretreatment IgA titer, while prognostic factors for local control of NPC included total radiation dose received and pretreatment IgG titer.

A comparative study of undifferentiated nasopharyngeal carcinoma treated with radiotherapy or combined treatment with zorubicin-cisplatin and radiotherapy.

Undifferentiated nasopharyngeal carcinoma has been related to the Epstein-Barr virus. These tumors are known to be radiosensitive and chemosensitive. While radiotherapy (RT) allows for a high rate of local control, 80% of all patients die from or with metastatic spread. This study analyzed 61 patients treated with RT alone and 28 treated with zorubicin (ZRB)-cisplatin (CDDP) and RT between 1977 and 1990. All patients treated with RT received 60-74 Gy in 6-7 weeks. Patients treated with combined therapy received ZRB 250 mg/m2 on the 1st day and CDDP 30 mg/m2 from the 2nd to 5th day. The interval between cycles was 4 weeks. Following treatment with chemotherapy patients were then given RT. The 5-year survival rate was 20% for patients with T1 and T2 tumors when treated with RT alone and 54% when treated with chemotherapy (CT). This was 25% for T3 and T4 lesions with RT only and 27% for RT with CT. Survival of patients with N0 and N1 lesions was 41% after RT and 60% after RT with CT. This decreased to 10% for N2 and N3 lesions treated with RT and 30% with RT and CT.