Late onset of hepatitis B virus reactivation following hematopoietic stem cell transplantation: successful treatment with combined entecavir plus tenofovir therapy.

Prophylaxis with lamivudine (LAM) is recommended for hepatitis B core antibody-positive allogenic hematopoietic stem cell transplant (HSCT) recipients, but the optimal timing for the institution and duration of the prophylaxis is still unknown. Furthermore, considering the high rate of mortality associated with hepatitis B virus reactivation (HBV-R), the most potent and long-term effective antiviral regimen should be considered. We report here a case of late onset of HBV-R after a long-term prophylaxis with LAM in a patient who underwent HSCT for non-Hodgkin lymphoma and who was successfully treated with a combination antiviral regimen including entecavir and tenofovir disoproxil fumarate.

Immune reconstitution inflammatory syndrome associated with Aspergillus terreus pulmonary infection in an autologous stem cell transplant recipient.

We describe an autologous stem cell transplant recipient who developed immune reconstitution inflammatory syndrome (IRIS) associated with Aspergillus terreus invasive pulmonary infection after recovery from neutropenia. Clinical and radiological worsening of pulmonary invasive aspergillosis coincident with a robust decline of serum galactomannan values and rising neutrophil counts should be interpreted as IRIS and should not require changes to antifungal therapy.

Chylous ascites secondary to B-cell non Hodgkin's lymphoma in a patient with the acquired immune deficiency syndrome (AIDS).

In the present article we describe a patient with AIDS and chylous ascites secondary to B-cell non Hodgkin's lymphoma. A 43 years old homosexual HIV-positive man. Complained of abdominal fullness, diarrhea and a rapidly increase in abdominal girth of 1 week duration. A diagnostic paracentesis was performed and revealed a milky fluid with high triglyceride levels. All blood tests and analysis of the peritoneal fluid with polymerase chain reaction for DNA sequence of broad-range bacterial Post Voiding Residual volume, Mycobacterium tuberculosis, Kaposi Sarcoma associated Herpes virus and Epstein Barr Virus were negative. CT scan did not demonstrate any evidence for cancer. An exploratory laparotomy was thus performed. A mass spreading along the mesenteric route to the omentum was found and a debulking resection was performed. The final pathology report was of diffuse, CD20-positive, CD3-negative, Epstein Barr Virus-negative, large B-Cell non Hodgkin's lymphoma. Subsequently, he underwent five cycles of CHOP (cyclofosfamide, doxorubicin, vincristin, prednison) chemotherapy with further partial regression of the abdominal tumour. Five months after the initial diagnosis of lymphoma, the patient relapsed and was treated with high-dose BEAM (carmustine, etoposide, cytosine, arabinoside, melphalan) chemotherapy followed by CD34 stem-cell transplantations salvage therapy. This notwithstanding, the patient died due to intestinal secondary to tumor relapse 2 months later.

Treatment of advanced mycosis fungoides by allogeneic stem-cell transplantation with a nonmyeloablative regimen.

SUMMARY: Given the poor prognosis of patients with advanced cutaneous T-cell lymphoma and the high transplant-related mortality associated with conventional allogeneic bone marrow transplantation, we performed nonmyeloablative transplantation of allogeneic stem cells (ASCT) from HLA-identical siblings in three patients with this disease. All patients achieved full donor engraftment, clearance of clonal T cells leading to durable complete remissions but experienced high incidence of infections, which proved fatal in one case. These results suggest that nonmyeloablative ASCT is a novel and potentially curative therapy for patients with advanced T-cell lymphomas who have a histocompatible sibling.

Long-term remission of Kaposi sarcoma-associated herpesvirus-related multicentric Castleman disease with anti-CD20 monoclonal antibody therapy.

Kaposi sarcoma-associated herpesvirus (KSHV)-related multicentric Castleman disease (MCD) is potentially lethal. Growing evidence indicates that, as in Epstein-Barr virus-driven lymphoproliferative disorders after transplantation, KSHV DNA burden in peripheral blood mononuclear cells (PBMCs) may represent the most accurate marker of disease activity. This report describes a patient with human immunodeficiency virus who was followed up clinically and by quantitative polymerase chain reaction for KSHV DNA sequences in PBMCs for more than 3 years following the diagnosis of KSHV-related MCD. Therapy with the antiherpesvirus agent cidofovir, antihuman interleukin-6 antibody BE-8, antiblastic chemotherapy, and combination antiretroviral agents did not achieve durable clinical or virologic remission of the disease. By contrast, administration of the anti-CD20 monoclonal antibody rituximab was well tolerated and allowed a 14-month remission of clinical symptoms and KSHV viremia. Rituximab should be added to the therapeutic armamentarium for KSHV-related MCD.

Human herpesvirus 8 DNA in the skin and blood of patients with Mediterranean Kaposi's sarcoma: clinical correlations.

BACKGROUND: Kaposi's sarcoma is a multifocal lympho-angioproliferative disease that appears in elderly subjects of Mediterranean origin (classical form), young Africans and immunodepressed patients (as a result of organ transplantation or AIDS). In 1994, DNA sequences of a new human herpesvirus, called HHV-8, were detected in skin lesions and peripheral blood of patients with AIDS-related Kaposi's sarcoma by confirmational display analysis and polymerase chain reaction. OBJECTIVE: As HHV-8 in peripheral blood mononuclear cells is detected in about 50% of Mediterranean Kaposi's sarcoma patients and its presence fluctuates in time in the same patient, maybe its detection correlates with the clinical behaviour of the disease. METHODS: By using routine and nested polymerase chain reaction we evaluated the presence of HHV-8-specific DNA sequences in the skin lesions, perilesional healthy skin and peripheral blood mononuclear cells of a group of 40 HIV-negative patients with Mediterranean Kaposi's sarcoma. RESULTS: HHV-8 DNA sequences have been found in 40/40 (100%) lesional skin of Mediterranean Kaposi's sarcoma, in 35/40 (85%) perilesional apparently normal skin and in 24/40 (60%) peripheral blood monuclear cell samples. The results of polymerase chain reaction on peripheral blood monuclear cells were positive in 41% of the patients with slowly evolving disease as opposed to 74% of those with rapidly evolving disease, and in 47.6% of the patients with stage I-II disease as opposed to 73.6% of those with stage III-IV. CONCLUSION: The detection of HHV-8 in peripheral blood monuclear cells seems to correlate with the more aggressive stages and the rapid evolution behaviour of Mediterranean Kaposi's sarcoma.

Activation of latent Kaposi's sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator.

Kaposi's sarcoma-associated herpesvirus (KSHV) is strongly linked to Kaposi's sarcoma, primary effusion lymphomas, and a subset of multicentric Castleman's disease. The mechanism by which this virus establishes latency and reactivation is unknown. KSHV Lyta (lytic transactivator, also named KSHV/Rta), mainly encoded by the ORF 50 gene, is a lytic switch gene for viral reactivation from latency, inasmuch as it is both essential and sufficient to drive the entire viral lytic cycle. Here we show that the Lyta promoter region was heavily methylated in latently infected cells. Treatment of primary effusion lymphoma-delivered cell lines with tetradecanoylphorbol acetate caused demethylation of the Lyta promoter and induced KSHV lytic phase in vitro. Methylation cassette assay shows demethylation of the Lyta promoter region was essential for the expression of Lyta. In vivo, biopsy samples obtained from patients with KSHV-related diseases show the most demethylation in the Lyta promoter region, whereas samples from a latently infected KSHV carrier remained in a methylated status. These results suggest a relationship among a demethylation status in the Lyta promoter, the reactivation of KSHV, and the development of KSHV-associated diseases.

Differential viral protein expression in Kaposi's sarcoma-associated herpesvirus-infected diseases: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease.

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is linked to KS, primary effusion lymphomas (PEL), and a subset of multicentric Castleman's disease (MCD). Transcript mapping studies using PEL cell lines have allowed preliminary classification of viral gene expression into constitutive (class I) and inducible (class II/III) categories. To determine whether viral gene expression differs in vivo, we examined tissue sections of KSHV-infected disorders, using specific antibodies against proteins that are representative of the different expression classes of KSHV genes. ORF73/LANA appears to be a surrogate marker for KSHV infection because it is constitutively expressed in vitro and in vivo in all KSHV-infected cells. Expression of vIRF1, vIL6, and PF-8 proteins in the infected B cells of MCD lymph nodes reproduces the expression pattern observed in TPA-stimulated KSHV-infected B-cell lines. In contrast, the protein expression of the inducible viral genes that we tested in KS and PEL biopsies is restricted to PF-8 and vIL6, respectively. The tightly restricted expression of KSHV proteins in vivo differs from the dysregulated expression of inducible KSHV genes in vitro and suggests that viral gene expression in KSHV-infected cell lines does not accurately reflect what occurs in diseased tissues. These differences may be related to either cell-specific or immune restriction of viral replication.

Lymphangiosarcoma of the pubic region: a rare complication arising in congenital non-hereditary lymphedema.

Lymphangiosarcoma is a rare, aggressive, vascular neoplasm arising in chronic congenital or acquired lymphedema. Although it is most frequently associated with post-mastectomy lymphedema (Stewart-Treves's syndrome), lymphangiosarcoma can exceptionally arise in congenital hereditary lymphedema (Milroy's syndrome and Meige's syndrome) and non-hereditary lymphedema (congenital, praecox or forme tarde lymphedemas). We report a case of lymphangiosarcoma of the pubic region, supported by immunohistochemical studies, in a 42-year-old woman affected by congenital, non-hereditary lymphedema of the left genital region and homolateral lower limb. In addition, molecular analysis demonstrated the absence of Kaposi's sarcoma-associated Herpes virus (KSHV) DNA sequences in tumour lesions. To our knowledge, this is the first case of lymphangiosarcoma associated with congenital non-hereditary lymphedema confined to the pubic region. The literature concerning the cases of lymphangiosarcoma arising in congenital hereditary and non-hereditary lymphedema is reviewed. Moreover, we emphasized the importance of regular clinical controls in all patients affected by chronic lymphedema. In fact, although the prognosis of this neoplasm is very poor, a prompt diagnosis and a rapid, ablative surgery associated with radiation therapy can increase the possibility of survival of these patients.

Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman's disease.

Castleman's disease is a rare B cell lymphoproliferative disorder related to excess interleukin-6 (IL-6)-like activity. Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8), which encodes a functional cytokine (vIL-6), has been found in some patients with Castleman's disease. Lymph nodes from 14 HIV-seronegative Castleman's disease patients were compared to hyperplastic lymph nodes from 25 HIV-seronegative patients as well as Kaposi's sarcoma lesions from 48 patients for KSHV infection and vIL-6, human IL-6, and Epstein-Barr virus EBER expression. While all Kaposi's sarcoma tissues examined were polymerase chain reaction-positive and all control lymph nodes were polymerase chain reaction-negative for KSHV, none had detectable vIL-6 expression. Six of 14 (43%) Castleman's tissues were positive for KSHV by polymerase chain reaction and all 6 had evidence of vIL-6 expression by immunohistochemistry. vIL-6-positive Castleman's disease patients generally had the multicentric plasma cell variant form of the disease and had a rapidly fatal clinical course frequently associated with autoimmune hemolytic anemia and gammopathy. In contrast, 7 (88%) of the 8 vIL-6-negative Castleman's disease patients had localized disease and have remained disease-free after therapy. KSHV vIL-6 expression appears to be limited to hematopoietic cells and is not present in Kaposi's sarcoma spindle cells. These data suggest that Castleman's disease is a syndrome of multiple etiologies involving aberrant IL-6 activity from either endogenous or viral sources.

Risk of Kaposi's sarcoma-associated herpes virus transmission from donor allografts among Italian posttransplant Kaposi's sarcoma patients.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly discovered herpes virus found in all forms of Kaposi's sarcoma (KS) including KS among immunosuppressed transplant patients. It is unknown whether this virus is transmitted by organ transplantation or is reactivated during immunosuppression among those patients infected before transplantation. To investigate the risk of KSHV transmission during organ transplantation, we conducted a case-control study of transplant recipients with and without KS matched to their respective donors. Sera were collected at time of transplantation and tested in a randomized and blinded fashion using four KSHV serologic assays testing for antibodies to both latent and lytic phase antigens. Ten (91%) of 11 organ recipients who developed KS were seropositive prior to transplantation by one or more of the assays compared with two (12%) of 17 control organ recipients (OR = 75, 95% CI = 4.7, 3500). KS cases were more likely to have been born in southern Italy where KS is endemic than the recipient controls or either donor group. Only four (36%) of 11 donors to case patients and three (18%) of 17 donors to control patients were seropositive (P = .38, two-tailed Fisher's exact test). KSHV transmission could not be ruled out for the single KS patient seronegative at transplantation and clear evidence for organ-related transmission was found for another KS patient outside of the case-control study. Antibodies to KSHV are detectable in the sera from most transplant recipients before initiation of immunosuppressive treatment suggesting that KS among immunosuppressed transplant patients is primarily due to virus reactivation. KSHV transmission, however, from an infected allograft can occur, and our study reports the first documented case of person-to-person transmission of KSHV.

Simultaneous onset of primary cutaneous B-cell lymphoma and human herpesvirus 8-associated Kaposi's sarcoma.

We report the simultaneous occurrence of Kaposi's sarcoma (KS) and primary cutaneous B-cell lymphoma (CBCL) of the leg in a 79-year-old woman, seronegative for HIV-1, HTLV-1 and HTLV-2. The CBCL underwent complete clinical remission after local radiotherapy, whilst the KS became disseminated within a year following diagnosis. However, 2 years after the diagnosis of KS, the patient died with neurological symptoms. These were presumed to be due to involvement of the central nervous system by lymphoma, although in the absence of an autopsy, this could not be proven. Skin biopsies from the original KS and CBCL lesions, as well as short-term culture of spindle cells from the KS lesion and peripheral blood mononuclear cells (PBMC), were studied by semiquantitative polymerase chain reaction (PCR) using primers specific for DNA sequences of a novel gamma-herpesvirus-8 (HHV-8). PCR studies were strongly positive for the virus on KS cells and PBMC; conversely, a low viral load was found on CBCL cells. A high titre of serum IgG antibodies reacting with the nuclei of the HHV-8 positive cell line BCP-1 was found. These data suggest that reactivation of latent infection with HHV-8 had occurred in this patient, and that HHV-8 is directly involved in KS, but not in CBCL of the leg, an aggressive variant of CBCL.