Kaposi sarcoma associated herpesvirus (KSHV), a γ2-herpesvirus, also known as human herpesvirus-8, is the etiologic agent of three virally associated tumors: Kaposi sarcoma, a plasmablastic form of ...multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These malignancies are predominantly seen in people with acquired immunodeficiencies, including acquired immunodeficiency syndrome and iatrogenic immunosuppression in the setting of organ transplantation, but can also develop in the elderly. Kaposi sarcoma (KS) is most frequent in regions with high KSHV seroprevalence, such as sub-Saharan Africa and some Mediterranean countries. In the era of combination antiviral therapy, inflammatory manifestations associated with KSHV-infection, including KSHV-MCD, a recently described KSHV-associated inflammatory cytokine syndrome and KS immune reconstitution syndrome also are increasingly appreciated. Our understanding of viral and immune mechanisms of oncogenesis continues to expand and lead to improved molecular diagnostics, as well as novel therapeutic strategies that employ immune modulatory agents, manipulations of the tumor microenvironment, virus-activated cytotoxic therapy, or agents that target interactions between specific virus-host cell signaling pathways. This review focuses on the epidemiology and advances in molecular and clinical research that reflects the current understanding of viral oncogenesis, clinical manifestations, and therapeutics for KSHV-associated tumors.
Chimeric antigen receptor (CAR) T cell therapies have dramatically improved treatment outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukemia, large B-cell lymphoma, ...follicular lymphoma, mantle cell lymphoma, and multiple myeloma. Despite unprecedented efficacy, treatment with CAR T cell therapies can cause a multitude of adverse effects which require monitoring and management at specialized centers and contribute to morbidity and non-relapse mortality. Such toxicities include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, neurotoxicity distinct from ICANS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, and immune effector cell-associated hematotoxicity that can lead to prolonged cytopenias and infectious complications. This review will discuss the current understanding of the underlying pathophysiologic mechanisms and provide guidelines for the grading and management of such toxicities.
This study was designed to determine the incidence of venous and arterial thromboembolic events (TEEs) in patients treated with cisplatin-based chemotherapy and to analyze the prognostic value of ...patients' baseline and treatment characteristics in predicting TEE occurrence.
We performed a large retrospective analysis of all patients treated with cisplatin-based chemotherapy for any type of malignancy at Memorial Sloan-Kettering Cancer Center in 2008. A TEE was cisplatin-associated if it occurred between the time of the first dose of cisplatin and 4 weeks after the last dose.
Among 932 patients, 169 (18.1%) experienced a TEE during treatment or within 4 weeks of the last dose. TEEs included deep vein thrombosis (DVT) alone in 49.7%, pulmonary embolus (PE) alone in 25.4%, DVT plus PE in 13.6%, arterial TEE alone in 8.3%, or DVT plus arterial TEE in 3.0%. TEEs occurred within 100 days of initiation of treatment in 88% of patients. By univariate analysis, sex, age, race, Karnofsky performance status (KPS), exposure to erythropoiesis-stimulating agents, presence of central venous catheter (CVC), site of cancer, stage of cancer, leukocyte and hemoglobin levels, and Khorana score were all identified as risk factors. However, by multivariate analysis, only age, KPS, presence of CVC, and Khorana score retained significance.
This large retrospective analysis confirms the unacceptable incidence of TEEs in patients receiving cisplatin-based chemotherapy. In view of the controversy associated with prophylactic anticoagulation in patients with cancer treated with chemotherapy, randomized studies are urgently needed in this specific cancer population treated with cisplatin-based regimens.
Primary effusion lymphoma (PEL) is an aggressive HIV-associated lymphoma with a relatively poor prognosis in the era of effective HIV therapy. Kaposi sarcoma herpesvirus (KSHV) is the etiologic ...agent, and ∼80% of tumors are coinfected with Epstein-Barr virus (EBV). A better understanding of how KSHV-related immune dysregulation contributes to the natural history of PEL will improve outcomes. Twenty patients with PEL diagnosed between 2000 and 2013, including 19 treated with modified infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone (EPOCH), were identified. We compared their clinical, virologic, and immunologic features vs 20 patients with HIV-associated diffuse large B-cell lymphoma and 19 patients with symptomatic interleukin (IL)-6 related KSHV-associated multicentric Castleman disease. Survival analyses of treated patients with PEL were then performed to identify prognostic factors and cancer-specific mortality. Compared with HIV-associated diffuse large B-cell lymphoma, PEL was associated with significant hypoalbuminemia (P < .0027), thrombocytopenia (P = .0045), and elevated IL-10 levels (P < .0001). There were no significant differences in these parameters between PEL and KSHV-associated multicentric Castleman disease. Median overall survival in treated patients with PEL was 22 months, with a plateau in survival noted after 2 years. Three-year cancer-specific survival was 47%. EBV-positive tumor status was associated with improved survival (hazard ratio, 0.27; P = .038), and elevated IL-6 level was associated with inferior survival (hazard ratio, 6.1; P = .024). Our analysis shows that IL-6 and IL-10 levels contribute to the natural history of PEL. Inflammatory cytokines and tumor EBV status are the strongest prognostic factors. Pathogenesis-directed first-line regimens are needed to improve overall survival in PEL.
•PEL in individuals with HIV is associated with a Kaposi sarcoma herpesvirus-driven IL-6 and IL-10–related syndrome.•EBV status of the tumor and elevated serum IL-6 levels are prognostic in PEL.
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The activation of signal transducers and activators of transcription 3 (STAT3) has been linked with the proliferation of a variety of human cancer cells, including multiple myeloma. Agents that can ...suppress STAT3 activation have potential for prevention and treatment of cancer. In the present report, we tested an agent, ursolic acid, found in basil, apples, prunes, and cranberries, for its ability to suppress STAT3 activation. We found that ursolic acid, a pentacyclic triterpenoid, inhibited both constitutive and interleukin-6-inducible STAT3 activation in a dose- and time-dependent manner in multiple myeloma cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, Janus-activated kinase 2, and extracellular signal-regulated kinase 1/2. Vanadate treatment reversed the ursolic acid-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that ursolic acid induced the expression of tyrosine phosphatase SHP-1 protein and mRNA. Moreover, knockdown of SHP-1 by small interfering RNA suppressed the induction of SHP-1 and reversed the inhibition of STAT3 activation, thereby indicating the critical role of SHP-1 in the action of this triterpene. Ursolic acid down-regulated the expression of STAT3-regulated gene products such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, and vascular endothelial growth factor. Finally, ursolic acid inhibited proliferation and induced apoptosis and the accumulation of cells in G1-G0 phase of cell cycle. This triterpenoid also significantly potentiated the apoptotic effects of thalidomide and bortezomib in multiple myeloma cells. Overall, these results suggest that ursolic acid is a novel blocker of STAT3 activation that may have a potential in prevention and treatment of multiple myeloma and other cancers.
Capsaicin, a constituent of green and red peppers, has been linked with suppression of tumorigenesis through a mechanism that is not well understood. Because the transcription factor signal ...transducer and activator of transcription 3 (STAT3) has been closely linked with tumorigenesis, we investigated the effect of this vanilloid on the STAT3 pathway in human multiple myeloma cells.
The effect of capsaicin on both constitutive and interleukin-6-induced STAT3 activation, associated protein kinases, and STAT3-regulated gene products involved in proliferation, survival and angiogenesis, cellular proliferation, and apoptosis in multiple myeloma cells was investigated.
We found that capsaicin inhibited constitutive activation of STAT3 in multiple myeloma cells in a dose- and time-dependent manner, with minimum effect on STAT5. Capsaicin also inhibited the interleukin-6-induced STAT3 activation. The activation of Janus-activated kinase 1 and c-Src, implicated in STAT3 activation, was also inhibited by the vanilloid, with no effect on extracellular signal-regulated kinase 1/2 activation. Pervanadate reversed the capsaicin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor. Finally, capsaicin induced the accumulation of cells in G(1) phase, inhibited proliferation, and induced apoptosis, as indicated by caspase activation. Capsaicin also significantly potentiated the apoptotic effects of Velcade and thalidomide in multiple myeloma cells. When administered i.p., capsaicin inhibited the growth of human multiple myeloma xenograft tumors in male athymic nu/nu mice.
Overall, these results suggest that capsaicin is a novel blocker of the STAT3 activation pathway, with a potential role in the prevention and treatment of multiple myeloma and other cancers.
There are significant disparities with regards to incidence, timely diagnosis, access to treatment, clinical trial participation and health care utilization that negatively impact outcomes for ...African American patients with multiple myeloma. Health care providers have a role in ameliorating these disparities with thoughtful consideration of historical, sociocultural, individual and disease characteristics that influence the care provided to African American patient population. This review by a group of experts committed to health disparity in multiple myeloma provides a snapshot of disparities at both biologic and non-biologic levels, barriers to clinical care, and best practices to ensure that African American patients receive the best care available.
Plasma cell proliferative disorders cause rare but extremely varied dermatologic manifestations that may occur as an accompaniment to established diagnoses, or may be a first clue of an underlying ...neoplasm in the setting of clinical suspicion. In some instances skin lesions result from aggregation of misfolded monoclonal immunoglobulins or their fragments, as in light chain-related systemic amyloidosis. On other occasions the cutaneous lesions result from deposits of malignant plasma cells or monoclonal proteins. In still others, the dermatologic manifestations are related to antibody activity of monoclonal protein, as in many cases of cryoglobulinemia. This report provides insights into the well-recognized cutaneous manifestations associated with plasma cell disorders.
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