Mark N. Polizzotto

Bisphosphonate-associated osteonecrosis of the auditory canal

An association between bisphosphonate exposure and mandibular and maxillary osteonecrosis has recently been described (Marx, 2003; Ruggiero et al, 2004). We present the first reported case of bisphosphonate-associated osteonecrosis occurring outside the oral cavity. The patient was a 64-year-old man with a 9-year history of immunoglobulin G (IgG) kappa multiple myeloma, for which he had received an autologous stem cell transplant. His maintenance therapy initially comprised interferon alpha with pamidronate 90 mg monthly. With disease progression after 5 years, zoledronate 4 mg monthly was substituted and dexamethasone 40 mg/d 4 d each month with lenalidomide 15 mg/d were added. During this time, his clinical course was complicated by the development of bilateral idiopathic exostoses of the external auditory canals, with recurrent superinfection, and by loosening of the upper right second molar and lower right second molar. The loose teeth were extracted and the left sided exostosis was removed without complication; no intervention was made on the right ear. He subsequently presented with painful, non-healing sockets at the site of the tooth extractions. Examination revealed ulcerated mucosa and exposed devitalised bone at these sites. Computed tomography showed an area of periodontal necrosis, with formation of a sequestrum. There was no clinical or radiographic evidence of myeloma deposition or infection. No tissue biopsy was performed because of concerns regarding healing. Six months later, routine examination revealed a new area of painless ulceration of the left auditory canal at the site of the previous surgery. Necrotic bone was exposed, extending beyond the margins of ulceration. There had been no recent infection or trauma. Computed tomography and galliumlabelled white cell scanning confirmed an area of necrotic bone at this site. There was, again, no clinical or radiographic evidence of myeloma deposition or infection. In view of these findings, a diagnosis of bisphosphonate-associated osteonecrosis of the jaw and auditory canal was made. The lesions improved with cessation of the bisphosphonate, local debridement and oral antibiotics. Further investigation of the pathogenesis and incidence of bisphosphonate-associated osteonecrosis is warranted. We postulate that the association between the development of this condition and trauma resulted from a reduced ability of bone to respond to physiological demands in the presence of bisphosphonate-induced reduced osseous remodelling and blood flow (Wood et al, 2002). While the oral cavity, with its high local bacterial load and probability of exposure of bone to the environment, is particularly susceptible, the present case demonstrates that this phenomenon may be generalised. We suggest that clinicians maintain a high index of suspicion for this condition in patients receiving long-term bisphosphonates and that trauma to bone at any site, including surgery, be avoided where possible.

High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy

Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a lymphoproliferative disorder most commonly observed in HIV-infected patients. It is characterized by KSHV-infected plasmablasts that frequently express lytic genes. Patients manifest inflammatory symptoms attributed to overproduction of KSHV viral IL-6, human IL-6, and human IL-6. There is no standard therapy and no established response criteria. We investigated an approach targeting 2 KSHV lytic genes, ORF36 and ORF21, the protein of which, respectively, phosphorylate ganciclovir and zidovudine to toxic moieties. In a pilot study, 14 HIV-infected patients with symptomatic KSHV-MCD received high-dose zidovudine (600 mg orally every 6 hours) and the oral prodrug, valganciclovir (900 mg orally every 12 hours). Responses were evaluated using new response criteria. A total of 86% of patients attained major clinical responses and 50% attained major biochemical responses. Median progression-free survival was 6 months. With 43 months of median follow-up, overall survival was 86% at 12 months and beyond. At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load. The most common toxicities were hematologic. These observations provide evidence that therapy designed to target cells with lytic KSHV replication has activity in KSHV-MCD. This trial was registered at www.clinicaltrials.gov as #NCT00099073.

Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome

Soon after the discovery of Kaposi sarcoma (KS)-associated herpesvirus (KSHV), it was appreciated that this virus was associated with most cases of multicentric Castleman disease (MCD) arising in patients infected with human immunodeficiency virus. It has subsequently been recognized that KSHV–MCD is a distinct entity from other forms of MCD. Like MCD that is unrelated to KSHV, the clinical presentation of KSHV–MCD is dominated by systemic inflammatory symptoms including fevers, cachexia, and laboratory abnormalities including cytopenias, hypoalbuminemia, hyponatremia, and elevated C-reactive protein. Pathologically KSHV–MCD is characterized by polyclonal, IgM-lambda restricted plasmacytoid cells in the intrafollicular areas of affected lymph nodes. A portion of these cells are infected with KSHV and a sizable subset of these cells express KSHV lytic genes including a viral homolog of interleukin-6 (vIL-6). Patients with KSHV–MCD generally have elevated KSHV viral loads in their peripheral blood. Production of vIL-6 and induction of human (h) IL-6 both contribute to symptoms, perhaps in combination with overproduction of IL-10 and other cytokines. Until recently, the prognosis of patients with KSHV–MCD was poor. Recent therapeutic advances targeting KSHV-infected B cells with the anti-CD20 monoclonal antibody rituximab and utilizing KSHV enzymes to target KSHV-infected cells have substantially improved patient outcomes. Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Its clinical manifestations resemble those of KSHV–MCD but lymphadenopathy is not prominent and the pathologic nodal changes of KSHV–MCD are absent. Patients with KICS exhibit elevated KSHV viral loads and elevation of vIL-6, homolog of human interleukin-6 and IL-10 comparable to those seen in KSHV–MCD; the cellular origin of these is a matter of investigation. KICS may contribute to the inflammatory symptoms seen in some patients with severe KS or primary effusion lymphoma. Additional research is needed to better define the clinical spectrum of KICS and its relationship to KSHV–MCD. In additional, research is needed to better understand the pathogenesis and epidemiology of both KICS and KSHV–MCD, as well as the optimal therapy for both of these disorders.

Expression of “suppressor of cytokine signalling” (SOCS) genes in the developing and adult mouse nervous system

Growth factor and cytokine signalling in the developing nervous system has multiple effects, ranging from cell differentiation and cell survival to modulation of cell phenotype. Molecules that can regulate growth factor signalling pathways will therefore be of importance in determining the cellular response to factor stimulation. Members of a recently described gene family, the suppressor of cytokine signalling (SOCS) family, can regulate signalling events downstream of predominantly cytokine stimulation and may have important roles in the nervous system. We have examined the temporal and spatial expression of SOCS‐1, SOCS‐2, and SOCS‐3 in the developing and adult nervous system by use of Northern analysis and in situ hybridisation. All three genes were expressed in the brain, with maximal expression from embryonic day 14 to postnatal day 8 and declining thereafter, with SOCS‐2 being the most highly expressed. In situ hybridisation analysis showed that SOCS‐1 and SOCS‐3 had a low and widespread pattern of expression, whereas SOCS‐2 expression was higher and tightly regulated. Its expression pattern indicated that SOCS‐2 was expressed exclusively in neurons and that it was switched on developmentally at the time of neuronal differentiation. J. Comp. Neurol. 423:348–358, 2000.

Fluid skills: Drinking games and alcohol consumption among Australian university students

The objective of this study was to assess participation in drinking games among Australian university students; to determine the range of games played, their context and participant motivations; and to analyse the impact of games on alcohol consumption and its adverse consequences. We used a cross-sectional survey incorporating structured interviews and a self-administered questionnaire with students between 18 and 25 years of age at the University of Western Australia. This was a qualitative assessment of drinking game typology and contexts and participant motivation. Quantitative outcomes were rate and frequency of participation in drinking games; amount and rate of alcohol consumption during games; incidence of adverse outcomes following participation. Twenty-seven interview responses and 256 questionnaire responses were analysed for qualitative and quantitative outcomes, respectively. The qualitative analysis enabled categorisation of drinking games by skill and competitive nature, with varying influence on hazardous drinking. Common reported motivations for play included boredom, social pressure and social unease. The associated heavy drinking and possible hazards were well recognised but did not affect the decision to play. In the quantitative arm, most drinkers (74%) reported having participated in a drinking game. Game players reported playing an average of four drinking games in the previous 6 months. An average of six standard drinks was consumed during the most recent game. Pressure to participate from others was reported by 60% of game participants, while 50% reported that they had placed pressure on others to participate. Half (51%) reported an adverse outcome following participation. Loss of consciousness due to drinking was experienced or witnessed by 89% of game players, of whom 63% reported that the person was put to bed, while 54% reported that the person was watched. Participation in drinking games was common, and plays an important social role in this group. Drinking games were associated commonly with binge drinking and adverse outcomes. Future harm minimisation strategies targeting this group should address the particular risks of these games.

Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease.

Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder. Human (h) IL-6 and a KSHV-encoded homolog, viral IL-6, have been hypothesized to contribute to its pathogenesis, but their relative contributions to disease activity is not well understood. We prospectively characterized KSHV viral load (VL), viral (v) and hIL-6, and other cytokines during KSHV-MCD flare and remission in 21 patients with 34 flares and 20 remissions. KSHV-VL, vIL-6, hIL-6, IL-10, and to a lesser extent TNF-α, and IL-1β were each elevated during initial flares compared with remission. Flares fell into 3 distinct IL-6 profiles: those associated with elevations of vIL6-only (2 flares, 6%), hIL-6 elevations only (17 flares, 50%), and elevations in both hIL-6 and vIL-6 (13 flares, 38%). Compared with hIL-6-only flares, flares with elevated hIL-6 plus vIL-6 exhibited higher C-reactive protein (CRP) (P = .0009); worse hyponatremia (P = .02); higher KSHV VL (P = .016), and higher IL-10 (P = .012). This analysis shows vIL-6 and hIL-6 can independently or together lead to KSHV-MCD flares, and suggests that vIL-6 and hIL-6 may jointly contribute to disease severity. These findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. This trial was registered at clinicaltrials.gov as #NCT099073.

Kaposi Sarcoma–Associated Herpesvirus-Associated Malignancies: Epidemiology, Pathogenesis, and Advances in Treatment ☆

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.

Reducing the risk of transfusion‐transmissible viral infection through blood donor selection: the Australian experience 2000 through 2006

BACKGROUND: Selection of voluntary donors who are at low risk of transfusion‐transmissible viral infection (TTVI) is central in maintaining the safety of the blood supply. Evaluation of its effectiveness and the dynamics of the process may offer opportunities to further improve transfusion safety.

Phase II Study of Bevacizumab in Patients With HIV-Associated Kaposi's Sarcoma Receiving Antiretroviral Therapy

PURPOSE Alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposis sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti-VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS. PATIENTS AND METHODS Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately. RESULTS Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T(1)), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/μL. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2). CONCLUSION Bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients.

Kaposi Sarcoma Herpesvirus Promotes Endothelial-to-Mesenchymal Transition through Notch-Dependent Signaling

Endothelial-to-mesenchymal transition (EndMT) is now widely considered a pivotal contributor to cancer progression. In this study, we show that the Kaposis sarcoma (KS)-associated herpesvirus (KSHV) is a sufficient cause of EndMT, potentially helping to explain the aggressiveness of KS that occurs commonly in AIDS patients. Upon KSHV infection, primary dermal microvascular endothelial cells lost expression of endothelial markers and acquired expression of mesenchymal markers, displaying new invasive and migratory properties along with increased survival. KSHV activated Notch-induced transcription factors Slug and ZEB1, and canonical Notch signaling was required for KSHV-induced EndMT. In contrast, KSHV did not utilize the TGFβ signaling pathway, which has also been linked to EndMT. Within KS lesions, KSHV-infected spindle cells displayed features compatible with KSHV-induced EndMT including a complex phenotype of endothelial and mesenchymal properties, Notch activity, and nuclear ZEB1 expression. Our results show that KSHV engages the EndMT program to increase the invasiveness and survival of infected endothelial cells, traits that likely contribute to viral persistence and malignant progression. One important implication of our findings is that therapeutic approaches to disrupt the Notch pathway may offer novel approaches for KS treatment.