Paul G. Rubinstein

Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells

Classical Hodgkin lymphoma (cHL) is characterized by sparsely distributed Hodgkin and Reed-Sternberg (HRS) cells amid reactive host background, complicating the acquisition of neoplastic DNA without extensive background contamination. We overcame this limitation by using flow-sorted HRS and intratumor T cells and optimized low-input exome sequencing of 10 patient samples to reveal alterations in genes involved in antigen presentation, chromosome integrity, transcriptional regulation, and ubiquitination. β-2-microglobulin (B2M) is the most commonly altered gene in HRS cells, with 7 of 10 cases having inactivating mutations that lead to loss of major histocompatibility complex class I (MHC-I) expression. Enforced wild-type B2M expression in a cHL cell line restored MHC-I expression. In an extended cohort of 145 patients, the absence of B2M protein in the HRS cells was associated with lower stage of disease, younger age at diagnosis, and better overall and progression-free survival. B2M-deficient cases encompassed most of the nodular sclerosis subtype cases and only a minority of mixed cellularity cases, suggesting that B2M deficiency determines the tumor microenvironment and may define a major subset of cHL that has more uniform clinical and morphologic features. In addition, we report previously unknown genetic alterations that may render selected patients sensitive to specific targeted therapies.

Malignancies in HIV/AIDS: From Epidemiology to Therapeutic Challenges

The incidence of AIDS-defining cancers (ADCs) – Kaposi sarcoma, primary central nervous system lymphoma, non-Hodgkin lymphoma, and cervical cancer – although on the decline since shortly after the introduction of HAART, has continued to be greater even in treated HIV-infected persons than in the general population. Although the survival of newly infected people living with HIV/AIDS now rivals that of the general population, morbidity and mortality associated with non-AIDS-defining cancers (NADCs) such as lung, liver, anal, and melanoma are significant and also continue to rise. Increasing age (i.e. longevity) is the greatest risk factor for NADCs, but longevity alone is not sufficient to fully explain these trends in cancer epidemiology. In this review, we briefly review the epidemiology and etiology of cancers seen in HIV/AIDS, and in this context, discuss preclinical research and broad treatment considerations. Investigation of these considerations provides insight into why malignancies continue to be a major problem in the current era of HIV/AIDS care.

Long-term survival in AIDS-related primary central nervous system lymphoma

Background. The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. Methods. To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). Results. We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART. Conclusion. Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

Thalidomide-associated thrombosis in the treatment of HIV-associated severe aphthous disease: a case report and review of the literature.

Venous thrombosis is a well-described complication of thalidomide therapy in patients with multiple myeloma (MM). However, an association between thalidomide use and thrombosis in HIV-positive patients has not been previously described. We present the case of a 48-year-old HIV-positive man who developed a deep venous thrombosis while on thalidomide for the treatment of severe aphthous ulcers. We review the management of severe aphthous disease and the potential adverse effects of thalidomide therapy. We examine the association between thalidomide and thrombosis in patients with MM and discuss how the same relationship may or may not exist in HIV-positive patients. Although the strength of the association between thalidomide use and thrombosis in HIV-positive patients being treated for aphthous disease remains unclear, HIV providers should be aware of the potential risk of thrombosis in all patients receiving thalidomide.

Stroger Hospital of Cook County (CCH) AIDS malignancy project: The CHAMP study—A 13-year, single institution retrospective study of cancers in patients infected with HIV.

1551 Background: CCH is the largest health provider for HIV patients in Chicago and has one of the largest HIV outpatient clinics in the United States, the Ruth M. Rothstein CORE Center (CC). Per year, over 5000 HIV + individuals are treated at the CC with over 500 HIV-infected individuals treated at CCH. Most studies of non-AIDS defining (NADC) and AIDS defining cancers (ADC) cover wide areas. Insights into the prevalence, type of cancer, and characteristics of HIV + cancer patients found in the inner city and underserved populations have been under represented in the literature. To this end, we examined all of the malignancies presenting to either the CC or CCH for the past 13 years. METHODS We identified via CCH, CC, and pharmacy databases all HIV infected patients with a cancer ICD9 codes from 1998-2010. HIV characteristics, cancer type, and patient demographics were confirmed by chart review. One-way Anova was used to show statistical significant between the prevalence among the different sub populations. RESULTS After initial screening, 404 cancers were confirmed, representing 21 malignancies. 56% were ADC, with 104 (25%) non-hodgkins lymphoma (NHL), 111(28%) Kaposi sarcoma, and 11(2.7%) cases of cervical cancer. Of the 104 NHL, the most common were DLBCL 61%, Burkitts (BL) 21%, and primary CNS lymphoma 7.6%. The most frequent NADC was anal cancer (n=30) and Hodgkin lymphoma (n=29). 70% of all cancers were stage III or above. HIV + patients at the CC were 71% African American (AA) and 19% Hispanic (Hsp) (compared to 26% and 23% in the Chicago population, respectively). In our study, AA represents 64% of all HIV cancers with Hsp and Caucasians 17% each. Though Caucasians with HIV and cancer in our cohort have the highest prevalence of cancer, 1.06%, vs. 0.69% AA vs. 0.60 Hsp (P< 0.001). The Male:Female ratio of all HIV malignancies in our cohort are 5.1:1. CONCLUSIONS Our data show a race disparity isolated to AA compared to the general population, and a male predominance. Although the Caucasian-HIV population is the smallest, they have the highest cancer prevalence.