Incidence Of Kaposi's Sarcoma Research Articles

Incidence of AIDS-Related Kaposi Sarcoma in All 50 United States From 2000 to 2014.

Although declining rates of incident AIDS-related Kaposi sarcoma (KS) have been reported, KS incidence rates have noted race/ethnic, age, and geographic diversity. We performed a comprehensive assessment of recent secular trends in AIDS-related KS incidence in the United States. We identified incident KS diagnosed in men aged 20-54 years (who comprise most AIDS-related KS in the United States) using the US Cancer Statistics registry data. Joinpoint analysis assessed for trends in age-adjusted incidence rates between 2000 and 2014 calculating average annual percentage changes (AAPCs) with 95% confidence intervals. Heat maps were generated to compare age-adjusted HIV incidence rates with KS incidence rates. Age-adjusted KS incidence rates nationwide decreased from 1.44/100,000 to 0.95/100,000 between 2000 and 2014. Observed rate changes varied across subgroups; eg, there were significant decreases in 30-44 years (AAPC = -5.4%), particularly in Whites and Blacks, significant increases among 20-29 years (AAPC = 2.7), primarily in Blacks, and stable rates among 45-54 years (AAPC = -0.03). In Southern United States, the incidence rates among Blacks did not significantly change. The states with highest average age-adjusted rates over the study period were Georgia (2.71/100,000), New York (2.16/100,000), California (2.02/100,000), Florida (1.90/100,000), and Texas (1.39/100,000), with significantly decreasing trends over time, except Georgia where rates increased (AAPC = 1.8). Although KS incidence rates have decreased nationally, age, racial, and geographic disparities persist, including increasing risk among younger Black men and particularly elevated rates in some southern states and urban areas. Further research is needed to address racial and geographic AIDS-related KS disparities.

The DNase Activity of Kaposi's Sarcoma-Associated Herpesvirus SOX Protein Serves an Important Role in Viral Genome Processing during Lytic Replication.

The Kaposi's sarcoma-associated herpesvirus (KSHV) alkaline exonuclease SOX, encoded by open reading frame 37 (ORF37), is a bifunctional early-lytic-phase protein that possesses alkaline 5'-to-3' DNase activity and promotes host shutoff at the mRNA level during productive lytic infection. While the SOX protein is well characterized for drastically impairing cellular gene expression, little is known about the impact of its DNase activity on the KSHV genome and life cycle and the biology of KSHV infections. Here, we introduced a previously described DNase-inactivating Glu129His (Q129H) mutation into the ORF37 gene of the viral genome to generate ORF37-Q129H recombinant virus (the Q129H mutant) and investigated the effects of loss or inactivation of DNase activity on viral genome replication, cleavage, and packaging. For the first time, we provide experimental evidence that the DNase activity of the SOX protein does not affect viral latent/lytic DNA synthesis but is required for cleavage and processing of the KSHV genome during lytic replication. Interestingly, the Q129H mutation severely impaired intranuclear processing of progeny virions compared to the wild-type ORF37, as assessed by pulsed-field and Gardella gel electrophoresis, electron microscopy, and single-molecule analysis of replicating DNA (SMARD) assays. Complementation with ORF37-wt (wild type) or BGLF5 (the KSHV protein homolog in Epstein-Barr virus) in 293L/Q129H cells restored the viral genome encapsidation defects. Together, these results indicated that ORF37's proposed DNase activity is essential for viral genome processing and encapsidation and, hence, can be targeted for designing antiviral agents to block KSHV virion production.IMPORTANCE Kaposi's sarcoma (KS)-associated herpesvirus is the causative agent of multiple malignancies, predominantly in immunocompromised individuals, including HIV/AIDS patients. Reduced incidence of KS in HIV/AIDS patients receiving antiherpetic drugs to block lytic replication confirms the role of lytic DNA replication and gene products in KSHV-mediated tumorigenesis. Herpesvirus lytic replication results in the production of complex concatemeric DNA, which is cleaved into unit length viral DNA for packaging into the infectious virions. The conserved herpesviral alkaline exonucleases play an important role in viral genome cleavage and packaging. Here, by using the previously described Q129H mutant virus that selectively lacks DNase activity but retains host shutoff activity, we provide experimental evidence confirming that the DNase function of the KSHV SOX protein is essential for viral genome processing and packaging and capsid maturation into the cytoplasm during lytic replication in infected cells. This led to the identification of ORF37's DNase activity as a potential target for antiviral therapeutics.

Quantitative RNAseq analysis of Ugandan KS tumors reveals KSHV gene expression dominated by transcription from the LTd downstream latency promoter.

KSHV is endemic in Uganda and the HIV epidemic has dramatically increased the incidence of Kaposi sarcoma (KS). To investigate the role of KSHV in the development of KS, we obtained KS biopsies from ART-naïve, HIV-positive individuals in Uganda and analyzed the tumors using RNAseq to globally characterize the KSHV transcriptome. Phylogenetic analysis of ORF75 sequences from 23 tumors revealed 6 distinct genetic clusters with KSHV strains exhibiting M, N or P alleles. RNA reads mapping to specific unique coding sequence (UCDS) features were quantitated using a gene feature file previously developed to globally analyze and quantitate KSHV transcription in infected endothelial cells. A pattern of high level expression was detected in the KSHV latency region that was common to all KS tumors. The clear majority of transcription was derived from the downstream latency transcript promoter P3(LTd) flanking ORF72, with little evidence of transcription from the P1(LTc) latency promoter, which is constitutive in KSHV-infected lymphomas and tissue-culture cells. RNAseq data provided evidence of alternate P3(LTd) transcript editing, splicing and termination resulting in multiple gene products, with 90% of the P3(LTd) transcripts spliced to release the intronic source of the microRNAs K1-9 and 11. The spliced transcripts encode a regulatory uORF upstream of Kaposin A with alterations in intervening repeat sequences yielding novel or deleted Kaposin B/C-like sequences. Hierarchical clustering and PCA analysis of KSHV transcripts revealed three clusters of tumors with different latent and lytic gene expression profiles. Paradoxically, tumors with a latent phenotype had high levels of total KSHV transcription, while tumors with a lytic phenotype had low levels of total KSHV transcription. Morphologically distinct KS tumors from the same individual showed similar KSHV gene expression profiles suggesting that the tumor microenvironment and host response play important roles in the activation level of KSHV within the infected tumor cells.

Similar Immunological Profiles Between African Endemic and Human Immunodeficiency Virus Type 1-Associated Epidemic Kaposi Sarcoma (KS) Patients Reveal the Primary Role of KS-Associated Herpesvirus in KS Pathogenesis.

Kaposi sarcoma (KS)-associated herpesvirus (KSHV) is etiologically linked to all KS forms, but mechanisms underlying KS development are unclear. The incidence of KS in human immunodeficiency virus type 1-infected (HIV-1+) individuals implicates immune dysregulation; however, the lack of characterization of KSHV immune responses in endemic KS makes the role of HIV-1 unclear. The study objective was to investigate the HIV-1 and KSHV roles in viral nucleic acid detection, antibody responses, and cytokine responses in polymerase chain reaction-confirmed epidemic KS and endemic KS patients and non-cancer controls from sub-Saharan Africa. KSHV viral DNA (vDNA), total anti-KSHV antibody, KSHV neutralizing antibody (nAb), and cytokines were quantified. KSHV vDNA was detectable in tumors but variably in plasma and peripheral blood mononuclear cells. Consistent with elevated antibody-associated cytokines (interleukin [IL] 6, IL-5, and IL-10), nAb titers were higher in epidemic KS and endemic KS patients than in controls (P < .05). Despite HIV-1 coinfection in epidemic KS, nAb titers were similar between epidemic KS and endemic KS patients (P = 0.3). Similarities in antibody and cytokine responses between epidemic and endemic KS patients suggest that KSHV drives KS pathogenesis, whereas HIV-1 exacerbates it.

High Cancer Burden Among Antiretroviral Therapy Users in Malawi: A Record Linkage Study of Observational Human Immunodeficiency Virus Cohorts and Cancer Registry Data.

With antiretroviral therapy (ART), AIDS-defining cancer incidence has declined and non-AIDS-defining cancers (NADCs) are now more frequent among human immunodeficiency virus (HIV)-infected populations in high-income countries. In sub-Saharan Africa, limited epidemiological data describe cancer burden among ART users. We used probabilistic algorithms to link cases from the population-based cancer registry with electronic medical records supporting ART delivery in Malawi's 2 largest HIV cohorts from 2000-2010. Age-adjusted cancer incidence rates (IRs) and 95% confidence intervals were estimated by cancer site, early vs late incidence periods (4-24 and >24 months after ART start), and World Health Organization (WHO) stage among naive ART initiators enrolled for at least 90 days. We identified 4346 cancers among 28 576 persons. Most people initiated ART at advanced WHO stages 3 or 4 (60%); 12% of patients had prevalent malignancies at ART initiation, which were predominantly AIDS-defining eligibility criteria for initiating ART. Kaposi sarcoma (KS) had the highest IR (634.7 per 100 000 person-years) followed by cervical cancer (36.6). KS incidence was highest during the early period 4-24 months after ART initiation. NADCs accounted for 6% of new cancers. Under historical ART guidelines, NADCs were observed at low rates and were eclipsed by high KS and cervical cancer burden. Cancer burden among Malawian ART users does not yet mirror that in high-income countries. Integrated cancer screening and management in HIV clinics, especially for KS and cervical cancer, remain important priorities in the current Malawi context.

Risk of Kaposi sarcoma after solid organ transplantation in the United States.

Due to treatment with immunosuppressive medications, solid organ transplant recipients have elevated risk for Kaposi sarcoma (KS), which is caused by human herpesvirus 8 (HHV8). Other risk factors for KS are poorly understood. We linked the United States solid organ transplant registry with 17 population-based cancer registries to ascertain KS incidence among 244,964 transplant recipients from 1987-2014. To compare incidence rates of KS according to patient and transplant characteristics, we calculated incidence rate ratios (IRRs) using Poisson regression. To compare associations of KS with other skin cancers occurring before or within 12 months of KS diagnosis, we computed odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. All statistical tests were two-sided. We identified 163 KS cases during follow-up. Among transplant recipients, we found significantly increased risk of KS associated with male sex (IRR = 1.87; 95%CI:1.32,2.71), nonwhite race (IRR = 2.67; 95%CI:1.92,3.72), non-US citizenship (IRR = 2.10; 95%CI:1.19,3.47), lung transplant (IRR = 2.22; 95%CI:1.03,4.24, vs. kidney), and older age at transplant. KS risk decreased significantly with time since transplant and recent calendar year, however, no specific induction or maintenance medication was associated with KS. KS incidence was not significantly associated with ambient ultraviolet radiation (IRR = 1.32 95%CI:0.87,2.02, tertile 3 vs. 1). KS incidence has decreased in recent calendar years. In a cross-sectional sample, we found cutaneous squamous cell carcinoma was associated with KS (OR = 4.83; 95%CI:1.30,14.69). KS risk factors included those potentially associated with HHV8 infection and increased immunosuppression. Our findings suggest that transplant recipients with a non-KS skin cancer may also be at high KS risk.

Impact of Protease Inhibitors on HIV-Associated Kaposi Sarcoma Incidence: A Systematic Review.

Protease inhibitors (PIs) may inhibit Kaposi sarcoma (KS) carcinogenesis. However, PI-based antiretroviral therapy (ART) is rarely a first-line choice in people living with HIV (PLWH) because of cost and toxicities. This is the first systematic review to assess KS incidence stratified by ART type. We searched PubMed to identify original, full research reports of KS incidence in ART-treated adult PLWH, stratified by ART class, published between 1996 and 2017. For overlapping cohorts, we included only the most recent study and supplemented data with earlier relevant analyses. We described study design, sociodemographic characteristics, statistical adjustment factors, and KS incidence. We identified 3 unique retrospective cohort studies, and supplemented one of the studies with results from 6 previous subgroup reports, which included 242,309 PLWH and 3570 incident KS cases. Overall, KS crude incidence decreased by a factor of 10 between untreated and ART-treated PLWH; CD4-adjusted KS incidence decreased by ∼50%, with either non-nucleoside reverse transcriptase inhibitor- or PI-based ART. A single study measured a cumulative dose-/time-dependent effect of ART, which reported a relative risk reduction in only the cohort receiving boosted PI-based ART. Other studies defined ART categories by first-line therapy only. The risk of incident KS was significantly reduced, regardless of ART class even after adjusting for CD4 count. The quality of evidence (ie, most studies categorizing users by first-line ART) does not permit KS risk reduction comparisons across ART types. Given the limited number and retrospective nature of these studies, prospective data are indicated.

Spectrum of Primary Cancer Diagnoses Among Patients at Uganda Cancer Institute in 2015 and 2016

Background: Most recent cancer registry data suggests a change in cancer occurrence in Uganda with a decrease in incidence of Kaposi sarcoma (KS) but an increase in cervical, prostate and breast cancer. Anecdotal data suggest that KS, non-Hodgkin's lymphoma and breast cancer were the most common cancers among patients at Uganda Cancer Institute (UCI) by 2006. Aim: To describe the spectrum of cancer diagnoses among new patients that presented for care at UCI over the past 2-years. Methods: We conducted a cross sectional study of patients admitted into care at UCI with a histologic or clinical diagnosis of cancer from January 2015 to December 2016. Cancer diagnoses were reported as proportions by gender and age - children (0-14 years) and adults (above 14 years). Results: Overall, 8279 new patients were registered during the study period but only 7588 (92%) were recorded in the electronic database and had information on cancer diagnosis. Of these, 53% were admitted in 2015, and 55% were females. Median age was 48 years (IQR: 34-62). Among 2997 female adults, 30% had cervical, 17% breast, 5% Kaposi sarcoma (KS), 4% leukemia and 3.9% esophageal cancer. Among 2136 male adults, 17% had KS, 12% prostate, 10% esophageal, 6% leukemia and 4% colorectal cancer. Among the 486 children, 17% had leukemia, 16.7% nephroblastoma (Wilms tumor), 15.9% Burkitt lymphoma (BL), 8% rhabdomyosarcoma, and 6% Kaposi sarcoma. Conclusion: The distribution of cancer diagnoses among patients seen at UCI reflects the population level cancer incidence with cervical, breast, KS, prostate, esophageal, and colorectal cancer in adults, and nephroblastoma in children as the leading cause of cancer related morbidity. The overrepresentation of leukemia may be due to referral bias but warrants further study. The correlation of our findings with incidence data suggests that missing information did not significantly skew our findings. However more investments are needed to improve the quality of data captured electronically.

Kaposi Sarcoma of the Gastrointestinal Tract in the Era of Combination Anti-Retro Viral Therapy

AIDS related Kaposi sarcoma (KS) is the most common tumor identified in HIV patients. Classically presents as cutaneous vascular endothelial tumors associated with HHV-8 infection. Visceral manifestation in the absence of cutaneous manifestation is uncommon. The annual incidence of Kaposi sarcoma in the United States has been steadily declining with the advent of highly potent combination anti-retroviral therapy (ART). We present an unfortunate case of a HIV positive male with extensive gastrointestinal Kaposi sarcoma. 50 year old male with prior diagnosis of HIV, non-compliant with ART presented with weight loss, abdominal pain, distention, vomiting and diarrhea for 3 months. Examination revealed a cachectic appearing male, moderate abdominal distention with mild diffuse tenderness throughout the abdomen. No cutaneous lesions identified on examination. Blood work significant for anemia, leukopenia, elevated HIV viral load >210,000 with a low CD4 count of 100. Stool studies for ova and parasites were negative. CT imaging revealed long segment mural thickening extending from the terminal ileum, descending colon to the rectum with multiple dilated fluid filled loops of small bowel with scattered large to small extensive mesenteric lymphadenopathy. EGD revealed multiple raised red to purplish nodular lesions in the oropharynx, esophagus, stomach and duodenum. Similar lesions were found on colonoscopy throughout the colon and terminal ileum associated with significant edema and narrowing in the region of the terminal ileum and sigmoid colon (Image 1). Biopsy from various sites revealed spindle cell proliferation with extravasation of red blood cells (Image2). Immunostain positive for HHV-8 consistent with the diagnosis of Kaposi's sarcoma (Image3). Patient improved on ART and was later discharged home with plans for outpatient chemotherapy. Significant advancements in the field of ART has led to a decrease in the prevalence of Kaposi sarcoma in the 21st century. Incidence of KS has shown a significant decline in United states from 47 cases per 1 million people in the 1990 to 6 cases per 1 million people because of highly effective treatments available for HIV/AIDS. Gastrointestinal manifestations commonly reported are abdominal pain, malabsorption, bleeding and rarely obstruction. GI manifestation can be easily missed in the absence of cutaneous manifestation, hence a high degree of suspicion can lead to early diagnosis and improved outcomes.2984_A Figure 1. Colonoscopy images showing multiple raised red to purple nodules throughout the colon2984_B Figure 2. H&E stain of the duodenal mucosa showing scattered bland spindle cell proliferation with extravasated red blood cells.2984_C Figure 3. Immunostain positive for HHV -8

Differential Immune Responses in Epidemic and Endemic Tanzanian Kaposi Sarcoma Patients

Background: Mechanisms underlying Kaposi sarcoma (KS) development are unclear. The high incidence of KS in HIV-1+ individuals implicates immune dysregulation in epidemic KS (EpKS) development. In African endemic KS (EnKS), the immune response is uncharacterized. Aim: The aim was to assess a comparative quantification between newly diagnosed Tanzanian EpKS and EnKS patients, and asymptomatic controls. We also report the first comparison of KSHV NAb prevalence and titer between EpKS and EnKS patients. Methods: To compare innate and adaptive immune responses, we recruited histologically confirmed Tanzanian EpKS and EnKS patients, as well as noncancer controls. After differential detection of KSHV nucleic acids in tissues, neutralizing antibody (NAb), levels of cytokines/chemokines, and T-cell differentiation subsets were quantified. The Mann-Whitney U-test was used to assess median differences between groups. All tests were 2-tailed and P-values &lt; 0.05 were considered significant. Results: A total of 180 patients have been recruited in this study. In addition, a comparable 25 EpKS and 10 EnKS as well as 10 noncancer controls were recruited for this study. KSHV was significantly more frequently detected in EpKS patients than in EnKS. While all EpKS, and some EnKS patients mounted NAb responses, the EpKS patients had higher prevalence and titer of NAb compared with EnKS patients ( P = 0.001). Levels of the cytokines IP-10 and IL-10 were higher in EpKS vs EnKS patients ( P = 0.006 and P = 0.005 respectively), whereas, IL-4 was lower in EpKS vs EnKS patients ( P = 0.004). The levels of all 14 cytokines/chemokines measured were comparable between EnKS patients and HIV− controls ( P &lt; .05 ). The distribution of CD4+ and CD8+ T-cells was similar between EpKS and EnKS such as naive and effector T-cells were depleted while central memory T-cells were elevated in both KS forms. Conclusion: The detection of similar abnormalities in T-cell differentiation subsets in both EpKS and EnKS as compared with controls, suggests that KSHV-induced T-cell dysfunction plays a major role in the disease, and that HIV-1 coinfection is only exacerbating and accelerating KSHV pathogenesis and KS development.

The world-wide incidence of Kaposi's sarcoma in the HIV/AIDS era.

Kaposi's sarcoma (KS) is a multicentric angioproliferative cancer of endothelial origin typically occurring in the context of immunosuppression or immunodeficiency. Consequently, KS is one of the most common cancers in HIV-infected individuals and frequently occurs among transplant recipients. Nevertheless, its incidence in different populations is not well understood. We searched online databases for publications on KS incidence. A random-effect meta-analysis was performed to combine the KS incidences and incidence rate ratios (IRRs) for associated risk factors. Seventy-six eligible studies representing 71 time periods were included. For HIV-infected people, the overall KS incidence was 481.54 per 100000 person-years with a 95% confidential interval (CI) of 342.36-677.32 per 100000 person-years. HIV-infected men who have sex with men (MSM) had the highest incidence of KS (1397.11 per 100000 person-years; 95% CI 870.55-2242.18 per 100000 person-years). The incidence of KS was significantly lower in female than in male individuals (IRR 3.09; 95% CI 1.70-5.62). People receiving highly active antiretroviral therapy (HAART) had a lower incidence compared with people who had never received HAART (IRR 6.57; 95% CI 1.91-24.69). The incidence of KS was 68.59 (95% CI 31.39-149.86) per 100000 person-years in transplant recipients, 52.94 (95% CI 39.90-70.20) per 100000 person-years in children with HIV infection, and 1.53 (95% CI 0.33-7.08) per 100000 person-years in the general population. Globally, a relatively high incidence of KS was found among HIV-seropositive people and, in particular, in HIV-infected MSM. The introduction of HAART has largely prevented the development of KS, but it has not entirely removed the challenge of KS. In Africa, in particular, KS imposes a very heavy disease burden, which can mainly be attributed to the high prevalence of KS-associated herpesvirus and poor access to HAART.

Kaposi sarcoma incidence in females is nearly four-fold higher in the Lower Rio Grande Valley compared to the Texas average

The Lower Rio Grande Valley (LRGV) is located on U.S.-Mexican border with a population that is 90% Hispanic [1]. Comprised of Hidalgo, Cameron, Starr and Willacy counties, this region has the highest poverty rate and one of the highest incidences of Type 2 diabetes in the United States [2–4]. Previous studies demonstrated a high prevalence of Human Herpes Virus 8 (HHV8) in the LRGV [5–7]. HHV8 infection has been causally linked to Kaposi Sarcoma (KS) [8]. Here, we retrospectively examine the incidence of KS in the LRGV in a set of HIV-negative Hispanic patients. Strikingly, the incidence of KS was higher in LRGV women compared to the Texas state average (nearly four-fold higher in McAllen-Edinburg-Pharr Metro Statistical Area). This unique profile aligns with the increased HHV8 prevalence in the LRGV, suggesting that HHV8 contributes to a high incidence of HIV-negative KS on the U.S.–Mexican border in Texas.

Incidence of AIDS-Related Kaposi Sarcoma in All 50 United States from 2000 to 2014

Incidence of AIDS-Related Kaposi Sarcoma in All 50 United States from 2000 to 2014

Histopathological review of dermatological malignancies in Makurdi, North Central Nigeria

Objective: Dermatological malignancies are among the common forms of cancer worldwide, especially Caucasians, and are noted to be in the skins of Africans and Negroid. The study aims to determine the frequency and patterns of dermatological malignancies in Benue State University Teaching Hospital (BSUTH), Makurdi, Nigeria. Methods: This was a 5-year retrospective study of skin samples seen at the Department of Anatomical Pathology, BSUTH, Makurdi, between March 2012 and February 2017. Results: A total of 215 skin biopsies were seen at the department during the study. Of these, 151 cases were dermatological malignancies constituting 70.2% of all skin lesions. Majority of these malignancies occurred between the fourth and fifth decades with a male-to-female ratio of 1.4:1. Kaposi sarcoma (KS) was the most common dermatological malignancy (n = 78; 52%). Squamous cell carcinoma constituted second majority (n = 30, 20%), followed by malignant melanoma (n = 22.1, 14.7%), dermatofi brosarcoma protuberans (n = 17, 11.3%), and basal cell carcinoma (n = 9, 6%). Leg, foot, and forearm were the common sites affected. Conclusion: KS was the most common dermatological malignancy in the study. Nearly all patients were HIV/AIDS positive. The findings in this study are similar to those from other parts of Africa and Nigeria. Therefore, HIV/AIDS control can substantially reduce the incidence, morbidity, and mortality of KS.

Pulmonary Kaposi Sarcoma: A Cryptic Angiosarcomatous Malignancy With Fatal Outcome

SESSION TITLE: Lung Cancer 1 SESSION TYPE: Affiliate Case Report Slide PRESENTED ON: Monday, October 30, 2017 at 03:15 PM - 04:15 PM INTRODUCTION: Pulmonary kaposi sarcoma (KS) is a rare neoplasm in HIV patients due to Human Herpes Virus-8 (HHV-8). Lack of specific symptomatology impede a high clinical suspicion leading to a delay in initiation of appropriate therapy. CASE PRESENTATION: A 22-year-old female with congenital HIV, off combined antiretroviral therapy (cART), presented with stabbing chest pain, chronic cough and dyspnea. On exam, she had rhonchi, distended abdomen, splenomegaly and diffuse lymphadenopathy. No oral or skin lesions. Laboratory tests showed cytopenias and acute kidney injury. CD4 131/9%. Quantiferon Gold negative. CT angiogram demonstrated diffuse interstitial infiltrates, hepatic lesions, ascites and mediastinal and inguinal lymphadenopathy. She underwent inguinal lymph node excisional biopsy which was consistent with metastatic KS. cART were promptly initiated. Bronchoscopy was performed to assess for hemoptysis. It revealed hyperemic lesions throughout the tracheobronchial tree. On day 11 of cART, patient developed respiratory failure requiring intubation. Despite starting steroids, she rapidly declined and developed multiorgan dysfunction before expiring on comfort measures. DISCUSSION: Although KS incidence is the highest among malignancies in AIDS patients, diagnosis is delayed as 70% of patients lack cutaneous manifestations. Median survival was 2 to 6 months before advent of cART. Early initiation of chemotherapy is delayed but recommended in pulmonary KS, even without significant change in survival time. While endobronchial biopsies are discouraged, visualization of pathognomic lesions, or BAL for HHV-8 PCR may prove beneficial. Deleterious outcomes including death are common. Although rarely reported, KS-related inflammatory response immune system (IRIS) can occur as early as second week of cART. Chemotherapy combined with cART can control the symptoms of IRIS and resolve KS. Our patient had a rapid clinical deterioration with fatal outcome before chemotherapy could be initiated. CONCLUSIONS: Pulmonary KS warrants a high clinical suspicion and prompt initiation of chemotherapy. Although rarely encountered by pulmonologists, recognition of the characteristic lesions on bronchoscopic visualization is mandated in order to make an accurate diagnosis. In this era of potent cART, careful monitoring for KS-related IRIS after starting cART is crucial. Despite combination of cART and chemotherapy, the prognosis is reported dismal. Reference #1: Connick E et al. Clin Infect Dis. 2004 Reference #2: Garay SM et al. Chest. 1987 Reference #3: Odongo FC. Case Rep Infect Dis. 2013 DISCLOSURE: The following authors have nothing to disclose: Zahia Esber, Sarah Barbour, Jason Stansberry No Product/Research Disclosure Information

HIV-associated Kaposi sarcoma and related diseases.

: The search for the etiologic agent for Kaposi sarcoma led to the discovery of Kaposi sarcoma-associated herpesvirus (KSHV) in 1994. KSHV, also called human herpesvirus-8, has since been shown to be the etiologic agent for several other tumors and diseases, including primary effusion lymphoma (PEL), an extracavitary variant of PEL, KSHV-associated diffuse large B-cell lymphoma, a form of multicentric Castleman disease, and KSHV inflammatory cytokine syndrome. KSHV encodes several genes that interfere with innate and specific immunity, thwart apoptosis, enhance cell proliferation and cytokine production, and promote angiogenesis, and these play important roles in disease pathogenesis. HIV is an important cofactor in Kaposi sarcoma pathogenesis, and widespread use of antiretroviral therapy has reduced Kaposi sarcoma incidence. However, Kaposi sarcoma remains the second most frequent tumor arising in HIV-infected patients in the United States and is particularly common in sub-Saharan Africa. KSHV prevalence varies substantially in different populations. KSHV is secreted in saliva, and public health measures to reduce its spread may help reduce the incidence of KSHV-associated diseases. Although there have been advances in the treatment of Kaposi sarcoma, KSHV-multicentric Castleman disease, and PEL, improved therapies are needed, especially those that are appropriate for Kaposi sarcoma in resource-poor regions.

Disparities in Kaposi sarcoma incidence and survival in the United States: 2000-2013.

ObjectiveGeographic and racial disparities may contribute to variation in the incidence and outcomes of HIV-associated cancers in the United States.MethodUsing the Surveillance, Epidemiology, and End Results (SEER) database, we analyzed Kaposi sarcoma (KS) incidence and survival by race and geographic region during the combined antiretroviral therapy era. Reported cases of KS in men from 2000 to 2013 were obtained from 17 SEER cancer registries. Overall and age-standardized KS incidence rates were calculated and stratified by race and geographic region. We evaluated incidence trends using joinpoint analyses and calculated adjusted hazard ratios (aHR) for overall and KS-specific mortality using multivariable Cox proportional hazards models.ResultsOf 4,455 KS cases identified in men younger than 55 years (median age 40 years), the annual percent change (APC) for KS incidence significantly decreased for white men between 2001 and 2013 (APC -4.52, p = 0.02). The APC for AA men demonstrated a non-significant decrease from 2000–2013 (APC -1.84, p = 0.09). Among AA men in the South, however, APC has significantly increased between 2000 and 2013 (+3.0, p = 0.03). In addition, compared with white men diagnosed with KS during the same time period, AA men were also more likely to die from all causes and KS cancer-specific causes (aHR 1.52, 95% CI 1.34–1.72, aHR 1.49, 95% CI 1.30–1.72 respectively).ConclusionAlthough overall KS incidence has decreased in the U.S., geographic and racial disparities in KS incidence and survival exist.

High Prevalence of Distinct Human Herpesvirus 8 Contributes to the High Incidence of Non-acquired Immune Deficiency Syndrome-Associated Kaposi's Sarcoma in Isolated Japanese Islands.

Non-acquired immune deficiency syndrome (AIDS) Kaposi's sarcoma (KS) is extremely rare in Japan but highly endemic in Okinawa, especially in Miyako Islands. We aimed to elucidate the exact incidence and cause of this high prevalence. Non-AIDS KS cases in Okinawa Prefecture over the past 31 years were reviewed, and human herpesvirus 8 (HHV8) seroprevalence in Miyako Islands was determined. We examined whole-genome sequences of 3 HHV8 strains and performed whole-exome sequencing of 4 male patients from Miyako Islands. Approximately half of the non-AIDS KS cases in Okinawa Prefecture were from Miyako Islands. The age-adjusted incidence rate was 0.87/105 per year for Miyako Islands and 0.056/105 per year for the rest of Okinawa. Human herpesvirus 8 seroprevalence was 15.4% in Miyako Islands. The 3 HHV8 genomes isolated from Miyako islanders formed a phylogenetically branch distinct from those of previously sequenced HHV8 strains and shared specific mutations in 9 proteins. These mutations were verified in Okinawan patients other than those from Miyako Islands. Whole-exome sequencing of the 4 male Miyako Islanders did not reveal shared pathogenic mutations. Miyako Islands are an endemic area of non-AIDS KS. The high rate of a distinct HHV8 may contribute to the high incidence of KS in the region.

Comparison of Kaposi Sarcoma Risk in Human Immunodeficiency Virus-Positive Adults Across 5 Continents: A Multiregional Multicohort Study.

We compared Kaposi sarcoma (KS) risk in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America. We included cohort data of human immunodeficiency virus (HIV)-positive adults who started ART after 1995 within the framework of 2 large collaborations of observational HIV cohorts. We present incidence rates and adjusted hazard ratios (aHRs). We included 208140 patients from 57 countries. Over a period of 1066572 person-years, 2046 KS cases were diagnosed. KS incidence rates per 100000 person-years were 52 in the Asia-Pacific and ranged between 180 and 280 in the other regions. KS risk was 5 times higher in South African women (aHR, 4.56; 95% confidence intervals [CI], 2.73-7.62) than in their European counterparts, and 2 times higher in South African men (2.21; 1.34-3.63). In Europe, Latin, and North America KS risk was 6 times higher in men who have sex with men (aHR, 5.95; 95% CI, 5.09-6.96) than in women. Comparing patients with current CD4 cell counts ≥700 cells/µL with those whose counts were <50 cells/µL, the KS risk was halved in South Africa (aHR, 0.53; 95% CI, .17-1.63) but reduced by ≥95% in other regions. Despite important ART-related declines in KS incidence, men and women in South Africa and men who have sex with men remain at increased KS risk, likely due to high human herpesvirus 8 coinfection rates. Early ART initiation and maintenance of high CD4 cell counts are essential to further reducing KS incidence worldwide, but additional measures might be needed, especially in Southern Africa.

Combination antiretroviral therapy and cancer risk.

To review the newest research about the effects of combination antiretroviral therapy (cART) on cancer risk. HIV+ persons are at increased risk of cancer. As this risk is higher for malignancies driven by viral and bacterial coinfections, classifying malignancies into infection-related and infection-unrelated has been an emerging trend. Cohorts have detected major reductions in the incidence of Kaposi sarcoma and non-Hodgkin lymphoma (NHL) following cART initiation among immunosuppressed HIV+ persons. However, recent randomized data indicate that cART reduces risk of Kaposi sarcoma and NHL also during early HIV infection before overt immunosuppression occurs. Long-term effects of cART exposure on cancer risk are not well defined; according to basic and epidemiological research, there might be specific associations of each cART class with distinct patterns of cancer risk. The relationship between cART exposure and cancer risk is complex and nuanced. It is an intriguing fact that, whether initiated during severe immunosuppression or not, cART reduces risk of Kaposi sarcoma and NHL. Further research should identify mediators of the benefit of immediate cART initiation in reducing cancer risk, understand the relationship between long-term cART exposure and cancer incidence and assess whether adjuvant anti-inflammatory therapies can reduce cancer risk during treated HIV infection.