Treatment Of Kaposi's Sarcoma Research Articles

Classic Kaposi's sarcoma: A review of 156 cases

Abstract Background Kaposi's sarcoma (KS) is a reactive, multifocal, multicentric, angiogenic neoplastic proliferation that is thought to originate from endothelial cells that are infected with human herpesvirus-8 (HHV-8). This report examines a cohort of patients with classic Kaposi's sarcoma (KS) evaluated at the national institute of oncology over the 13-year period. Methods A retrospective analysis of 156 patients with classic KS, between January 2000 and November 2013, was performed. This study focused on the clinical presentation, staging, diagnosis, and treatment of classic KS. Results One hundred fifty-six patients (median age 69 and 115 male) were enrolled into the study. Median age at diagnosis was 69 (range: 32–95 years). Male/female ratio was 2.80. The most common location was the lower limbs. There were 75 stage I patients (48.1%), 8 stage II patients (22.4%), 31 stage III patients (19.9%) and 15 stage IV patients (9.6%). Surgery was the most common local treatment method (43%). 44 patients (28.2%) received radiotherapy (RT) at diagnosis. Cytotoxic treatment with chemotherapy or interferon-α was administered in 57 patients. Visceral involvement was observed in 10 patients (lung: nine patients, liver: one patient) and bone metastasis occurred in two patients at relapse. Conclusion This study is one of the largest reported series. Further studies are required and it will be important to standardize the assessment of disease activity and clinical response.

Abstract 5140: Lipoxins and their role in Kaposi's sarcoma-associated herpesvirus (KSHV) infection and pathogenesis

Abstract Lipoxins are host anti-inflammatory molecules, which play a vital role in restoring tissue homeostasis. The efficacy of lipoxins and their analog epilipoxins in treating inflammation and related diseases have been well documented. Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL) are two well-known inflammation-related diseases caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Controlling inflammation is one of the strategies adopted to treat KS and PEL, a primary motivation for exploring and evaluating the therapeutic potential of using lipoxins. Our study demonstrates how KSHV manipulates and downregulates the secretion of the anti-inflammatory lipoxin A4 in host cells and the viral factors involved in this process using in vitro KS and PEL cells as models. Presence of lipoxin receptor [ALX/Formyl peptidyl receptor (FPR)] in human KS patient tissue sections and in vitro KS and PEL cell models offers a novel possibility for treating KS and PEL with lipoxins. Treating de novo KSHV-infected endothelial cells with lipoxin and epilipoxin creates an anti-inflammatory environment by decreasing levels of NFκB, AKT, ERK1/2, COX-2, and 5-lipoxygenase. Lipoxin treatment on CRISPR/CAS9 technology-mediated ALX/FPR gene-deleted U2OS cells revealed the importance of the lipoxin receptor ALX for effective lipoxin signaling. A viral miRNA cluster was identified as the primary factor contributing to the downregulation of lipoxin A4 secretion in host cells. The KSHV miRNA cluster probably targets enzyme 15-lipoxygenase, which is involved in lipoxin A4 synthesis. Lipoxin treatment in KSHV-infected cells has been shown to reduce cell proliferation and cell survival. Latency factor LANA-1 levels were found to decrease on lipoxin and epilipoxin treatment. Several pro-apoptotic gene levels were upregulated on lipoxin treatment. Several host transcription factors were found to play an important role in regulating KSHV life cycle. This study provides a new insight into the treatment of KS and PEL using nature's own anti-inflammatory molecule, lipoxin. Citation Format: Neelam Sharma-Walia, Jayashree A. Chandrasekharan. Lipoxins and their role in Kaposi's sarcoma-associated herpesvirus (KSHV) infection and pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5140.

Successful Treatment of Kaposi Sarcoma with Triple Visceral Localization After Kidney Transplant

Successful Treatment of Kaposi Sarcoma with Triple Visceral Localization After Kidney Transplant

Ribonucleotide Reductase Inhibitor 3-AP Induces Oncogenic Virus Infected Cell Death and Represses Tumor Growth.

Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human malignancies, particularly Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation while still lacking of effective therapeutic options. We recently found that the ribonucleotide reductase (RR) subunit M2 is potentially regulated by the key oncogenic HGF/c-MET pathway in KSHV-related lymphoma cells. One of RR inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) effectively induced apoptosis of KSHV+ lymphomas and suppressed tumor progression in vivo. In the current study, we found that 3-AP treatment selectively inhibited the proliferation of KSHV-infected endothelial cells, the major cellular components of KS, through inducing DNA damage, reducing the levels of intracellular iron and reactive oxygen species (ROS) and increasing viral lytic gene expression. By using a KS-like nude mouse model, we found that 3-AP treatment significantly suppressed KSHV induced tumorigenesis in vivo. Taken together, our data demonstrate targeting RR by 3-AP may represent a promising strategy for improving the treatment of KS in future.

Assessing the outcomes of HIV-infected persons receiving treatment for Kaposi sarcoma in Conakry-Guinea

BackgroundMédecins Sans Frontières is supporting comprehensive HIV care and treatment for Kaposi Sarcoma (KS) in Guinea, where antiretroviral coverage is low and access to KS treatment is very limited. We aimed to evaluate treatment response and survival outcomes of epidemic KS in this setting.MethodsRetrospective survival analysis of routinely collected clinical data of HIV-infected patients with clinically diagnosed KS, receiving ART and chemotherapy consisting of a combination of bleomycin and vincristine at the Donka National Hospital in Conakry between 2012 and 2015.ResultsA total of 225 patients were enrolled for KS treatment within the three-year period. Late presentation with stage T1 disease was common (82.7%). At the end of a median of 8 cycles of chemotherapy (IQR: 2–12), complete remission was observed in 65 (28.9%), partial remission in 53 (23.6%), stable disease in 15 (6.7%) and unknown response for all 92 (40.9%) patients who dropped out of care. The chances of achieving complete remission doubled after each additional cycle of chemotherapy (aOR = 2.09 95% CI: 1.44–3.01) but were reduced by about two-thirds for each additional month delay between treatment and onset of KS (aOR = 0.31, 95% CI: 0.11–0.86). Treatment response was seriously compromised in patients with woody skin oedema (aOR = 0.05, 95% CI: 0.01–0.38) and those with prior chemotherapy (aOR = 0.21, 95% CI: 0.05–0.80). The median survival time was 7.6 months (95% CI: 5.9–9.8). Attrition from care was reduced by 22% for every additional cycle of chemotherapy administered (aH0R = 0.78, 95% CI: 0.71–0.84) and was lower in those with complete remission compared with those with partial or no response (aHR = 0.05, 95% CI: 0.007–0.43).ConclusionThere has been an increased access to KS treatment. The overall response rate is 52.4%, which is considered a satisfactory result. Poor outcomes were common and were largely due to late presentation and defaulting on treatment. Efforts towards early HIV/KS diagnosis and adherence to a full round of chemotherapy are needed for optimising outcomes. Newer drugs may be required for patients previously exposed to chemotherapy.

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.

An In Vitro Model for Studying Cellular Transformation by Kaposi Sarcoma Herpesvirus.

Kaposi sarcoma (KS) is an unusual tumor composed of proliferating spindle cells that is initiated by infection of endothelial cells (EC) with KSHV, and develops most often in the setting of immunosuppression. Despite decades of research, optimal treatment of KS remains poorly defined and clinical outcomes are especially unfavorable in resource-limited settings. KS lesions are driven by pathological angiogenesis, chronic inflammation, and oncogenesis, and various in vitro cell culture models have been developed to study these processes. KS arises from KSHV-infected cells of endothelial origin, so EC-lineage cells provide the most appropriate in vitro surrogates of the spindle cell precursor. However, because EC have a limited in vitro lifespan, and as the oncogenic mechanisms employed by KSHV are less efficient than those of other tumorigenic viruses, it has been difficult to assess the processes of transformation in primary or telomerase-immortalized EC. Therefore, a novel EC-based culture model was developed that readily supports transformation following infection with KSHV. Ectopic expression of the E6 and E7 genes of human papillomavirus type 16 allows for extended culture of age- and passage-matched mock- and KSHV-infected EC and supports the development of a truly transformed (i.e., tumorigenic) phenotype in infected cell cultures. This tractable and highly reproducible model of KS has facilitated the discovery of several essential signaling pathways with high potential for translation into clinical settings.

An APE1 inhibitor reveals critical roles of the redox function of APE1 in KSHV replication and pathogenic phenotypes.

APE1 is a multifunctional protein with a DNA base excision repair function in its C-terminal domain and a redox activity in its N-terminal domain. The redox function of APE1 converts certain transcription factors from inactive oxidized to active reduced forms. Given that among the APE1-regulated transcription factors many are critical for KSHV replication and pathogenesis, we investigated whether inhibition of APE1 redox function blocks KSHV replication and Kaposi’s sarcoma (KS) phenotypes. With an shRNA-mediated silencing approach and a known APE-1 redox inhibitor, we demonstrated that APE1 redox function is indeed required for KSHV replication as well as KSHV-induced angiogenesis, validating APE1 as a therapeutic target for KSHV-associated diseases. A ligand-based virtual screening yielded a small molecular compound, C10, which is proven to bind to APE1. C10 exhibits low cytotoxicity but efficiently inhibits KSHV lytic replication (EC50 of 0.16 μM and selective index of 165) and KSHV-mediated pathogenic phenotypes including cytokine production, angiogenesis and cell invasion, demonstrating its potential to become an effective drug for treatment of KS.

Leveraging HIV Research and Implementation for Cancer and Noncommunicable Diseases in Malawi

Abstract 33 Background: Enabled by collaboration and political stability, Malawi is a global leader for HIV research and implementation. We undertook this work to identify ways to leverage successes in HIV treatment and research for cancer and noncommunicable diseases (NCDs). Methods: Over more than two decades, investment from the National Institutes of Health (NIH) and other funders has allowed Malawi participation in international HIV networks. As these sought to address HIV-positive cancer, investment occurred to increase pathology, improve cancer registration, scale up cervical cancer screening, and improve nursing and pharmacy skills for chemotherapy administration. This allowed Malawi to participate in multinational clinical trials for HIV-positive Kaposi sarcoma treatment and cervical cancer prevention. Building on this, Malawi was one of six countries in 2014 to receive an NIH U54 consortium award for HIV-positive malignancies and was one of six countries added to the National Cancer Institute (NCI) AIDS Malignancy Consortium. In 2016, expanding beyond HIV-positive cancer, Malawi was one of three countries invited to join a new NCI–International Agency for Research on Cancer esophageal cancer consortium, one of five recipients of a new NCI Burkitt lymphoma award, and one of six recipients of a new NCI P20 grant for a regional center of research excellence for NCDs. Malawi is also one of 11 countries to convene a Lancet noncommunicable diseases and injury poverty commission for NCDs and injury. Finally, partners have improved surveillance and treatment for hypertension, diabetes, injury, and sickle cell anemia, in part, through a national Knowledge Translation Platform for HIV-NCD integration. With this support and funding, career development opportunities are embedded for Malawian NCD researchers. Results: Building on successes in HIV treatment and research, Malawi has become a global leader for cancer and NCD research and implementation. Conclusion: Continue developing a multilateral national platform for NCD research and implementation that is globally impactful and can lead to measurable outputs for individual cancer and NCD focus areas. Funding: National Institutes of Health. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST No COIs from the authors.

Diagnosis and Treatment of Kaposi Sarcoma.

Kaposi sarcoma (KS) is the most common neoplasm of people living with HIV today. In Sub-Saharan Africa, KS is among the most common cancers in men, overall. Not only HIV-positive individuals present with KS; any immune compromised person infected with KS-associated herpesvirus (KSHV) or human herpesvirus 8 is at risk: the elderly, children in KSHV-endemic areas, and transplant recipients. KS diagnosis is based on detection of the viral protein latency-associated nuclear antigen (LANA) in the biopsy, but not all cases of KS are the same or will respond to the same therapy. Standard KS therapy has not changed in 20 years, but newer modalities are on the horizon and will be discussed.

Clinical and laboratory characteristics, staging, and outcomes of individuals with AIDS-associated Kaposi's sarcoma at an university hospital.

BackgroundKaposi's sarcoma continues to be the most common human immunodeficiency virus - associated neoplasm with considerable morbidity and mortality.ObjectiveTo describe the clinical and laboratory characteristics, initial staging, and outcomes of aids patients with Kaposi's sarcoma at an university hospital of Recife, Pernambuco.MethodsThis is a descriptive study with analytic character, retrospective, of a case series between 2004 and 2014.ResultsOf the 22 patients included in the study, 20 were aged <40 years (72.7%). The majority had CD4+ T lymphocyte counts of <200 cells/mm3 (77.3%) and human immunodeficiency virus loads of <100,000 copies/mL (78.9%). Lesions were most commonly observed on the skin (90%), and internal organs were affected in 11 of the 22 patients. Only 7 (31.8%) of the 22 patients were undergoing antiretroviral therapy (ART) at the time of Kaposis sarcoma diagnosis, and the initial disease staging classification was high risk (Aids Clinical Trials Group Oncology Committee) in 19 of the 22 patients (86.4%). Regarding Kaposi's sarcoma treatment, 17 of 22 patients (77.3%) underwent systemic chemotherapy + ART and 5 were treated exclusively with ART. Eight of the 22 patients died (36.5%); of these, 87.5% had died within one year of Kaposi's sarcoma diagnosis.Limitation of the studyWithout a control group, this study cannot be used to generate hypotheses.ConclusionsDespite the association between aids and late Kaposi's sarcoma diagnosis in the study population, including an unfavorable risk at the time of staging, a lower mortality rate was observed relative to other studies; this might be related to access to a specialized health service.

High-dose-rate brachytherapy in the treatment of skin Kaposi sarcoma.

PurposeThe aim of the study is to review our experience in treatment of Kaposi sarcoma (KS) lesions with high-dose-rate (HDR) brachytherapy.Material and methodsWe present five new KS lesions (three patients) that were treated in our hospital from May 2016 to February 2017 with HDR brachytherapy using Valencia applicators. The treatment was delivered in 5 Gy fractions over five sessions, on alternate days. Total dose of 25 Gy (EQD2 31.25 Gy) was delivered. All patients were male, Caucasian, without a history of HIV, organ transplantation, or current immunosuppressive therapy. The median age was 76 years.ResultsAll lesions (100%) were located in lower limbs (60% in the ankle, 20% in the leg, and 20% in the foot), and their development was progressive. No lesion was greater than 2 cm (range, 0.5-1.5 cm). With a median follow-up of 15 months, all patients had a complete response to the treatment, with no evidence of local recurrence or tumor progression. Most of the patients (80%) had no acute toxicity; only one patient developed erythema grade 2.ConclusionsHDR brachytherapy could be a good option of treatment for these types of lesions, especially in elderly patients, or when cosmetic results are not good after surgery. Brachytherapy with the Valencia applicator, using hypofractionated regimen provides excellent results in terms of cosmetic and local control, and furthermore, facilitates treatment compliance, which is very relevant in elderly patients. HDR brachytherapy offers a simple, safe, quick, and attractive non-surgical treatment option.

310P Oral leukoplakia in women treated with long-term pegylated liposomal doxorubicin

Background Pegylated liposomal doxorubicin (PLD) is approved forthe treatmentof Kaposi's sarcoma and recurrent ovarian cancer. Some case series have recently reported thatlong-termtreatmentwithPLDmaycausesquamouscellcarcinomaofthetongue and oral cavity. However, the natural history of these carcinomas is not fully understood. This study aimed to investigate changes in the oral cavity ofpatients treated with PLD. Methods After approval by the institutional review board, we searched medical records and found 16 patients with recurrent ovarian cancer who were administered more than 10cyclesofPLD.Inourhospital,everypatienttreatedwithPLDhasanoral examinationeachtimebeforetheadministrationofPLDforthepurposeofdetecting stomatitis.Weretrospectivelyreviewedthemedicalrecordsofthose16patients. Results ThemediannumberofcyclesofPLDwas13,andthemediandoseofPLDwas 625mg/m2.Leukoplakia,whichisknownasaprecancerouslesionoftheoralcavity,was diagnosed in six patients. Squamous cell carcinoma of the oral cavity was not observed in the patients included in our study. Among the six patients, the median number of cycles ofdiagnosis ofleukoplakiawas 16 (range, 9-19) andthe median dose ofPLD was 745 mg/m2. A strong tendency between the dose of PLD and leukoplakia was indicated usingthe Pearson correlation coefficient(0.84). Conclusions >Patientswithleukoplakiaoftheoralcavitywerefoundamongthose treatedwithlong-termPLDadministration.Theproportionofleukoplakiaincreasedin adose-dependentmanner.SquamouscellcarcinomaoftheoralcavityinducedbyPLD may be shown to arise from leukoplakia. Therefore, a periodic oral check is recommended, especially for patients who are administered more than 10 cycles ofPLD, to avoid squamous cell carcinoma ofthe oralcavity.Clinical trial indentification: 2016-1017 Legal entity responsible for the study Hidetaka Nomura Funding N/A Disclosure All authors have declared no conflicts ofinterest.

Altering the Anti-inflammatory Lipoxin Microenvironment: a New Insight into Kaposi's Sarcoma-Associated Herpesvirus Pathogenesis.

KSHV infection has been shown to upregulate several host proinflammatory factors, which aid in its survival and pathogenesis. The influence of KSHV infection on anti-inflammatory molecules is not well studied. Since current treatment methods for KS and PEL are fraught with unwanted side effects and low efficiency, the search for new therapeutics is therefore imperative. The use of nature's own molecule lipoxin as a drug is promising. This study opens up new domains in KSHV research focusing on how the virus modulates lipoxin secretion and warrants further investigation of the therapeutic potential of lipoxin using in vitro cell models for KS and PEL.

Clinical presentation and treatment outcome of HIV associated Kaposi sarcoma in a tertiary health centre in Nigeria

Objective: Kaposi sarcoma (KS) is the most common tumour among AIDS patients and is considered as an AIDS defining illness. However, the introduction of HAART has led to a decline in the incidence of the disease among these patients. The objective of this study is to review the clinical presentation, treatment and outcome of HIV associated KS in a tertiary health facility in Nigeria. Methods: Records of all patients that were managed with HIV associated KS from January 2012 to December 2014 at Aminu Kano Teaching Hospital were reviewed and data obtained was analysed using a computer statistical software. Results: During the period under review, 3705 patients were recruited in the antiretroviral treatment (ART) clinic out of which 24 were found to have HIV associated KS giving a period prevalence of 0.65%. The male to female ratio was 2.4:1. The mean age of the patients was 39.46 (±8.75) years. Six cases (25%) were diagnosed to have HIV as a result of KS. The remaining 75% were all on 1st line ARVs. Nine patients (37.5%) had treatment for Tuberculosis before they were diagnosed with KS. Based on the ACTG classification, 58.3% were poor risk group. Treatments given to the patients include HAART for 2 patients and 4 patients (16.7%) absconded. The remaining 18 patients had chemotherapy in the form of combination of intravenous Adriamycin, Bleomycin and Vincristine (ABV) with variable outcomes. Five patients failed ABV and had Paclitaxel given. At the end of the chemotherapy, 14 patients (58.3%) were in remission with 5 (20.8%) mortalities. There is no statistically significant difference between CD4 count before and after chemotherapy (P&gt;0.05) Conclusions: Majority of our patients are classified poor risk. Paclitaxel can be used as second line treatment. Treatment of KS does not improve CD4 count in patients with HIV. There is need to clinically identify patients with KS early in ART centre in order to improve outcome.

Demographic Characteristics and Preliminary Outcomes in a Cohort of HIV-Positive Patients With Kaposi's Sarcoma in a High ART Coverage Setting: A Report from Botswana

Abstract 50 Objective: Despite antiretroviral treatment coverage exceeding 90% by government estimates, Kaposi sarcoma (KS) remains the most prevalent malignancy in Botswana. Incidence has decreased minimally over the last decade. We sought to explore reasons for persistent high incidence and describe KS outcomes. Methods: Since 2010, consenting patients presenting to one of three oncology centers for KS treatment were enrolled prospectively and followed quarterly. Baseline HIV testing performed and records abstracted through April 2015. Results: 207 KS patients enrolled, 60% (125) with clinical diagnosis, 34% (71) with pathologic diagnosis, and 11 (6%) with radiologic/other diagnosis. Median age at diagnosis was 37 years (IQR: 11.9) and 63% (133) male. At presentation, 65% (134) had cutaneous and 24% (49) had disseminated disease. Revised ACTG staging was 8% (17) stage I, 54% (112) stage II, 35% (73) stage III. Nearly all, 98% (199), were HIV-infected with median nadir CD4 190 cells/μL (IQR: 208). Among HIV-infected patients, 68% (109) were not on ART at time of KS diagnosis and 26% (42) were diagnosed within first six months of ART. Of those not yet on ART, 72% (47) of men and 28% (18) of women had CD4 &lt;250 cells/μL, p=.0004. Few cases, 6 (10%), developed in patients on ART for &gt;6 months. Patients not on ART were referred to start. 71% (146) received chemotherapy and 7% (15) required radiation. After median follow-up 19 months, 21% (43) patients had died. Estimated 3-year OS was 76% (95% CI: 69-82%). Gender, ART duration, disease extent, and stage did not significantly predict survival. Conclusions: With high population ART coverage, KS development among individuals with CD4&lt;250 cells/μL accounts for majority of cases referred for oncologic treatment. ART delay, particularly among men, also contributed to persistent KS burden. Overall survival with KS in Botswana is similar to US and Europe. Initiation of ART at higher CD4 thresholds is needed to control the KS epidemic. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Shekinah N. Elmore No relationship to disclose Elizabeth S. Bigger No relationship to disclose Mukendi K.A. Kayembe No relationship to disclose Zola Musimar No relationship to disclose Gita Suneja No relationship to disclose Jason A. Efstathiou Honoraria: Medivation/Astellas, Bayer Healthcare Pharmaceuticals Consulting or Advisory Role: Medivation/Astellas, Bayer Healthcare Pharmaceuticals Scott Dryden-Peterson Patents, Royalties, Other Intellectual Property: UpToDate

Pulmonary Kaposi Sarcoma: An Uncommon Cause of Respiratory Failure in the Era of Highly Active Antiretroviral Therapy-Case Report and Review of the Literature.

Kaposi Sarcoma (KS) is the most common malignancy associated with Acquired Immune Deficiency Syndrome (AIDS) and is caused by Human Herpesvirus 8 (HHV 8) or Kaposi Sarcoma Herpesvirus (KSHV). In about 90% of cases Kaposi Sarcoma is associated with cutaneous lesions; however visceral disease can occur in the absence of cutaneous involvement. In the era of Highly Active Antiretroviral Therapy (HAART), the incidence of KS has declined. Clinical features of pulmonary KS might be difficult to distinguish from pneumonia in the immunocompromised patients and could lead to diagnostic challenges. First-line treatment of KS is with HAART and the incidence has declined with its use. Systemic chemotherapy may play a role depending on the extent of the disease. We report the case of a young man who presented with pulmonary symptoms and was later found to have pulmonary KS. Interestingly this diagnosis was made in the absence of the classic skin lesions. His disease was complicated by progressive respiratory failure and he eventually died.

Vinorelbine therapy in classic Kaposi's sarcoma: a retrospective study of 20 patients.

Systemic chemotherapy is the main treatment of diffuse and/or aggressive classic Kaposi's sarcoma (KS) but there are no standard treatment guidelines and published literature regarding vinorelbine is lacking. To assess the safety and effectiveness of intravenous vinorelbine in the treatment of classic KS. We performed a retrospective study of a departmental database in histologically proven classic KS. Twenty patients received intravenous vinorelbine as cycles of 20 mg/m(2) once every two weeks for 5 cycles and subsequently at a dose of 30 mg/m(2) once every three weeks. Of 19 assessable patients, three (16%) had a complete remission and 11 (58%) had a partial response, for an overall response rate of 74%. The remaining 5 patients had a stable disease (26%). Grade 3 or 4 toxicities were neutropenia (3/20 patients), deep vein thrombosis (1/20 patients) and constipation (1/20 patients). The median progression-free survival from the start of therapy until the development of progressive disease was 35.1 months. Vinorelbine is an effective and overall well tolerated treatment for classic KS.

Cellular MicroRNA Let-7a Suppresses KSHV Replication through Targeting MAP4K4 Signaling Pathways

BackgroundKaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is the etiologic agent of KS, the most common AIDS-related malignancy. The majority of KS tumor cells harbor latent KSHV virus but only a small percentage undergoes spontaneous lytic replication. Viral reactivation from latency is crucial for the pathogenesis and development of KS, but the cellular mechanisms underlying the switch between viral latency and replication are not well understood.MethodsThe level of let-7 miRNAs and MAP4K4 in KSHV infected 293T cells were quantified by real-time PCRs. Let-7 expression was silenced by the miRNA sponge technique. In let-7a transfected 293T cells, the expression of MAP4K4 was measured by real-time PCR and western blot. Luciferease expression was employed to examine the effect of let-7a on the 3’-untranslated region (UTR) of the MAP4K4 gene in 293T cells. Real-time PCR was used to quantify the KSHV copy numbers in BC-3 cells in which the expression of let-7a and/or MAP4K4 were altered. Finally, ERK, JNK and p38 protein production and their phosphorylation status were detected by western blots in let-7a or MAP4K4 transfected BCBL-1 cells.ResultsThe expression of microRNA let-7 was dramatically decreased in KSHV infected 293T cells, but that of MAP4K4 was increased significantly. Let-7a is physically associated with and targets the MAP4K4 3’UTR, and inhibits MAP4K4 expression at both mRNA and protein levels. MAP4K4 stimulates KSHV reactivation from latency, whereas let-7a inhibits the function of MAP4K4 by reversing the function of MAP4K4 on JNK, phospho-JNK and phospho-ERK1/2 levels.ConclusionOur results establish that let-7a specifically suppresses MAP4K4 expression, and further inhibits KSHV reactivation by interfering with the function of MAP4K4 on the MAPK pathway, highlighting let-7a as a potential treatment for KS.

KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi's sarcoma.

Kaposi's sarcoma (KS) is a vascular neoplasm caused by infection of endothelial or endothelial precursor cells with the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8). Research efforts have focused on defining the molecular events explaining how KSHV promotes pathological angiogenesis and KS tumor formation. mTOR/HIF-1 is a fundamental pathway driving these processes through the upregulation of angiogenic and inflammatory proteins, including VEGF, ANGPTL4, and ANGPT2. Interestingly, HIF-1 has also been implicated in the upregulation of metabolic genes associated with aerobic glycolysis and the growth of solid tumors. However, whether HIF-1 plays a role in regulating cell metabolism in KS remains unexplored. Here, we show that the HIF-1 metabolic effector, pyruvate kinase 2 (PKM2), is upregulated upon KSHV infection of endothelial cells and is necessary to maintain aerobic glycolysis in infected cells. We further demonstrate that PKM2 regulates KS angiogenic phenotype by acting as a coactivator of HIF-1 and increasing the levels of HIF-1 angiogenic factors, including VEGF. Indeed, inhibition of PKM2 expression blocked endothelial cell migration and differentiation and the angiogenic potential of KSHV-infected cells. We also investigated whether PKM2 regulates the angiogenic dysregulation induced by the KSHV-encoded G protein-coupled receptor (vGPCR), a viral oncogene that promotes Kaposi's sarcomagenesis through the upregulation of HIF angiogenic factors. Interestingly, we found that PKM2 controls vGPCR-induced VEGF paracrine secretion and vGPCR oncogenesis. Our findings provide a molecular mechanism for how HIF-1 dysregulation fuels both angiogenesis and tumor metabolism in KS and support further investigations on therapeutic approaches targeting HIF-1 and PKM2 for KS treatment.