Treatment Of Kaposi's Sarcoma Research Articles

Clinical Significance of Elevated KSHV Viral Load in HIV-Related Kaposi's Sarcoma Patients in South Africa.

Kaposi's sarcoma (KS) is an AIDS-defining illness caused by Kaposi's sarcoma-associated herpesvirus (KSHV) predominantly in the context of HIV-related immune suppression. We aimed to explore the usefulness of KSHV DNA viral load (VL) measurement in predicting the severity, response to treatment and outcome of KS. We retrospectively assessed a cohort of KS patients (n = 94) receiving treatment at Groote Schuur Hospital, Cape Town, South Africa. Demographic and clinical data, KS staging and response to treatment were extracted from patient files, while long-term survival was ascertained from hospital records. KSHV serology and VL and hIL-6 were determined empirically from patients' blood. All patients were HIV-positive adults, the majority of whom were on HAART at the time of recruitment. KSHV VL was detectable in 65 patients' blood (median: 280.5/106 cells (IQR: 69.7-1727.3)) and was highest in patients with S1 HIV-related systemic disease (median 1066.9/106 cells, IQR: 70.5-11,269.6). KSHV VL was associated with the S1 stage in a binomial regression controlling for confounders (adjusted odds ratio 5.55, 95% CI: 1.28-24.14, p = 0.022). A subset of six patients identified to have extremely high KSHV VLs was predominantly T1 stage with pulmonary KS, and most had died at follow-up. In our cohort, elevated KSHV VL is associated with systemic HIV-related illness in KS disease. Extremely high KSHV VLs warrant further investigation for patients potentially requiring intensive treatment and investigation for progression or diagnosis of concurrent KSHV lytic syndromes.

Evaluating Kaposi Sarcoma in Kidney Transplant Patients: A Systematic Review and Meta-Analysis.

Kaposi's sarcoma (KS) is a malignancy that commonly appears as lesions on the skin or mucosal surfaces but can also develop in other organs. This cancer is usually caused by the human herpesvirus 8 (HHV-8), recently known as Kaposi's sarcoma-associated herpesvirus (KSHV). KS is rare in the general population but can develop in kidney transplant recipients with varying incidence due to immunocompromised status from immunosuppression. The main aim of the present systematic review was to identify the prevalence and treatment of KS in kidney transplant patients. PubMed, Cochrane Library, and Google Scholar databases were searched for studies until October 2023. Full-text studies with similar research objectives were included, while non-English articles, reviews, case reports, ongoing clinical trials, and studies evaluating KS in HIV patients or after other solid organ transplants were excluded. All studies were observational; therefore, methodological quality was assessed using the Newcastle-Ottawa Scale. The statistical analyses were performed with the Comprehensive Meta-Analysis (CMA) software (Biostat, Inc.Englewood, NJ). The pooled analysis from the 15 studies includedshowed that KS develops in 1.5% of kidney transplant recipients and is more prevalent in African (1.7%) and Middle Eastern (1.7%) recipients than in Western recipients (0.07%). KS was also significantly more prevalent among male recipients than female recipients (OR: 2.36; p < 0.0001). Additionally, cyclosporine-based immunosuppression accounts for most KS incidences (79.6%) compared to azathioprine-based immunosuppression (28.2%). Furthermore, reduction or withdrawal of immunosuppression alone resulted in 47.8% KS complete remissions. Post-kidney transplantation KS is more frequent among males and patients of Middle Eastern and African origin. However, the gender difference may be attributed to most patients undergoing kidney transplants being male. Therefore, if gender balance is considered in future studies, then the difference might be insignificant. Based on our results, we can concur that the mainstay treatment for post-transplant KS is reduction or withdrawal of immunosuppression. However, the patients should be closely monitored to avoid KS recurrence and kidney rejection. Furthermore, there is an increased risk for KS with the use of cyclosporine-based immunosuppression. However, this does not mean that the withdrawal of this immunosuppression agent might result in improved KS outcomes because the withdrawal of azathioprine with or without cyclosporine reduction has also led to improved outcomes.

Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKƴ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Description of Patients with HIV and Multicentric Castleman's Disease at the National Institute of Cancerology- Mexico: A 9-Year Experience

Castleman disease is a diverse group of lymphoproliferative disorders with four variants sharing common morphological features on lymph node biopsy but having different etiologies, presentations, treatments, and outcomes. It is classified into unicentric and multicentric variants (MCD), the latter being a systemic disease with multiple lymphadenopathy, where the most common pathological finding is changes in plasma cell type. Based on etiopathogenic characteristics, it can be divided into Kaposi sarcoma herpesvirus (HHV8)-associated, idiopathic, and those related to an overlap with POEMS syndrome. This disease can occur in both HIV-positive individuals and immunocompromised individuals due to other causes. Here, we report our experience with a cohort of HIV-associated MCD cases from 2014 to 2022. A total of 21 patients diagnosed with HIV and HHV8-associated MCD were observed at INCAN during the study period. The majority were men (95%), with a median age of 33y (range, 25 to 54y). The main histologic MCD type was plasma cells (52%), followed by the mixed variant (28%) and the hyaline vascular type (19%). Almost half of the patients were newly diagnosed with HIV (43%), and half of them had a CD4 cell count below 200 cells/mm3 at the time of MCD diagnosis (48%). Only 38% of known HIV patients were taking combination antiretroviral therapy (cART) at the moment of MCD diagnosis. The vast majority (95.2%) were HHV-8 positive by immunohistochemistry, and 66.7% were associated with Kaposi sarcoma. About 52.4% of cases had another active opportunistic infection documented. The most frequently associated infection was syphilis (33.3%), EBV coinfection (23.8%), hepatitis B (14.3%), hepatitis C (4.8%), and CMV viremia (4.8%). 90% of patients developed B symptoms, 71% had fever, 100% had palpable adenopathy, 71% developed hepatosplenomegaly, and 19% had pleural effusion at presentation. In blood analysis, elevated LDH was present in 42.9%, hypoalbuminemia in 71.4%, thrombocytopenia (&amp;lt;100,000) in 35%, anemia (Hb &amp;lt; 8g/dl) in 20%, and renal failure (GFR &amp;lt;30 ml/min/1.73m2) in 10% of cases. The treatment for Kaposi sarcoma at entry was a bleomycin and vincristine-based regimen in 52% of patients, with a median of 2 cycles (range 1-7). Five patients (23%) achieved a complete response without requiring additional treatment. Three patients (14%) with MCD attack criteria resolved systemic symptoms only with cART. Unfortunately, 14% of patients died before receiving treatment, and 38% were managed with “wait and watch” because they did not meet the criteria for MCD attack. The remaining 47% received treatment, with the most common regimens being R-Dox (20%), RCHOP (30%), CHOP (30%), Dox-liposomal (10%), and R-Etoposide (10%), with a median of 4 cycles (range 1-7). Eight patients (38%) received ganciclovir maintenance treatment until reaching negative HHV8 viral load. During the 9 years of follow-up, a total of 5 patients (23.8%) died, with 80% of them experiencing disease progression. The overall survival at 24 months was 77% (figure 1) , and the median survival was not reached at the time of evaluation. In conclusion, our patients with HIV-associated MCD demonstrated similarities to global epidemiological data, with a predominant male population and onset between the fourth and fifth decade of life. The most common histology was the plasmacytic cell subtype, and B symptoms were frequently observed. Hepatosplenomegaly was more prevalent than previously described, anemia and thrombocytopenia appeared to be more common hematological manifestations than reported. Due to a significant percentage of patients having uncontrolled HIV at diagnosis, and unknown KS at the same time of the diagnosis, further research is needed to establish a direct association with MCD and HIV pathophysiology in which clinical manifestations of the disease are diverse an lack specificity, and the prognosis varies greatly. Additionally, concomitant infections may play a role as activators of systemic inflammation and require active screening for MCD in patients with these characteristics. While Kaposi sarcoma treatment was effective in controlling both diseases in some cases, additional management may be necessary, with promising results seen with different treatments. Early intervention for cytokine release syndrome is essential to improve patient outcomes. 1.Blood 2020 Apr16;135(16):1353-64. 2.Nat Rev Dis 2021 Nov 25;7(1):84

Lymphedema and Kaposi sarcoma: A narrative review

Kaposi sarcoma (KS), due to HHV-8 infection is classified in 4 subtypes: epidemic, endemic, HIV-related and iatrogenic essentially after organ transplant. Lymphedema is a complication of KS. We reviewed the interactions between HHV-8 infection and lymphedema according an analysis of the literature. HHV-8 can infect different types of cells, among them a privileged tropism for lymphatic endothelial cells. It induces multi-centric endothelial proliferation leading to the occlusion of lymphatic vascular lumen. Lymphatic obstruction progressively lead to the blockage of lymphatic drainage, lymph stasis and lymphedema. Lymphedema mostly involved the lower limb affected by KS. It can then develop simultaneously or after the appearance of KS lesions but also be the first sign of KS, a long time before KS skin lesion onset. Lymphedema diagnosis is clinical and lymphoscintigraphy can confirm it if necessary. Lymphedema may be associated with active lesions of KS or non-evolutive, with only cicatricial lesions. KS should be treated according to the KS subtype, aggressive form, with local or systemic treatments associating with causal treatment, such as HIV infection or reducing immuno-suppressive drugs in transplant patients. In most of the cases, KS treatment may slightly reduce (or not) lymphedema volume which remains a chronic disease. Lymphedema management should be associated in order to reduce the volume and then stabilizing it. Low-stretch bandage, elastic garments and skin care are the cornerstone of treatment. Lymphedema is a frequent complication of KS, and may reveal KS or occurs throughout its course. Association of KS and lymphedema must be known because lymphedema is a chronic disease affecting the quality of life. Beyond the treatment of KS, its management must be specific including a long follow-up to optimize the patient's observance required to maintain the best lymphedema control.

Exploring the interactions of antihistamine with retinoic acid receptor beta (RARB) by molecular dynamics simulations and genome-wide meta-analysis

Kaposi sarcoma (KS) is one of the most common AIDS-related malignant neoplasms, which can leave lesions on the skin among HIV patients. These lesions can be treated with 9-cis-retinoic acid (9-cis-RA), an endogenous ligand of retinoic acid receptors that has been FDA-approved for treatment of KS. However, topical application of 9-cis-RA can induce several unpleasant side effects, like headache, hyperlipidemia, and nausea. Hence, alternative therapeutics with less side effects are desirable. There are case reports associating over-the-counter antihistamine usage with regression of KS. Antihistamines competitively bind to H1 receptor and block the action of histamine, best known for being released in response to allergens. Furthermore, there are already dozens of antihistamines that are FDA-approved with less side effects than 9-cis-RA. This led our team to conduct a series of in-silico assays to determine whether antihistamines can activate retinoic acid receptors. First, we utilized high-throughput virtual screening and molecular dynamics simulations to model high-affinity interactions between antihistamines and retinoic acid receptor beta (RARβ). We then performed systems genetics analysis to identify a genetic association between H1 receptor itself and molecular pathways involved in KS. Together, these findings advocate for exploration of antihistamines against KS, starting with our two promising hit compounds, bepotastine and hydroxyzine, for experimental validation study in the future.

Effectiveness and safety of conventional systemic treatments in classical and endemic Kaposi sarcoma: A multicentric retrospective study of 110 patients.

e21584 Background: Apart from post-transplant Kaposi sarcoma (KS), 2 major subtypes of non-HIV-related KS are described: classical Kaposi sarcoma (CKS) in patients originated from Mediterranean countries and endemic KS (EKS) in patients of sub-Saharan Africa origin. Some patients with aggressive EKS or CKS require systemic treatments among which liposomal anthracycline (LA), taxanes and, to a lesser extent, low dose interferon (LDI) are generally recommended as first lines. Recently, anti-PD1 have shown promising results in an early phase II trial. At the dawn of a turning point in therapeutic era, we aim to map the effectiveness and safety of the main conventional systemic treatments usually available in KS. Methods: We performed a national multicentric retrospective study including all patients receiving a systemic treatment for a histologically proven KS between January 1st 2013 to July 1st 2019. HIV infected patients and patients treated with immunosuppressive drugs were excluded. Overall response was defined as a decrease of more than 50% of lesion area and serious adverse events encompassed grade 3 and 4 toxicity. Results: A total of 110 patients were included. Sixty-nine had CKS (62.7%) and 41 had EKS (37.2) with a median age at diagnosis of 69 (IQR: 57-77) and 41 years (37-59) (p = 0.011), respectively. At the time of diagnosis, EKS was associated with greater systemic involvement compared with CKS (36.6% vs 14.9%, p = 0.017). First-line therapy was initiated within a median of 13.8 months (2.9-43) after KS diagnosis. The 3 main regimens were taxanes (27.3%), LA (19.1%) and LDI (19.1%) with response rates of 82.8%, 80% and 52.6% (p = 0.063), respectively. The cumulative incidence of a second line of treatment in the first 2 years of follow-up was 49.5% (CI95% 38.7-59.4), without significant difference according to the different regimens. Toxicity, regardless of grade, was reported more frequently with LDI (55.3%) and taxanes (47.8%) than with LA (30.4%) (p = 0.035). Poor tolerability led to discontinuation of LDI more frequently than LA (OR = 4.17, p = 0.048), without difference for taxanes. There was no difference in serious adverse events between the 3 main regimens. CKS and EKS didn’t differ regarding overall response rate or time to next treatment regardless of treatment regimens. However, response rates tended to decrease as the lines went on for EKS (from 77.5% in 1st to 33.3% in 3rd line, p = 0.005), in contrast to CKS who maintained a sustained response, with more frequent systemic involvement (56% vs 25.4%, p = 0.002) during EKS course. Conclusions: Herein, we highlight LA, taxanes and LDI are safe and effective treatments for non-immunodeficient KS. Furthermore, EKS differed from CKS, occurring in younger patients, with more frequent systemic involvement and response loss through therapeutic lines, emphasizing the need to evaluate new agents in this form of KS.

A false positive 68Ga-DOTA-TATE involvement in an adrenal mass: Kaposi Sarcoma

Abstract Introduction Pheochromocytomas (PCC) are rare tumors (0.8/100000) arising from adrenal medulla cells. The most common symptom of PCC is persistent high blood pressure. Apart from symptomatic cases, PCCs can also be asymptomatic and can be detected incidentally. Surgical treatment is urgent if catecholamine hypersecretion is detected. After the detection of hormonal hyperfunction in patients with PCC, the diagnosis is confirmed by anatomical and functional imaging. As we all know, there is no possibility of histopathological diagnosis before surgery in PCC. Therefore, rare coexistence of false positive Ga68-DOTA-TATE uptake and falsely high urinary catecholamine metabolite levels may lead to adrenalectomy of the patients without PCC. Here we describe a patient who underwent adrenalectomy with a prediagnosis of PCC but received a different pathological diagnosis. Clinical Case A 50-year-old male patient who was diagnosed with AIDS after being investigated for fever of unknown origin was referred to the endocrinology department because of a mass in the left adrenal gland. The patient had complaints of headache, palpitation and sweating. On physical examination, there was a red nodular lesion on his face and a palpable lymph node in the inguinal region. His blood pressure was 160/100 mm-Hg, pulse was 100/min and body temperature were 37.1°C. Ambulatory blood pressure measurements showed that the patient's blood pressure was constantly high. Non-contrast CT showed a tumor of 20×15 mm in size (Hounsfield Unit:38) in the left adrenal gland (Fig-1). In terms of hormonal hyperfunction, no cortisol or aldosterone hypersecretion was detected, but urine normetanephrine was found to be 4 times higher than the upper normal limit (Table 1). Functional imaging revealed pathologically increased Ga68-DOTA-TATE uptake in the left adrenal mass and multiple lymph nodes (SUVmax 5.9 and 3.2) (Fig-1). The pathology of the patient who underwent simultaneous inguinal lymph node excision and adrenalectomy was reported as Kaposi sarcoma (KS). The patient is currently receiving treatment for AIDS and KS. Conclusion KS is a type of cancer that occurs especially in immunocompromised patients. Although there have been publications in the last decade suggesting that 18F-FDG-PET/CT imaging may be beneficial in KS, there are no articles recommending the use of Ga68-DOTA-TATE. Upregulation of neuroendocrine genes has also been shown in publications investigating KS, which is thought to originate from endothelial cells. This may explain why there is Ga68-DOTA-TATE involvement in these lesions. Pheochromocytoma is referred to as “the great mimicker” in the articles of radiology and its similarity with all types of adrenal lesions causes PCC to not be excluded by anatomical imaging. We wanted to share these two diseases, which are very unlikely to come together and cause confusion, and explain the factors that can lead to this confusion.

Overall improved survival of patients with Kaposi Sarcoma and lagging survival of HIV-infected patients with Kaposi Sarcoma in a National Cancer Database Analysis, 2004-2018

To the Editor: Kaposi Sarcoma (KS) is a relatively rare cutaneous and mucous membrane cancer,1 disproportionately affecting HIV-infected patients in the United States.2 Since large KS multi-center studies are outdated, we aimed to update demographics and characterize trends in KS presentation and treatment.

Literature review: Kaposi’s sarcoma pathogenesis, symptoms, diagnostic and therapeutic innovations

Paulina Petraitytė1 1 Vilnius University, Faculty of Medicine, Vilnius, Lithuania. Abstract Introduction. Kaposi’s sarcoma is a complex multifactorial angioproliferative disease caused by a virus and damage to the immune system. Clinically malignant blood or lymphatic vascular disease of many vascular nodules in the skin and internal organs. Four subtypes of the disease are distinguished, ranging from slow, only with skin lesions to lightning, which is characterized by severe visceral damage and complications. Materials and methods. Sources were colected using the PubMed database. Mainly 4 filters were used in the search: “Kaposi sarcoma”, “HHV-8”, “Kaposi sarcoma treatment”, “Kaposi sarcoma HIV”. Additionally we applied language, type, publication access, and time filters. Used sources were published in the last 10 years. Innovations in treatment and diagnostics are reviewed using sources published in 2019-2021. A total of 21 bibliographic records were used in the review. After a thorough review of the titles, abstracts, and full text, 16 publications were selected and an additional 5 publications were selected manually. Aim. To review the latest data on the clinical, diagnostic, and therapeutic features of Kaposi’s sarcoma. Results and Conclusions. Kaposi’s sarcoma is a significant diagnostic challenge in a physician’s professional practice. The main goal of treatment of Kaposi’s sarcoma is to inhibit the progression of the disease and to improve the patient’s general and physical well-being. In order to do that and prevent further complications this article comments on newest local, systemic and combined treatments. Key words: Kaposi’s sarcoma, rash, AIDS, HHV-8.

Telling the story of intersectional stigma in HIV-associated Kaposi's sarcoma in western Kenya: a convergent mixed-methods approach.

IntroductionThe experience of stigma can be multifaceted for people with HIV and cancer. Kaposi's sarcoma (KS), one of the most common HIV‐associated cancers in sub‐Saharan Africa, often presents with visible skin lesions that may put people at risk for stigmatization. In this way, HIV‐associated KS is unique, as people with KS can experience stigma associated with HIV, cancer, and skin disease simultaneously. The aim of this study is to characterize the intersectionality of HIV‐related, cancer‐related and skin disease‐related stigma in people living with HIV and KS.MethodsWe used a convergent mixed‐methods approach nested within a longitudinal study of people with HIV‐associated KS in western Kenya. Between February 2019 and December 2020, we collected quantitative surveys among all participants and conducted semi‐structured interviews among a purposive sample of participants. Quantitative surveys were adapted from the abridged Berger HIV Stigma Scale to assess overall stigma, HIV‐related stigma, cancer‐related stigma, and skin disease‐related stigma. Qualitative data were coded using stigma constructs from the Health Stigma and Discrimination Framework.ResultsIn 88 semi‐structured interviews, stigma was a major barrier to KS diagnosis and treatment among people with HIV‐associated KS. Participant's stories of stigma were dominated by HIV‐related stigma, more than cancer‐related or skin disease‐related stigma. However, quantitative stigma scores among the 117 participants were similar for HIV‐related (Median: 28.00; IQR: 28.0, 34.0), cancer‐related (Median: 28.0; IQR: 28.0, 34.8), and skin disease‐related stigma (Median: 28.0; IQR: 27.0, 34.0). In semi‐structured interviews, cancer‐related and skin disease‐related stigma were more subtle contributors; cancer‐related stigma was linked to fatalism and skin‐related stigma was linked to visible disease. Participants reported resolution of skin lesions contributed to lessening stigma over time; there was a significant decline in quantitative scores of overall stigma in time since KS diagnosis (adjusted β = –0.15, p <0.001).ConclusionsThis study highlights the role mixed‐method approaches can play in better understanding stigma in people living with both HIV and cancer. While HIV‐related stigma may dominate perceptions of stigma among people with KS in Kenya, intersectional experiences of stigma may be subtle, and quantitative evaluation alone may be insufficient to understand intersectional stigma in certain contexts.

Treatments for AIDS/HIV-related Kaposi sarcoma: A systematic review of the literature.

Treatment guidelines are not well established in AIDS-related Kaposi sarcoma (KS). We aim to review the evidence on efficacy of treatments for AIDS-related Kaposi sarcoma. We searched the Cochrane Library, PubMed, and Embase Database from date of database inception till July 2020. Randomized controlled trials reporting intervention consisting of any type of treatment compared to control/placebo to a different treatment modality or different combination of treatment/treatment doses with a diagnosis of AIDS-related KS are selected. Primary outcomes were response rates defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Secondary outcomes were cosmesis and adverse outcomes such as pain and erythema. Thirteen out of 536 articles met our eligibility criteria. Three studies reported the efficacy of chemotherapy, two studies looked at different doses of radiotherapy regimes, and three studies compared different antiretroviral therapy (ART) and chemotherapy regimens. Other studies reported topical therapies such as alitretinoin gel, IM862, and bHCG injection which showed varied efficacies. Lack of standardization classification of disease activity and clinical outcomes and treatment modalities precluded meaningful comparison of studies. The evidence of efficacy of any particular intervention is overall varied and there was insufficient evidence to recommend any particular intervention. We have provided an overview of treatments for KS but larger studies need to be carried out to verify the efficacy of treatment options reported in the literature.

Kaposi's sarcoma-associated herpes virus-derived microRNA K12-1 over-activates the PI3K/Akt pathway to facilitate cancer progression in HIV-related gastrointestinal Kaposi's sarcoma.

Kaposi's sarcoma-associated herpes virus (KSHV) initiate and accelerate the development of Kaposi's sarcoma (KS), and KSHV possesses many cancer-associated genes, including KSHV-derived microRNA miR-K12-1, which has been identified to be closely associated with KS progression. However, the detailed mechanisms by which miR-K12-1 facilitates HIV-related gastrointestinal KS development are still not fully delineated. This study strived to evaluate the effect of miR-K12-1 on the progression of HIV-related gastrointestinal KS. The expression levels of miR-K12-1 in HIV-related gastrointestinal KS tissues were determined by RT-qPCR. Proliferation and apoptosis were assessed by colony formation, CCK-8 and flow cytometry, respectively. The expression of all proteins was detected by Western blot. The in vivo effect of miR-K12-1 on the formation of a tumor was explored by using the mouse xenograft model. In this study, we uncovered that KSHV-miR-K12-1 was upregulated in HIV-related gastrointestinal KS tissues and associated with poor outcome in HIV-related gastrointestinal KS patients. Compared with the control group, after miR-K12-1 inhibitor transfection, BCBL-1 cell viability was decreased, and the cell apoptosis was significantly increased, whereas transfection of miR-K12-1 mimics promoted cell proliferation and mitosis. In addition, our rescuing experiments verified that miR-K12-1 promoted cell proliferation via activating the PI3K/Akt pathway, and inhibition of the PI3K/Akt pathway by LY294002 abrogated the tumor-promoting effects of miR-K12-1 in HIV-related gastrointestinal KS. In summary, we concluded that KSHV-derived miR-K12-1 activate the PI3K/Akt pathway to initiate and accelerate the development of KS, which convinces us that miR-K12-1 can be used as potential biomarkers for KS diagnosis, treatment and prognosis.

Reflectance confocal microscopy for Kaposi's sarcoma treatment monitoring after intralesional vincristine chemotherapy.

Kaposi's sarcoma (KS) is a multifocal systemic disease, originating from endothelial cells mainly affecting elderly men. Intralesional chemotherapy with vinblastine or vincristine is an effective and well‐tolerated treatment in patients presenting single nodules on the skin. Despite reflectance confocal microscopy represents a useful diagnostic method for many dermatological diseases, to date, there are few data regarding the use of RCM in mucocutaneous KS. Objective of this study was to evaluate the use of RCM for therapeutic follow‐up in KS patients treated with intralesional vincristine. An observational retrospective study involving patients with a histological diagnosis of classic KS was conducted. All patients were treated with intralesional vincristine; reflectance confocal microscopy images were taken for each patient at baseline (T0) and 1 month after vincristine injection. Four male patients with a median age of 76.8 years were included in the study and four nodules (one for each patient) were evaluated with RCM examination before and after vincristine injections. At 1 month from intralesional vincristine treatment, therapeutic response was confirmed at RCM examination; a reduction of inflammatory cell at the stratum spinosum level in all evaluated lesions was observed; at papillary dermis levels, black luminal structures were decreased in diameter and superficial linear canalicular structures were not represented. Aggregates of inflammatory cells and of hemosiderin deposition, at the dermal level, were reduced in number. Reflectance confocal microscopy showed to be a promising method to evaluate vincristine therapeutic response in patients with KS; further studies evaluating RCM use in KS patients in order to monitor treatment efficacy are still required.

Topical treatments for Kaposi sarcoma: A systematic review.

BackgroundWhile treatment options exist for solitary or disseminated Kaposi sarcoma (KS) disease, there are currently no standardized clinical treatment guidelines for cutaneous KS.ObjectiveThis systematic review seeks to identify safe and effective topical treatments for cutaneous KS lesions.MethodsWe conducted a systematic review using peer‐reviewed articles from January 1970 to September 2021 published in the PubMed/MEDLINE and EMBASE databases.ResultsFrom the initial search that yielded 590 studies, 34 met the inclusion criteria and were selected. Of the 34 studies, seven were clinical trials, 26 were case reports/series and one was a multicentre study. A total of 634 patients were included in our review. The three most common topical treatments used for cutaneous KS were imiquimod, alitretinoin and timolol. Topical alitretinoin was used in three case reports and three clinical trials. Topical imiquimod was used in eight case reports, one prospective phase II cohort study and one comparative single‐blinded non‐controlled clinical study. Topical timolol was used in nine case reports/series. Our review also identified reports of less widely used topical treatments for cutaneous KS. These include topical diphencyprone (DPCP), all‐trans‐retinoic‐acid, rapamycin and bleomycin‐dimethylsulfoxide (BLM‐DMSO) which achieved variable response rates but have not been widely studied.ConclusionTopical alitretinoin, imiquimod and timolol demonstrated positive responses for cutaneous KS and the treatments were well tolerated. These three topical treatment modalities could be considered by clinicians when treating cutaneous KS.

Effectiveness and Safety of Treatment with Neodymium:YAG Laser 1064 nm in Patients with Classic and Epidemic Kaposi Sarcoma.

Kaposi’s sarcoma (KS) is a vascular neoplasm Herpes Virus 8 (HHV8), which can affect the skin, mucous membranes and viscera. There is currently no standard treatment for KS; this study evaluated the efficacy and safety of Neodymium:YAG (Nd:YAG) laser 1064 nm treatment in patients with classic and HIV-associated KS. 15 patients with classic KS (group A) and 15 with epidemic KS (group B), with exclusively cutaneous localization, were treated with Nd:YAG laser 1064 nm. Four treatment sessions were performed at 4 weeks intervals. 24/30 (80%) of treated patients underwent clinical improvement. Better results have been obtained in HIV-positive patients, especially in terms of reduced lesion size and the flattening of elevated lesions. The 1064 nm Nd:YAG laser is effective and safe in the treatment of classic and epidemic KS, especially in patients with symptomatic, slow-progressing local disease, where other treatment options may be inappropriate.

Beyond T Staging in the "Treat-All" Era: Severity and Heterogeneity of Kaposi Sarcoma in East Africa.

Although many patients with Kaposi sarcoma (KS) in sub-Saharan Africa are diagnosed with AIDS Clinical Trials Group (ACTG) T1 disease, T1 staging insufficiently captures clinical heterogeneity of advanced KS. Using a representative community-based sample, we detailed disease severity at diagnosis to inform KS staging and treatment in sub-Saharan Africa. We performed rapid case ascertainment on people living with HIV, aged 18 years or older, newly diagnosed with KS from 2016 to 2019 at 3 clinic sites in Kenya and Uganda to ascertain disease stage as close as possible to diagnosis. We reported KS severity using ACTG and WHO staging criteria and detailed measurements that are not captured in the current staging systems. We performed rapid case ascertainment within 1 month for 241 adults newly diagnosed with KS out of 389 adult patients with suspected KS. The study was 68% men with median age 35 years and median CD4 count 239. Most of the patients had advanced disease, with 82% qualifying as ACTG T1 and 64% as WHO severe/symptomatic KS. The most common ACTG T1 qualifiers were edema (79%), tumor-associated ulceration (24%), extensive oral KS (9%), pulmonary KS (7%), and gastrointestinal KS (4%). There was marked heterogeneity within T1 KS, with 25% of patients having 2 T1 qualifying symptoms and 3% having 3 or more. Most of the patients newly diagnosed with KS had advanced stage disease, even in the current antiretroviral therapy "treat-all" era. We observed great clinical heterogeneity among advanced stage patients, leading to questions about whether all patients with advanced KS require the same treatment strategy.

Clinical characteristics and successful treatment outcomes of children and adolescents with Kaposi sarcoma in Southwestern Tanzania

The HIV/AIDS epidemic has driven the rise in cases of Kaposi sarcoma (KS) among children and adolescents living with HIV in countries with high Human gammaherpesvirus 8 (HHV-8) seroprevalence, such as Tanzania, where specialized oncology programs are sparse. Consequently, descriptions of successful treatment of KS in children and adolescents by general pediatricians are important. A retrospective analysis was performed of children and adolescents diagnosed with KS and treated with chemotherapy and combination antiretroviral therapy (cART) at the Baylor College of Medicine Children’s Foundation Tanzania Center of Excellence – Mbeya between 2011 and 2017. Sixty-one patients were diagnosed with KS with a median age of 12.6 years (interquartile range (IQR) 9.4 − 15.5). Diagnosis was confirmed by histopathology in 36% (22/61). Among HIV positive patients (59/61), 78% (46/59) were on cART at KS diagnosis. Severe immunosuppression was present in 63% (35/56) of those with CD4 data and 44% (27/61) had SAM. Advanced-stage T1 disease was present in 64% (39/61), including 28% (17/61) with visceral/disseminated KS. Two-year estimated overall survival (OS) was 72% (95% Confidence Interval (CI): 58%–82%) and median follow up for survivors was 25.7 months (IQR 14.2–53.8). No patients were lost to follow up. Two-year OS was 63% (95% CI: 44%–77%) in patients with severe immune suppression and 60% (95% CI: 37%–76%) in patients with SAM. Among patients with visceral/disseminated KS, 53% (9/17) survived. This retrospective analysis demonstrated favorable outcomes in a complex cohort of children and adolescents with KS treated with chemotherapy by general pediatricians in Tanzania.

Prospective cohort study of Kaposi sarcoma treated under real-world conditions in Malawi.

11569 Background: Kaposi sarcoma (KS) is the leading cancer in Malawi (34% of cancers). Outside of clinical trials, prospective KS studies from sub-Saharan Africa (SSA) are few and limited by loss to follow up. We conducted a prospective KS cohort study of standard of care bleomycin/vincristine (BV) at Lighthouse HIV clinic, in Lilongwe, Malawi. Methods: We enrolled pathologically confirmed, newly diagnosed, HIV+ KS patients from Feb 2017 to Jun 2019. We collected clinical and treatment characteristics, toxicity, and outcomes of KS with follow-up censored Jun 2020. Patients were treated with bleomycin (25 mg/m2) and vincristine (0.4 mg/m2) every 14 days for a planned maximum of 16 cycles. STATA v13.0 was used to calculate descriptive statistics and Kaplan Meier survival analysis. Toxicity was graded using NCI CTCAE v5.0. Results: We enrolled 138 participants, median age 36 (IQR 32-44) and 110 (80%) male. By ACTG staging, 107 (78%) were T1 (tumour severity), 46 (33%) were S1 (illness severity) and 46 (33%) had Karnofsky performance status ≤70. Presenting symptoms included edema in 69 (53%), visceral disease in 9 (7%), and oral involvement in 43 (33%). Prior to KS diagnosis, 70 (51%) participants were aware of being HIV+ for median 17 months (IQR 6-60) and had been on ART for median 16 months (IQR 6-60). Median CD4 count was 197 (IQR 99-339), median HIV-viral load was 2.6 log copies/mL (IQR 1.6 – 4.8) and 57% were HIV-suppressed ( &lt; 1000 HIV copies/ml). The median number of cycles was 16 (IQR 7-16). 62 (45%) participants missed at least one dose due to stock out. Amongst patients with missed doses, the median number was 3 (IQR 2-4) for bleomycin and 2 (IQR 1-3) for vincristine. 14 (10%) participants experienced at least one reduced dose due to toxicity. 5 (4%) participants suffered grade ≥3 anaemia, 13 (9%) grade ≥3 neutropenia, and one participant had grade 4 bleomycin-induced dermatitis. There was no reported grade ≥3 bleomycin lung toxicity or vincristine-induced neuropathy. Of 115 evaluable participants, responses at the end of therapy were: complete response in 52 (45%), partial response in 27 (23%) stable disease in 5 (4%), and progressive disease in 31 (28%). Median duration of follow-up was 20 months. At censoring, 69 (50%) were alive, 36 (26%) dead, and 33 (24%) lost to follow-up. Overall survival is shown Table as crude and worst-case scenario; worst-case assumes all participants lost to follow up died. Conclusions: Here, we present one of the most complete characterizations of KS presentation and treatment from SSA. As in other studies from the region, the majority of patients presented with advanced disease, chemotherapy stock-outs and loss to follow up were common, and mortality was high. Studies are planned to understand the virologic characteristics, improve therapies, and better implement existing therapies.[Table: see text]

Outcomes of AIDS-associated Kaposi sarcoma in Mozambique after treatment with pegylated liposomal doxorubicin

BackgroundKaposi’s sarcoma (KS) is a common HIV-associated malignancy frequently associated with poor outcomes. It is the most frequently diagnosed cancer in major cities of Mozambique. Antiretroviral therapy is the cornerstone of KS treatment, but many patients require cytotoxic chemotherapy. The traditional regimen in Mozambique includes conventional doxorubicin, bleomycin and vincristine, which is poorly tolerated. In 2016, pegylated liposomal doxorubicin was introduced at a specialized outpatient center in Maputo, Mozambique.MethodsWe performed a prospective, single-arm, open-label observational study to demonstrate the feasibility, safety, and outcomes of treatment with pegylated liposomal doxorubicin (PLD) in patients with AIDS-associated Kaposi sarcoma (KS) in a low-resource setting. Chemotherapy-naïve adults with AIDS-associated KS (T1 or T0 not responding to 6 months of antiretroviral therapy) were eligible if they were willing to follow up for 2 years. Patients with Karnofsky scores < 50 or contraindications to PLD were excluded. One hundred eighty-three patients were screened and 116 participants were enrolled. Patients received PLD on three-week cycles until meeting clinical stopping criteria. Follow-up visits monitored HIV status, KS disease, side effects of chemotherapy, mental health (PHQ-9) and quality of life (SF-12). Primary outcome measures included vital status and disease status at 6, 12, and 24 months after enrollment.ResultsAt 24 months, 23 participants (20%) had died and 15 (13%) were lost to follow-up. Baseline CD4 < 100 was associated with death (HR 2.7, 95%CI [1.2–6.2], p = 0.016), as was T1S1 disease compared to T1S0 disease (HR 2.7, 95%CI [1.1–6.4], p = 0.023). Ninety-two participants achieved complete or partial remission at any point (overall response rate 80%), including 15 (13%) who achieved complete remission. PLD was well-tolerated, and the most common AEs were neutropenia and anemia. Quality of life improved rapidly after beginning PLD.DiscussionPLD was safe, well-tolerated and effective as first-line treatment of KS in Mozambique. High mortality was likely due to advanced immunosuppression at presentation, underscoring the importance of earlier screening and referral for KS.