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Purpose There is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD. Methods Pharmacokinetic studies of PLD were performed as part of phase I and II studies in 70 patients with solid tumors or Kaposi’s sarcoma. The effects of monocyte count, age, gender, and body composition on PLD clearance were examined. Results There was a 15.3-fold variability in PLD clearance. Body surface area-based dosing did not significantly reduce the variability in PLD clearance. The mean ± SD clearance for patients <60 years old and ≥60 years old were 54.6 ± 28.5 and 23.3 ± 10.8 mL/h/m 2 , respectively ( P  < 0.0001), and for female and male patients were 23.7 ± 18.8 and 55.6 ± 26.8 mL/h/m 2 , respectively ( P  < 0.0001). A reduction in pre-cycle monocyte count was associated with a greater reduction in PLD clearance. Conclusions Age, gender, and monocyte counts appear to correlate with PLD clearance. Further investigation of the association between these factors, PLD pharmacokinetics, and clinical outcomes (efficacy and toxicity) is warranted. These effects on the pharmacokinetics of PLD may be an approach for personalizing PLD therapy and may affect other pegylated liposomes and nanoparticle agents.

Cancer is a leading cause of death in patients with AIDS. The incidence of AIDS-defining cancers has been stable owing to highly active antiretroviral therapy, but among patients who survive AIDS for long periods, the incidence of common age-related cancers is increasing.

Background Classical Kaposi's sarcoma (CKS) is a rare angioproliferative disease associated with HHV-8, usually seen in the Mediterranean and Middle East regions. Knowing the subtypes, affected regions, and factors influencing prognosis is important for disease management. Objective To analyze the demographic characteristics, prognostic factors, treatment modalities, and survival of patients diagnosed with CKS. Methods Our center's records of patients diagnosed with CKS between January 2010 and December 2021 were retrospectively analyzed. Thirty-eight patients with histopathologically proven CKS were included in the study. Demographic and clinical characteristics of the patients, macroscopic, histopathologic, and immunohistochemical features of the lesions, treatments, and responses to treatment were evaluated. Kaplan–Meier survival curves were used to estimate survival outcomes, and log-rank test analyses were performed for intergroup comparisons. Results The median age at diagnosis of the patients was 71.0(39.0–93.0) years. Ten patients were female, and 28 were male. At the time of diagnosis, 63.2% of the patients had localised disease, nine patients were locally advanced, and five patients were metastatic. The tumor was most commonly localised in the lower extremity (65.8%), followed by the upper extremity. The median follow-up period was 69 (49–77.6) months. Local recurrence was detected in 24 patients during the follow-up. Median overall survival was not reached (NR) in localised disease(95% CI: 70.5-NR). In locally advanced disease, it was 31.1 months (95% CI: 13.8–63.0). In metastatic disease, it was 16.3 (95% CI: 12.6–20.0) months ( p  = 0.005). Conclusion This study emphasizes that CKS in our centre predominantly affects older males and typically manifests with nodular, early-stage lesions at the time of diagnosis. The majority of patients exhibited localised disease with no evidence of systemic involvement, while lymphedema was a frequent accompanying condition. Ulcerative manifestations were relatively uncommon, and survival outcomes varied significantly based on disease stage, with a marked decline in overall survival for patients with metastatic disease. The findings emphasize the importance of early diagnosis and the development of tailored treatment strategies to improve patient outcomes.

Kaposi sarcoma (KS) is an intermediate-grade vascular tumour that has undergone major treatment and diagnostic breakthroughs following the discovery of Human herpesvirus 8 (HHV8). Whilst classically described in Eastern European populations, the endemic and epidemic forms of KS have facilitated its association with AIDS. This was led by the detection of HHV8 by PCR, and thereafter, immunohistochemically. This not only enabled the recognition and diagnosis of complex histopathological KS subtypes but also facilitated distinction from its mimickers, including acroangiodermatitis and pyogenic granuloma. Recent advances in the viral genomics of HHV8 have expanded the diagnostic landscape of KS clinically and molecularly. The latent phase of replication in the HHV8 lifecycle reveals numerous angiogenic and inflammatory factors. Novel therapies targeting these viral–human molecular interactions may prove useful. However, this is highly dependent on the clonal nature of KS. Conflicting research outcomes demonstrate varying viewpoints on the clonal (monoclonal/oligoclonal/polyclonal) nature of KS, heightening the tumoural versus inflammatory pseudoneoplastic controversy. Understanding the clinical context of KS is fundamental to understanding its clonality, and a dearth of this clinical information in recent studies appears to be the critical factor in determining the true clonal nature of KS. The current molecular landscape, histopathology, treatment options, and opinions on clonality are critically reviewed.

Kaposi sarcoma (KS) is a vascular tumor caused by human herpesvirus 8, also known as Kaposi sarcoma herpesvirus. There are 4 distinct subtypes: classic, endemic, iatrogenic, and epidemic (HIV-associated). A fifth subtype is increasingly recognized: non-epidemic KS in men who have sex with men (MSM) who are HIV-negative. Our primary objective was to characterize non-epidemic KS to identify associated risk factors, presentation, treatment course, and prognosis of these patients. This retrospective cohort included all patients evaluated at Memorial Sloan Kettering Cancer Center from 2000 to 2022 with pathologically proven KS who identified as MSM status, without diagnosis of HIV. Data were collected on demographics, comorbidities, coinfections, treatments, and outcomes. Seventy-two patients were identified. The median age at the time of diagnosis was 58. At initial diagnosis, 44% of patients underwent observation, 51% received localized treatment and 5% received systemic treatment. In follow-up, 47% of patients had a progression of disease requiring recurrent treatment: 25% received localized treatment while 18% received chemotherapy. In follow-up, 7 patients died, with only 2 deaths attributed to KS; 10% of patients were diagnosed with a lymphoproliferative disorder. This study is the largest yet to characterize the non-epidemic KS subtype in HIV-negative MSM. These individuals are younger, HIV-negative, MSM with a favorable prognosis. Additional research is needed to understand the potential risk associated with lymphoproliferative disorders.

Non-AIDS-defining cancers are a growing source of morbidity for people with HIV globally. Although people living with HIV have a disproportionately increased risk of developing virally mediated cancers, cancer burden for common non-AIDS-defining cancers that are not virally associated and are linked to ageing, such as prostate cancer, is becoming higher than for virally mediated cancers. Ageing, behavioural, and HIV-specific factors drive the incidence and affect the outcomes of non-AIDS-defining cancers, presenting different challenges for addressing global morbidity and mortality from non-AIDS-defining cancer. Although large population-based studies have shown that people living with HIV with non-AIDS-defining cancers have poorer cancer outcomes than do people without HIV, current guidelines emphasise that people living with HIV with non-AIDS-defining cancers should receive standard, guideline-based treatment, and infectious disease and oncology providers should work closely to address potential drug interactions between antiretroviral therapy and antineoplastic treatment. Most trials target preventive measures focusing on non-AIDS-defining cancers. However, treatment trials for the optimal management of people living with HIV and non-AIDS-defining cancer, including interventions such as immunotherapies, are needed to improve non-AIDS-defining cancer outcomes.

Three-dimensional (3D) cell culture is well documented to regain intrinsic metabolic properties and to bettermimic the in vivo situation than two-dimensional (2D) cell culture. Particularly, proline metabolism is critical for tumorigenesis since pyrroline-5-carboxylate (P5C) reductase (PYCR/P5CR) is highly expressed in various tumors and its enzymatic activity is essential for in vitro 3D tumor cell growth and in vivo tumorigenesis. PYCR converts the P5C intermediate to proline as a biosynthesis pathway, whereas proline dehydrogenase (PRODH) breaks down proline to P5C as a degradation pathway. Intriguingly, expressions of proline biosynthesis PYCR gene and proline degradation PRODH gene are up-regulated directly by c-Myc oncoprotein and p53 tumor suppressor, respectively, suggesting that the proline-P5C metabolic axis is a key checkpoint for tumor cell growth. Here, we report a metabolic reprogramming of 3D tumor cell growth by oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), an etiological agent of Kaposi’s sarcoma and primary effusion lymphoma. Metabolomic analyses revealed that KSHV infection increased nonessential amino acid metabolites, specifically proline, in 3D culture, not in 2D culture. Strikingly, the KSHV K1 oncoprotein interacted with and activated PYCR enzyme, increasing intracellular proline concentration. Consequently, the K1-PYCR interaction promoted tumor cell growth in 3D spheroid culture and tumorigenesis in nude mice. In contrast, depletion of PYCR expression markedly abrogated K1-induced tumor cell growth in 3D culture, not in 2D culture. This study demonstrates that an increase of proline biosynthesis induced by K1-PYCR interaction is critical for KSHV-mediated transformation in in vitro 3D culture condition and in vivo tumorigenesis.

The human gamma herpesviruses, Kaposi sarcoma-associated virus (KSHV) and EBV, are associated with multiple cancers. Recent evidence suggests that EBV and possibly other viruses can manipulate the tumor microenvironment through the secretion of specific viral and cellular components into exosomes, small endocytically derived vesicles that are released from cells. Exosomes produced by EBV-infected nasopharyngeal carcinoma cells contain high levels of the viral oncogene latent membrane protein 1 and viral microRNAs that activate critical signaling pathways in recipient cells. In this study, to determine the effects of EBV and KSHV on exosome content, quantitative proteomics techniques were performed on exosomes purified from 11 B-cell lines that are uninfected, infected with EBV or with KSHV, or infected with both viruses. Using mass spectrometry, 871 proteins were identified, of which ∼360 were unique to the viral exosomes. Analysis by 2D difference gel electrophoresis and spectral counting identified multiple significant changes compared with the uninfected control cells and between viral groups. These data predict that both EBV and KSHV exosomes likely modulate cell death and survival, ribosome function, protein synthesis, and mammalian target of rapamycin signaling. Distinct viral-specific effects on exosomes suggest that KSHV exosomes would affect cellular metabolism, whereas EBV exosomes would activate cellular signaling mediated through integrins, actin, IFN, and NFκB. The changes in exosome content identified in this study suggest ways that these oncogenic viruses modulate the tumor microenvironment and may provide diagnostic markers specific for EBV and KSHV associated malignancies.

Kaposi’s sarcoma (KS) is a cancer affecting skin and internal organs for which the Kaposi’s sarcoma associated herpesvirus (KSHV) is a necessary cause. Previous work has pursued KS diagnosis by quantifying KSHV DNA in skin biopsies using a point-of-care (POC) device which performs quantitative loop-mediated isothermal amplification (LAMP). These previous studies revealed that extracting DNA from patient biopsies was the rate limiting step in an otherwise rapid process. In this study, a simplified, POC-compatible alkaline DNA extraction, ColdSHOT, was optimized for 0.75 mm human skin punch biopsies. The optimized ColdSHOT extraction consistently produced 40,000+ copies of DNA per 5 µl reaction from 3 mg samples—a yield comparable to standard spin column extractions—within 1 h without significant equipment. The DNA yield was estimated sufficient for KSHV detection from KS-positive patient biopsies, and the LAMP assay was not affected by non-target tissue in the unpurified samples. Furthermore, the yields achieved via ColdSHOT were robust to sample storage in phosphate-buffered saline (PBS) or Tris-EDTA (TE) buffer prior to DNA extraction, and the DNA sample was stable after extraction. The results presented in this study indicate that the ColdSHOT DNA extraction could be implemented to simplify and accelerate the LAMP-based diagnosis of Kaposi’s sarcoma using submillimeter biopsy samples.

Kaposi Sarcoma (KS) is a complex tumor caused by KS-associated herpesvirus 8 (KSHV). Histological analysis reveals a mixture of “spindle cells”, vascular-like spaces, extravasated erythrocytes, and immune cells. In order to elucidate the infected and uninfected cell types in KS tumors, we examined twenty-five skin and blood samples from sixteen subjects by single cell RNA sequence analyses. Two populations of KSHV-infected cells were identified, one of which represented a CD34 -negative proliferative fraction of endothelial cells, and the second representing CD34 -positive cells expressing endothelial genes found in a variety of cell types including high endothelial venules, fenestrated capillaries, and endothelial tip cells. Although both infected clusters contained cells expressing lytic and latent KSHV genes, the CD34 + cells expressed more K5 and less K12. Novel cellular biomarkers were identified in the KSHV infected cells, including the sodium channel SCN9A. The number of KSHV positive cells was found to be less than 10% of total tumor cells in all samples and correlated inversely with tumor-infiltrating immune cells. T-cell receptor clones were expanded in KS tumors and blood, although in differing magnitudes. Changes in cellular composition in KS tumors after treatment with antiretroviral therapy alone, or immunotherapy were noted. These studies demonstrate the feasibility of single cell analyses to identify prognostic and predictive biomarkers.