HIV-1 Tat Promotes Kaposi's Sarcoma-Associated Herpesvirus (KSHV) vIL-6-Induced Angiogenesis and Tumorigenesis by Regulating PI3K/PTEN/AKT/GSK-3β Signaling Pathway

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is etiologically associated with KS, the most common AIDS-related malignancy. KS is characterized by vast angiogenesis and hyperproliferative spindle cells. We have previously reported that HIV-1 Tat can trigger KSHV reactivation and accelerate Kaposin A-induced tumorigenesis. Here, we explored Tat promotion of KSHV vIL-6-induced angiogenesis and tumorigenesis. Tat promotes vIL-6-induced cell proliferation, cellular transformation, vascular tube formation and VEGF production in culture. Tat enhances vIL-6-induced angiogenesis and tumorigenesis of fibroblasts and human endothelial cells in a chicken chorioallantoic membrane (CAM) model. In an allograft model, Tat promotes vIL-6-induced tumorigenesis and expression of CD31, CD34, SMA, VEGF, b-FGF, and cyclin D1. Mechanistic studies indicated Tat activates PI3K and AKT, and inactivates PTEN and GSK-3β in vIL-6 expressing cells. LY294002, a specific inhibitor of PI3K, effectively impaired Tat's promotion of vIL-6-induced tumorigenesis. Together, these results provide the first evidence that Tat might contribute to KS pathogenesis by synergizing with vIL-6, and identify PI3K/AKT pathway as a potential therapeutic target in AIDS-related KS patients. © 2013 Zhou et al

Comparison of laparoscopy and open radical nephrectomy of renal cell cancer

The aim of this study was to summarize the current evidence to evaluate the effects of laparoscopic radical nephrectomy (LRN) and open radical nephrectomy (ORN) in the treatment of renal cell carcinoma

Deaths and adverse events from adjuvant therapy with immune checkpoint inhibitors in solid malignant tumors: A systematic review and network meta‐analysis

Abstract Background By prolonging overall survival and reducing disease recurrence rates, immune checkpoint inhibitors (ICIs) are an emerging adjuvant therapy option for patients with resectable malignant tumors. However, the safety profile (deaths and adverse events [AEs]) of adjuvant ICIs has not been fully described. Methods We searched the literature for phase III randomized clinical trials that compared PD‐1, PD‐L1, and CTLA‐4 inhibitors in solid malignant tumors. Incidences of death, discontinuation, AEs of any cause, treatment‐related adverse events (TRAEs), and immune‐related adverse events (IRAEs) were extracted for the network meta‐analysis. Network meta‐analyses with low incidence and poor convergence are reported as incidences with 95% confidence intervals (95% CIs). Results Ten randomized clinical trials that included 9243 patients who received ICI adjuvant therapy were eligible. In total, 21 deaths due to TRAEs were recorded, with an overall incidence of 0.40% (95% CI: 0.26–0.61). The treatment‐related mortality rates for ipilimumab (0.76%, 95% CI: 0.31–1.55) and atezolizumab (0.56%, 95% CI: 0.18–1.31) were higher than for pembrolizumab (0.24%, 95% CI: 0.10–0.56) and nivolumab (0.30%, 95% CI: 0.08–0.77). The most frequent causes of death were associated with the gastrointestinal (0.10%, 95% CI: 0.04–0.24) and pulmonary (0.08%, 95% CI: 0.03–0.21) systems. Compared with the control arm, we found that nivolumab (odds ratio [OR]: 2.73, 95% CI: 0.49–15.85) and atezolizumab (OR: 12.43, 95% CI: 2.42–78.48) caused the fewest grade ≥3 TRAEs and IRAEs. Commonly reported IRAEs of special interest were analyzed, and two agents were found to have IRAEs with incidences >10%, i.e., hepatitis for atezolizumab (14.80%, 95% CI: 12.53–17.32) and hypophysitis for ipilimumab (13.53%, 95% CI: 11.38–15.90). Conclusions Ipilimumab and atezolizumab were correlated with higher treatment‐related death rates than pembrolizumab and nivolumab, in which the gastrointestinal and pulmonary systems were mostly involved. Regarding severe TRAEs and IRAEs, nivolumab and atezolizumab are likely to be the safest agent, respectively. This study will guide clinical practice for ICI adjuvant therapies

Exploration of the immunogenetic landscape of hyperprogressive disease after combined immunotherapy in cancer patients

Summary: The immune-genetic changes that occur in cancer patients experiencing hyperprogressive disease (HPD) during combined immunotherapy are unclear. In this study, HPD patients with pre- and post-HPD samples and non-HPD patients with solid tumors were molecularly characterized by genetic and tumor immune microenvironment (TiME) analyses of paired samples by whole-exome sequencing, RNA sequencing, and multiplex immunofluorescence. The genetic analysis of paired samples showed that almost all the tumor driver gene mutations were preserved between pre- and post-HPD tumors. HPD patients had higher frequencies of mutations in TP53 and CNN2, and a significantly higher mutant-allele tumor heterogeneity than non-HPD patients. Tumor IL-6 mRNA was upregulated in post-HPD samples vs. pre-HPD, accompanied by a potential immune suppressive TiME with an elevated M2/M1 ratio. Salvage treatment with irinotecan plus bevacizumab was effective in one HPD patient, who experienced prolonged survival. These genetic features and TiME characteristics might help identify the features of HPD after immunotherapy

Circulating tumor cells in the pulmonary vein increase significantly after lobectomy: A prospective observational study

Background It has been reported that there are more circulating tumor cells (CTCs) in the pulmonary vein (PV) than in the peripheral blood; however, it is unclear whether the CTC count changes in the PV after resection of a lung lobe. Methods Thirty‐three lung cancer patients were recruited for the study, including 17 who underwent lobectomy via video‐assisted thoracoscopic surgery and 16 via open thoracotomy. Sixty‐six blood specimens were sampled from the PV before the PV was interrupted and after lobectomy. The CTCs were quantified using the oHSV1‐hTERT‐GFP method. Results Before PV interruption, the CTC (pre‐CTC) detection rate was 79.0% (26/33), the mean number of CTCs was 3.36 (median 2, range: 0–18), and there was no significant relationship between the pre‐CTC count and clinical factors, such as histologic findings and pathological T stage (P > 0.05). After lobectomy, the CTC (post‐CTC) detection rate was 100% (33/33), the average number of CTCs was 14.88 (median 11, range: 1–69), and the post‐CTC count was significantly higher in patients in whom the PV was interrupted prior to the pulmonary artery (PA) than in patients in whom the PA was interrupted before the PV (P = 0.016). Overall, the CTC count was significantly higher following surgery (P < 0.001). Conclusion Post‐CTC counts were significantly higher than pre‐CTC counts, suggesting that surgical manipulation may potentially dislodge tumor cells into the PV. Interrupting the PV prior to the PA during lobectomy may prevent partial CTC entry into the circulation

Neutrophil extracellular traps in relationship to efficacy of systemic therapy for metastatic renal cell carcinoma

Abstract Background The efficacy of systemic therapy regimens, such as immune checkpoint inhibitors and tyrosine kinase inhibitors (IO‐TKI) and targeted therapy, for metastatic clear cell renal cell carcinoma (ccRCC) remains unpredictable due to the lack of effective biomarkers. Neutrophil extracellular trap (NET) plays an important role in promoting ccRCC. This study explores the NET predictive value of the efficacy in metastatic ccRCC. Methods In this retrospective study, patients with metastatic ccRCC who received targeted drugs and IO‐TKI were included. Immunofluorescence staining was utilized to quantify the levels of tissue NETs through cell counts of H3Cit(+) and MPO(+) cells. Results A total of 183 patients with metastatic ccRCC were enrolled, including 150 patients who received TKIs and 33 patients who received IO‐TKI. The levels of NETs in tumor tissue were significantly higher than in para‐tumor tissue (p < 0.001). In terms of predicting drug efficacy, a correlation between NET levels and progression‐free survival (PFS) was observed in the TKI with metachronous metastasis group (HR 1.73 [95% CI 1.02–2.91], log‐rank p = 0.037), while no correlation was observed in the TKI with synchronous metastasis group and IO‐TKI group. Regarding overall survival (OS), activated NET levels were associated with poor OS in both TKI (HR 1.60 [95% CI 1.05–2.43], log‐rank p  = 0.017) and IO‐TKI group (HR 4.35 [95% CI 1.06–17.82], log‐rank p =0.047). IMDC score (HR 1.462 [95% CI 1.030–2.075], p = 0.033) and tumor tissue NET levels (HR 1.733 [95% CI 1.165–2.579], p = 0.007) were independent prognostic risk factors for OS in patients with metastatic ccRCC.NET level was associated with poor OS in both TKI (HR 1.60 [95% CI 1.05–2.43], log‐rank p  = 0.017). Conclusions The active NET levels in tumor tissue can predict drug efficacy in patients with metastatic ccRCC who received systemic therapy. Elevated levels of NETs in tumor tissue were also associated with poor efficacy in OS