Experiences of Family Caregivers Providing Home Care to Older Patients With Cancer: A Qualitative Study.

BACKGROUND: Older patients with cancer receive anticancer therapy in outpatient settings, and care-related issues may occur after discharge, which often requires family caregivers (FCs) to play a significant role in providing cancer care at home. However, relatively few studies have been focused on exploring the care experiences of these FCs. PURPOSE: The aim of this study was to explore the care experiences of FCs caring for older family members with cancer at home. METHODS: A qualitative study design and in-depth individual interviews were used to explore the at-home care experiences of FCs of older patients with cancer. The research was conducted in chemotherapy outpatient settings of a medical center in northern Taiwan. Content analysis was used to analyze data. The analyses focused on first extracting meaningful units from the text and then inducting categories from these units and determining the major themes. RESULTS: Twenty FCs were interviewed. The three themes identified included (a) increased information needs and challenges in diet preparation and treatment decision making, (b) personal and patient-induced emotional stress, and (c) life rebalancing through the care experience. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings highlight the educational requirements, especially related to meeting personal dietary needs and obtaining psychological support, for FCs caring for older patients with cancer to help them rebalance their life.

Decisional conflict and its determinants among patients with cancer undergoing immunotherapy combined with chemotherapy or targeted therapy: a cross-sectional study.

Decisional conflict might occur during shared decision-making (SDM) because immunotherapy is a rather novel treatment option for patients with cancer. To explore the prevalence and severity of physical and psychological symptoms and the effort invested in SDM in relation to decisional conflict among patients with cancer undergoing immunotherapy combined with chemotherapy or targeted therapy. This was a cross-sectional survey study. The SURE version of the Decisional Conflict Scale was used to screen cancer patients' decisional conflict status. Demographic or clinical characteristics, physical symptoms and psychological distress; efforts invested in the SDM process were also assessed as potential factors related to decisional conflict. One hundred seventeen patients surveyed, the prevalence of fatigue (79.5%), sleep disturbance (78.6%), poor appetite (67.5%), and pain (58.1%) symptoms were high and the severity was at moderate levels. The prevalence of pruritus (40.2%), rash (34.2%), dry skin (41.9%), and diarrhea (17.1%) symptoms were low and the severity was at mild levels. 65.8% of patients reported uncertainty, with mild to moderate levels. Furthermore, 97.4% of the patients made some effort in SDM, and the effort level was moderate (mean: 5.56 ± 2.02). 64.1% of patients were certain that immunotherapy was the best option. Age, uncertainty, and effort in the SDM process were major factors related to decisional conflict. We observed that older patients (age: ≥ 65) and those with higher uncertainty levels and less effort in SDM reported higher levels of decisional conflict. Future studies should explore older patients' decisional related needs of immunotherapy. Interventions should be designed to reduce the uncertainty experienced by patients with cancer and enhance their understanding of immunotherapy to enable them to take more effort in the SDM process.

Aucubin enhances the antitumor activity of cisplatin through the inhibition of PD-L1 expression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality in the world. However, the anticancer effects of aucubin against HCC have yet to be reported. Cisplatin often decreased CD8+ tumor-infiltrating lymphocytes in the tumor microenvironment through increasing programmed death-ligand 1 (PD-L1) expression, which seriously affected the prognostic effect of cisplatin in the treatment of patients with HCC. Therefore, it is necessary to identify a novel therapeutic avenue to increase the sensitivity of cisplatin against HCC. PURPOSE: This study aims to evaluate the anti-tumor effect of aucubin on HCC, and also to reveal the synergistic effects and mechanism of aucubin and cisplatin against HCC. STUDY DESIGN AND METHODS: An H22 xenograft mouse model was established for the in vivo experiments. Cancer cell proliferation was detected by MTT assay. RT-qPCR was performed to analyze CD274 mRNA expression in vitro. Western blotting was employed to determine the expression levels of the PD-L1, p-Akt, Akt, p-ß-catenin, and ß-catenin in vitro. Immunofluorescence was carried out to examine ß-catenin nuclear accumulation in HCC cells. Immunohistochemistry was used to detect tumoral PD-L1 and CD8α expression in xenograft mouse model. RESULTS: Aucubin inhibits tumor growth in a xenograft HCC mouse model, but did not affect HCC cell viability in vitro. Aucubin treatment significantly inhibited PD-L1 expression through inactivating Akt/ß-catenin signaling pathway in HCC cells. Overexpression of PD-L1 dramatically reversed aucubin-mediated tumoral CD8+ T cell infiltration and alleviated the antitumor activity of aucubin in xenograft mouse model. Moreover, Cisplatin could induce the expression of PD-L1 through the activation of the Akt/ß-catenin signaling pathway in HCC cells, which can be blocked by aucubin in vitro. In xenograft mouse model, cisplatin treatment induced PD-L1 expression and alleviated the infiltration of CD8+ T lymphocytes in the tumor microenvironment. Aucubin not only abrogated cisplatin-induced PD-L1 expression but also enhanced the antitumor efficacy of cisplatin in a mouse xenograft model of HCC. CONCLUSION: Aucubin exerts antitumor activity against HCC and also enhances the antitumor activity of cisplatin by suppressing the Akt/ß-catenin/PD-L1 axis.

DKK1 promotes NUAK1 transcriptional expression through the activation Akt in hepatocellular carcinoma.

NUAK1 is a serine/threonine kinase that has been shown to be associated with poor prognosis in several cancers. Although NUAK1 is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC), the actual role of NUAK1 and the mechanism of its overexpression in HCC has yet to be reported. In the present study, we found that NUAK1 expression was significantly increased in human HCC tumor tissues. Overexpression of NUAK1 dramatically enhanced HCC cells proliferation and migration in vitro. Stable induction of NUAK1 expression promoted tumor growth and tumor metastases to the lungs in the subcutaneous xenograft models and intravenous metastasis models. At the cellular level, enforced expression of Dickkopf-1 (DKK1) activated the Akt signaling pathway, thereby promoting the mRNA and protein expression of NUAK1 in HCC cells. By contrast, depletion of DKK1 was found to attenuate the mRNA and protein expression of NUAK1. In the subcutaneous xenograft models, stable induction of DKK1 expression not only accelerated tumor growth but also increased p-Akt and NUAK1 expression; whereas knockdown of DKK1 inhibited tumor growth, p-Akt and NUAK1 expression. Furthermore, immunohistochemical analysis of 20 HCC clinical samples showed that the expression level of NUAK1 was positively correlated with DKK1 and p-Akt. Taken together, we provide the first evidence that DKK1 promotes NUAK1 transcriptional expression via the activation Akt in HCC.

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma.

BACKGROUND: Spermine is frequently elevated in tumor tissues and body fluids of cancer patients and is critical for cancer cell proliferation, migration and invasion. However, the immune functions of spermine in hepatocellular carcinoma progression remains unknown. In the present study, we aimed to elucidate immunosuppressive role of spermine in hepatocellular carcinoma and to explore the underlying mechanism. METHODS: Whole-blood spermine concentration was measured using HPLC. Human primary HCC tissues were collected to examine the expression of CaSR, p-Akt, ß-catenin, STT3A, PD-L1, and CD8. Mouse model of tumorigenesis and lung metastasis were established to evaluate the effects of spermine on hepatocellular carcinoma. Western blotting, immunofluorescence, real time PCR, digital Ca2+ imaging, and chromatin immunoprecipitation assay were used to investigate the underlying mechanisms by which spermine regulates PD-L1 expression and glycosylation in hepatocellular carcinoma cells. RESULTS: Blood spermine concentration in the HCC patient group was significantly higher than that in the normal population group. Spermine could facilitate tumor progression through inducing PD-L1 expression and decreasing the CD8+ T cell infiltration in HCC. Mechanistically, spermine activates calcium-sensing receptor (CaSR) to trigger Ca2+ entry and thereby promote Akt-dependent ß-catenin stabilization and nuclear translocation. Nuclear ß-catenin induced by spermine then activates transcriptional expression of PD-L1 and N-glycosyltransferase STT3A, while STT3A in turn increases the stability of PD-L1 through inducing PD-L1 protein N-glycosylation in HCC cells. CONCLUSIONS: This study reveals the crucial function of spermine in establishing immune privilege by increasing the expression and N-glycosylation of PD-L1, providing a potential strategy for the treatment of hepatocellular carcinoma. Video Abstract.

HGF/c-MET pathway contributes to cisplatin-mediated PD-L1 expression in hepatocellular carcinoma.

Cisplatin has been reported to promote the expression of programmed cell death ligand-1 (PD-L1) in some cancer cells. However, the underlying mechanism through which PD-L1 is transcriptionally regulated by cisplatin in hepatocellular carcinoma (HCC) cells remains largely unknown. In the present study, we found that the expression of hepatocyte growth factor (HGF), p-Akt, p-ERK, and PD-L1 was increased in cisplatin-treated SNU-368 and SNU-739 cells. HGF stimulation also increased PD-L1 expression in these cells. Moreover, Inhibition of HGF/c-MET, PI3K/Akt, and MEK/ERK signaling pathways can dramatically block cisplatin or HGF-induced PD-L1 expression in SNU-368 and SNU-739 cells. In vivo, combination PHA665752 with cisplatin significantly reduced tumor weight with increased infiltration of CD8+ T cells in the tumor. Taken together, our study suggested that HGF/c-Met axis-induced the activation of PI3K/Akt and MEK/ERK pathways contributes to cisplatin-mediated PD-L1 expression. These findings may provide an alternative avenue for the treatment of HCC.