The Role of Nurses in the Management of Adverse Events in Patients Receiving First-Line Axitinib Plus Immuno-Oncology Agents for Advanced Renal Cell Carcinoma.

OBJECTIVES: The recent approval of first-line tyrosine kinase inhibitor plus immuno-oncology agent combination therapy for the treatment of advanced renal cell carcinoma offers substantially improved response rates and survival compared with the previous standard of care. This expansion of treatment options has also led to a greater range and complexity of potential treatment-related adverse events related to overlapping toxicities. The aim of this article is to discuss the management of common treatment-emergent adverse events (AEs) associated with axitinib plus immuno-oncology therapy, highlight the specific roles of oncology nurses in managing these events, and provide AE management resources to aid oncology nurses in their care of patients with advanced renal cell carcinoma. DATA SOURCES: Author experience, journal articles, and treatment guidelines were used. CONCLUSION: The use of oncology nurses and nurse-led innovations to monitor and assess treatments can have a positive impact on the management of AEs in cancer patients by identifying those who are most at risk, providing regular assessment, appropriate patient education, and supporting the monitoring of patient safety. IMPLICATIONS FOR NURSING PRACTICE: Skilled oncology nurses should be a key part of a team that addresses the supportive care needs and management of AEs that are associated with novel cancer treatments. Early and ongoing communication between the patient and oncology nurses regarding the development of adverse events is a critical component of maximizing treatment outcomes and quality of life.

Real-World Therapy Management and Outcomes of First-Line Axitinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma in the United States.

Background: Combination axitinib plus pembrolizumab is a standard of care in the first-line treatment of patients with advanced clear cell renal cell carcinoma (RCC). This analysis describes the clinical characteristics, treatment management and outcomes of patients receiving first-line (1L) axitinib plus pembrolizumab in a real-world US setting. Methods: Electronic health record (EHR)-derived data from the Flatiron Health Database, which includes ~280 cancer clinics across 800 sites in the US, were used. Patients had confirmed Stage IV or metastatic RCC and initiated 1L axitinib plus pembrolizumab on or after 1/1/2018 to 3/31/2021. Outcomes were best overall response rate; real-world progression-free survival (rwPFS) and overall survival (OS) at landmark time periods (3, 6, 9, and 12 months). Therapy management (TM) included dose hold, dose change and discontinuation. Data are reported as medians (IQR) unless otherwise noted. Results: 355 patients received 1L axitinib plus pembrolizumab, with median follow-up of 9.7 (0.1-24.3) months. IMDC Risk Score was favorable, intermediate, and poor in 27 (7.6%), 126 (35.5%), and 76 (21.4%) patients, respectively (23.4% intermediate/poor, 12.1% unknown). 270 patients (76.1%) received only 1L axitinib plus pembrolizumab and 85 patients (24.3%) received ≥1 subsequent line of treatment; cabozantinib was the most frequent subsequent line of treatment (47.9%). rwPFS at 3 months and 1 year was 77.2% and 39.3%, respectively. OS ranged from 90.8% at 3 months to 73.5% at 1 year. Best overall response rate was 47.9%. Toxicity was the most common reason for first TM events of dose hold, change and discontinuation at, 58.6%, 58.5%, and 45.8%, respectively. Over 80% of patients with TM were able to continue with 1L axitinib plus pembrolizumab. Conclusions: In a real-world setting, axitinib plus pembrolizumab was effective as a 1L treatment for patients with advanced RCC. Dose holds, changes and discontinuation were driven by treatment-related toxicity. Dose holds may represent an effective TM strategy to toxicity.

Constitutive Stat3 activation alters behavior of hair follicle stem and progenitor cell populations.

STATs play crucial roles in a wide variety of biological functions, including development, proliferation, differentiation and migration as well as in cancer development. In the present study, we examined the impact of constitutive activation of Stat3 on behavior of keratinocytes, including keratinocyte stem cells (KSC) in vivo. BK5.Stat3C transgenic (Tg) mice, which express a constitutively active form of Stat3 (Stat3C) in the basal layer of the epidermis and in the bulge region KSCs exhibited a significantly reduced number of CD34+/α6 integrin+ cells compared to non-transgenic (NTg) littermates. There was a concomitant increase in the Lgr-6, Lrig-1, and Sca-1 populations in the Tg mice in contrast to the CD34 and Keratin-15 positive population. In addition, increased expression of c-myc, ß-catenin, and epithelial-mesenchymal transition (EMT)-related genes as well as decreased expression of α6-integrin was observed in the hair follicles of Tg mice. Notably, Sca-1 was found to be a direct transcriptional target of Stat3 in keratinocytes. The current data suggest that elevated Stat3 activity leads to depletion of hair follicle KSCs along with a concomitant increase of stem/progenitor cells above the bulge region. Overall, the current data indicate that Stat3 plays an important role in keratinocyte stem/progenitor cell homeostasis.

Stat3 binds to mtDNA and regulates mitochondrial gene expression in keratinocytes.

The nuclear transcription factor signal transducer and activator of transcription 3 (Stat3) has recently been reported to have a localized mitochondrial regulatory function. Current data suggest that mitochondrial Stat3 (mitoStat3) is necessary for maximal mitochondrial activity and for Ras-mediated transformation independent of Stat3 nuclear activity. We have previously shown that Stat3 has a pivotal role in epithelial carcinogenesis. Therefore, the aim of the current study was to determine the role of mitoStat3 in epidermal keratinocytes. Herein, we show that normal and neoplastic keratinocytes contain a pool of mitoStat3. EGF and 12-O-tetradecanoylphorbol-13-acetate induce Stat3 mitochondrial translocation mediated through the phosphorylation of Stat3 at Ser727. In addition, we report that mitoStat3 binds mtDNA and associates with the mitochondrial transcription factor A. Furthermore, Stat3 ablation resulted in an increase of mitochondrial-encoded gene transcripts. An increase in key nuclear-encoded metabolic genes, PGC-1α and NRF-1, was also observed in Stat3-null keratinocytes; however, no changes in nuclear-encoded electron transport chain gene transcripts or mtDNA copy number were observed. Collectively, our findings suggest a heretofore-unreported function for mitoStat3 as a potential mitochondrial transcription factor in keratinocytes. This mitoStat3-mtDNA interaction may represent an alternate signaling pathway that could alter mitochondrial function and biogenesis and have a role in tumorigenesis.

Role of stat3 in skin carcinogenesis: insights gained from relevant mouse models.

Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic protein that is activated in response to cytokines and growth factors and acts as a transcription factor. Stat3 plays critical roles in various biological activities including cell proliferation, migration, and survival. Studies using keratinocyte-specific Stat3-deficient mice have revealed that Stat3 plays an important role in skin homeostasis including keratinocyte migration, wound healing, and hair follicle growth. Use of both constitutive and inducible keratinocyte-specific Stat3-deficient mouse models has demonstrated that Stat3 is required for both the initiation and promotion stages of multistage skin carcinogenesis. Further studies using a transgenic mouse model with a gain of function mutant of Stat3 (Stat3C) expressed in the basal layer of the epidermis revealed a novel role for Stat3 in skin tumor progression. Studies using similar Stat3-deficient and gain-of-function mouse models have indicated its similar roles in ultraviolet B (UVB) radiation-mediated skin carcinogenesis. This paper summarizes the use of these various mouse models for studying the role and underlying mechanisms for the function of Stat3 in skin carcinogenesis. Given its significant role throughout the skin carcinogenesis process, Stat3 is an attractive target for skin cancer prevention and treatment.

Targeted disruption of stat3 reveals a major role for follicular stem cells in skin tumor initiation.

The initiation stage of mouse skin carcinogenesis involves the induction of mutations in keratinocyte stem cells (KSC), which confers a selective growth advantage allowing clonal expansion during tumor promotion. Targeted disruption of signal transducer and activator of transcription 3 (Stat3) in bulge region KSCs was achieved by treating K15.CrePR1 x Stat3(fl/fl) mice with RU486. Deletion of Stat3 prior to skin tumor initiation with 7,12-dimethylbenz(a)anthracene significantly increased the number of apoptotic KSCs and decreased the frequency of Ha-ras codon 61 A(182)-->T transversion mutations in this cell population compared with wild-type littermates. Targeted disruption of Stat3 in bulge region KSCs at the time of initiation also dramatically reduced the number of skin tumors (by approximately 80%) produced following promotion with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. These results show that Stat3 is required for the survival of bulge region KSCs during tumor initiation. Furthermore, these data provide direct evidence that bulge region KSCs are the primary targets for the initiation of skin tumors in this model system.