Electronic Patient-Reported Outcome-Based Symptom Management Versus Usual Care After Lung Cancer Surgery: Long-Term Results of a Multicenter, Randomized, Controlled Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported superior symptom control of electronic patient-reported outcome (ePRO)-based symptom management after lung cancer surgery for up to 1 month postdischarge. Here, we present the long-term results (1-12 months) of this multicenter, randomized trial, where patients were assigned 1:1 to receive postoperative ePRO-based symptom management or usual care daily postsurgery, twice weekly postdischarge until 1 month, and at 3, 6, 9, and 12 months postdischarge. Long-term patient-reported outcomes were assessed with MD Anderson Symptom Inventory-Lung Cancer module. Per-protocol analyses were performed with 55 patients in the ePRO group and 57 in the usual care group. At 12 months postdischarge, the ePRO group reported significantly fewer symptom threshold events (any of the five target symptom scored ≥4; median [IQR], 0 [0-0] v 0 [0-1]; P = .040) than the usual care group. From 1 to 12 months postdischarge, the ePRO group consistently reported significantly lower composite scores for physical interference (estimate, -0.86 [95% CI, -1.32 to -0.39]) and affective interference (estimate, -0.70 [95% CI, -1.14 to -0.26]). Early intensive ePRO-based symptom management after lung cancer surgery reduced symptom burden and improved functional status for up to 1 year postdischarge, supporting its integration into standard care.

Chemopreventive Effects of Polysaccharides and Flavonoids from Okra Flowers in Azomethane/Dextran Sulfate Sodium-Induced Murine Colitis-Associated Cancer.

Okra flowers are a good source of polysaccharides and flavonoids, with biological activities of anti-inflammatory action and modulation of the gut microbiota. Previously, we reported that flavonoid-rich extracts from okra flowers (AFE) presented effective anti-colorectal cancer (CRC) activity in CRC cells as well as xenograft models, but their role in colitis-associated cancer (CAC) is unidentified. In this study, we aimed to evaluate the effects of AFE and APE (polysaccharides extracted from okra flowers) on the CAC symptoms of azoxymethane (AOM)/dextran sodium sulfate (DSS)-intervened mice. The results showed that APE and AFE exert potent efficacy in inhibiting colitis and colorectal tumorigenesis stimulated by AOM/DSS, characterized by decreased colonic shortening, DAI score, and tumor numbers. Compared with the control group, APE/AFE alleviated the microbiota dysbiosis driven by AOM/DSS. In addition, AFE elicited its anticancer activity through regulation of NFκB/IL-6/Stat3, JAK2/Stat3, MAPKs, PI3K/AKT, and Wnt/ß-catenin signal transductions in AOM/DSS mice, which was consistent with a vitro model of CT26 cells, while APE treatment exhibited anticancer activity through regulation of Nrf2/IL-6, MAPKs, PI3K/AKT, and Wnt/ß-catenin signal transductions in the AOM/DSS mouse model. Collectively, our studies revealed, for the first time, that flavonoids and polysaccharides from okra flowers possess the ability to attenuate colitis and colorectal tumorigenesis, with them having great potential to become promising candidates against CRC.

Current Status in Rechallenge of Immunotherapy.

The treatment of malignant tumors has entered the era of immunotherapy, and immune checkpoint inhibitors (ICIs) have brought significant benefits to patients. However, some patients are required to discontinue treatment with ICIs owing to factors such as disease progression and intolerable side effects. Faced with limited subsequent treatment options and complex medical needs, we searched PubMed, Embase, Cochrane library, and the NIH clinical trials database and found that ICI rechallenge could be a relevant clinical strategy. The factors that could affect the rechallenge efficacy include the patients' characteristics, therapeutic strategy selection, and the timing of treatment. Multiple factors are used to identify target population, of which clinical features and PD-L1 expression are more potential. Both single ICI rechallenge and combination therapy may have survival benefits. Patients who have tolerated initial immunotherapy well could undergo ICI rechallenge, while patients who have experienced grade 3 or higher immune-related adverse events should be carefully assessed prior to rechallenge. Interventions and the interval between two courses of ICI will clearly have an impact on the efficacy of subsequent treatment. Preliminary data evaluation supports further investigation on ICI rechallenge to identify the factors that could contribute to its efficacy.

Patient-reported outcome (PRO)-based symptom assessment in patients with advanced lung cancer receiving first-line combination immunotherapy: a protocol for a multicenter, prospective, observational study.

BACKGROUND: Immunotherapy is currently applied in the first-line treatment regimens for numerous advanced cancers, especially advanced lung cancer. Immune-related adverse events (irAEs) resulting from immunotherapy can vary in severity and cause a substantial symptom burden to patients. However, there are limited data on symptom burden in patients with advanced lung cancer following immunotherapy. To address this deficit, this study aims to provide insight into the symptom burden and severity through patient-reported outcome measurements and conduct an analysis of temporal trends and clinical consequences of symptom burden in patients with advanced lung cancer receiving combination immunotherapy. METHODS: We will prospectively recruit 168 eligible patients from 14 hospitals in China. Eligible patients will be aged ≥ 18 years, pathologically diagnosed with locally advanced or stage IV primary lung cancer without surgical indications, and agreed to receive immunotherapy in combination with other therapies. The primary outcome of this study is the symptom burden of patients during the immunotherapy course. Longitudinal symptom data will be collected using the MD Anderson Symptom Inventory-Lung Cancer module (MDASI-LC) and the symptomatic irAEs scale at baseline (once before treatment) and weekly after treatment, until 1 month after the last treatment cycle has been completed. The trajectory of symptom burden following combination immunotherapy will be depicted, and by linking it to clinical outcomes (the secondary outcome and exploratory outcome of this study), the consequence of symptom burden in patients with advanced lung cancer receiving combination immunotherapy will be examined further. DISCUSSION: This study intends to establish longitudinal symptom trajectories in patients with lung cancer receiving immunotherapy, and explore its association with clinical outcomes. These findings may serve as an important reference for clinicians in the symptomatic management of patients with lung cancer receiving immunotherapy. TRIAL REGISTRATION NUMBER: ChiCTR2200061540. Registered on June 28, 2022.

Contribution of skeletal muscle to cancer immunotherapy: A focus on muscle function, inflammation, and microbiota.

Sarcopenia, characterized by degenerative and systemic loss of skeletal muscle mass and function, is a multifactorial syndrome commonly observed in individuals with cancer. Additionally, it represents a poor nutritional status and indicates possible presence of cancer cachexia. Recently, with the extensive application of cancer immunotherapy, the effects of sarcopenia/cachexia on cancer immunotherapy, have gained attention. The aim of this review was to summarize the influence of low muscle mass (sarcopenia/cachexia) on the response and immune-related adverse events to immunotherapy from the latest literature. It was revealed that low muscle mass (sarcopenia/cachexia) has detrimental effects on cancer immunotherapy in most cases, although there were results that were not consistent with this finding. This review also discussed potential causes of the paradox, such as different measure methods, research types, muscle indicators, time point, and cancer type. Mechanically, chronic inflammation, immune cells, and microbiota may be critically involved in regulating the efficacy of immunotherapy under the condition of low muscle mass (sarcopenia/cachexia). Thus, nutritional interventions will likely be promising ways for individuals with cancer to increase the efficacy of immunotherapy in the future, for low muscle mass (sarcopenia/cachexia) is an important prognostic factor for cancer immunotherapy.

Component analysis and anti-pulmonary fibrosis effects of Rosa sterilis juice.

Rosa sterilis is a new variety of Rosa roxburghii Tratt, and is rich in bioactive substances, but its role in pulmonary fibrosis has not been elucidated. The purpose of this study was to investigate the potential components of Rosa sterili juice (RSJ) and its anti-pulmonary fibrosis effects. We employed HPLC-Q-Exactive Orbitrap-MS, HPLC, and ICP-MS to analyze the composition of RSJ, and carried out free radical scavenging assays to determine its antioxidant activity. Then, the anti-pulmonary fibrosis effect of RSJ was evaluated using the bleomycin-induced mice model and the TGF-ß1-induced cell model. A total of 49 components were identified in RSJ, and the vitamin C content was 11.29 ± 0.05 mg mL-1. Catechin was the most abundant phenol, and potassium was the highest mineral element in RSJ. Attractively, we found that RSJ alleviated bleomycin-induced inflammation infiltration and tissue injury, and inhibited TGF-ß1-induced epithelial-mesenchymal transition and fibroblast differentiation through the Smad2/3 signaling pathway. In conclusion, we discovered a new health-protective activity of Rosa sterilis, and the high levels of polyphenols, flavonoids, and vitamin C may be the basic anti-fibrosis substances.

Flavonoid-rich extracts from okra flowers exert antitumor activity in colorectal cancer through induction of mitochondrial dysfunction-associated apoptosis, senescence and autophagy.

Okra flowers contain a higher content of total flavonoids than most other flowers; however little research has been conducted on their potential benefits, including antitumor activity. In this study, we extracted and purified flavonoids from okra flower (AFE), and aimed to evaluate the effect of AFE and its underlying mechanism on colorectal cancer (CRC) cell growth in vitro and in vivo. Here, we identify that AFE is a safe, natural antioxidant and exerts significant antitumor efficacy on the inhibition of CRC cell proliferation and metastasis as well as tumour growth in vivo. We further reveal that AFE inhibits CRC cell proliferation by inducing mitochondrial dysfunction, which results from the activation of p53 and induction of apoptosis and senescence, and inhibits autophagic degradation. Furthermore, AFE inhibited migration and invasion of CRC cells by regulating the balance of MMP2/TIMP2 and MMP9 expression levels. Of note, administration of AFE as a preventive agent achieves a more effective antitumor effect than the therapeutic agent in a xenograft mouse model. Our results reveal, for the first time, that AFE is a safe, natural antioxidant with significant antitumor efficacy, which has great potential in the application for CRC prevention and treatment.

Pectolinarigenin inhibits cell viability, migration and invasion and induces apoptosis via a ROS-mitochondrial apoptotic pathway in melanoma cells.

Pectolinarigenin a plant secondary metabolite that has various biological effects, including the inhibition of melanogenesis and tumor growth. Melanoma has a high degree of malignancy, with rapid metastasis and severe drug resistance, explaining the need for new candidate drugs that inhibit tumor growth and metastasis. However, the pharmacological action and mechanism of pectolinarigenin on the growth and metastasis of melanoma remain elusive. Thus, the present study aimed to investigate the role of pectolinarigenin in melanoma cell proliferation, apoptosis, migration and invasion. Apoptotic and metastasis-associated proteins were analyzed using western blotting. The results demonstrated that pectolinarigenin treatment resulted in growth inhibition and apoptosis induction in melanoma cells, arising from the loss of mitochondrial transmembrane potential, reactive oxygen species and the altered expression of apoptosis-associated proteins. In addition, wound-healing and Transwell assays demonstrated the potential of pectolinarigenin to impair the migration and invasion of melanoma cells in accordance with the changes in the expression of the associated proteins. Therefore, the results of the present study suggested that pectolinarigenin may serve a pivotal role in promoting melanoma cell apoptosis and reducing metastasis, and may thus be a promising potential candidate for an anti-melanoma treatment strategy.

Inhibition of Stat3 Signaling Pathway by Natural Product Pectolinarigenin Attenuates Breast Cancer Metastasis.

Background: Breast cancer is the most common female cancer with considerable metastatic potential, which urges the need for developing novel potential drug candidate to inhibit tumor metastasis. Signal transducer and activator of transcription 3 (Stat3) have critical roles in cancer growth and metastasis and have been confirmed as a promising anticancer target. Here, we report our finding with pectolinarigenin, a flavonoid compound isolated from the aerial parts of Cirsium chanroenicum. Methods: The role of Pec. in cell proliferation, cell apoptosis, and cell migration and invasion in three breast cancer cells (4T1, MDA-MB-231, MCF-7) was investigated. Cell proliferation was determined by MTT assay, cell apoptosis was determined by flow cytometry, and protein expression was detected by western blotting. Tumor xenograft mice model and breast tumor metastasis model in vivo were built to further assess the effects of Pec. on 4T1 cells. Results: Intraperitoneal administrations of pectolinarigenin significantly inhibited breast cancer metastasis to lungs without affecting the tumor growth of incubated 4T1 breast cancer cells. Pectolinarigenin could also recruit CD8+ T cells to mediate tumor immune response. Furthermore, pectolinarigenin markedly impaired cancer cell migration and invasion by down-regulating phosphorylated-Stat3, and expression of matrix metalloproteinase (MMP)-2, MMP-9, while up-regulating the expression of TIMP2. We also found that pectolinarigenin inhibited breast cancer cell proliferation and induced apoptosis via mitochondrial-related apoptosis pathway, reduced mitochondrial membrane potential and the expression of Bcl-2, increased expression of Bax, and cleaved caspase-3 as well as disturbed the ROS generation. Conclusions: Pectolinarigenin might potentially be a candidate for metastasis of breast cancer by mediating Stat3 pathway.

[The Extract from Punica Granatum (Pomegranate) Leaves Promotes Apoptosis and Impairs Metastasis in Prostate Cancer Cells].

OBJECTIVE: To investigate the effects of pomegranate leaves extract(PLE)on proliferation,apoptosis and metastasis of prostate cancer cells. METHODS: The proliferation of TRAMP-C1,DU145,PC3 prostate cancer cells treated with different concentrations of PLE (final mass concentrations were 12.5,25,50,100, 200 µg/mL,respectively) for different time (24,48,72 h) was detected by MTT assay. Colony formation assay was performed to verify the long-term effects of PLE on the proliferation of DU145 and PC3 cells.After being treated with PLE for 48 h,Hoechst-33258 staining was used to observe the changes in the nucleus,the cell apoptotic rate was detected by flow cytometry,and wound-healing migration assay was perform to test the change of migration. RESULTS: In comparison with the control group,PLE in the range of 12.5-200 µg/mL had a certain inhibitory effect on the proliferation of TRAMP-C1,DU145 and PC3 cells ( P<0.05).In the range of 6.25-100 µg/mL,the number of colony formation of DU145 and PC3 was significantly reduced( P<0.01).After PLE treated for 48 h, the apoptotic features of nuclear fragmentation and the formation apoptotic body was observed in PC3. With the increase of concentration,the apoptotic rate increased gradually ( P<0.05),and the ability of cells to migrate to the scratch area was significantly weaker than the control group ( P<0.01). CONCLUSION: PLE has effect on proliferation,apoptosis and metastasis of prostate cancer cells.

Hinokiflavone induces apoptosis in melanoma cells through the ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion.

Melanoma, the highest degree of malignancy, is one of the most common skin tumors. However, there is no effective strategy to treat melanoma in current clinical practice. Therefore, it is urgent to find an efficient drug to overcome melanoma. Here, the in vitro anticancer effects of a natural product named hinokiflavone on three melanoma carcinoma cell lines (human melanoma A375 and CHL-1 cells, murine melanoma B16-F10 cells) and mechanisms of action were explored. The results of MTT assay revealed that hinokiflavone inhibited cell proliferation of these cell lines in a dose- and time-dependent manner. Interestingly, hinokiflavone showed low toxicity to normal liver cells. Flow cytometry assay and EdU incorporation assay indicated that hinokiflavone affected A375 and B16 cells survival by inducing apoptosis and blocking cell cycle progression at S phase in a concentration-dependent manner. Moreover, hinokiflavone enhanced the reactive oxygen species (ROS) and decreased the mitochondrial membrane potential obviously. Furthermore, hinokiflavone effectively impaired A375 cells migration and invasion, and down-regulated the expression of matrix metalloproteinase (MMP) MMP2 and MMP9. The above-mentioned results demonstrated that hinokiflavone could be a novel chemotherapeutic agent in melanoma treatment by inhibiting cell proliferation, inducing apoptosis and cell cycle arresting and blocking cell migration and invasion.

Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models.

Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity in vitro and in vivo. BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs), and increase of the MMPs inhibitor (TIMP-2) expression. Moreover, in our animal experiment, intraperitoneal administration of 10 mg/kg/day BA suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without obvious side effects. Furthermore, histological and immunohistochemical analyses showed a decrease in MMP-9 positive cells, MMP-2 positive cells and Ki-67 positive cells and an increase in cleaved caspase-3 positive cells upon BA administration. Notably, BA reduced the number of myeloid-derived suppressor cells (MDSCs) in the lungs and tumors. Interestingly, in our caudal vein model, BA also obviously suppressed 4T1 tumor pulmonary metastases. These findings suggested that BA might be a potential agent for inhibiting the growth and metastasis of breast cancer.

The extract from Punica granatum (pomegranate) peel induces apoptosis and impairs metastasis in prostate cancer cells.

Prostate cancer is a big threat to male for its poor prognosis and high mortality rate. Natural compounds are important resources of many anticancer drugs. Pomegranate is a kind of antioxidant-rich fruit and its peel and seed has potential anticancer activities. In this study, we aimed to investigate the effects of pomegranate peel extract (PoPx) on the apoptosis and metastasis of prostate cancer cells and the related mechanism. We found that PoPx showed growth inhibition on prostate cancer cells. Nuclei morphological and flow cytometer (FCM) analysis indicated that PoPx could induce prostate cancer apoptosis. Further investigation indicated that mitochondrial mediated intrinsic pathway is involved in the apoptosis. Exposure to PoPx led to loss of mitochondrial transmembrane potential (Δym), accumulation of reactive oxygen species (ROS). Western blot analysis showed that PoPx could increase the expression ratio of Bax/Bcl2 and activation of apoptosis executor caspase 3. Wound healing assay and transwell migration and invasion assay implied that PoPx has the potential to inhibit migration and invasion, two critical steps in prostate cancer metastasis. Downregulation of MMP2/MMP9 and upregulation of TIMP2 showed accordance with the inhibition of migration and invasion. In summary, the present data showed that PoPx could be a promising drug candidate to treat prostate cancer, showing us a better way to develop novel drugs from natural compounds.

Punica granatum (pomegranate) leaves extract induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in non-small cell lung cancer in vitro.

Most conventional treatments on non-small cell lung carcinoma always accompany with awful side effects, and the incidence and mortality rates of this cancer are increasing rapidly worldwide. The objective of this study was to examine the anticancer effects of extract of Punica granatum (pomegranate) leaves extract (PLE) on the non-small cell lung carcinoma cell line A549, H1299 and mouse Lewis lung carcinoma cell line LL/2 in vitro, and explore its mechanisms of action. Our results have shown that PLE inhibited cell proliferation in non-small cell lung carcinoma cell line in a concentration- and time-dependent manner. Flow cytometry (FCM) assay showed that PLE affected H1299 cell survival by arresting cell cycle progression in G2/M phase in a dose-dependent manner and inducing apoptosis. Moreover, PLE could also decrease the reactive oxygen species (ROS) and the mitochondrial membrane potential (ΔYm), indicating that PLE may induce apoptosis via mitochondria-mediated apoptotic pathway. Furthermore, PLE blocked H1299 cell migration and invasion, and the reduction of matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed in vitro. These results suggested that PLE could be an effective and safe chemotherapeutic agent in non-small cell lung carcinoma treatment by inhibiting proliferation, inducing apoptosis, cell cycle arrest and impairing cell migration and invasion.