Hematological toxicity of cyclin-dependent kinase 4/6 inhibitors in patients with breast cancer: a network meta-analysis and pharmacovigilance study.

OBJECTIVES: We aimed to evaluate and compare the risk of hematological adverse events (AEs) associated with CDK4/6 inhibitors using data from randomized controlled trials (RCTs) and Food and Drug Adverse Event Reporting System (FAERS) database. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for RCTs related to abemaciclib, palbociclib, and ribociclib. A network meta-analysis (NMA) was conducted to compare the risks of hematological AEs, and a disproportionality analysis was performed to detect signals of hematological AEs. RESULTS: 16 RCTs comprising 16,350 breast cancer patients were included. Palbociclib and ribociclib had similar risks for hematological AEs, except a higher risk of grade 3-4 leukopenia observed with palbociclib (risk ratio [RR]: 7.84, 95% confidence interval [95%CI]: 1.33-41.28). Abemaciclib had a higher risk of anemia than both ribociclib (grade 1-4: RR: 2.23, 95% CI: 1.25 - 3.96; grade 3-4: RR: 3.52, 95% CI: 1.59 - 8.11) and palbociclib (grade 1-4: RR: 1.65, 95%CI: 1.03 - 2.59), but a lower risk of grade 3-4 of both leukopenia (RR: 0.12, 95%CI: 0.02 - 0.49) and neutropenia (RR: 0.15, 95%CI: 0.04 - 0.52) compared with palbociclib. Signals indicating occurrence of leukopenia, neutropenia, anemia, and thrombocytopenia were identified for three CDK4/6 inhibitors. CONCLUSION: Abemaciclib, palbociclib, and ribociclib showed significant but inconsistent hematological toxicity risks.

Cost-effectiveness analysis of tislelizumab plus chemotherapy as the first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma in China.

OBJECTIVE: We aimed to investigate the cost-effectiveness of tislelizumab plus chemotherapy compared to chemotherapy alone as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (OSCC). METHODS: A partitioned survival model was developed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy versus chemotherapy alone in patients with advanced or metastatic OSCC over a 10-year lifetime horizon from the perspective of the Chinese healthcare system. Costs and utilities were derived from the drug procurement platform and published literature. The model outcomes comprised of costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were conducted to address uncertainty and ensure the robustness of the model. RESULTS: Tislelizumab plus chemotherapy yielded an additional 0.337 QALYs and incremental costs of $7,117.007 compared with placebo plus chemotherapy, generating an ICER of $21,116.75 per QALY, which was between 1 time ($12,674.89/QALY) and 3 times GDP ($38,024.67/QALY) per capita. In one-way sensitivity analysis, the ICER is most affected by the cost of oxaliplatin, paclitaxel and tislelizumab. In the probabilistic sensitivity analysis, when the willingness-to-pay threshold was set as 1 or 3 times GDP per capita, the probability of tislelizumab plus chemotherapy being cost-effective was 1% and 100%, respectively. CONCLUSION: Tislelizumab plus chemotherapy was probably cost-effective compared with chemotherapy alone as the first-line treatment for advanced or metastatic OSCC in China.

Diagnostic efficacy of contrast-enhanced ultrasound, dynamic contrast-enhanced MRI combined with tumor markers AFP and DCP for primary hepatocellular carcinoma.

The purpose of this study was to investigate the diagnostic efficacy of contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) combined with tumor markers alpha-fetoprotein (AFP) and des-γ-carboxyl prothrombin (DCP) for primary hepatic carcinoma (PHC). A total of 70 patients with PHC (PHC group), 42 patients with liver cyst (benign liver disease group (BLDG)) and 30 healthy people (healthy group (HG)) were selected as the research objects. CEUS and DCE-MRI were performed by American GE Vivid E9 color Doppler ultrasound system and Siemens 1.5T magnetic resonance imager, respectively. The levels of AFP and DCP were detected by ABBOTT i2000SR chemiluminescence instrument and enzyme-linked immunoassay (ELISA), respectively. In DCE-MRI examination, the portal phase and prolonged phase were mostly low signal in T1-weighted imaging (T1WI) sequence, and arterial phase was mostly high signal in T2WI sequence. In CEUS, most lesions showed hyper-enhancement in arterial phase, and hypo-enhancement in portal phase and delayed phase. AFP and DCP levels in PHC group were significantly higher than that in BLDG group and HG group. There were statistically significant differences among the three groups. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of combined diagnosis were statistically significant when compared with CEUS, AFP and DCP alone and either AFP or DCP positive. CEUS, DCE-MRI combined with tumor markers AFP and DCP have high sensitivity, specificity and accuracy in the diagnosis of PHC, which can more accurately diagnose the lesion type, provide basis for further treatment, and is worthy of clinical application.

CircTMEM30A/hsa-miR-130a-3p regulates TNFα and promotes the malignant progression of COPD with primary lung cancer.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and lung cancer is the most common respiratory diseases among smokers. Lung cancer is one of the most common malignancy. COPD patients are at high risk of lung cancer, but the specific pathogenesis is still unclear. In recent years, circRNAs have become the focus of lung cancer research. This study investigated the effect of CircTMEM30A on COPD and lung cancer and its possible molecular mechanisms. METHODS: QPCR was used to detect the expression of CircTMEM30A in COPD patients, lung cancer patients, and COPD patients with lung cancer. CircTMEM30A was transfected with PPF, HFL1, A549 and NCI-H446 cells, and the transfection efficiency was verified by real-time quantitative PCR. The effects of CircTMEM30A on the proliferation, migration and invasion of fibroblasts and lung cancer cells were detected by MTT, Transwell and scratch tests. The target gene of CircTMEM30A was verified by luciferase reporter assay. Real-time quantitative PCR was used to detect the expression level of CircTMEM30A target gene. RESULTS: CircTMEM30A was the most highly expressed in COPD patients with lung cancer. Overexpression of CircTMEM30A enhanced the effects of proliferation, migration and invasion of fibroblasts and lung cancer cells, down-regulated the expression of E-cadherin, up-regulated the expression of Vimentin, and promoted EMT. After knocking down CircTMEM30A, the migration and invasion ability of lung cancer cells was significantly reduced. Bioinformatics retrieval and luciferase reporter gene confirmed that CircTMEM30A could be bind to miR-130a, while TNFα gene was the target gene of miR-130a. Further studies showed that overexpression of miR-130a and knockdown of TNFα reversed the promoting effect of CircTMEM30A on lung cancer cells. CONCLUSIONS: CircTMEM30A was highly expressed in COPD patients with lung cancer, and miR-130a was low expressed in lung cancer cells. CircTMEM30A regulated the expression of TNFα through miR-130a, thereby affecting the progression of COPD and lung cancer. CircTMEM30A may be a therapeutic target for COPD patients with lung cancer.

Cost-effectiveness of PARP inhibitors in malignancies: A systematic review.

OBJECTIVES: Poly (ADP-ribose) polymerase inhibitor (PARPi) have become a mainstay for the treatment of BRCA-mutant malignancies. PARPis are likely to be more effective but also bring an increase in costs. Thus, we aimed at evaluating the cost effectiveness of PARPis in the treatment of malignancies. METHODS: Studies of cost effectiveness of PARPis were searched from PubMed, Web of Science, and Cochrane Library. Key information was extracted from the identified studies and reviewed. Quality of the included studies was evaluated using Quality of Health Economic Studies (QHES) instrument. Modeling techniques, measurement of parameters and uncertainty analysis were analyzed across studies. Interventions and cost-effectiveness results were reported stratified by patient population. RESULTS: Among the 25 studies identified, we included 17 on ovarian cancer, 2 on breast cancer, 3 on pancreatic cancer, and 3 on prostate cancer that involved olaparib, niraparib, rucaparib, and talazoparib. All studies had a QHES score of above 75. In the maintenance therapy of ovarian cancer, additional administration of olaparib was cost-effective for newly diagnosed patients after first-line platinum-based chemotherapy but was not cost-effective for platinum-sensitive recurrent patients in majority studies. However, the economic value of other PARPis in ovarian cancer as well as all PARPis in other tumors remained controversial. Cost-effectiveness of PARPi was primarily impacted by the costs of PARPi, survival time, health utility and discount rate. Moreover, genetic testing improved the cost-effectiveness of PARPi treatment. CONCLUSIONS: PARPi is potentially cost-effective for patients with ovarian, pancreatic, or prostate cancer. Genetic testing can improve the cost-effectiveness of PARPi.

Study on the Application Value of Concurrent Chemoradiotherapy and Clinical Nursing Pathway for Postoperative Patients with Esophageal Cancer.

Backgrounds: To observe the value of concurrent chemoradiotherapy and clinical nursing pathway for postoperative patients with esophageal cancer (EC). Methods: A total of 88 postoperative EC patients were divided into the radiotherapy group (RG group, 44 cases) and the chemoradiotherapy group (CRG group, 44 cases). The RG group received single three-dimensional conformal radiotherapy+clinical nursing pathway, and the CRG group was combined with chemotherapy on this basis. The 5-year overall survival rate, progression-free survival rate, pathological remission and survival rate, lymph node metastasis and survival rate, quality of life analysis, tumor-related factor level, and incidence of adverse reactions were compared between the two groups. Results: The overall survival rates at 1, 3, and 5 years were 93.18%, 56.82%, and 50.0% in the CRG group and 86.36%, 52.27%, and 43.18% in the RG group, respectively. The 5-year progression-free survival rate of the CRG group was 60.87%, which was clearly higher than that of the RG group (33.33%). The 1-, 3-, and 5-year overall survival rates of pCR and NpCR patients were 90.48%, 80.95%, and 61.90% and 89.55%, 44.78%, and 38.81%, respectively. The overall 1-year, 3-year, and 5-year survival rates were 81.08%, 37.84, and 24.32% and 96.08%, 66.67%, and 62.75% in patients with lymph node metastasis and nonlymph node metastasis, respectively, with statistical significant differences. The emotional function, physical function, cough, pain, and eating difficulty in the CRG group were better than those in the RG group. After treatment, serum CEA, SCC, CYFRA21-1, and CA199 levels in the CRG group were obviously downregulated compared with those in the RG group. There was no obvious difference in the incidence of adverse reactions between the CRG group and the RG group. Conclusion: Single radiotherapy and concurrent chemoradiotherapy can be used as effective means in the treatment of EC. Moreover, the quality of life and survival time of the concurrent chemoradiotherapy group were dramatically better than those of the single radiotherapy group, and the antitumor ability of the concurrent chemoradiotherapy group was stronger.

Pharmacist-led standardization of total parenteral nutrition improves postoperative nutritional status in colorectal cancer patients.

Background: Total parenteral nutrition (TPN) is an essential treatment for patients who undergo abdominal surgery. Due to the gap of knowledge background between clinicians and pharmacists, the participation of the latter may improve TPN standardization. However, the impact on clinical outcome is unknown. In this study, we evaluated the impact of appropriacy and efficacy of TPN prescription, after a pharmacist-led TPN standardization program introduced. Methods: A pharmacist-led TPN standardization program was introduced in the Zhejiang Cancer Hospital and the clinical outcomes were assessed. The TPN standardization program includes a pre-established standard multidisciplinary evaluation standard, a computerized TPN management system and regular evaluations of TPN prescription performed by pharmacists. Any concerns were identified and improved via discussed with doctors. To evaluate the effect of pharmacists' intervention in nutritional status and postoperative complications, an observational before-and-after cohort study was performed. All patients admitted in hospital with colorectal cancer (CRC) and receiving abdominal surgery in June 2019 (pre-intervention cohort) and June 2020 (post-intervention cohort) were retrospectively analyzed. Nutritional status of patients was evaluated using the levels of postoperative serum albumin, prealbumin, total protein, and their decrease extent. Surgical or TPN-related complications and recovery time were collated as the clinical outcomes. Results: There were no significant differences in the basic clinical information of the two cohorts, suggesting that the two groups are comparable. The average postoperative prealbumin levels were elevated in 2020 compared to 2019 (192.3±5.5 mg/L for 2019 and 229.5±4.8 mg/L for 2020, P<0.001). In addition, the post-intervention cohort showed a lower postoperative infection rate (11.6% vs. 18.2%), shorter duration of infection (9.4±1.4 vs. 7.7±1.0 days), lower incidence of postoperative albumin decrease (25.2% vs. 76.7%), prealbumin decrease (71.5% vs. 78.9%), and total protein decrease (25.2% vs. 72.2%), and lower incidence of TPN-related hypoglycemia (5.4% vs. 15.3%). Conclusions: Pharmacist-led TPN standardization improved the postoperative clinical outcomes in patients with colorectal cancer (CRC).

Luteolin attenuated cisplatin-induced cardiac dysfunction and oxidative stress via modulation of Keap1/Nrf2 signaling pathway.

Cardiovascular complications are a well-documented limitation of cancer chemotherapy. Cisplatin-induced cardiotoxicity threatens the health and life of patients, and limits the application of cisplatin. Oxidative stress is the main mechanism underlying cisplatin-induced cardiac toxicity. Luteolin (Lut) has been reported to possess cardioprotective properties by activating nuclear factor-E2-related factor 2 (Nrf2) -mediated antioxidant response. However, the effect of Lut on cisplatin-induced cardiac damage remains unclear. In this study, we revealed that Lut exerted a protective effect against cisplatin-induced cardiac dysfunction and injury in vivo. In HL-1 cells, Lut was observed to dramatically reduce cisplatin-induced apoptosis and oxidative stress by modulating the Kelch-like epichlorohydrin-associated protein 1 (Keap1)/Nrf2 pathway. Altogether, these findings suggested that Lut showed promise in attenuating cisplatin-induced cardiac injury and might be considered a protective drug candidate for chemotherapy-associated cardiovascular complications.

Retracted: Targeting Transforming Growth Factor-Beta1 (TGF-ß1) Inhibits Tumorigenesis of Anaplastic Thyroid Carcinoma Cells Through ERK1/2-NFκB-PUMA Signaling.

The in vitro experiments of TGF-ß1 and the results of RT-PCR could not be repeated. In order not to affect others, the authors have asked for a retraction. Reference: Qiang Yin, Shan Liu, Anbing Dong, Xiufang Mi, Fengyun Hao, Kejun Zhang. Targeting Transforming Growth Factor-Beta1 (TGF-ß1) Inhibits Tumorigenesis of Anaplastic Thyroid Carcinoma Cells Through ERK1/2-NFkappakB-PUMA Signaling. Med Sci Monit 2016; 22: 2267-2277. DOI: 10.12659/MSM.898702.

Modified microvessel density based on perfusion distance: a preferable NSCLC prognostic factor.

Background: Despite the vital role of blood perfusion in tumor progression, the prognostic value of typical blood perfusion markers, such as microvessel density (MVD) or microvessel area (MVA), in patients with non-small cell lung cancer (NSCLC) is still unclear. This study established a modified MVD (mMVD) measurement based on perfusion distance and determined its prognostic value in patients with NSCLC. Methods: A total of 100 patients with NSCLC were enrolled in this retrospective study. The intratumor microvessels of NSCLC patients were visualized using immunohistochemical staining for CD31. The blood perfusion distance was evaluated as the distance from each vessel to its nearest cancer cell (Dmvcc), and the cutoff value for prognosis was determined. Apart from the total MVD (tMVD), microvessels near cancer cells within the cutoff-Dmvcc were counted as mMVD. Predictive values for mortality and recurrence were evaluated and compared. Results: The Dmvcc ranged from 1.6 to 269.8 µm (median, 13.1 µm). The mMVD (range: 2-70; median 23) was counted from tMVD according to the cutoff-Dmvcc (~20 µm). Compared with tMVD, a larger fraction of mMVD (80% vs. 2.9%) played a significant role in overall survival, with an improved area under the receiver operating characteristic (ROC) curve (AUC) (0.74 vs. 0.56). A high mMVD was an independent positive indicator of overall survival (OS) and progression-free survival (PFS). In contrast, tMVD was only related to PFS at the optimal cutoff. Conclusions: Perfusion-distance-based mMVD is a promising prognostic factor for NSCLC patients with superior sensitivity, specificity, and clinical applicability compared to tMVD. This study provides novel insights into the prognostic role of tumor vessel perfusion in patients with NSCLC.

miR-455 Inhibits the Viability and Invasion by Targeting RAB18 in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) has been regarded as the fifth most common cancer worldwide with a low prognosis. miR-455 usually played the role of a tumor suppressor in multiple cancers. The aim of this study was to investigate the roles of miR-455 in HCC. MATERIALS AND METHODS: Cell viability and invasion were measured by CCK8 and Transwell assays. Luciferase reporter assay was performed to verify that miR-455 directly binds to the 3'-noncoding region (UTR) of RAB18 mRNA in Huh7 cells. RESULTS: The expression of miR-455 was lower in HCC tissues and cell lines than in nontumor tissues and normal cell line, and downregulation of miR-455 was connected with worse outcome of HCC patients. miR-455 suppressed cell proliferation in vitro and in vivo, and it inhibited the abilities of cell invasion and EMT in HCC. RAB18 was upregulated in HCC tissues and cell lines, and the expression of RAB18 was regulated by miR-455. RAB18 reversed partial roles of miR-455 on cell viability and invasion in HCC. CONCLUSION: miR-455 inhibited cell viability and invasion by directly targeting the 3'-UTR of RAB18 mRNA of hepatocellular carcinoma.

miR-26a suppresses osteosarcoma migration and invasion by directly targeting HMGA1.

Osteosarcoma (OS) is identified as the most commonly diagnosed malignant cancer of bone, and has approximately three million new cases annually. miR-26a plays an important role in the development of various types of cancer. We investigated whether miR-26a can regulate the migration and invasion of OS by targeting high-mobility group A1 HMGA1. Western blot analysis was used to identify the changes of protein levels. Reverse transcription-quantitative PCR was used to test expression levels of genes and miR-26a. Luciferase reporter assay was used to test the specific target gene of miR-26a. Transwell assay was employed to determine the migration and invasion of OS cell lines. In the present study, miRNA-26a was frequently downregulated in OS tissues and cells. Overexpression of miR-26a inhibited cell migration and invasion in vitro. In addition, miR-26a downregulated HMGA1 by targeting its 3'-UTR and knockdown of HMGA1 significantly suppressed the migration and invasion of two osteosarcoma cell lines in vitro. miR-26a suppressed the migration and invasion of OS cells by targeting HMGA1, suggesting that miR-26a/HMGA1 axis provides a new prospective therapeutic strategy for OS.

Targeting Transforming Growth Factor-Beta1 (TGF-ß1) Inhibits Tumorigenesis of Anaplastic Thyroid Carcinoma Cells Through ERK1/2-NFκkB-PUMA Signaling.

BACKGROUND The transforming growth factor-beta (TGF-ß) signaling pathway plays a critical role in promoting tumor growth. TGF-ß1was found to be overexpressed in anaplastic thyroid cancer (ATC). We therefore tested our hypothesis that targeting TGF-ß1 inhibits tumorigenesis of ATC cells. MATERIAL AND METHODS Effects of TGF-ß1 stimulation or TGF-ß1 inhibition by small interfering RNA (TGF-ß1siRNA) on proliferation, colony formation, and apoptosis in 8505C cells in vitro was detected using siRNAs and inhibitors to examine the TGF-ß1 signaling pathway. A subcutaneously implanted tumor model of 8505C cells in nude mice was used to assess the effects of TGF-ß1 inhibition on tumorigenesis development. RESULTS TGF-ß1siRNAs decreased proliferation and colony formation, and increased apoptosis in 8505C cells in vitro and inhibited tumor growth in vivo. TGF-ß1siRNA inhibited phosphorylation ERK1/2 (pERK1/2) and increased p65-dependant PUMA mRNA and protein expression. Knockdown of p65 or PUMA by siRNA reduced TGF-ß1siRNA-induced apoptosis, as well as caspase-3 and PARP activation. Upregulation of p65 or PUMA expression by TGF-ß1siRNA requires pERK1/2 inhibition. TGF-ß1 shRNA inhibited tumor growth in vivo. CONCLUSIONS Therapies targeting the TGF-ß1 pathway may be more effective to prevent primary tumor formation. The ability of this therapy to decrease tumorigenesis may be related to ERK1/2/NF-κB/PUMA signaling.