Ferroptotic therapy in cancer: benefits, side effects, and risks.

Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Originally investigated as a targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential to complement chemotherapy, immunotherapy, and radiotherapy in various cancer types. However, it can lead to side effects, including immune cell death, bone marrow impairment, liver and kidney damage, cachexia (severe weight loss and muscle wasting), and secondary tumorigenesis. In this review, we discuss the advantages and offer an overview of the diverse range of documented side effects. Furthermore, we examine the underlying mechanisms and explore potential strategies for side effect mitigation.

A nomogram for the prediction of survival for colorectal signet ring cell carcinoma after surgery: A population-based study.

The aim was to construct and verify a nomogram-based assessment of cancer-specific survival (CSS) in patients with colorectal signet ring cell carcinoma after surgery. Patients were collected from Surveillance, Epidemiology, and End Results program between 2004 and 2015. Independent prognostic indicators were determined in the training cohort by Cox regression model. We identified 2217 eligible patients, who were further categorized into the training set (n = 1693) as well as the validation set (n = 524). Multivariate analysis revealed that age at diagnosis, gender, grade, tumor size, T stage, N stage, and M stage were independent predictive indicators. Then, the above 7 predictive factors were incorporated into a nomogram model to assess CSS, which showed good calibration and discrimination capacities in both sets. Both internal and external calibration plot diagrams revealed that the actual results were consistent with the predicted outcomes. The time-independent area under the curves for 3-year and 5-year CSS in the nomogram were larger than American Joint Committee on Cancer and Surveillance, Epidemiology, and End Results summary stage system. Moreover, decision curve analysis indicated the clinical utility of the nomogram. The nomogram demonstrated favorable predictive accuracy of survival in colorectal signet ring cell carcinoma patients after surgery, which should be further confirmed before clinical implementation.

Development and validation of a nomogram to predict overall survival for cervical adenocarcinoma: A population-based study.

This study aimed to develop and validate a nomogram for predicting the overall survival of cervical adenocarcinoma (CAC) patients using a large database comprising patients with different ethnicities. We enrolled primary CAC cases with complete clinicopathological and survival data from the Surveillance, Epidemiology, and End Results program during 2004 to 2015. For training set samples, this work applied the Cox regression model to obtain factors independently associated with patient prognosis, which could be incorporated in constructing the nomogram. Altogether 3096 qualified cases were enrolled, their survival ranged from 0 to 155 (median, 45.5) months. As revealed by multivariate regression, age, marital status, tumor size, grade, International Federation of Gynecology and Obstetrics (FIGO) classification, pelvic lymph node metastasis, surgery, and chemotherapy served as the factors to independently predict CAC (all P < .05). We later incorporated these factors for constructing the nomogram. According to the concordance index determined, this nomogram had superior discrimination over FIGO classification system (all P < .001). Based on calibration plot, the predicted value was consistent with actual measurement. As revealed by time-independent area under the curves, our constructed nomogram had superior 5-year overall survival over FIGO system. Additionally, according to decision curve analysis, our constructed nomogram showed high clinical usefulness as well as favorable discrimination. Our constructed nomogram attains favorable performances, indicating that it may be applied in predicting survival for CAC patients.

Marital status is an independent prognostic factor for cervical adenocarcinoma: A population-based study.

Marriage has been reported as a beneficial factor associated with improved survival among cancer patients, but conflicting results have been observed in cervical adenocarcinoma (AC). Thus, this study is aimed to examine the relationship between the prognosis of cervical AC and marital status. Eligible patients were selected from 2004 to 2015 using the surveillance, epidemiology and end results (SEER) database. Cancer-specific survival (CSS) and overall survival (OS) were compared between married and unmarried groups. A total of 3096 patients had been identified, with married ones accounting for 51.29% (n = 1588). Compared to unmarried groups, more patients in the married group were relatively younger (aged ≤ 45) and belonged to white race, with grade I/II, Federation of International of Gynecologists and Obstetricians (FIGO) stage I/II and tumor size ≤4 cm. Apart from that, more patients received surgery, whereas fewer patients received chemotherapy and radiotherapy (all P < 0.05). The 5-year CSS and OS rates were 80.16% and 78.26% in married patients, 68.58% and 64.62% in the unmarried group (P < .0001). Multivariate analysis showed that marital status was an independent prognostic factor, and the married group performed better CSS (hazard ratio [HR]: 0.770; 95% confidence interval [CI]: 0.663-0.895; P = .001) as well as OS (HR: 0.751; 95%CI: 0.653-0.863; P < .001). As demonstrated by the results of subgroup analysis, married patients had better CSS and OS survival than unmarried ones in nearly all the subgroups. Marital status was identified as an independent prognostic factor for improved survival in patients with cervical AC.

[Retracted] MicroRNA­874 inhibits proliferation and invasion of pancreatic ductal adenocarcinoma cells by directly targeting paired box 6.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the data shown for the cell migration and invasion assays in Figs. 2C, 4C and 5C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 18: 1188­1196, 2018; DOI: 10.3892/mmr.2018.9069].

Construction and validation a nomogram to predict overall survival for colorectal signet ring cell carcinoma.

To construct and validate a nomogram to predict the overall survival (OS) of colorectal signet ring cell carcinoma (SRCC). The potentially eligible cases were obtained against the SEER database from 2004 to 2015. Log-rank test and Cox analysis were conducted to identify the independent prognostic factors for predicting OS. The identified prognostic factors were later integrated for the construction of an OS prediction nomogram. Altogether 2904 eligible cases were identified, and the median survival time was 18 (range: 0-155) months. As suggested by multivariate analysis, age, primary site, grade, tumor size, T stage, N stage, M stage, surgery, lymph node dissection and chemotherapy were identified as the independent factors for predicting OS. Afterwards, the above variables were incorporated into the nomogram. The C-index indicated better discriminatory ability of the nomogram than AJCC 8th TNM staging and SEER summary stage systems (both P < 0.001). Calibration plots further showed good consistency between the nomogram prediction and actual observation. The time independent area under the curves (tAUCs) for 3-year and 5-year OS in nomogram were larger than AJCC and SEER summary stage system. The constructed nomogram could potentially predict the survival of colorectal SRCC individuals.

Marital status and survival of patients with colorectal signet ring cell carcinoma: a population-based study.

The prognostic role of marital status on colorectal signet ring cell carcinoma (SRCC) has not been studied. In this study, the correlation of marital status with prognosis of colorectal SRCC was analyzed. Eligible subjects were extracted from the Surveillance, Epidemiology, and End Results (SEER) dataset from 2004 to 2015, followed by comparison of cancer-specific survival (CSS) and overall survival (OS) between married and unmarried group. 3152 patients were identified including 1777 married patients (56.38%). Married populations tended to be more patients aged < 65, male, receiving chemotherapy, and less black race and large tumor size compared to unmarried group (all P < 0.05).Moreover, 5-year CSS (30.04% vs. 28.19%, P = 0.0013) and OS rates (26.68% vs. 22.94%, P < 0.0001) were superior in married population. Multivariate analysis revealed that marital status was an independent favorable prognostic indicator, and married population had better CSS (HR: 0.898; 95% CI: 0.822-0.980; P = 0.016) and OS (HR: 0.898; 95%CI: 0.827-0.975; P = 0.011).In addition, CSS as well as OS were superior in married populations than unmarried ones in most subgroups. Marital status was an independent prognostic factor for survival in patients with colorectal SRCC. Additionally, married patients obtained better survival advantages.

Radiotherapy after mastectomy has significant survival benefits for inflammatory breast cancer: a SEER population-based retrospective study.

OBJECTIVES: The survival benefit of postmastectomy radiotherapy (PMRT) has not been fully proven in inflammatory breast cancer (IBC). Thus, in the present research, we aimed at elucidating the effects of PMRT on the survival of IBC patients. METHODS: Eligible patients were collected from the Surveillance, Epidemiology, and End Results (SEER) dataset between 2010 and 2013. The Kaplan-Meier method along with the log-rank test was utilized for the comparison of both the overall survival (OS) andthe cancer-specific survival (CSS) in patients undergoing PMRT or not. Additionally, multivariate survival analysis of CSS and OS were performed using the Cox proportional hazard model. RESULTS: In total, 293 eligible cases were identified, with the median follow-up time of 27 months (range: 5-59 months). After propensity score matching (PSM), 188 patients (94 for each) were classified intothe No-PMRT and the PMRT group. Consequently, significantly higher OS rates were detected in the PMRT group compared with the No-PMRT group prior to PSM (P = 0.034), and significantly higher CSS (P = 0.013) and OS (P = 0.0063) rates were observed following PSM. Furthermore, multivariate analysis revealed thatPMRT [CSS (HR: 0.519, 95% CI [0.287-0.939], P = 0.030); OS (HR: 0.480, 95% CI [0.269-0.859], P = 0.013)], as well as Her2+/HR+ subtype, was independent favorable prognostic factors.Besides, black ethnicity, AJCC stage IV and triple-negative subtype were independent unfavorable prognostic factors. Further subgroup analysis revealed that most of the study population could benefit from PMRT, no matter OS or CSS. CONCLUSIONS: Our findings support that PMRT could improve the survival of IBC patients.

Nomogram predicting overall survival of rectal squamous cell carcinomas patients based on the SEER database: A population-based STROBE cohort study.

We aimed to evaluate the prognostic value of clinical and pathologic factors in rectal squamous cell carcinomas (SCC) and to construct a nomogram for their outcome prediction.The study cohort was selected from Surveillance, Epidemiology, and End Results (SEER) program between January 2004 and December 2013. Univariate and multivariate analyses were performed using Cox proportional hazards regression model to evaluate the prognostic value of involved variables. All prognostic factors were combined to construct a nomogram to predict the overall survival (OS), followed by discrimination as well as calibration plots and receiver operating characteristic (ROC) curves for assessing the predictive accuracy of the nomogram.We identified 806 patients with a median follow-up time of 35 months. Multivariate analyses revealed that marital status (P < .001), age (P < .001), T stage (P = .008), M stage (P < .001), surgery (P = .004), chemotherapy (P = .003) and radiotherapy (P = .016) were independent prognostic factors of OS. Finally, the 7 variables were combined to construct a 3-year and 5-year OS nomogram. The concordance indexes (C-indexes) of OS were 0.756 (95% CI, 0.726-0.786) for the internal validation and 0.729 (95% CI, 0.678-0.780) for the external validation. Additionally, there was superior discrimination power of the nomogram over the SEER stage or the 8th edition AJCC TNM staging classification (P < .001). Calibration plots further showed good consistency between the nomogram prediction and actual observation. The area under the curve (AUC) of ROC curves for 3-year OS was 0.811 (95% CI: 0.769-0.853) in the training cohort and 0.748 (95% CI: 0.681-0.815) in the validation cohort. The AUC for 5-year OS was 0.770 (95% CI: 0.721-0.819) in the training cohort and 0.797 (95% CI: 0.731-0.863) in the validation cohort. Finally, Kaplan-Meier analysis further validates the predictive potential of the nomogram.Marital status, age, T stage, M stage, surgery, chemotherapy and radiotherapy were significantly associated with OS of patients with rectal SCC. This predictive model has the potential to provide an individualized risk estimate of survival in patients with rectal SCC.

Construction and validation of a nomogram to predict overall survival in patients with inflammatory breast cancer.

In the present study, we examined the factors affecting survival of women with inflammatory breast cancer (IBC) and constructed and validated a nomogram to predict overall survival (OS) in these patients. The cohort was selected from the Surveillance, Epidemiology, and End Results (SEER) program between 1 January 2004 and 31 December 2013. Univariate and multivariate Cox proportional hazards regression models were constructed. A nomogram was developed based on significant prognostic indicators of OS. The discriminatory and predictive capacities of the nomogram were assessed using Harrell's concordance index (C-index) and calibration plots. A total of 1651 eligible patients were identified, with a median survival time of 31 months (range 0-131 months), and the 3- and 5-year OS rates were 52.8% and 39.5%, respectively. Multivariate analysis revealed that race (P < .001), marital status (P = .011), N stage (P = .002), M stage (P < .001), hormone receptor (P < .001), human epidermal growth factor receptor-2 (HER2) (P = .001), surgery (P < .001), chemotherapy (P < .001), and radiotherapy (P = .010) were independent prognostic indicators of IBC. These nine variables were incorporated to construct a nomogram. The C-indexes of the nomogram were 0.738 (95% confidence interval [CI]: 0.717, 0.759) and 0.741 (95% CI: 0.717, 0.765) for the internal and external validations, respectively. The nomogram had a better discriminatory capacity for predicting OS than did the SEER summary stage (P < .001) or the American Joint Committee on Cancer tumor-node metastasis staging systems (8th edition; P < .001). The calibration plot revealed satisfactory agreement between the findings and predicted outcomes in both the internal and external validations. The nomogram-based 3- and 5-year OS predictions for patients with IBC exhibited superior accuracy over the existing models.

Long noncoding RNA DLEU1 aggravates glioma progression via the miR-421/MEF2D axis.

BACKGROUND: Long noncoding RNA (lncRNA) deleted in lymphocytic leukemia 1 (DLEU1) was reported to be involved in the development and progression of multiple cancers. However, the accurate expression pattern, biological function and potential molecular mechanism of DLEU1 in glioma are not yet known. The present study investigated the role of DLEU in the development and progression of glioma, as well as the potential mechanism played by DLEU1 in glioma. MATERIALS AND METHODS: The levels of DLEUI in glioma tissues and cell lines were examined using quantitative real-time PCR. The potential effects of DLEU1 on the proliferation, mobility, invasion and apoptosis of glioma cells were evaluated using corresponding in vitro experiments. The association between DLEU1 and microRNA (miR)-421 was also determined using luciferase reporter activity and RNA immunoprecipitation (RIP) assays. RESULTS: The results revealed that DLEU1 was significantly upregulated in glioma tissues and cell lines. Increased DLEU1 was positively associated with the high-grade carcinoma (III-IV). Functional studies revealed that knockdown of DLEU1 expression by siRNA led to decreased proliferation, migration and invasion and increased apoptosis in human glioma cells. Furthermore, luciferase reporter activity and RIP assays confirmed that DLEUI could act as a competing endogenous RNA (ceRNA) for miR-421 that functioned as a tumor suppressor in glioma. Moreover, inhibition miR-421 partially restored the effect of DLEU1 knockdown on the glioma cells. DLEU1 could regulate myocyte enhancer factor 2D (MEF2D) expression, a known target of miR-421 in glioma cells. CONCLUSION: Taken together, these findings suggested that DLEU1 regulated MEF2D expression to promote glioma progression by sponging miR-421 and that DLEU1 might be a potential therapeutic target for glioma.

Correction: Systematic review and meta-analysis comparing zoledronic acid administered at 12-week and 4-week intervals in patients with bone metastasis.

[This corrects the article DOI: 10.18632/oncotarget.19856.].

MicroRNA­874 inhibits proliferation and invasion of pancreatic ductal adenocarcinoma cells by directly targeting paired box 6.

Studies have demonstrated that a number of microRNAs (miRNAs) are dysregulated in pancreatic ductal adenocarcinoma (PDAC), and alterations in their expression may affect the onset and progression of PDAC. Therefore, the expression patterns, biological functions and associated molecular mechanisms of miRNAs in PDAC should be elucidated for the development of novel therapeutic methods. Previous studies reported significant miRNA­874 (miR­874) dysregulation in multiple types of human cancer. However, the expression pattern, possible roles and underlying mechanisms of miR­874 in PDAC remain to be elucidated. This study evaluated miR­874 expression in PDAC and examined its biological functions and underlying mechanism of action in PDAC progression. miR­874 expression was downregulated in PDAC tissues and cell lines. Functional experiments demonstrated that upregulation of miR­874 inhibited cell proliferation and invasion in PDAC. Additionally, paired box 6 (PAX6) was predicted as a putative target of miR­874 using bioinformatics analysis. Further experiments demonstrated that PAX6 may be the direct target gene of miR­874 in PDAC. PAX6 knockdown exhibited similar inhibitory effects to miR­874 overexpression in PDAC cells. In addition, restored PAX6 expression may reverse the suppressive roles of miR­874 overexpression in PDAC cells. The results demonstrated that miR­874 may serve tumor suppressive roles in PDAC by directly targeting PAX6. Therefore, miR­874 may exhibit potential applications for treatment of patients with PDAC.

Systematic review and meta-analysis comparing zoledronic acid administered at 12-week and 4-week intervals in patients with bone metastasis.

Zoledronic acid is used to treat patients with bone metastasis, but the optimal dosing interval remains controversial. We therefore performed a systematic review and meta-analysis to compare the efficacy and safety of a 12-week interval of zoledronic acid with the standard 4-week interval. Three randomized controlled trials comprising 2650 patients were analyzed. Using a random-effects model, pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. No differences in the occurrence of skeletal-related events (SREs: RR = 0.98; 95% CI = 0.86-1.12; P = 0.80) or grade 3/4 adverse events (RR = 0.91; 95% CI = 0.69-1.20; P = 0.52) were observed between the 12-week and 4-week groups. The 12-week group tended to have lower incidences of osteonecrosis of the jaw [13 (0.98%) vs. 23 (1.73%)] and kidney dysfunction [21 (1.68%) vs. 31 (2.45%)] than the 4-week group, though the difference did not reach statistical significance (RR = 0.58, 95% CI: 0.30-1.12; P = 0.11); (RR = 0.67, 95% CI: 0.39-1.15, P = 0.15). These data show that zoledronic acid administered at 12-week intervals instead of 4-week intervals does not increase the risk of SREs, and may reduce the incidence of osteonecrosis of the jaw and kidney dysfunction. This suggests the 12-week interval with zoledronic acid may be an acceptable treatment option.

MicroRNA­382 inhibits cell proliferation and invasion of retinoblastoma by targeting BDNF­mediated PI3K/AKT signalling pathway.

It has previously been demonstrated that multiple microRNAs (miRNAs or miRs) are aberrantly expressed in retinoblastoma (RB) and contribute to RB initiation and progression. miR­382 has been revealed to be aberrantly expressed and therefore exhibits a key role in the progression of various types of cancer. However, the expression pattern, functional roles and underlying molecular mechanism of miR­382 in RB remain unknown. The present study investigated the expression levels of miR­382 and its effects on RB cells and the underlying regulatory mechanism of its action. It was demonstrated that miR­382 was downregulated in RB tissues and cell lines. Upregulation of miR­382 inhibited RB cell proliferation and invasion in vitro. Additionally, brain­derived neurotrophic factor (BDNF) was identified as a novel target of miR­382 in RB. BDNF was upregulated in RB tissues and negatively associated with miR­382 expression levels. Furthermore, BDNF overexpression rescued the tumour­suppressing effects on RB cells induced by miR­382. miR­382 inactivated the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signalling pathway in RB. These findings suggested that miR­382 serves as a tumour suppressor in RB, in part, by targeting the BDNF­mediated PI3K/AKT signalling pathway. The results of the present study suggest a potential therapeutic strategy for treating RB patients in the future.