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In the past decade, cancer immunotherapy has achieved great success owing to the unravelling of unknown molecular forces in cancer immunity. However, it is critical that we address the limitations of current immunotherapy, including immune-related adverse events and drug resistance, and further enhance current immunotherapy. Lipids are reported to play important roles in modulating immune responses in cancer. Cancer cells use lipids to support their aggressive behaviour and allow immune evasion. Metabolic reprogramming of cancer cells destroys the equilibrium between lipid anabolism and catabolism, resulting in lipid accumulation within the tumour microenvironment (TME). Consequently, ubiquitous lipids, mainly fatty acids, within the TME can impact the function and phenotype of infiltrating immune cells. Determining the complex roles of lipids and their interactions with the TME will provide new insight for improving anti-tumour immune responses by targeting lipids. Herein, we present a review of recent literature that has demonstrated how lipid metabolism reprogramming occurs in cancer cells and influences cancer immunity. We also summarise the potential for lipid-based clinical translation to modify immune treatment.

Breast cancer (BC) is one of the commonly occurring malignancies in females worldwide. Despite significant advances in therapeutics, the mortality and morbidity of BC still lead to low survival and poor prognosis due to the drug resistance. There are certain chemotherapeutic, endocrine, and target medicines often used for BC patients, including anthracyclines, taxanes, docetaxel, cisplatin, and fluorouracil. The drug resistance mechanisms of these medicines are complicated and have not been fully elucidated. It was reported that non-coding RNAs (ncRNAs), such as micro RNAs (miRNA), long-chain non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) performed key roles in regulating tumor development and mediating therapy resistance. However, the mechanism of these ncRNAs in BC chemotherapeutic, endocrine, and targeted drug resistance was different. This review aims to reveal the mechanism and potential functions of ncRNAs in BC drug resistance and to highlight the ncRNAs as a novel target for achieving improved treatment outcomes for BC patients.

ObjectiveTo compare the dosimetric parameters of different radiotherapy plans [helical tomotherapy (HT), volume-modulated arc therapy (VMAT), and fixed-field intensity-modulated radiation therapy (FF-IMRT)] for locally advanced nasopharyngeal carcinoma (NPC).MethodsA total of 15 patients with locally advanced NPC were chosen for this retrospective analysis and replanned for HT, VMAT, and FF-IMRT. The prescribed planning target volume (PTV) dose for the primary tumor and metastatic lymph nodes was 70 Gy (2.12 Gy/fraction, delivered over 33 fractions). The prescribed PTV dose for the high-risk subclinical region was 59.4 Gy (1.8 Gy/fraction, delivered over 33 fractions). The dosimetric parameters of the PTV and organs at risk (OARs) and the efficiency of radiation delivery were assessed and compared using the paired-samples t-test.ResultsCompared with VMAT and FF-IMRT plans, HT plans significantly improved the mean conformity index (CI) and homogeneity index (HI). The HT plans reduced the maximum doses delivered to OARs, such as the brainstem, spinal cord, and optic nerves, and significantly reduced the volume delivered to the high-dose region, especially when examining the V30 value of the parotid glands. However, VMAT reduced the treatment time and improved the efficiency of radiation delivery compared with HT.ConclusionsFor locally advanced NPC, the results showed that HT and VMAT possessed better target homogeneity and conformity, reducing the dose delivered to OARs compared with conventional FF-IMRT, with HT achieving the best effect. Among the techniques studied, VMAT had the shortest radiation delivery time. The results of this study can provide guidance for the selection of appropriate radiation technologies used to treat patients with locally advanced NPC who are undergoing concurrent chemoradiotherapy.

The differential diagnosis of lymphadenopathy is important for predicting prognosis, staging, and monitoring the treatment, especially for cancer patients. Conventional computed tomography and magnetic resonance imaging characterize lymph node (LN) with disappointing sensitivity and specificity. Conventional ultrasound with the advantage of high resolution has been widely used for the LN evaluation. Ultrasound elastography (UE) using color map or shear wave velocity can non-invasively demonstrate the stiffness and homogeneity of both the cortex and medulla of LNs and can detect early circumscribed malignant infiltration. There is a need of a review to comprehensively discuss the current knowledge of the applications of various UE techniques in the evaluation of LNs. In this review, we discussed the principles of strain elastography and shear wave-based elastography, and their advantages and limitations in the evaluation of LNs. In addition, we comprehensively introduced the applications of various UE techniques in the differential diagnosis of reactive LNs, lymphoma, metastatic LNs, and other lymphadenopathy. Moreover, the applications of endoscopic UE and endobronchial UE are also discussed, including their use for improving the positive rate of diagnosis of fine-needle aspiration biopsy.

PurposeTo compare survival in different strategies, preoperative systemic treatment versus upfront surgery, in HER2-positive early breast cancer patients in the real world.MethodsAccording to the actual upfront treatment, eligible patients from 2012 to 2015 were classified as preoperative systemic treatment or upfront surgery group prospectively. The primary endpoint is disease-free survival; the second endpoint is overall survival. All the outcomes were examined in the propensity score matching model and inverse probability of treatment weighting model.ResultsIncluded in the analysis were 1,067 patients (215 in the preoperative systemic treatment group, 852 in the upfront surgery group). In the propensity score matching model (matching at 1:1 ratio), the disease-free survival of the preoperative systemic treatment group was significantly higher than that of the upfront surgery group (hazard ratio, 0.572, 95%CI, 0.371–0.881, P, 0.012). In the inverse probability of treatment weighting model, there was no significant difference in disease-free survival between the two groups (hazard ratio, 0.946, 95%CI, 0.763–1.172, P, 0.609). For overall survival, there was no significant difference between the two groups.ConclusionThe HER2-positive patients who accepted preoperative systemic treatment had better disease-free survival than those who underwent upfront surgery by real-world statistic methods.Clinical Trial RegistrationClinicaltrials.gov, identifier NCT04249440.

The Exocrine Differentiation and Proliferation Factor (EXDPF) gene could promote exocrine while inhibit endocrine functions. Although it is well known that ovary is an endocrine organ, the functions of EXDPF in ovarian cancer development is still unknown. This study demonstrated that EXDPF gene is significantly higher expressed in ovarian tumors compared to normal ovarian tissue controls. EXDPF DNA amplification was exhibited in lots of human tumors including 7.19% of ovarian tumors. Also, high expression of EXDPF positively correlated with poor overall survival (OS) of ovarian cancer patients. EXDPF expression could be universally detected in most epithelial ovarian cancer cells (SKOV3, IGROV1, MACS, HO8910PM, ES2, COV362 and A2780) tested in this study. Knock-down of EXDPF by siRNA delivered by plasmid or lentivirus largely inhibited ovarian cancer cells, IGROV1 and SKOV3 proliferation, migration and tumorigenesis in vitro and/or in vivo. Knock-down of EXDPF sensitized SKOV3 cells to the treatment of the front-line drug, paclitaxel. Mechanism study showed that EXDPF enhanced DNA replication pathway to promote ovarian cancer tumorigenesis. In conclusion, this study demonstrated that EXDPF could be a potential therapeutic target as a pro-oncogene of ovarian cancer.

ObjectiveTo evaluate the effectiveness of a novel computerized quantitative analysis based on histopathological and computed tomography (CT) images for predicting the postoperative prognosis of esophageal squamous cell carcinoma (ESCC) patients.MethodsWe retrospectively reviewed the medical records of 153 ESCC patients who underwent esophagectomy alone and quantitatively analyzed digital histological specimens and diagnostic CT images. We cut pathological images (6000 × 6000) into 50 × 50 patches; each patient had 14,400 patches. Cluster analysis was used to process these patches. We used the pathological clusters to all patches ratio (PCPR) of each case for pathological features and we obtained 20 PCPR quantitative features. Totally, 125 computerized quantitative (20 PCPR and 105 CT) features were extracted. We used a recursive feature elimination approach to select features. A Cox hazard model with L1 penalization was used for prognostic indexing. We compared the following prognostic models: Model A: clinical features; Model B: quantitative CT and clinical features; Model C: quantitative histopathological and clinical features; and Model D: combined information of clinical, CT, and histopathology. Indices of concordance (C-index) and leave-one-out cross-validation (LOOCV) were used to assess prognostic model accuracy.ResultsFive PCPR and eight CT features were treated as significant indicators in ESCC prognosis. C-indices adjusted for LOOCV were comparable among four models, 0.596 (Model A) vs. 0.658 (Model B) vs. 0.651 (Model C), and improved to 0.711with Model D combining information of clinical, CT, and histopathology (all pConclusionQuantitative prognostic modeling using a combination of clinical data, histopathological, and CT images can stratify ESCC patients with surgery alone into high-risk and low-risk groups.

Background and PurposeThe optimal treatment modality for clinically positive lateral pelvic lymph node (LPLN) from locally advanced rectal cancer (LARC) is unknown. Thus, we aimed to analyze the optimal radiotherapy dose for clinically positive LPLN from LARC.Materials and MethodsWe retrospectively evaluated distal LARC (i.e., within 8 cm from the anal verge) patients with clinically positive LPLN (i.e., ≥7 mm in the short axis). They were divided into two groups based on whether or not they received simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT)–based chemoradiotherapy. The total radiotherapy dose on LPLN were 56-60Gy for SIB-IMRT group and 41.8Gy for non-SIB-IMRT group. The clinical parameters and regrowth rate of LPLN were then compared between the two groups.ResultsA total of 151 patients were evaluated, and 83 and 68 patients were classified to the SIB-IMRT and non-SIB-IMRT group, respectively. The median follow-up period was 22.6 months, and the 2-year LPLN regrowth rate was significantly different between the SIB-IMRT group and the non-SIB-IMRT group (0% vs 10.8%, P=0.024). Further, SIB-IMRT yielded a significantly lower 2-year LPLN regrowth rate in patients whose LPLN measured ≥8 mm in the short axis (0% vs. 15.9%, P=0.019) or ≥10 mm in the long axis (0% vs. 17.6%, P=0.024) compared to patients who were in non-SIB-IMRT group. Meanwhile, there was no significant difference in grade II radiation-related toxicity (30.1% vs. 39.1%, P=0.217) and surgical complications (21.8% vs. 12.2%, P=0.198) between the two groups.ConclusionSIB-IMRT–based neoadjuvant chemoradiotherapy is beneficial for eliminating clinically positive LPLN from LARC without increasing the incidence of radiotherapy-related toxicity and surgical complications, and patients with larger LPLN may gain benefit from this technique.

Magnesium, the second most predominant intracellular cation, plays a crucial role in many physiological functions; magnesium-based biomaterials have been widely used in clinical application. In a variety of cancer types, the high intracellular concentration of magnesium contributes to cancer initiation and progression. Therefore, we initiated this study to investigate the likelihood of confounding magnesium with cancer therapy. In this study, the anti-tumor activity of magnesium and underlying mechanisms were assessed in bladder cancer both in vitro and in vivo. The results indicated that the proliferation of bladder cancer cells was inhibited by treatment with a high concentration of MgCl2 or MgSO4. The apoptosis, G0/G1 cell cycle arrest, autophagy, and ER stress were promoted following treatment with MgCl2. However, the migratory ability of MgCl2 treated cells was similar to that of control cells, as revealed by the trans-well assay. Besides, no significant difference was observed in the proportion of CD44 or CD133 positive cells between the control and MgCl2 treated cells. Thus, to improve the therapeutic effect of magnesium, VPA was used to treat cancer cells in combination with MgCl2. As expected, combination treatment with MgCl2 and VPA could markedly reduce proliferation, migration, and in vivo tumorigenicity of UC3 cells. Moreover, the Wnt signaling was down-regulated, and ERK signaling was activated in the cells treated with combination treatment. In conclusion, the accurate utilization of MgCl2 in targeting autophagy might be beneficial in cancer therapy. Although further studies are warranted, the combination treatment of MgCl2 with VPA is an effective strategy to improve the outcome of chemotherapy.

BackgroundTo evaluate the dosimetric parameters of different bone marrow sparing strategies and radiotherapy technologies and determine the optimal strategy to reduce hematologic toxicity associated with concurrent chemoradiation (cCRT) for cervical cancer.MethodsA total of 15 patients with Federation International of Gynecology and Obsterics (FIGO) Stage IIB cervical cancer treated with cCRT were re-planned for bone marrow (BM)-sparing plans. First, we determined the optimal BM sparing strategy for intensity modulated radiotherapy (IMRT), including a BMS-IMRT plan that used total BM sparing (IMRT-BM) as the dose-volume constraint, and another plan used os coxae (OC) and lumbosacral spine (LS) sparing (IMRT-LS+OC) to compare the plan without BM-sparing (IMRT-N). Then, we determined the optimal technology for the BMS-IMRT, including fixed-field IMRT (FF-IMRT), volumetric-modulated arc therapy (VMAT), and helical tomotherapy (HT). The conformity and homogeneity of PTV, exposure volume of OARs, and efficiency of radiation delivery were analyzed.ResultsCompared with the IMRT-N group, the average volume of BM that received ≥10, ≥20, ≥30, and ≥40 Gy decreased significantly in both two BM-sparing groups, especially in the IMRT-LS+OC group, meanwhile, two BMS-IMRT plans exhibited the similar effect on PTV coverage and other organs at risk (OARs) sparing. Among three common IMRT techniques in clinic, HT was significantly less effective than VMAT and FF-IMRT in the aspect of BM-Sparing. Additionally, VMAT exhibited more efficient radiation delivery.ConclusionWe recommend the use of VMAT with OC and LS as separate dose-volume constraints in cervical cancer patients aiming at reducing hematologic toxicity associated with cCRT, especially in developing countries.

Objective: The prognosis of patients with prostate cancer (PCa) has improved in recent years, but treatment-related cardiotoxicity remains unclear. This study investigated the heart-specific mortality and prognostic factors of patients with PCa after radiotherapy (RT) or radical prostatectomy (RP), and compared their long-term heart-specific mortality with that of the general male population.Materials and Methods: Data were taken from the Surveillance, Epidemiology, and End Result (SEER) database. Patients with PCa were included who underwent RT or RP from 2000 to 2012, and were followed through 2015. A cumulative mortality curve and a competitive risk regression model were applied to assess the prognostic factors of heart-specific mortality. Standardized mortality rates (SMRs) were calculated.Results: Of 389,962 men, 49.7% and 50.3% received RP and RT, respectively. The median follow-up was 8.3 years. For patients given RT, in about 9 years postdiagnosis, the cumulative mortality due to heart-specific disease exceeded that due to PCa. In patients who underwent RP, cumulative mortality from heart-specific disease or PCa was comparable. Relative to the general male population, overall, the heart-specific mortality of patients with PCa receiving RT or RP was not higher, but in patients aged 70 to 79 years, those given RT experienced slightly higher heart-specific mortality than the age-matched general population.Conclusions: Patients with PCa treated with RT or RP overall do not incur risk of heart-specific mortality higher than that of the general male population, except for patients aged 70–74 years receiving RT.

PurposeWe aim to compare the radiomic features and parameters on 2-deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) between patients with endometrial cancer with Lynch syndrome and those with endometrial cancer without Lynch syndrome. We also hope to explore the biologic significance of selected radiomic features.Materials and MethodsWe conducted a retrospective cohort study, first using the 18F-FDG PET/CT images and clinical data from 100 patients with endometrial cancer to construct a training group (70 patients) and a test group (30 patients). The metabolic parameters and radiomic features of each tumor were compared between patients with and without Lynch syndrome. An independent cohort of 23 patients with solid tumors was used to evaluate the value of selected radiomic features in predicting the expression of the programmed cell death 1 (PD1), using 18F-FDG PET/CT images and RNA-seq genomic data.ResultsThere was no statistically significant difference in the standardized uptake values on PET between patients with endometrial cancer with Lynch syndrome and those with endometrial cancer without Lynch syndrome. However, there were significant differences between the 2 groups in metabolic tumor volume and total lesion glycolysis (p < 0.005). There was a difference in the radiomic feature of gray level co-occurrence matrix entropy (GLCMEntropy; p < 0.001) between the groups: the area under the curve was 0.94 in the training group (sensitivity, 82.86%; specificity, 97.14%) and 0.893 in the test group (sensitivity, 80%; specificity, 93.33%). In the independent cohort of 23 patients, differences in GLCMEntropy were related to the expression of PD1 (rs =0.577; p < 0.001).ConclusionsIn patients with endometrial cancer, higher metabolic tumor volumes, total lesion glycolysis values, and GLCMEntropy values on 18F-FDG PET/CT could suggest a higher risk for Lynch syndrome. The radiomic feature of GLCMEntropy for tumors is a potential predictor of PD1 expression.

Background: Long non-coding RNA CASC2 (lncRNA CASC2) has been found to be down-regulated in esophageal squamous cell carcinoma (ESCC). However, the effect of CASC2 on cisplatin-treated ESCC was unclear. The present study aimed to evaluate the role of CASC2 in cisplatin-treated ESCC cells. Methods: The expression levels of CASC2 and miR-181a were detected by qRT-PCR. Cell viability was measured by MTT assay. The cytotoxicity effect was detected by lactate dehydrogenase (LDH) release assay. Cell apoptosis was tested by flow cytometry. The protein levels of protein kinase B (Akt) and p-Akt were detected by western blotting. Results: The results showed that CASC2 was low-expressed in ESCC cell lines. Overexpression of CASC2 enhanced the inhibitory effect of cisplatin on cell viability and promoted cisplatin-induced LDH release and apoptosis. We also found that miR-181a expression levels were increased in ESCC cell lines. MiR-181a inhibitor enhanced the antitumor activity of cisplatin, which was similar with the effect of CASC2. CASC2 directly interacted with miR-181a and inhibited the miR-181a expression. MiR-181a reversed the effects of CASC2 on antitumor activity of cisplatin. In addition, we also found that CASC2 suppressed the Akt pathway by inhibiting miR-181a. Conclusions: CASC2 promoted the antitumor activity of cisplatin through inhibiting Akt pathway via negatively regulating miR-181a in ESCC cells. The results provide a new insight for ESCC therapy.

Novel inhibitors are urgently needed for use as targeted therapies to improve the overall survival (OS) of patients with ovarian cancer. Here, we show that cell division cycle 25B (CDC25B) is over-expressed in ovarian tumors and associated with poor patient prognosis. All previously reported CDC25B inhibitors have been identified by their ability to reversibly inhibit the catalytic dephosphorylation activity of CDC25B in vitro; however, none of these compounds have entered clinical trials for ovarian cancer therapy. In this study, we synthesized a novel small molecule compound, WG-391D, that potently down-regulates CDC25B expression without affecting its catalytic dephosphorylation activity. The inhibition of CDC25B by WG-391D is irreversible, and WG-391D should therefore exhibit potent antitumor activity against ovarian cancer. WG-391D induces cell cycle progression arrest at the G2/M phase. Half maximal inhibitory concentration (IC50) values of WG-391D for inhibition of the proliferation and migration of eight representative ovarian cancer cell lines (SKOV3, ES2, OVCAR8, OVTOKO, A2780, IGROV1, HO8910PM, and MCAS) and five primary ovarian tumor cell lines (GFY004, GFY005, CZ001, CZ006, and CZ008) were lower than 10 and 1 μM, respectively. WG-391D inhibited tumor growth in nude mice inoculated with SKOV3 cells or a patient-derived xenograft (PDX). The underlying mechanisms were associated with the down-regulation of CDC25B and subsequent inactivation of cell division cycle 2 (CDC2) and the serine/threonine kinase, AKT. In conclusion, this study demonstrates that WG-391D exhibits strong antitumor activity against ovarian cancer and indicates that the down-regulation of CDC25B by inhibitors could provide a rationale for ovarian cancer therapy.

Glioma stem cells (GSCs) have been considered to be responsible for treatment failure due to their self-renewal and limitless proliferative property. Recently, the Na+/K+-ATPase a1 (ATP1A1) subunit was described as a novel therapeutic target for gliomas. Interestingly, our previous proteomics study revealed that ATP1A1 is remarkably overexpressed in GSCs. In the current study, we investigated the role of ATP1A1 in regulating growth, survival, and tumorigenicity of primary human GSCs and the underlying molecular mechanism. We tested RNA and protein expression of ATP1A1 in glioma tissues and GSCs. In addition, we knocked down ATP1A1 in GSCs and assessed the effects thereof on growth, survival, and apoptosis. The role of ATP1A1 in signaling pathways was investigated in vitro. We found that the ATP1A1 expression level was associated with the grade of glioma. Knockdown of ATP1A1 in GSCs in vitro inhibited cell proliferation and survival, increased apoptosis, and halted cell-cycle progression at the G1 phase. Cell proliferation and survival were resumed upon rescue of ATP1A1 expression in ATP1A1-knockdown GSCs. The ERK1/2 and AKT pathways were inhibited through suppression of Src phosphorylation by ATP1A1 knockdown. Collectively, our findings suggest that ATP1A1 overexpression promotes GSC growth and proliferation by affecting Src phosphorylation to activate the ERK1/2 and AKT signaling pathways.