Vascular compactness of unruptured brain arteriovenous malformation predicts risk of hemorrhage after stereotactic radiosurgery.

The aim of the study was to investigate whether morphology (i.e. compact/diffuse) of brain arteriovenous malformations (bAVMs) correlates with the incidence of hemorrhagic events in patients receiving Stereotactic Radiosurgery (SRS) for unruptured bAVMs. This retrospective study included 262 adult patients with unruptured bAVMs who underwent upfront SRS. Hemorrhagic events were defined as evidence of blood on CT or MRI. The morphology of bAVMs was evaluated using automated segmentation which calculated the proportion of vessel, brain tissue, and cerebrospinal fluid in bAVMs on T2-weighted MRI. Compactness index, defined as the ratio of vessel to brain tissue, categorized bAVMs into compact and diffuse types based on the optimal cutoff. Cox proportional hazard model was used to identify the independent factors for post-SRS hemorrhage. The median clinical follow-ups was 62.1 months. Post-SRS hemorrhage occurred in 13 (5.0%) patients and one of them had two bleeds, resulting in an annual bleeding rate of 0.8%. Multivariable analysis revealed bAVM morphology (compact versus diffuse), bAVM volume, and prescribed margin dose were significant predictors. The post-SRS hemorrhage rate increased with larger bAVM volume only among the diffuse nidi (1.7 versus 14.9 versus 30.6 hemorrhage per 1000 person-years in bAVM volume < 20 cm3 versus 20-40 cm3 versus > 40 cm3; p = 0.022). The significantly higher post-SRS hemorrhage rate of Spetzler-Martin grade IV-V compared with grade I-III bAVMs (20.0 versus 3.3 hemorrhages per 1000 person-years; p = 0.001) mainly originated from the diffuse bAVMs rather than the compact subgroup (30.9 versus 4.8 hemorrhages per 1000 person-years; p = 0.035). Compact and smaller bAVMs, with higher prescribed margin dose harbor lower risks of post-SRS hemorrhage. The post-SRS hemorrhage rate exceeded 2.2% annually within the diffuse and large (> 40 cm3) bAVMs and the diffuse Spetzler-Martin IV-V bAVMs. These findings may help guide patient selection of SRS for the unruptured bAVMs.

Predictive Value of the Interaction between CEA and Hemoglobin in Neoadjuvant CCRT Outcomes in Rectal Cancer Patients.

The adoption of neoadjuvant concurrent chemoradiotherapy (CCRT) has reshaped the therapeutic landscape, but response prediction remains challenging. This study investigates the interaction between pre-CCRT carcinoembryonic antigen (CEA) and post-CCRT hemoglobin (Hb) levels in predicting the response of locally advanced rectal cancer (LARC) to CCRT. Retrospective data from 93 rectal cancer patients receiving neoadjuvant CCRT were analyzed. Univariate analyses assessed clinical factors associated with tumor regression grade (TRG) and T-stage outcomes. Machine learning identified predictive biomarkers. Interaction effects between CEA and Hb were explored through subgroup analyses. Post-CCRT Hb varied between pre-CCRT CEA groups. The interaction between pre-CCRT CEA and post-CCRT Hb influenced TRG. Males with normal pre-CCRT CEA and anemia showed better treatment responses. Females with elevated pre-CCRT CEA and post-CCRT anemia exhibited poorer responses. The interaction effect between them was significant, indicating that their relationship with TRG was not additive. Inflammatory biomarkers, WBC, neutrophil count, and post-CCRT platelet level correlated with CCRT response. Contrasting with previous findings, anemia was a predictor of better treatment response in males with normal pre-CCRT CEA. The interaction between pre-CCRT CEA and post-CCRT Hb levels predicts the response of LARC to CCRT. CEA, Hb, and sex should be considered when assessing treatment response. Inflammatory biomarkers contribute to response prediction. Understanding these complex relationships can enhance personalized treatment approaches in rectal cancer patients.

Tumor-Associated Macrophages Affect the Tumor Microenvironment and Radioresistance via the Upregulation of CXCL6/CXCR2 in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma is the sixth most diagnosed malignancy and the fourth most common cause of cancer-related mortality globally. Despite progress in the treatment of liver cancer, nonsurgical treatments remain unsatisfactory, and only 15% of early-stage cases are surgically operable. Radiotherapy (RT) is a non-surgical treatment option for liver cancer when other traditional treatment methods are ineffective. However, RT has certain limitations, including eliciting poor therapeutic effects in patients with advanced and recurrent tumors. Tumor-associated macrophages (TAMs) are major inflammatory cells in the tumor microenvironment that are key to tumor development, angiogenesis, invasion, and metastasis, and they play an essential role in RT responses. METHODS: We used big data analysis to determine the potential of targeting CXCL6/CXCR2. We enrolled 50 patients with liver cancer who received RT at our hospital. Tumor tissue samples were examined for any relationship between CXCL6/CXCR2 activity and patient prognosis. Using a cell coculture system (Transwell), we cocultured Huh7 liver cancer cells and THP-1 monocytes with and without CXCL6/CXCR2 small interfering RNA for 72 h. RESULTS: The overexpression of CXCL6/CXCR2 was highly correlated with mortality. Our tissue study indicated a positive correlation between CXCL6/CXCR2 and M2-TAMs subsets. The coculture study demonstrated that THP-1 monocytes can secrete CXCL6, which acts on the CXCR2 receptor on the surface of Huh7 cells and activates IFN-g/p38 MAPK/NF-κB signals to promote the epithelial-mesenchymal transition and radio-resistance. CONCLUSIONS: Modulating the TAM/CXCL6/CXCR2 tumor immune signaling axis may be a new treatment strategy for the effective eradication of radiotherapy-resistant hepatocellular carcinoma cells.

Effectiveness of Stereotactic Ablative Radiotherapy for Systemic Therapy Respondents with Inoperable Pulmonary Oligometastases and Oligoprogression.

Stereotactic ablative radiotherapy (SABR) may improve survival in patients with inoperable pulmonary oligometastases. However, the impact of pulmonary oligometastatic status after systemic therapy on SABR outcomes remains unclear. Hence, we investigated the outcomes of SABR in 45 patients with 77 lung tumors and the prognostic value of pulmonary oligoprogression. Eligibility criteria were pulmonary oligometastases (defined as ≤5 metastatic lung tumors), controlled extrapulmonary disease (EPD) after front-line systemic therapy, SABR as primary local treatment for inoperable pulmonary metastases, and consecutive imaging follow-up. Oligometastatic lung tumor was classified into controlled or oligoprogressive status. Overall survival (OS), in-field progression-free survival (IFPFS), out-field progression-free survival (OFPFS), and prognostic variables were evaluated. With 21.8 months median follow-up, the median OS, IFPFS, and OFPFS were 28.3, not reached, and 6.5 months, respectively. Two-year OS, IFPFS, and OFPFS rates were 56.0%, 74.2%, and 17.3%, respectively. Oligoprogressive status (p = 0.003), disease-free interval < 24 months (p = 0.041), and biologically effective dose (BED10) < 100 Gy (p = 0.006) were independently associated with inferior OS. BED10 ≥ 100 Gy (p = 0.029) was independently correlated with longer IFPFS. Oligoprogressive status (p = 0.017) and EPD (p = 0.019) were significantly associated with inferior OFPFS. Grade ≥ 2 radiation pneumonitis occurred in four (8.9%) patients. Conclusively, SABR with BED10 ≥ 100 Gy could provide substantial in-field tumor control and longer OS for systemic therapy respondents with inoperable pulmonary oligometastases. Oligoprogressive lung tumors exhibited a higher risk of out-field treatment failure and shorter OS. Hence, systemic therapy should be tailored for patients with oligoprogression to reduce the risk of out-field treatment failure. However, in the absence of effective systemic therapy, SABR is a reasonable alternative to reduce resistant tumor burden.

Compactness index: a radiosurgery outcome predictor for patients with unruptured brain arteriovenous malformations.

OBJECTIVE: The goal of the study was to define and quantify brain arteriovenous malformation (bAVM) compactness and to assess its effect on outcomes after Gamma Knife radiosurgery (GKRS) for unruptured bAVMs. METHODS: Unsupervised machine learning with fuzzy c-means clustering was used to differentiate the tissue constituents of bAVMs on T2-weighted MR images. The percentages of vessel, brain, and CSF were quantified. The proposed compactness index, defined as the ratio of vasculature tissue to brain tissue, categorized bAVM morphology into compact, intermediate, and diffuse types according to the tertiles of this index. The outcomes of interest were complete obliteration and radiation-induced changes (RICs). RESULTS: A total of 209 unruptured bAVMs treated with GKRS were retrospectively included. The median imaging and clinical follow-up periods were 49.2 and 72.3 months, respectively. One hundred seventy-three bAVMs (82.8%) achieved complete obliteration after a median latency period of 43.3 months. The rates of RIC and permanent RIC were 76.1% and 3.8%, respectively. Post-GKRS hemorrhage occurred in 14 patients (6.7%), resulting in an annual bleeding risk of 1.0%. Compact bAVM, smaller bAVM volume, and exclusively superficial venous drainage were independent predictors of complete obliteration. Diffuse bAVM morphology, larger bAVM volume, and higher margin dose were independently associated with RICs. CONCLUSIONS: The compactness index quantitatively describes the compactness of unruptured bAVMs. Moreover, compact bAVMs may have a higher obliteration rate and a smaller risk of RICs than diffuse bAVMs. This finding could help guide decision-making regarding GKRS treatment for patients with unruptured bAVMs.

Genome-Wide Association Study Identifies Multiple Susceptibility Loci for Malignant Neoplasms of the Brain in Taiwan.

Primary brain malignancy is a rare tumor with a global incidence of less than 10 per 100,000 people. Hence, there is limited power for identifying risk loci in individual studies, especially for Han Chinese. We performed a genome-wide association study (GWAS) in Taiwan, including 195 cases and 195 controls. We identified five new genes for malignant neoplasms of the brain: EDARADD (rs645507, 1p31.3, p = 7.71 × 10-5, odds ratio (OR) = 1.893), RBFOX1 (rs8044700, p = 2.35 × 10-5, OR = 2.36), LMF1 (rs3751667, p = 7.24 × 10-7, OR = 2.17), DPP6 (rs67433368, p = 8.32 × 10-5, OR = 3.94), and NDUFB9 (rs7827791, p = 9.73 × 10-6, OR = 4.42). These data support that genetic susceptibility toward GBM or non-GBM tumors is highly distinct, likely reflecting different etiologies. Combined with signaling analysis, we found that RNA modification may be related to major risk factors in primary malignant neoplasms of the brain.

To Optimize Radiotherapeutic Plans for Superior Tumor Coverage Predicts Malignant Glioma Prognosis and Normal Tissue Complication Probability.

Background: Radiotherapy (RT) provides a modern treatment to enhance the malignant glioma control rate. The purpose of our study was to determine the effect of tumor coverage on disease prognosis and to predict optimal RT plans to achieve a lower normal tissue complication probability (NTCP). Methods: Ten malignant-glioma patients with tumors adjacent to organs at risk (OARs) were collected. The patients were divided into two groups according to adequate coverage or not, and prognosis was analyzed. Then, using intensity-modulated radiation therapy (IMRT), volume-modulated arc therapy (VMAT), and helical tomotherapy (TOMO) to simulate new treatment plans for 10 patients, the advantages of these planning systems were revealed for subsequent prediction of NTCP. Results: The results of clinical analysis indicated that overall survival (p = 0.078) between the adequate and inadequate groups showed no differences, while the adequate group had better recurrence-free survival (p = 0.018) and progression-free survival (p = 0.009). TOMO had better CI (p < 0.001) and also predicted a lower total-irradiated dose to the normal brain (p = 0.001) and a lower NTCP (p = 0.027). Conclusions: The TOMO system provided optimal therapeutic planning, reducing NTCP and achieving better coverage. Combined with the clinical results, our findings suggest that TOMO can make malignant glioma patients close to OARs achieve better disease control.

Effect of the simulated half leaf width of a multileaf collimator on volumetric modulated arc therapy plan quality in hippocampal avoidance whole-brain radiotherapy.

PURPOSE: Whole-brain radiotherapy (WBRT) is commonly used in patients with multiple brain metastases. Compared with conventional WBRT, hippocampal avoidance WBRT (HA-WBRT) more favorably preserves cognitive function and the quality of life. The hippocampal volume is considerably small (approximately 3.3 cm3 ). Therefore, downsizing the leaf width of a multileaf collimator (MLC) may provide higher spatial resolution and better plan quality. Volumetric modulated arc therapy (VMAT) could simulate the half MLC leaf width through couch shifting between arcs. This study investigated changes in VMAT quality for HA-WBRT with a simulated fine MLC leaf width. METHODS: We included 18 patients with brain metastasis. All target and avoidance structures were contoured by an experienced radiation oncologist. The prescribed dose was 30 Gy in 10 fractions. For each patient, three different treatment plans were generated for comparison: VMAT with couch-shift, VMAT without couch-shift, and TomoTherapy. All treatment plans fulfilled Radiation Therapy Oncology Group (RTOG) 0933 criteria for HA-WBRT. The Wilcoxon paired signed-rank test was used to compare different treatment plans. RESULTS: VMAT with couch-shift had the better average conformity index (0.823) with statistically significant difference compared to VMAT without couch-shift (0.810). VMAT with couch-shift (0.219) had a more favorable average homogeneity index (HI) than did VMAT without couch-shift (0.230), although the difference was not significant. TomoTherapy had an optimal average HI of 0.070. In terms of the hippocampus, all three treatment plans met the RTOG 0933 criteria. VMAT with couch-shift had a lower average Dmax (15.2 Gy) than did VMAT without couch-shift (15.3 Gy, p = 0.071) and TomoTherapy (15.5 Gy, p = 0.133). The average D100% of hippocampus was the same for both VMAT with and without couch-shift (8.5 Gy); however, TomoTherapy had a lower average D100% value of 7.9 Gy. The treatment delivery time was similar between VMAT with and without couch-shift (average, 375.0 and 369.6 s, respectively). TomoTherapy required a long average delivery time of 1489.9 s. CONCLUSION: The plan quality of VMAT for HA-WBRT was improved by using the couch-shift technique to simulate the half MLC leaf width. However, the improvement was not statistically significant except conformity index. The downsizing effect decreased with the use of the sophisticated grade of VMAT. TomoTherapy offered superior plan quality but required the longest delivery time.

Effect of hyaluronic acid on radiotherapy-induced mucocutaneous side effects: a meta-analysis of randomized controlled trials.

PURPOSE: Radiotherapy (RT)-induced mucocutaneous side effects remain a clinical challenge in cancer patients. Hyaluronic acid (HA), a key molecule in tissue regeneration, may relieve these side effects. The aim of the study is to investigate the effects of HA on RT-induced side effects in patients with cancer. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) was carried out. PubMed, Embase, and Cochrane Library were searched for published studies. A meta-analysis was conducted to calculate the pooled effect size using a random-effect model. RESULTS: Fifteen trials with 1131 patients were included. The HA group demonstrated a significant improvement in skin pain scores (mean difference [MD]: - 1.14, 95% confidence interval [CI]: - 2.21 to - 0.08) at week 4, and significantly decreased pain frequency (risk ratio [RR]: 0.47, 95% CI: 0.24 to 0.93) at 5 to 8 weeks when compared with the control group. The HA group also exhibited a significantly lower incidence of desquamation (RR: 0.27, 95% CI: 0.15 to 0.5) at 4 to 5 weeks and the most severe mucosal problems (RR: 0.14, 95% CI: 0.04 to 0.45) compared with the control group. Moreover, the HA group had a significantly lower incidence of bleeding (RR: 0.18, 95% CI: 0.05 to 0.65) than the control group at 4 months and 18 months. CONCLUSION: HA treatment may reduce RT-induced mucosal problems and pain. Moreover, HA is safe and has the potential for application in diverse forms and textures for pharmacotherapeutic use. Additional trials involving a higher number of patients are recommended.

PDK1 Inhibitor BX795 Improves Cisplatin and Radio-Efficacy in Oral Squamous Cell Carcinoma by Downregulating the PDK1/CD47/Akt-Mediated Glycolysis Signaling Pathway.

Background: Oral squamous cell carcinoma (OSCC) has a high prevalence and predicted global mortality rate of 67.1%, necessitating better therapeutic strategies. Moreover, the recurrence and resistance of OSCC after chemo/radioresistance remains a major bottleneck for its effective treatment. Molecular targeting is one of the new therapeutic approaches to target cancer. Among a plethora of targetable signaling molecules, PDK1 is currently rising as a potential target for cancer therapy. Its aberrant expression in many malignancies is observed associated with glycolytic re-programming and chemo/radioresistance. Methods: Furthermore, to better understand the role of PDK1 in OSCC, we analyzed tissue samples from 62 patients with OSCC for PDK1 expression. Combining in silico and in vitro analysis approaches, we determined the important association between PDK1/CD47/LDHA expression in OSCC. Next, we analyzed the effect of PDK1 expression and its connection with OSCC orosphere generation and maintenance, as well as the effect of the combination of the PDK1 inhibitor BX795, cisplatin and radiotherapy in targeting it. Results: Immunohistochemical analysis revealed that higher PDK1 expression is associated with a poor prognosis in OSCC. The immunoprecipitation assay indicated PDK1/CD47 binding. PDK1 ligation significantly impaired OSCC orosphere formation and downregulated Sox2, Oct4, and CD133 expression. The combination of BX795 and cisplatin markedly reduced in OSCC cell's epithelial-mesenchymal transition, implying its synergistic effect. p-PDK1, CD47, Akt, PFKP, PDK3 and LDHA protein expression were significantly reduced, with the strongest inhibition in the combination group. Chemo/radiotherapy together with abrogation of PDK1 inhibits the oncogenic (Akt/CD47) and glycolytic (LDHA/PFKP/PDK3) signaling and, enhanced or sensitizes OSCC to the anticancer drug effect through inducing apoptosis and DNA damage together with metabolic reprogramming. Conclusions: Therefore, the results from our current study may serve as a basis for developing new therapeutic strategies against chemo/radioresistant OSCC.

Impact of respiratory motion in dosimetric and clinical advantages for adjuvant left-sided breast radiotherapy.

We investigated the organ-sparing effect of the deep inspiration breath hold (DIBH) technique among different levels of lung expansion for left-side breast radiotherapy. This retrospective study enrolled 30 patients who received adjuvant left breast radiotherapy after breast-conserving surgery (BCS). Simulation scans of both DIBH and deep breathing four-dimensional computed tomography (4DCT) were acquired, and three treatment plans were generated for each patient. One plan was based on the DIBH images, and the other two plans were based on the mid-lung expansion (ME) and initial lung expansion (IE) phases retrieved from 4DCT data sets. Dosimetric comparisons and normal tissue complication probability (NTCP) models were conducted. We used image registration for displacement analysis and sought potential factors related to the dose benefit of DIBH. The DIBH plans resulted significantly lower doses to the heart, left ventricle (LV) and left anterior descending coronary artery (LAD), including the high- to low-dose areas, followed by the ME plans and IE plans (p < 0.05). DIBH reduced the risk of long-term cardiac mortality by 40% and radiation pneumonitis of the left lung by 37.96% compared with the IE plans (p < 0.001). The reduction in the mean dose to the heart and LV significantly correlated with anterior displacement of the left lung. The DIBH technique is a feasible tool to provide dosimetric and clinical advantages for adjuvant left-sided breast radiotherapy. Breathing pattern and the level of lung expansion seem to play an important role.

miR-671-5p Inhibition by MSI1 Promotes Glioblastoma Tumorigenesis via Radioresistance, Tumor Motility and Cancer Stem-like Cell Properties.

MicroRNAs (miRNAs) could be potential biomarkers for glioblastoma multiforme (GBM) prognosis and response to therapeutic agents. We previously demonstrated that the cancer stem cell marker Musashi-1 (MSI1) is an RNA binding protein that promotes radioresistance by increasing downstream RNA stability. To identify that MSI1 interacts with miRNAs and attenuates their function, we also get candidate miRNAs from the mRNA seq by predicting with TargetScan software. miR-671-5p in GBM cells interacts with MSI1 by intersecting the precipitated miRNAs with the predicted miRNAs. Notably, overexpression of MSI1 reversed the inhibitory effect of miR-671-5p. The phenotype of miR-671-5p in GBM cells could affect radiosensitivity by modulating the posttranscriptional activity of STAT3. In addition, miR-671-5p could attenuate tumor migration and cancer stem cell (CSC) characteristics by repressing the posttranscriptional activity of TRAF2. MSI1 may regulate GBM radioresistance, CSCs and tumor motility through miR-671-5p inhibition to increasing STAT3 and TRAF2 presentation. In vivo, the GBM tumor size was inversely correlated with miR-671-5p expression, but tumorigenesis was promoted by STAT3 and TRAF2 activation in the miR-671-5p-positive GBM population. miR-671-5p could be activated as a novel therapeutic target for GBM and has potential application as a predictive biomarker of glioblastoma prognosis.

Optimal tumor coverage with different beam energies by IMRT, VMAT and TOMO: Effects on patients with proximal gastric cancer.

To compare the effects of different photon energies on radiation planning by intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and helical tomotherapy (TOMO) for proximal gastric cancer (PGC). Network analysis with microarray procession and gene ontology were used to identify the effect of radiotherapy (RT) on PGC. Then, we retrospectively analyzed 8 PGC patients after receiving irradiation with a prescribed dose of 50.4 Gy. The Pinnacle treatment planning system (TPS, V9.8) was used to generate IMRT and VMAT plans by using 6 or 10 MV. TOMO plans were calculated on the Tomotherapy Planning Station Hi-Art Version 4.2.3 workstation (Tomotherapy Incorporated, Madison, WI, USA). PGC is associated with high DNA repair ability. TOMO plan results in higher tumor coverage and a better conformity index than IMRT and VMAT. 10-MV VMAT yields better dosimetric quality of the gradient index than 6-MV VMAT (P = .012). TOMO was associated with a lower irradiation dose in the mean dose to the right kidney (P = .049), left kidney and heart than 6-MV IMRT and 6-MV VMAT. 6-MV IMRT plan presented a higher dose of lung Dmean (P = .017) than 10-MV IMRT. Additionally, VMAT, using a planning energy of 6 MV, was associated with a significantly higher left kidney Dmean (P = .018) and V10 (P = .036) than a planning energy of 10 MV. TOMO is a better RT plan not only for tumor coverage but also for sparing organs at risk. IMRT and VMAT plans with 10 MV beams are more suitable than 6 MV beams for PGC treatment.

Targeting the Epigenetic Non-Coding RNA MALAT1/Wnt Signaling Axis as a Therapeutic Approach to Suppress Stemness and Metastasis in Hepatocellular Carcinoma.

BACKGROUND: With recorded under-performance of current standard therapeutic strategies as highlighted by high rates of post-treatment (resection or local ablation) recurrence, resistance to chemotherapy, poor overall survival, and an increasing global incidence, hepatocellular carcinoma (HCC) constitutes a medical challenge. Accumulating evidence implicates the presence of HCC stem cells (HCC-SCs) in HCC development, drug-resistance, recurrence, and progression. Therefore, treatment strategies targeting both HCC-SCs and non-CSCs are essential. METHODS: Recently, there has been an increasing suggestion of MALAT1 oncogenic activity in HCC; however, its role in HCC stemness remains unexplored. Herein, we investigated the probable role of MALAT1 in the SCs-like phenotype of HCC and explored likely molecular mechanisms by which MALAT1 modulates HCC-SCs-like and metastatic phenotypes. RESULTS: We showed that relative to normal, cirrhotic, or dysplastic liver conditions, MALAT1 was aberrantly expressed in HCC, similar to its overexpression in Huh7, Mahlavu, and SK-Hep1 HCC cells lines, compared to the normal liver cell line THLE-2. We also demonstrated a positive correlation between MALAT1 expression and poor cell differentiation status in HCC using RNAscope. Interestingly, we demonstrated that shRNA-mediated silencing of MALAT1 concomitantly downregulated the expression levels of ß-catenin, Stat3, c-Myc, CK19, vimentin, and Twist1 proteins, inhibited HCC oncogenicity, and significantly suppressed the HCC-SCs-related dye-effluxing potential of HCC cells and reduced their ALDH-1 activity, partially due to inhibited MALAT1-ß-catenin interaction. Additionally, using TOP/FOP (TCL/LEF-Firefly luciferase) Flash, RT-PCR, and western blot assays, we showed that silencing MALAT1 downregulates ß-catenin expression, dysregulates the canonical Wnt signaling pathway, and consequently attenuates HCC tumorsphere formation efficiency, with concurrent reduction in CD133+ and CD90+ HCC cell population, and inhibits tumor growth in SK-Hep1-bearing mice. Conclusions: Taken together, our data indicate that MALAT1/Wnt is a targetable molecular candidate, and the therapeutic targeting of MALAT1/Wnt may constitute a novel promising anticancer strategy for HCC treatment.

Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma.

Resistance to radiotherapy (IR), with consequent disease recurrence, continues to limit the efficacy of contemporary anticancer treatment for patients with hepatocellular carcinoma (HCC), especially in late stage. Despite accruing evidence implicating the PI3K/AKT signaling pathway in cancer-promoting hypoxia, cancerous cell proliferation and radiotherapy-resistance, it remains unclear which molecular constituent of the pathway facilitates adaptation of aggressive HCC cells to tumoral stress signals and drives their evasion of repeated IR-toxicity. This present study investigated the role of PDK1 signaling in IR-resistance, enhanced DNA damage repair and post-IR relapse, characteristic of aggressive HCC cells, while exploring potential PDK1-targetability to improve radiosensitivity. The study employed bioinformatics analyses of gene expression profile and functional protein-protein interaction, generation of IR-resistant clones, flow cytometry-based ALDH activity and side-population (SP) characterization, siRNA-mediated loss-of-PDK1function, western-blotting, immunohistochemistry and functional assays including cell viability, migration, invasion, clonogenicity and tumorsphere formation assays. We showed that the aberrantly expressed PDK1 characterizes poorly differentiated HCC CVCL_7955, Mahlavu, SK-HEP1 and Hep3B cells, compared to the well-differentiated Huh7 or normal adult liver epithelial THLE-2 cells, and independently activates the PI3K/AKT/mTOR signaling. Molecular ablation of PDK1 function enhanced susceptibility of HCC cells to IR and was associated with deactivated PI3K/AKT/mTOR signaling. Additionally, PDK1-driven IR-resistance positively correlated with activated PI3K signaling, enhanced HCC cell motility and invasiveness, augmented EMT, upregulated stemness markers ALDH1A1, PROM1, SOX2, KLF4 and POU5F1, increased tumorsphere-formation efficiency and suppressed biomarkers of DNA damage-RAD50, MSH3, MLH3 and ERCC2. Furthermore, the acquired IR-resistant phenotype of Huh7 cells was strongly associated with significantly increased ALDH activity, SP-enrichment, and direct ALDH1-PDK1 interaction. Moreover, BX795-mediated pharmacological inhibition of PDK1 synergistically enhances the radiosensitivity of erstwhile resistant cells, increased Bax/Bcl-2 apoptotic ratio, while suppressing oncogenicity and clonogenicity. We provide preclinical evidence implicating PDK1 as an active driver of IR-resistance by activation of the PI3K/AKT/mTOR signaling, up-modulation of cancer stemness signaling and suppression of DNA damage, thus, projecting PDK1-targeting as a putative enhancer of radiosensitivity and a potential new therapeutic approach for patients with IR-resistant HCC.

Dosimetric comparison of helical tomotherapy, volumetric-modulated arc therapy, intensity-modulated radiotherapy, and field-in-field technique for synchronous bilateral breast cancer.

PURPOSE: To compare the dosimetric characteristics of helical tomotherapy (HT), volumetric-modulated arc therapy (VMAT), intensity-modulated radiotherapy (IMRT), and tangential field-in-field technique (FIF) for the treatment of synchronous bilateral breast cancer (SBBC). METHODS AND MATERIALS: Ten patients with early-stage unilateral breast cancer were selected for simulating the patients with SBBC in this retrospective analysis. Treatment plans with HT, VMAT, IMRT, and FIF were generated for each patient with a total dose of 50.4 Gy in 28 fractions to the target. Plan quality, namely conformity index (CI), homogeneity index (HI), dose-volume statistics of organs at risk (OARs), and beam-on time (BOT), were evaluated. RESULTS: HT plans showed a lower mean heart dose (3.53 ± 0.31Gy) compared with the other plans (VMAT = 5.6 ± 1.36 Gy, IMRT = 3.80 ± 0.76 Gy, and FIF = 4.84 ± 2.13 Gy). Moreover, HT plans showed a significantly lower mean lung dose (p < 0.01) compared with the other plans: mean right lung doses were 6.81 ± 0.67, 10.32 ± 1.04, 9.07 ± 1.21, and 10.03 ± 1.22 Gy and mean left lung doses were 6.33 ± 0.87, 8.82 ± 0.91, 7.84 ± 1.07, and 8.64 ± 0.99 Gy for HT, VMAT, IMRT, and FIF plans, respectively. The mean dose to the left anterior descending artery was significantly lower in HT plans (p < 0.01) than in the other plans: HT = 19.41 ± 0.51 Gy, VMAT = 25.77 ± 7.23 Gy, IMRT = 27.87 ± 6.48 Gy, and FIF = 30.95 ± 10.17 Gy. FIF plans showed a worse CI and HI compared with the other plans. VMAT plans showed shorter BOT (average, 3.9 ± 0.2 minutes) than did HT (average, 11.0 ± 3.0 minutes), IMRT (average, 6.1 ± 0.5 minutes), and FIF (average, 4.6 ± 0.7 minutes) plans. CONCLUSIONS: In a dosimetric comparison for SBBC, HT provided the most favorable dose sparing of OARs. However, HT with longer BOT may increase patient discomfort and treatment uncertainty. VMAT enabled shorter BOT with acceptable doses to OARs and had a better CI than did FIF and IMRT.

CD44-associated radioresistance of glioblastoma in irradiated brain areas with optimal tumor coverage.

Glioblastoma multiforme (GBM) requires radiotherapy (RT) as its definitive management. However, GBM still has a high local recurrence rate even after RT. Cancer stem-like cells (CSCs) might enable GBM to evade irradiation damage and cause therapeutic failure. The optimal RT plan should achieve a planning target volume (PTV) coverage of more than 95% but cannot always meet the requirements. Here, we demonstrate that irradiation with different tumor coverage rates to different brain areas has similar effects on GBM. To retrospectively analyze the relationship between PTV coverage and the survival rate in 26 malignant glioblastoma patients, we established primary cell lines from patient-derived malignant glioblastoma cells with the PTV95 (PTV coverage of more than 95%) program (GBM-MG1 cells) and the Non-PTV95 (poor PTV coverage of less than 95%) program (GBM-MG2 cells). The clinical results of PTV95 and Non-PTV95 showed no difference in the overall survival (OS) rate (P = .390) between the two different levels of PTV coverage. GBM-MG1 (PTV95 program) cells exhibited higher radioresistance than GBM-MG2 (Non-PTV95 program) cells. CD44 promotes radioresistance, CSC properties, angiogenesis and cell proliferation in GBM-MG1 (PTV95 program) cells. GBM patients receiving RT with the PTV95 program exhibited higher radioresistance, CSC properties, angiogenesis and cell proliferation than GBM patients receiving RT with the Non-PTV95 program. Moreover, CD44 plays a crucial role in these properties of GBM patients with the PTV95 program.

Effectiveness of stereotactic ablative radiotherapy in patients with advanced hepatocellular carcinoma unsuitable for transarterial chemoembolization.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) can deliver tumoricidal doses and achieve long-term control in early hepatocellular carcinoma (HCC). However, limited studies have investigated the safety and effectiveness of SABR in patients with advanced diseases that is unsuitable for transarterial chemoembolization (TACE). METHODS: In this observational study, we reviewed the medical records of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease treated with linear accelerator-based SABR between 2008 and 2016. Their tumors were either refractory to TACE or TACE was contraindicated. Overall survival (OS), in-field progression-free survival (IFPFS), and out-field progression-free survival were calculated using Kaplan-Meier analysis. The Cox regression model was used to examine the effects of variables. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03) and whether patients developed radiation-induced liver disease (RILD) after SABR. RESULTS: This study included 32 patients. The mean maximal tumor diameter and tumor volumes were 4.7 cm and 135.9 ml, respectively. Patients received linear accelerator-based SABR with a median prescribed dose of 48 Gy (30-60 Gy) in three to six fractions. Based on the assessment of treatment response by using the Response Evaluation Criteria in Solid Tumors (version 1.1), 19% of patients achieved a complete response and 53% achieved a partial response. After a median follow-up of 18.1 months (4.0-65.9 months), 10, 19, and 9 patients experienced in-field failure, out-field hepatic recurrence, and extrahepatic metastases, respectively. The estimated 2-year OS and IFPFS rates were 54.4% and 62.7%, respectively. In a multivariate analysis, a pretreatment Cancer of the Liver Italian Program (CLIP) score of ⩾2 (p = 0.01) was a prognostic factor for shorter OS, and a biologically effective dose (BED) of < 85 Gy10 (p = 0.011) and a Child-Pugh score of ⩾6 (p = 0.014) were prognostic factors for inferior IFPFS. In this study five and eight patients developed classic and nonclassic RILD, respectively. CONCLUSIONS: SABR can serve as a salvage treatment for patients with HCC with BCLC stage C disease unsuitable for TACE, in particular, in those with a baseline CLIP score of ⩽1. A BED10 of ⩾85 Gy is an appropriate prescribed dose for tumor control. Because out-field relapse is the major cause of treatment failure, SABR in combination with novel systemic modalities should be investigated in future studies.

CD47-SIRPα Signaling Induces Epithelial-Mesenchymal Transition and Cancer Stemness and Links to a Poor Prognosis in Patients with Oral Squamous Cell Carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC), with high mortality rates, is one of the most diagnosed head and neck cancers. Epithelial-to-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs) are two keys for therapy-resistance, relapse, and distant metastasis. Accumulating evidence indicates that aberrantly expressed cluster of differentiation (CD)47 is associated with cell-death evasion and metastasis; however, the role of CD47 in the generation of CSCs in OSCC is not clear. METHODS: We investigated the functional roles of CD47 in OSCC cell lines SAS, TW2.6, HSC-3, and FaDu using the bioinformatics approach, immunoblotting, immunofluorescence staining, and assays for cellular migration, invasion, colony, and orosphere formation, as well as radiosensitivity. RESULTS: We demonstrated increased expression of CD47 in OSCC patients was associated with an estimated poorly survival disadvantage (p = 0.0391) and positively correlated with the expression of pluripotency factors. Silencing CD47 significantly suppressed cell viability and orosphere formation, accompanied by a downregulated expression of CD133, SRY-Box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and c-Myc. In addition, CD47-silenced OSCC cells showed reduced EMT, migration, and clonogenicity reflected by increased E-cadherin and decreased vimentin, Slug, Snail, and N-cadherin expression. CONCLUSION: Of therapeutic relevance, CD47 knockdown enhanced the anti-OSCC effect of radiotherapy. Collectively, we showed an increased CD47 expression promoted the generation of CSCs and malignant OSCC phenotypes. Silencing CD47, in combination with radiation, could provide an alternative and improved therapeutic efficacy for OSCC patients.

Prognostic and predictive factors for clinical and radiographic responses in patients with painful bone metastasis treated with magnetic resonance-guided focused ultrasound surgery.

Background: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is an alternative local therapy for patients with painful bone metastasis. However, little is known about the prognostic and predictive factors of MRgFUS in treating bone metastasis. Materials and methods: This retrospective study analyzed the performance status, treated site, pretreatment pain score, pretreatment tumor volume and lesion coverage volume factor (CVF) of 31 patients who underwent MRgFUS. A numerical rating scale for pain was used at the same time to assess the clinical response. Radiographic responses were evaluated using a modified version of The University of Texas MD Anderson Cancer Center criteria and reference to the MR imaging or computed tomography scans obtained 3 months after treatment. Univariate and multivariate logistic regression analyses were conducted to examine the effect of variables on clinical and radiographic responses. Results: The overall clinical response rate was 83.9% and radiographic response rate was 67.7%. Multivariate logistic regression analysis revealed that the better pretreatment Karnofsky performance status (KPS) (odds ratio: 1.220, 95% confidence interval (CI): 1.033-1.440; p = 0.019) was significantly associated with a more positive clinical response, and that the lesion CVF (odds ratio: 1.183, 95% CI: 1.029-1.183; p = 0.0055) was an independent prognostic factor for radiographic responses. The radiographic response of patients with lesion CVF ≥70% and CVF <70% were 91.7% and 52.6%, respectively (p = 0.0235). Conclusion: The pretreatment KPS was an independent prognostic factor for clinical responses, and lesion CVF was an independent prognostic factor for radiographic responses.