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Bone metastasis has been reported in up to 70% of patients with advanced breast cancer. A total of 55.76% of skeletal metastases in women were derived from breast cancer. However, patients with bone metastasis from an occult primary breast cancer are a rare subset of patients. Here, we present the case of a 38-year-old woman who had sternum pain for 4 months. A whole-body PET-CT scan revealed that the FDG uptake of both the sternum and internal mammary node was significantly increased. The final diagnosis of occult breast cancer was established by immunohistochemical (IHC) staining, which is of great significance for identifying the origin of a metastatic tumor despite no visualized lesions of mammary glands.

Abstract As one of the four major means of cancer treatment including surgery, radiotherapy (RT), chemotherapy, immunotherapy, RT can be applied to various cancers as both a radical cancer treatment and an adjuvant treatment before or after surgery. Although RT is an important modality for cancer treatment, the consequential changes caused by RT in the tumor microenvironment (TME) have not yet been fully elucidated. RT-induced damage to cancer cells leads to different outcomes, such as survival, senescence, or death. During RT, alterations in signaling pathways result in changes in the local immune microenvironment. However, some immune cells are immunosuppressive or transform into immunosuppressive phenotypes under specific conditions, leading to the development of radioresistance. Patients who are radioresistant respond poorly to RT and may experience cancer progression. Given that the emergence of radioresistance is inevitable, new radiosensitization treatments are urgently needed. In this review, we discuss the changes in irradiated cancer cells and immune cells in the TME under different RT regimens and describe existing and potential molecules that could be targeted to improve the therapeutic effects of RT. Overall, this review highlights the possibilities of synergistic therapy by building on existing research.

Objectives: The goal of our bioinformatics study was to comprehensively analyze the association between the whole calpain family members and the progression and prognosis of hepatocellular carcinoma (HCC).Methods: The data were collected from The Cancer Genome Atlas (TCGA). The landscape of the gene expression, copy number variation (CNV), mutation, and DNA methylation of calpain members were analyzed. Clustering analysis was performed to stratify the calpain-related groups. The least absolute shrinkage and selection operator (LASSO)-based Cox model was used to select hub survival genes.Results: We found 14 out of 16 calpain members expressed differently between tumor and normal tissues of HCC. The clustering analyses revealed high- and low-risk calpain groups which had prognostic difference. We found the high-risk calpain group had higher B cell infiltration and higher expression of immune checkpoint genes HAVCR2, PDCD1, and TIGHT. The CMap analysis found that the histone deacetylase (HDAC) inhibitor trichostatin A and the PI3K-AKT-mTOR pathway inhibitors LY-294002 and wortmannin might have a therapeutic effect on the high-risk calpain group. The DEGs between calpain groups were identified. Subsequent univariate Cox analysis of each DEG and LASSO-based Cox model obtained a calpain-related prognostic signature. The risk score model of this signature showed good ability to predict the overall survival of HCC patients in TCGA datasets and external validation datasets from the Gene Expression Omnibus database and the International Cancer Genome Consortium database.Conclusion: We found that calpain family members were associated with the progression, prognosis, and drug response of HCC. Our results require further studies to confirm.

Abstract Background The role of adjuvant radiation in pancreatic adenocarcinoma (PDAC) remains unclear. We aimed to investigate the efficacy of gemcitabine combined with stereotactic body radiation therapy (SBRT) as adjuvant therapy for resected stage II PDAC. Methods In this single-center randomized controlled trial, patients with stage II PDAC that underwent margin-negative resection were randomly assigned to gemcitabine-alone adjuvant chemotherapy or adjuvant SBRT followed by gemcitabine chemotherapy. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included locoregional recurrence-free survival (LRFS), overall survival (OS), and incidence of adverse events. Results Forty patients were randomly assigned to treatment between Sep 1, 2015 and Mar 31, 2018. Of these, 38 were included in the intention-to-treat analysis (20 in gemcitabine arm and 18 in gemcitabine plus SBRT arm). The median RFS and OS were 9.70, 28.0 months in the gemcitabine arm and 5.30, 15.0 months in the gemcitabine plus SBRT arm (RFS, P = 0.53; OS, P = 0.20), respectively. The median LRFS in both arms was unreached (P = 0.81). Grade 3 or 4 adverse events were all comparable between the two arms. Evaluation of data from the enrolled patients indicated that the addition of adjuvant SBRT was not associated with either better local disease control or recurrence-free survival. Conclusions Adjuvant SBRT neither provided a survival benefit nor improved local disease control in resected stage II PDAC. Trial registration ClinicalTrials.gov, NCT02461836 . Registered 03/06/2015

Abstract Background Gallbladder cancer (GBC) is an uncommon malignancy with high recurrent rate and poor prognosis. This study investigates the recurrent patterns of postoperative GBC, with the aim to guide the adjuvant treatments, including the radiotherapy. Methods Retrospectively analyzed the 109 GBC patients who underwent surgery in our institution from January 2013 to 2018. Clinical follow-up revealed 54 recurrent cases, of which 40 had detailed locations of recurrence. The sites of recurrence were recorded and divided into the tumor bed, corresponding lymphatic drainage area, intrahepatic recurrence, and the other distant metastasis. Results The median follow-up time is 34 months (IQR: 11–64). The median disease-free survival (DFS) and overall survival (OS) were 48.8 months and 53.7 months, respectively. Through univariate analysis, risk factors for DFS and OS include tumor markers (CA199 and CEA), hepatic invasion, perineural invasion, lymphovascular invasion, TNM staging and tumor differentiation. Through multivariate analysis, risk factors for DFS include hepatic invasion and TNM staging, and for OS is TNM staging only. Of the 40 cases with specific recurrent sites, 29 patients (29/40, 72.5%) had recurrence in the potential target volume of postoperative radiotherapy (PORT), which include tumor bed and corresponding lymphatic drainage area. The common recurrent lymph node groups included abdominal para-aortic lymph node (No.16, 15/29), hepatoduodenal ligament lymph node (No.12, 8/29), retro-pancreatic head lymph node (No.13, 7/29) and celiac axis lymph node (No.9, 4/29). Twenty cases with recurrences inside the potential PORT target volume were accompanied by distant metastasis. Another 11 cases had distant metastasis alone, so totally 31 cases developed distant metastasis (31/40, 77.5%), including 18 cases with hepatic metastasis. Conclusion The recurrence and metastasis rates are high in GBC and adjuvant therapy is needed. Up to 75% of the recurrent cases occurred in the potential target volume of postoperative radiotherapy, suggesting that postoperative radiotherapy has the possible value of improving local-regional control. The potential target volume of radiotherapy should include the tumor bed, No.8, No.9, No.11, No.12, No.13, No.14, No. 16a2, No. 16b1 lymph node groups.

ObjectiveWe aim to explore the clinicopathological features associated with axillary node response and recurrence in breast cancer patients undergoing neoadjuvant treatment (NAT).MethodsWe retrospectively reviewed the medical records of 486 stage I to III breast cancer patients who received NAT and surgery between 2016 and 2021.ResultsA total of 486 cases were reviewed and 154 (31.7%) patients achieved breast pathological complete response (pCR) (ypT0/Tis). Of the 366 cases with initially cN+, 177 (48.4%) cases reach ypN0. Breast pCR is in high accordance to axillary pCR (81.5%). Hormone receptor (HR)-/HER2+ breast cancer patients have the highest axillary pCR rate (78.3%). Patients achieve axillary pCR have a significantly better disease-free survival (DFS) (P=0.0004). Further analysis reveals that the DFS of ypN0 and ypN1 cases are similar (P=0.9049). Moreover, DFS in patients with ypN0 (P

The objective of this study was to evaluate the discriminative capabilities of radiomics signatures derived from three distinct machine learning algorithms and to identify a robust radiomics signature capable of predicting pathological complete response (pCR) after neoadjuvant chemoradiotherapy in patients diagnosed with locally advanced rectal cancer (LARC). In a retrospective study, 211 LARC patients were consecutively enrolled and divided into a training cohort (n = 148) and a validation cohort (n = 63). From pretreatment contrast-enhanced planning CT images, a total of 851 radiomics features were extracted. Feature selection and radiomics score (Radscore) construction were performed using three different machine learning methods: least absolute shrinkage and selection operator (LASSO), random forest (RF) and support vector machine (SVM). The SVM-derived Radscore demonstrated a strong correlation with the pCR status, yielding area under the receiver operating characteristic curves (AUCs) of 0.880 and 0.830 in the training and validation cohorts, respectively, outperforming the RF and LASSO methods. Based on this, a nomogram was developed by combining the SVM-based Radscore with clinical indicators to predict pCR after neoadjuvant chemoradiotherapy. The nomogram exhibited superior predictive power, achieving AUCs of 0.910 and 0.866 in the training and validation cohorts, respectively. Calibration curves and decision curve analyses confirmed its appropriateness. The SVM-based Radscore demonstrated promising performance in predicting pCR for LARC patients. The machine learning-driven nomogram, which integrates the Radscore and clinical indicators, represents a valuable tool for predicting pCR in LARC patients.

AimThis study aimed to examine the effect of the weight initializers on the respiratory signal prediction performance using the long short-term memory (LSTM) model.MethodsRespiratory signals collected with the CyberKnife Synchrony device during 304 breathing motion traces were used in this study. The effectiveness of four weight initializers (Glorot, He, Orthogonal, and Narrow-normal) on the prediction performance of the LSTM model was investigated. The prediction performance was evaluated by the normalized root mean square error (NRMSE) between the ground truth and predicted respiratory signal.ResultsAmong the four initializers, the He initializer showed the best performance. The mean NRMSE with 385-ms ahead time using the He initializer was superior by 7.5%, 8.3%, and 11.3% as compared to that using the Glorot, Orthogonal, and Narrow-normal initializer, respectively. The confidence interval of NRMSE using Glorot, He, Orthogonal, and Narrow-normal initializer were [0.099, 0.175], [0.097, 0.147], [0.101, 0.176], and [0.107, 0.178], respectively.ConclusionsThe experiment results in this study indicated that He could be a valuable initializer in the LSTM model for the respiratory signal prediction.

Abstract Glioblastoma is the most common brain primary malignant tumor with the highest mortality. Boron neutron capture therapy (BNCT) can efficiently kill cancer cells on the cellular scale, with high accuracy, short course and low side-effects, which is regarded as the most promising therapy for malignant brain tumors like glioma. As the keypoint of BNCT, all boron delivery agents currently in clinical use are beset by insufficient tumor uptake, especially in the tumor nucleus, which limits the clinical application of BNCT. In this study, nuclear targeting of boron is achieved by DOX-CB, consisting of doxorubicin (DOX) and carborane (CB) utilizing the nuclear translocation property of DOX. The nucleus of GL261 cells takes up almost three times the concentration of boron required for BNCT. To further kill glioma and inhibit recurrence, a new multifunctional nanoliposome delivery system DOX-CB@lipo-pDNA-iRGD is constructed. It combines DOX-CB with immunotherapy strategy of blocking macrophage immune checkpoint pathway CD47-SIRPα by CRISPR-Cas9 system, coupling BNCT with immunotherapy simultaneously. Compared with clinical drug Borocaptate Sodium (BSH), DOX-CB@lipo-pDNA-iRGD significantly enhances the survival rate of tumor-bearing mice, reduces tumor stemness, and improves the prognosis. The excellent curative effect of this nanoliposome delivery system provides an insight into the combined treatment of BNCT. Graphical Abstract

BackgroundHepatocellular carcinoma (HCC) is the most prevalent pathological type of liver cancer worldwide with high mortality and poor prognosis. N6-methyladenosine (m6A) can modify RNAs such as mRNA, lncRNA, miRNA, and tRNA, thereby playing a critical role in the pathogenesis of HCC. However, the role of m6A-associated small nuclear RNA (snRNA) in the prognostic value and immunotherapeutic response in HCC remains unclear.Materials and methodsIn this study, snRNA expression data, gene mutation data, and clinical data of HCC patients were acquired from The Cancer Genome Atlas (TCGA) database. We used the least absolute shrinkage and selection operator (LASSO) Cox regression analysis to identify significant prognostic m6A-associated snRNAs, and then developed a multivariate Cox model based on the selected snRNAs. HCC patients were split into low- and high-risk groups based on the median risk score. We subsequently performed Kaplan-Meier curve analysis to estimate overall survival (OS) by clinicopathological characteristics and tumor mutational burden (TMB) status in low- and high-risk HCC patients. Finally, we compared the immunotherapeutic response as represented by tumor immune dysfunction and exclusion (TIDE) scores between the two risk groups.ResultsEight m6A-associated snRNAs were selected as independent predictors to develop the risk model. Our results revealed that the OS of HCC patients in the high-risk group was significantly worse than that in the low-risk group on clinicopathologic characteristics, including age (≤65 years and >65 years), gender (male), grade (G I-II and G III-IV) and TNM staging (Stage I-II and Stage III-IV). In addition, the OS of low-TMB and low-risk group was longer than that of high-TMB and high-risk group. The TIDE score indicated that HCC patients in the high-risk group were more susceptible to immunotherapy.ConclusionOur study suggests that m6A-associated snRNAs may be useful biomarkers for the prognosis of HCC and that m6A-associated snRNA models can predict the effect of immunotherapy in HCC patients.

Fusobacterium nucleatum (F. nucleatum) is originally an oral opportunistic pathogen and accumulating evidence links the presence of F. nucleatum with the pathogenicity, development, and prognosis of colorectal cancer (CRC). However, only limited preliminary data is available dealing with the role of F. nucleatum in other malignancies except for CRC. The present review aims to update and systematize the latest information about the mechanisms of F. nucleatum-mediating carcinogenesis, together with the detection rates, clinicopathological, and molecular features in F. nucleatum-associated malignancies. Comparing with adjacent non-tumorous tissue, previous studies have shown an overabundance of intratumoural F. nucleatum. Although the prognostic role of F. nucleatum is still controversial, a higher prevalence of F. nucleatum was usually associated with a more advanced tumor stage and a worse overall survival. Preliminary evidence have shown that epithelial-to-mesenchymal transition (EMT) and relevant inflammation and immune response aroused by F. nucleatum may be the probable link between F. nucleatum infection and the initiation of oral/head and neck cancer. Further studies are needed to elucidate the etiologic role of the specific microbiota and the connection between the extent of periodontitis and carcinogenesis in different tumor types. The mechanisms of how the antibiotics exerts the critical role in the carcinogenesis and antitumor effects in malignancies other than CRC need to be further explored.

Abstract Purpose Glioma is the most common type of primary brain tumor in adults, and it causes significant morbidity and mortality, especially in high‐grade glioma (HGG) patients. The accurate prognostic prediction of HGG is vital and helpful for clinicians when developing therapeutic strategies. Therefore, we propose a machine learning‐based survival prediction model by analyzing clinical and dose‐volume histogram (DVH) parameters, to improve the performance of the risk model in HGG patients. Methods Eight clinical variables and 39 DVH parameters were extracted for each patient, who received radiotherapy for HGG with active follow‐up. Ninety‐five patients were randomly divided into training and testing cohorts, and we employed random survival forest (RSF), support vector machine (SVM), and Cox proportional hazards (CPHs) models to predict survival. Calibration plots, concordance indexes, and decision curve analyses were used to evaluate the calibration, discrimination, and clinical utility of these three models. Results The RSF model showed the best performance among the three models, with concordance indexes of 0.824 and 0.847 in the training and testing sets, respectively, followed by the SVM (0.792/0.823) and CPH (0.821/0.811) models. Specifically, in the RSF model, we identified age, gross tumor volume (GTV), grade, Karnofsky performance status (KPS), isocitrate dehydrogenase (IDH), and D99 as important variables associated with survival. The AUCs of the testing set were 92.4%, 87.7%, and 84.0% for 1‐, 2‐, and 3‐year survival, respectively. According to this model, HGG patients can be divided into high‐ and low‐risk groups. Conclusion The machine learning‐based RSF model integrating both clinical and DVH variables is an improved and useful tool for predicting the survival of HGG patients.

Bone marrow involvement (BMI) of solid tumors is a special type of distant metastasis. It has an occult onset, atypical clinical and laboratory features, and a high mortality. We present a nasopharyngeal carcinoma case with cervical and axillary lymph nodes, bilateral lung, multiple bone, and bone marrow metastases, who was treated chemotherapy plus targeted therapy under the guidance of a patient-derived tumor xenograft (PDTX) model, followed by maintenance chemotherapy plus immunotherapy. The patient’s symptoms were relieved after four cycles of chemotherapy plus targeted therapy. His bone marrow biopsy turned negative after 7 months of therapy. In addition, his total peripheral T cells as well as the proportion of CD8+ T cells increased during the course of therapy. The combination of chemotherapy, targeted therapy, and immunotherapy provides an effective antitumor regimen for advanced NPC patients with BMI.

Background The RIPK4 (receptor-interacting protein kinase 4), a member of the RIPK family, acts as an important regulator of epidermal differentiation, cutaneous inflammation, and cutaneous wound repair. However, Until now, the role of RIPK4 in tumorigenesis remains elusive. There have been no studies exploring the effects of RIPK4 on the signaling pathway in cutaneous squamous cell carcinoma (SCC). It remains unknown whether RIPK4 expression, which can affect the degree of epidermal differentiation can also influence the radiosensitivity of skin SCC. It is urgent to fully elucidate the biological mechanism by which RIPK4 promotes carcinogenesis in skin SCC and determine whether RIPK4 expression levels predicts the sensitivity to radiotherapy in skin SCC. Methods Human skin SCC cell line, A431, was transfected with either small interfering RNAs (siRNAs) targeting RIPK4 (siR-RIPK4) or negative control siRNA (siR-NC). Western blotting was used to detect the expression of RIPK4 and Raf/MEK/ERK pathway-related proteins. The cells were irradiated using an X-ray irradiator at 6 MV with different radiation doses (0, 2, 6, and 10 Gy). Cell proliferation analysis, colony formation assay, transwell cell migration and invasion assay, cell cycle and apoptosis analysis were conducted to investigate the effect of RIPK4 silencing on skin SCC malignancy and radiosensitivity. Results RIPK4 protein expression was significantly decreased in the A431 cells transfected with siR-RIPK4, compared with the A431 cells transfected with siR-NC. RIPK4 silencing facilitated the proliferation, colony formation, migration, and invasion ability of A431 cell line, while cell cycle progression or cell apoptosis were not significantly influenced. In contrast with the previous literature, Raf/MEK/ERK pathway was not effected by RIPK4 knockdown in skin SCC. RIPK4 knockdown could not reverse the radiation resistance of A431 cells to irradiation in vitro. Conclusions In general, although depletion of RIPK4 cannot reverse the radiation resistance of A431 cells in vitro, it parallels higher malignancy potential in cutaneous SCC. To our knowledge, this is the first report of the effects of RIPK4 expression on the Raf/MEK/ERK signaling pathway and radiosensitivity in cutaneous SCC. The better understanding of the molecular mechanism of RIPK4 in cutaneous SCC may provide a promising biomarker for skin SCC prognosis and treatment.

ObjectivesThe proportion of elderly patients with esophageal cancer (EC) is increasing due to prolonged life expectancy and aging process. The aim of the study is to explore the optimal treatment strategy for elderly patients (aged ≥70 years) with locally advanced EC.MethodsEligible patients with cT2-4aNxM0 EC were identified in the Surveillance, Epidemiology, and End Results database from 2010 to 2016. Treatment patterns were divided into six groups: surgical resection (S), chemoradiotherapy (CRT), trimodality therapy (CRT+S), radiotherapy (RT), chemotherapy (CT), or observation with no treatment (Obs). Survival between groups was compared using the log-rank test, and the Cox proportional hazards model was used to identify factors associated with overall survival (OS).ResultsA total of 2917 patients with potentially curable EC were identified. Of all the patients included, 6.7%, 51.8%, 18.0%, 9.4% and 3.6%received S, CRT, CRT+S, RT, and CT, respectively, whereas 10.6% underwent Obs. The 3-year OS estimates were 30.2% (95% confidence interval [CI]: 23.5–38.9%), 25.4% (95% CI: 22.8–28.3%),44.3% (95% CI: 39.3–49.9%), 11.4% (95% CI: 7.7–17.0%), 16.1% (95% CI: 9.1–28.3%), and 5.6% (95% CI: 3.2–9.8%) for S, CRT, CRT+S RT, CT, and Obs (p

Abstract Background High‐quality randomized controlled trials have demonstrated the benefit of radiotherapy (RT) in patients with radical resected gastric cancer (GC), however, utilization rates of postoperative RT remain remarkably low. Patterns, incidences, and time of recurrence provide biological bases for clinical monitoring of GC patients and guiding potential complementary therapies. Thus, the aim of this study is to understand the location of locoregional recurrence which may allow individualized RT strategies and minimize radiation‐related toxic effects. Methods A relatively large sample of GC patients in a single institution who had undergone curative D2 resection was retrospectively reviewed and the relevant recurrence patterns were illustrated. Independent recurrence‐related risk factors were analyzed by logistic regression analysis. New logistic regression models were further developed to predict the probability of recurrence. Results Overall, among 776 GC patients who had continuous and complete follow‐up data, 300 cases relapsed after curative resection. Lymphovascular invasion, lymph node metastases, and tumor stage were indicators for early recurrence. Peritoneal, regional, local, and distant recurrence initially occurred in 51 (6.6%), 151 (19.4%), 56 (7.2%), and 164 (21.1%) patients, respectively. Among patients with regional recurrence, the most common sites were lymph node stations 16a2, 8, 12, 16b1, and 9. Remnant stomach recurrence was not so prominent that it seemed reasonable to be excluded from an irradiation field for patients with negative surgical/pathologic margins. Conclusions For GC patients who underwent radical D2 resection, distant and regional recurrences were still common. Besides, optimizing regional control of lymph nodes outside the D2 dissected area was crucial for rational design of the RT field. Furthermore, the new logistic regression models might act as useful tools to evaluate recurrence risk and determine which patients should receive postoperative chemoradiotherapy.

Abstract Background The incidence of anal squamous cell carcinoma (SCC) has been steadily growing globally in the past decade. Clinical data on anal SCC from China are rare. We conducted this study to describe the clinical and epidemiological characteristics of anal SCC in China and explore prognostic factors of outcomes among patients with anal SCC. Methods We audited demographic characteristics, relevant symptoms, risk factors, treatment modalities and outcomes for patients diagnosed with anal SCC at 11 medical institutions in China between January 2007 and July 2018. Results A total of 144 patients (109 females) were diagnosed with SCC during this period. Median age at initial diagnosis was 52.0 (interquartile range: 46.0–61.8) years. The most common symptoms were bleeding (n = 93, 64.6%), noticing a lump (n = 49, 34.0%), and pain (n = 47, 32.6%). The proportion of patients at the American Joint Committee on Cancer (AJCC) stages I-IV were 10 (6.9%), 22 (15.3%), 61 (42.4%) and 8 (5.6%), respectively, and AJCC stages in 43 (29.9%) patients were unknown. Thirty-six patients (25.0%) underwent abdominoperineal resection initially. Univariable analysis showed that T stage predicted recurrence-free survival (RFS) (Hazard ratio [HR] = 3.03, 95% Confidence interval [CI]: 1.10–8.37, p = 0.032), and age group (HR = 2.90, 95% CI: 1.12–7.49, p = 0.028), AJCC stage (HR = 4.56, 95% CI: 1.02–20.35, p = 0.046), and N stage (HR = 3.05, 95% CI: 1.07–8.74, p = 0.038) predicted overall survival (OS). Conclusions T stage was identified as prognostic factor of RFS, and age, AJCC stage, and N stage were identified as prognostic factors of OS. Improving symptom awareness and earlier presentation among patients potentially at risk for anal SCC should be encouraged. Familiarity with the standard treatment among health care providers in China should be further improved.

Abstract Background SOX2 is regarded as an important marker in stem cell. The change of SOX2 expression after adjuvant therapy in high grade glioma (HGG) remains unknown so far. Few patients with recurrent glioma have opportunity to undergo operation once again, so the recurrent glioma samples are scarce. This study tries to analyze SOX2 expression in paired primary and recurrent HGG, aims to better understand the transformation law of SOX2 after adjuvant therapy in HGG. Methods Twenty-four recurrent HGG patients who undergone a second resection were included. 16 patients received adjuvant therapy, the remaining 8 patients didn’t receive any adjuvant therapy at all. The protein expression of SOX2 in paired primary and recurrent HGG was tested by immunohistochemistry. The statistical analysis was conducted by IBM SPSS Statistics 19.0. Results In primary HGG, SOX2 expression of 3 + , 2 + , 1+ and 0+ were seen in 20 (83.3%), 1 (4.2%), 1 (4.2%) and 2 cases (8.3%), respectively. The expression of SOX2 was decreased in recurrent HGG compared to the paired primary sample (p = 0.001). The decrease of SOX2 was often seen in patients received chemotherapy, radiotherapy or both (p = 0.003). Patients with SOX2 high expression in primary glioma had a longer median PFS than those with SOX2 low expression with marginal statistic significance (12.7 vs. 5.4 months, p = 0.083). For cases with SOX2 high expression in the primary glioma, those had SOX2 low expression after recurrence seemed to have worse prognosis as compared to patients with stable SOX2 high expression (PFS: 10.4 vs. 14.9 months, p = 0.036; OS: 27.0 vs 49.5 months, p = 0.005). Conclusions This is the first study comparing the protein expression of SOX2 in recurrent HGG and its paired primary tumor. SOX2 high expression is common in brain HGG, a tendency of decreased SOX2 expression in recurrent gliomas was evidenced. Lower SOX2 expression was seen in those patients who received adjuvant chemotherapy and/or radiotherapy. Patients with low SOX2 expression in primary HGG usually have poorer prognosis, those with SOX2 expression decreased in recurrent HGG had worse outcome.

Abstract Background To explore the patterns of failures and areas at highest risk of recurrence for postoperative intrahepatic cholangiocarcinoma (IHCC), with the aim to guide IHCC adjuvant radiotherapy. Methods Patients with IHCC who had undergone radical surgery at our institution from July 2010 to August 2017 were retrospectively analyzed. The survival and prognostic factors were analyzed by univariate and multivariate analysis. All sites of recurrence were found out and classified as the surgical margin, regional lymph nodes, liver remnant and distant metastasis. According to the recurring area at highest risk, the target volume of adjuvant radiotherapy was proposed. Results The median follow-up time was 23.5 months (2–85 months). The median recurrence free survival (RFS) and overall survival (OS) were 12.1 months and 24.8 months, respectively. Seventy-three (73/127, 57.5%) IHCC patients developed tumor recurrence. Initial recurrences occurred in the potential postoperative radiotherapy (PORT) volume, remnant liver and distant sits were 46 (46/73, 63.0%), 36 (36/73, 49.3%) and 22 (22/73, 30.1%) cases, respectively. Of the 46 patients whose initial recurrence inside the potential PORT volume, 29 (29/73, 39.7%) developed recurrence only inside the potential PORT volume, including 13 tumor bed recurrences, 7 lymph node metastases, and 9 with both tumor bed recurrences and lymph node metastases. The most common lymph node metastases sites were nodes around the abdominal aorta, followed by lymph nodes along the celiac artery, the common hepatic artery, and in the hepatoduodenal ligament. Conclusions High proportion of the recurrences occurred only inside the potential PORT volume, implying adjuvant radiotherapy might improve the local-regional control. Surgical margins and lymph node stations No.16a2, 9, 8, 12, 13, and 14 are suggested to be included in the radiation volume.

Aim: The aim of our study was to investigate the potential predictive value of the combination of radiosensitivity gene signature and PD-L1 expression for the prognosis of locally advanced head and neck squamous cell carcinoma (HNSCC).Methods: The cohort was selected from The Cancer Genome Atlas (TCGA) and classified into the radiosensitive (RS) group and radioresistant (RR) group by a radiosensitivity-related gene signature. The cohort was also grouped as PD-L1-high or PD-L1-low based on PD-L1 mRNA expression. The least absolute shrinkage and selection operator (lasso)-based Cox model was used to select hub survival genes. An independent validation cohort was obtained from the Gene Expression Omnibus (GEO) database.Results: We selected 288 locally advanced HNSCC patients from TCGA. The Kaplan–Meier method found that the RR and PD-L1-high group had a worse survival than others (p = 0.033). The differentially expressed gene (DEG) analysis identified 553 upregulated genes and 486 downregulated genes (p < 0.05, fold change >2) between the RR and PD-L1-high group and others. The univariate Cox analysis of each DEG and subsequent lasso-based Cox model revealed five hub survival genes (POU4F1, IL34, HLF, CBS, and RNF165). A further hub survival gene-based risk score model was constructed, which was validated by an external cohort. We observed that a higher risk score predicted a worse prognosis (p = 0.0013). The area under the receiver operating characteristic curve (AUC) plots showed that this risk score model had good prediction value (1-year AUC = 0.684, 2-year AUC = 0.702, and 3-year AUC = 0.688). Five different deconvolution methods all showed that the B cells were lower in the RR and PD-L1-high group (p < 0.05). Finally, connectivity mapping analysis showed that the histone deacetylase (HDAC) inhibitor trichostatin A might have the potential to reverse the phenotype of RR and PD-L1-high in locally advanced HNSCC (p < 0.05, false discovery rate

Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l-carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg−1min−1) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P

The aim of our study was to perform a comprehensive analysis of the gene expression, copy number variation (CNV) and mutation of key mitophagy genes in the progression and prognosis of lung adenocarcinoma (LUAD). We obtained the data from The Cancer Genome Atlas (TCGA). Clustering analysis was performed to stratify the mitophagy related groups. The least absolute shrinkage and selection operator (LASSO) based cox model was used to select hub survival genes. An independent validation cohort was retrieved from Gene Expression Omnibus database. We found 24 out of 27 mitophagy genes were aberrantly expressed between tumor and normal samples. CNV gains were associated with higher expression of mitophagy genes in 23 of 27 mitophagy genes. The clustering analysis identified high and low risk mitophagy groups with distinct survival differences. The high risk mitophagy groups had higher tumor mutation burden, stemness phenotype, total CNVs and lower CD4+ T cells infiltration. Drugs targeted to high risk mitophagy groups were identified including the PI3K/AKT/mTOR inhibitor, HDAC inhibitor and chemotherapy agents such as cisplatin and gemcitabine. In addition, the differentially expressed genes (DEGs) were identified between mitophagy groups. Further univariate Cox analysis of each DEG and subsequent LASSO-based Cox model revealed a mitophagy-related prognostic signature. The risk score model of this signature showed a strong ability to predict the overall survival of LUAD patients in training and validation datasets. In conclusion, the mitophagy genes played an important role in the progression and prognosis of LUAD, which might provide useful information for the treatment of LUAD.

Background We investigated the miRNA-m6A related gene network and identified a miRNA-based prognostic signature in patients with esophageal cancer using integrated genomic analysis. Methods We obtained expression data for m6A-related genes and miRNAs from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Survival analysis was conducted to identify potential prognostic biomarkers. LASSO Cox regression was performed to construct the overall survival (OS) associated prediction signature. We used the Kaplan–Meier (K–M) curve and receiver operating characteristic (ROC) curves to explore the signature’s efficiency and accuracy. Interactions between the m6A-related genes and miRNAs were identified in starBase3.0 and used to construct the miRNA-m6A related gene network. Results We found that HNRNPC, YTHDF, ZC3H13, YTHDC2, and METTL14 were dysregulated in esophageal cancer tissues. Multivariate Cox regression analysis revealed that HNRNPC may be an independent risk factor for OS. Five hundred twenty-two potential upstream miRNAs were obtained from starBase3.0. Four miRNAs (miR-186, miR-320c, miR-320d, and miR-320b) were used to construct a prognostic signature, which could serve as a prognostic predictor independent from routine clinicopathological features. Finally, we constructed a key miRNA-m6A related gene network and used one m6A-related gene and four miRNAs associated with the prognosis. The results of our bioinformatics analysis were successfully validated in the human esophageal carcinoma cell lines KYSE30 and TE-1. Conclusion Our study identified a 4-miRNA prognostic signature and established a key miRNA-m6A related gene network. These tools may reliably assist with esophageal cancer patient prognosis.

Currently, mechanisms and therapeutic approaches have been thoroughly studied in various prevalent malignant tumors, such as breast and lung cancer. However, there is inevitable tumor progression and drug resistance. Uncovering novel treatment strategies to inhibit tumor development is important. Ferroptosis, a form of cell death associated with iron and lipid peroxidation, has drawn extensive attention. In this paper, we reviewed the underlying mechanisms of ferroptosis (i.e., iron, glutathione, and lipid metabolism) and its role in various tumors (i.e., lung cancer, liver carcinoma, breast cancer, and pancreatic cancer). Moreover, we summarized ferroptosis-related anti-tumor drugs and emphasized the potential of combined treatment of anti-tumor drugs and radiotherapy in an effort to provide novel anti-tumor treatments.

Immune checkpoint inhibitor therapy has become a promising option for the treatment of late-stage thymic epithelial tumors. In this manuscript, we presented a patient with metastatic thymoma administrated of anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab. Although the patient underwent a rapid and dramatic response to one dose of pembrolizumab, she suffered a storm of immune-therapy related toxicity events (irAEs), including liver and kidney dysfunction, hypothyroidism and myocarditis. We didn’t observe >grade 3 irAEs, and proceed with pembrolizumab therapy after the function recovered. Although no guidelines recommend dose reduction of immunotherapy re-treating following initial irAEs, we optimize dose of pembrolizumab to minimize the irAEs induced by PD-1 antibody while maintaining clinical effectiveness. Excitingly, we observe remarkable tumor remission and mild toxicities of half dose of pembrolizumab in this case. In conclusion, the clinical utilization of immunotherapy is an encouraging therapeutic alternative for advanced thymomas. At the same time, patients have to be monitored very carefully, because of the risk to develop irAEs.

Abstract Background Radiotherapy is one of the most important therapeutic strategies for treating cancer. For decades, studies concerning the outcomes of radiotherapy mainly focused on the biological effects of radiation on tumor cells. Recently, we have increasingly recognized that the complex cellular interactions within the tumor microenvironment (TME) are closely related to treatment outcomes. Main content As a critical component of the TME, fibroblasts participate in all stages of cancer progression. Fibroblasts are able to tolerate harsh extracellular environments, which are usually fatal to all other cells. They play pivotal roles in determining the treatment response to chemoradiotherapy. Radiotherapy activates the TME networks by inducing cycling hypoxia, modulating immune reaction, and promoting vascular regeneration, inflammation and fibrosis. While a number of studies claim that radiotherapy affects fibroblasts negatively through growth arrest and cell senescence, others argue that exposure to radiation can induce an activated phenotype in fibroblasts. These cells take an active part in constructing the tumor microenvironment by secreting cytokines and degradative enzymes. Current strategies that aim to inhibit activated fibroblasts mainly focus on four aspects: elimination, normalization, paracrine signaling blockade and extracellular matrix inhibition. This review will describe the direct cellular effects of radiotherapy on fibroblasts and the underlying genetic changes. We will also discuss the impact of fibroblasts on cancer cells during radiotherapy and the potential value of targeting fibroblasts to enhance the clinical outcome of radiotherapy. Conclusion This review provides good preliminary data to elucidate the biological roles of CAFs in radiotherapy and the clinical value of targeting CAFs as a supplementary treatment to conventional radiotherapy. Further studies to validate this strategy in more physiological models may be required before clinical trial.

Abstract Background Tumor-infiltrating lymphocytes (TILs) play a critical role in tumor immune surveillance and immune suppression. Understanding tumor infiltrating T cell subset density, location and PD-1/PD-L1 expression might provide insight for the prediction of tumor therapeutic response and clinical outcome. The purpose of this study was to evaluate the expression and localization of CD8, FoxP3, PD-1, and PD-L1 in primary tumor tissues and their effects on prognosis of stage IV M0 locally advanced nasopharyngeal carcinoma (NPC) patients. Methods Sixty NPC patients with stage IV M0 locally advanced disease were treated with definitive chemoradiation. Tumor biopsies from primary lesion were analyzed for the expression and localization of CD8, FoxP3, PD-1, and PD-L1 by immunohistochemistry. Their associations with local disease control and survival of NPC were analyzed. Results The average follow-up time was 43 months (range from 14 to 61 months). High expression of CD8+, FoxP3+, PD-1+ and PD-L1+ was observed in 60, 86.7, 56.7, and 91.7% of patients, respectively. There was no correlation between clinicopathological features and the expression of these immune markers. High PD-1 expression was found to be associated with lower local disease control (5-year LRFS 23.2% vs 96.8%, p

The aim of the current study was to evaluate the influence of severe radiation-induced lymphopenia (RIL) on the outcomes of esophageal cancer (EC). A systematic review and meta-analysis was performed through the PRISMA guideline. Seventeen studies were included in the current systematic review, with eight included in the meta-analyses. Meta-analyses found that severe RIL was associated with lower pathologic complete response (pCR) rate (odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.30–0.66, I2 = 0%), inferior overall survival (OS) (hazard ratio (HR) = 1.50, 95% CI = 1.29–1.75, I2 = 6%), and worse progression-free survival (PFS) (HR = 1.70, 95% CI = 1.39–2.07, I2 = 0%) of EC patients. The lymphocyte nadir was found during 4–6 weeks after the start of radiotherapy. The leading dosimetric factors associated with severe RIL included larger PTV, higher dose to heart and body, and higher effective dose to the immune cells (EDIC). Clinical risk factors for RIL mainly comprised lower baseline ALC, higher tumor length and clinical stage, and distal EC. In conclusion, severe RIL might be associated with a lower pCR rate and worse OS and PFS of EC patients. Minimizing the dosimetric risk factors, especially in patients with clinical risk factors, might benefit their outcomes.

Abstract Background Estrogen receptor (ER) expression is important for treatment selection and prognostication of breast cancer patients. Although the metastases are the main targets of endocrine therapy, ER status is often based on the primary tumor. However, ER expression in breast cancer primary lesion may not match with its synchronous metastatic lesions in some cases. In this study, we analyzed ER expression concordance between breast cancer primary tumor and metastatic lesions. Methods Paraffin blocks of 100 primary breast invasive ductal carcinoma cases with axillary lymph node metastases were collected. Five tissue cores were punched out from individual primary breast cancer, and one tissue core from each lymph node metastases to assemble tissue microarrays for ER staining. Samples were then scored as 0, 1+, 2+, and 3+ according to the number and intensity of ER stained tumor cells. Results For cases with ER 3+ (strong expression) in all cores of primary lesions (n = 38), ER expression in metastatic lymph node was found in 94.7% of the patients. 91.0% of the metastatic lymph nodes were ER positive, and 84.3% of them to be 3+. Among the 46 cases of ER negative expression in all cores of primary lesions, 39 of them had all the metastatic nodes being ER negative, and ER negative nodes were seen in 95.7% of the metastases. As for 16 cases of ER inconsistent expression in primary lesions, 4 cases showed negative ER expression in all metastatic nodes, 2 cases displayed diffuse consistent ER 3+ expression, and 10 cases displayed variant ER expression. Conclusions The findings suggest that ER expression concordance between breast cancer primary lesion and its matched metastatic lesions could be estimated by primary tumor ER expression pattern.

Localized nasopharyngeal cancer (NPC) is a highly curable disease, but the prognosis of certain cases is still poor. Distinguishing patients with a poor outcome is necessary when developing therapeutic strategies. The aim of this study was to investigate the characteristics of early death (ED) among patients with localized NPC, and to identify independent predictors of ED. Patients diagnosed with localized NPC were included from the Surveillance, Epidemiology, and End Results dataset, and univariate and multivariate logistic regression analyses were performed to identify ED predictors. A total of 752 patients with localized NPC were enrolled, including 198 cases of ED and 480 long-term survivors. Older age, unmarried status, and white race were risk factors for ED, whereas diagnosis in the recent period and undifferentiated non-keratinizing histology type were protective factors. In addition, for older patients, women and those without radiation treatment, there was less ED for married patients than unmarried patients. In conclusion, this population-based study provides an overview of the characteristics of ED patients with localized NPC. Age, race, marital status, year of diagnosis and histology type are risk factors for ED. Moreover, married patients are at a significantly lower risk of ED. This protective effect is especially pronounced in older people, women and those without radiation treatment.

Purpose: Colorectal liver metastasis (CRLM) is the major cause of death due to colorectal cancer. Although great efforts have been made in treatment of CRLM, about 60–70% of patients will develop hepatic recurrence. Hepatic steatosis was reported to provide fertile soil for metastasis. However, whether hepatic steatosis predicts higher incidence of CRLM recurrence is not clear. Therefore, we aimed to determine the role of hepatic steatosis in CRLM recurrence in the present study.Methods: Consecutive CRLM patients undergoing curative treatment were retrospectively enrolled and CT liver-spleen attenuation ratio was used to detect the presence of hepatic steatosis. In patients with hepatic steatosis, we also detected the presence of fibrosis. Besides, a systematic literature search was performed to do meta-analysis to further analyze the association between hepatic steatosis and CRLM recurrence.Results: A total of 195 eligible patients were included in our center. Patients with hepatic steatosis had a significantly worse overall (P = 0.0049) and hepatic recurrence-free survival (RFS) (P = 0.0012). Univariate and multivariate analysis confirmed its essential role in prediction of RFS. Besides, hepatic fibrosis is associated with worse overall RFS (P = 0.039) and hepatic RFS (P = 0.048). In meta-analysis, we included other four studies, with a total of 1,370 patients in the case group, and 3,735 patients in the control group. The odds ratio was 1.98 (95% CI: 1.25–3.14, P = 0.004), indicating that patients with steatosis had a significantly higher incidence of CRLM recurrence.Conclusion: In summary, patients with hepatic steatosis had a significantly worse overall and hepatic RFS and it's associated with higher incidence of CRLM recurrence.

AimImmune cells that infiltrate the tumor microenvironment (TME) are associated with cancer prognosis. The aim of the current study was to identify TME related gene signatures related to the prognosis of sarcoma (SARC) by using the data from The Cancer Genome Atlas (TCGA).MethodsImmune and stromal scores were calculated by estimation of stromal and immune cells in malignant tumor tissues using expression data algorithms. The least absolute shrinkage and selection operator (lasso) based cox model was then used to select hub survival genes. A risk score model and nomogram were used to predict the overall survival of patients with SARC.ResultsWe selected 255 patients with SARC for our analysis. The Kaplan–Meier method found that higher immune (p = 0.0018) or stromal scores (p = 0.0022) were associated with better prognosis of SARC. The estimated levels of CD4+ (p = 0.0012) and CD8+ T cells (p = 0.017) via the tumor immune estimation resource were higher in patients with SARC with better overall survival. We identified 393 upregulated genes and 108 downregulated genes (p < 0.05, fold change >4) intersecting between the immune and stromal scores based on differentially expressed gene (DEG) analysis. The univariate Cox analysis of each intersecting DEG and subsequent lasso-based Cox model identified 11 hub survival genes (MYOC, NNAT, MEDAG, TNFSF14, MYH11, NRXN1, P2RY13, CXCR3, IGLV3-25, IGHV1-46, and IGLV2-8). Then, a hub survival gene-based risk score gene signature was constructed; higher risk scores predicted worse SARC prognosis (p < 0.0001). A nomogram including the risk scores, immune/stromal scores and clinical factors showed a good prediction value for SARC overall survival (C-index = 0.716). Finally, connectivity mapping analysis identified that the histone deacetylase inhibitors trichostatin A and vorinostat might have the potential to reverse the harmful TME for patients with SARC.ConclusionThe current study provided new indications for the association between the TME and SARC. Lists of TME related survival genes and potential therapeutic drugs were identified for SARC.

Radiotherapy is an important treatment for glioblastoma (GBM), but there is no consensus on the target delineation for GBM radiotherapy. The Radiation Therapy Oncology Group (RTOG) and European Organisation for Research and Treatment of Cancer (EORTC) each have their own rules. Our center adopted a target volume delineation plan based on our previous studies. This study focuses on the recurrence pattern of GBM patients whose target delineations did not intentionally include the T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity area outside of the gross tumor volume (GTV). We prospectively collected 162 GBM cases and retrospectively analysed the clinical data and continuous dynamic magnetic resonance images (MRI) of 55 patients with recurrent GBM. All patients received concurrent radiotherapy and chemotherapy with temozolomide (TMZ). The GTV that we defined includes the postoperative T1-weighted MRI enhancement area and resection cavity. Clinical target volume 1 (CTV1) and CTV2 were defined as GTVs with 1 and 2 cm margins, respectively. Planning target volume 1 (PTV1) and PTV2 were defined as CTV1 and CTV2 plus a 3 mm margin with prescribed doses of 60 and 54 Gy, respectively. The first recurrent contrast-enhanced T1-weighted MRI was introduced into the Varian Eclipse radiotherapy planning system and fused with the original planning computed tomography (CT) images to determine the recurrence pattern. The median follow-up time was 15.8 months. The median overall survival (OS) and progression-free survival (PFS) were 17.7 and 7.0 months, respectively. Among the patients, 44 had central recurrences, two had in-field recurrences, one had marginal recurrence occurred, 11 had distant recurrences, and three had subependymal recurrences. Five patients had multiple recurrence patterns. Compared to the EORTC protocol, target delineation that excludes the adjacent T2/FLAIR hyperintensity area reduces the brain volume exposed to high-dose radiation (P = 0.000) without an increased risk of marginal recurrence. Therefore, it is worthwhile to conduct a clinical trial investigating the feasibility of intentionally not including the T2/FLAIR hyperintensity region outside of the GTV.

PurposeTo evaluate the impact of resection margin on recurrence pattern and survival for hepatocellular carcinoma (HCC) with narrow margin resection, with the aim to guide postoperative treatment.Materials and MethodsTwo hundred forty HCC patients after curative hepatectomy between 2014 and 2016 were reviewed retrospectively. The cases were divided into narrow-margin (width of resection margin

Purpose: This study aims to investigate PD-1/PD-L1 expression patterns in paired primary and recurrent gliomas. Methods: From January 2008 to December 2014, 42 patients who underwent surgical resections of primary and recurrent gliomas were retrospectively included. PD-1/PD-L1 protein expression in tumors was evaluated through immunohistochemistry. Results: In primary gliomas, PD-1 and PD-L1 expression was evident in 9 (22.0%) and 14 (33.3%) patients. In the paired recurrent glioma, PD-1 and PD-L1 expression was evident in 25 (61.0%) and 31 (74.0%) lesions. Both PD-1 and PD-L1 showed significantly enhanced expression after recurrence (p < 0.005; p < 0.005). For PD-L1 expression in recurrent gliomas, the adjuvant therapy group showed significantly increased expression compared to primary gliomas (p < 0.005). For PD-1- primary gliomas, if the matched recurrent gliomas showed PD-1+, the PFS became worse than the remaining recurrent gliomas PD-1- (12.7 vs. 25.9 months, p = 0.032). Interestingly, for PD-L1- primary gliomas, if the matched recurrent gliomas showed PD-L1+, the OS became better than the remaining recurrent gliomas PD-L1- (33.8 vs. 17.5 months, p < 0.001). Conclusions: In the study, we found the expression of PD-1/PD-L1 increased significantly in recurrent gliomas and the elevated level of PD-L1 was tightly associated with adjuvant treatment, suggesting the potential therapeutic and predictive value of PD-1 and PD-L1 in the treatment of recurrent gliomas.

Meningioma is the most common tumor of the central nervous system, most of which is benign. Even after complete resection, a high rate of recurrence of meningioma is observed. From in-depth study of its pathogenesis, it has been found that a number of chromosomal variations and abnormal molecular signals are closely related to the occurrence and development of malignancy in meningioma, which may provide the theoretical basis and potential direction for accurate and targeted treatment. We have reviewed advances in chromosomal variations and molecular mechanisms involved in the progression of meningioma, and have highlighted the association with malignant biological behavior including cell proliferation, angiogenesis, increased invasiveness, and inhibition of apoptosis. In addition, the chemotherapy of meningioma is summarized and discussed.

The receptor-interacting protein kinase 4 (RIPK4), a member of the RIPK family, was originally described as an interaction partner of protein kinase C (PKC) β and PKCδ. RIPK4 is identified as a key regulator of keratinocyte differentiation, cutaneous inflammation, and cutaneous wound repair. The mechanism by which RIPK4 integrates upstream signals to initiate specific responses remains elusive. Previous studies have indicated that RIPK4 can regulate several signaling pathways, including the NF-κB, Wnt/β-catenin, and RAF/MEK/ERK pathways. Furthermore, RIPK4-related biological signaling pathways interact with each other to form a complex network. Mounting evidence suggests that RIPK4 is aberrantly expressed in various kinds of cancers. In several types of squamous cell carcinoma (SCC), the mutations that drive aggressive SCC have been found in RIPK4. In addition, the function of RIPK4 in carcinogenesis is probably tissue-specific, since RIPK4 can play a dual role as both a tumor promoter and a tumor suppressor in different tumor types. Therefore, RIPK4 may represent as an independent prognostic factor and a promising novel therapeutic target, which can be used to identify the risks of patients and guide personalized treatments. In future, RIPK4-interacting pathways and precise molecular targets need to be investigated in order to further elucidate the mechanisms underlying epidermal differentiation and carcinogenesis.

Chemoresistance has been a significant problem affecting the efficacy of drugs targeting tumors for decades. MGMT, known as O6-methylguanine-DNA methyltransferase, is a DNA repair enzyme that plays an important role in chemoresistance to alkylating agents. Hence, MGMT is considered a promising target for tumor treatment. Several methods are employed to detect MGMT, each with its own advantages and disadvantages. Some of the detection methods are; immunohistochemistry, methylation-specific PCR (MSP), pyrophosphate sequencing, MGMT activity test, and real-time quantitative PCR. Methylation of MGMT promoter is a key predictor of whether alkylating agents can effectively control glioma cells. The prognostic value of MGMT in glioma is currently being explored. The expression of MGMT gene mainly depends on epigenetic modification–methylation of CpG island of MGMT promoter. CpG island covers a length of 762 bp, with 98 CpG sites located at the 5' end of the gene, ranging from 480 to 1,480 nucleotides. The methylation sites and frequencies of CpG islands vary in MGMT-deficient tumor cell lines, xenografts of glioblastoma and in situ glioblastoma. Methylation in some regions of promoter CpG islands is particularly associated with gene expression. The change in the methylation status of the MGMT promoter after chemotherapy, radiotherapy or both is not completely understood, and results from previous studies have been controversial. Several studies have revealed that chemotherapy may enhance MGMT expression in gliomas. This could be through gene induction or selection of high MGMT-expressing cells during chemotherapy. Selective survival of glioma cells with high MGMT expression during alkylating agent therapy may change MGMT status in case of recurrence. Several strategies have been pursued to improve the anti-tumor effects of temozolomide. These include the synthesis of analogs of O6-meG such as O6-benzylguanine (O6-BG) and O6-(4-bromothenyl) guanine (O6-BTG), RNAi, and viral proteins. This review describes the regulation of MGMT expression and its role in chemotherapy, especially in glioma. Targeting MGMT seems to be a promising approach to overcome chemoresistance. Further studies exploring new agents targeting MGMT with better curative effect and less toxicity are advocated. We anticipate that these developments will improve the current poor prognosis of glioma patients.

Abstract Background There is currently no worldwide consensus for the management of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). We evaluated the efficacy of stereotactic body radiotherapy (SBRT) as the initial treatment for HCC with extensive PVTT based on a relatively large number of patients. Methods In our multidisciplinary approach for patients with hepatobiliary tumors, SBRT is recommended for unresectable HCC with PVTT or those with contraindication for transarterial chemoembolization (TACE). The aim is to shrink the tumor thrombus and preserve adequate portal venous flow, thus facilitating subsequent treatments such as TACE and tumor resection. In the present study, 70 continuous cases of HCC patients with extensive PVTT initially treated with SBRT were studied. The median follow-up period was 9.5 months (range, 1.0–21.0 months). The dynamic changes of tumor thrombosis with time after SBRT were also analyzed. Results The median survival time for the whole group was 10.0 months (95% CI, 7.7–12.3 months), with a 6- and 12-month overall survival (OS) rate of 67.3%, and 40.0% respectively. Patients who received combined SBRT and TACE showed significantly longer OS than those without indication for TACE after SBRT (12.0 ± 1.6 vs. 3.0 ± 1.0 months). Patients with good response to radiation usually had better survival. SBRT was well tolerated in our patient series. Conclusions In conclusion, SBRT used as the initial treatment for HCC patients with extensive PVTT originally unsuitable for resection or TACE can achieve adequate thrombus shrinkage and portal vein flow restoration in the majority of cases. It could thus offer the patients an opportunity to undergo further treatment such as resection or TACE procedure. Such therapeutic strategy may result in survival advantage, especially for those who do receive combined modality with SBRT.

Abstract It has been reported that in patients with operable stage I non-small cell lung cancer (NSCLC), overall survival (OS) is better in those who undergo hypofractionated stereotactic radiation therapy (HSRT) than in those who undergo surgery. However, the reason that HSRT has a better OS has not been fully explored. Here, we analyzed reconstitution kinetics in immune cells in the peripheral blood of NSCLC patients after HSRT. We found that HSRT increased the frequency of total T cells, especially the proportion of CD8+ T cells, but decreased the frequency of inhibitory Tregs. Intracellular staining showed that after HSRT, peripheral CD8+ T cells were transformed into activated T cells, which express high levels of TNF-α, IFN-γ, granzyme B and IL-2. HSRT also increased the production of IL-2, TNF-α, and IFN-γ but down-regulated the production of TGF-β in CD4+ T cells. The frequencies of naïve B cells and double-negative B cells were lower, while the proportions of MZ-like B cells, transitional B cells and plasmablast cells were higher after HSRT. Collectively, our results demonstrate that HSRT activates the peripheral immune response and indicate the dynamic variation in peripheral lymphocytes after HSRT, which is very important for optimizing combination treatments in clinical practice.