Phase 1a study of ESG401, a Trop2 antibody-drug conjugate, in patients with locally advanced/metastatic solid tumors.

This phase 1a study assesses ESG401 in patients with heavily pretreated locally advanced or metastatic solid tumors, focusing on metastatic breast cancer. Forty patients are enrolled: three experience dose-limiting toxicities, establishing the maximum tolerated dose at 16 mg/kg on days 1, 8, and 15 of a 28-day cycle. The most common grade ≥3 treatment-related adverse events are neutropenia and leukopenia. Among 38 efficacy-evaluable patients, the objective response rate (ORR) is 34.2%, the disease control rate (DCR) is 65.8%, and the clinical benefit rate (CBR) is 50.0% (including stable disease for at least 6 months). The median progression-free survival is 5.1 months, and the median duration of response is 6.3 months. In patients receiving therapeutically relevant doses, the ORR, DCR, and CBR are 40.6%, 75.0%, and 56.3%, respectively. ESG401 demonstrates a favorable safety profile and promising antitumor activity in this heavily treated population. The trial is registered at ClinicalTrials.gov (NCT04892342).

Bridging Gaps in Oncology Nutrition Education and Teaching: A Comprehensive Analysis of Resident Physicians in China.

Residents are actively involved in patient assessment and all aspects of patient care, and they are critical in providing nutritional support education and treatment for patients with cancer. This study aims to assess the nutritional knowledge and performance of resident physicians, providing insights into existing gaps in awareness and practices related to cancer nutrition. A total of 300 resident physicians undergoing standardized residency training in China participated in this study. An anonymous online questionnaire covering demographic characteristics, nutritional knowledge, clinical practice, and training requirements was designed and administered through the "Wenjuanxing" platform. Data were collected from June 1, 2023, to July 31, 2023. Among the participants, only 40.00% demonstrated adequate knowledge of cancer nutrition, and merely 32.00% exhibited proficient performance in nutritional care. Socio-demographic analysis revealed that residents without affiliations and those specializing in obstetrics and gynecology had superior knowledge, while surgery specialists showed significantly worse performance. Most participants expressed a lack of exposure to cancer nutrition education during academic and standardized residency training. The study highlights the demand for enhanced education and the preference for case-based teaching methods. The findings underscore an urgent need for comprehensive oncology nutrition education within China's standardized residency training. Targeted interventions and curriculum enhancements are essential to improve medical talent development and enhance patient care outcomes in oncology. The study emphasizes the critical role of practical, case-based teaching methods in addressing identified gaps in nutritional knowledge and practices among resident physicians.

Exploring the cultivation of psychological resilience in medical students from the perspective of doctor-patient relationship.

The current medical model has transitioned from the original biomedical treatment model to a bio-psycho-social model, where patients now have higher demands for service awareness. Consequently, doctor-patient relationships have become a crucial aspect of the contemporary medical process. Currently, psychological resilience among medical students in China tends to be at a moderately lower level. Medical students often exhibit poor psychological qualities in handling contradictions in doctor-patient relationships. Moreover, there is a lack of emphasis on the education of corresponding psychological qualities for medical students during the teaching process. This deficiency is highly disadvantageous for medical students in their future management of doctor-patient relationships. The article explores how to cultivate psychological resilience in medical students and enhance their ability to handle conflicts in doctor-patient relationships from the perspective of doctor-patient relationships. The author suggests that schools should place greater emphasis on the psychological resilience of medical students, change teaching methods, incorporate online education to enhance the mentalization level of medical students, and propose an eight-week mindfulness cognitive therapy program to improve psychological resilience. The intervention process should consider establishing positive coping mechanisms, promoting good interpersonal relationships among medical students, and regulating individual negative emotions. Through simulating doctor-patient scenarios, teachers should consciously train the psychological resilience of medical students, improve their cognition and thinking abilities, and accelerate their psychological health recovery.

Radiation Therapy Changed the Second Malignancy Pattern in Rectal Cancer Survivors.

Background and Objectives: Radiotherapy (RT) plays an important role in the treatment for locally advanced rectal cancer patients. It can bring radio exposure together with the survival benefit. Cancer survivors are generally at an increased risk for second malignancies, and survivors receiving RT may have higher risks than survivors not receiving RT. Whether the risk of an all-site second malignancy may increase after RT is still debated. This study aims to compare the second malignancy pattern in rectal cancer survivors after RT. Materials and Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used for analysis. In total, 49,961 rectal cancer patients (20-84 years of age) were identified between 2000 and 2012 from 18 SEER registries. All patients underwent surgery. The occurrence of second malignancies diagnosed after rectal cancer diagnosis was compared in patients who received and did not receive RT. The standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were used. SEER*Stat was used to generate the 95% CIs for the SIR statistics using the exact method. Results: Of the total 49,961 patients, 5582 developed second malignancies. For all-site second primary malignancies, the age-adjusted SIRs were 1.14 (95% CI 1.1-1.18) and 1.00 (95% CI 0.96-1.04) in the no RT and RT groups, respectively. In 23,192 patients from the surgery-only group, 2604 had second malignancies, and in 26,769 patients who received RT, 2978 developed second malignancies. With respect to every site, the risk of secondary prostate cancer was significantly lower in the RT group (SIR = 0.39, 95% CI 0.33-0.46) than that in the surgery-only group (SIR = 1.04, 95% CI 0.96-1.12). Moreover, the risk of thyroid cancer was significantly higher in the RT group (SIR = 2.80, 95% CI 2.2-3.51) than that in the surgery-only group (SIR = 1.29, 95% CI 0.99-1.66). Conclusions: RT may change the second malignancy pattern in rectal cancer survivors; the risk of prostate cancer decreased, and the risk of thyroid cancer increased most significantly.

REV1: A novel biomarker and potential therapeutic target for various cancers.

Background: REV1 is a member of the translesion synthesis DNA polymerase Y family. It is an essential player in a variety of DNA replication activities, and perform major roles in the production of both spontaneous and DNA damage-induced mutations. This study aimed to explore the role of REV1 as a prognostic biomarker and its potential function regulating the sensitivity of anti-tumor drugs in various cancers. Methods: We analyzed the impact of REV1 gene alterations on patient prognosis and the impact of different REV1 single nucleotide polymorphisms (SNP) on protein structure and function using multiple online prediction servers. REV1 expression was assessed using data from Oncomine, TCGA, and TIMER database. The correlation between REV1 expression and patient prognosis was performed using the PrognoScan and Kaplan-Meier plotter databases. The IC50 values of anti-cancer drugs were downloaded from the Genomics of Drug Sensitivity in Cancer database and the correlation analyses between REV1 expression and each drug pathway's IC50 value in different tumor types were conducted. Results: Progression free survival was longer in REV1 gene altered group comparing to unaltered group [Median progression free survival (PFS), 107.80 vs. 60.89 months, p value = 7.062e-3]. REV1 SNP rs183737771 (F427L) was predicted to be deleterious SNP. REV1 expression differs in different tumour types. Low REV1 expression is associated with better prognosis in colorectal disease specific survival (DSS), disease-free survival (DFS), gastric overall survival (OS), post progression survival (PPS) and ovarian (OS, PPS) cancer while high REV1 expression is associated with better prognosis in lung [OS, relapse free survival (RFS), first progession (FP), PPS] and breast (DSS, RFS) cancer. In colon adenocarcinoma and rectum adenocarcinoma and lung adenocarcinoma, low expression of REV1 may suggest resistance to drugs in certain pathways. Conversely, high expression of REV1 in acute myeloid leukemia, brain lower grade glioma, small cell lung cancer and thyroid carcinoma may indicate resistance to drugs in certain pathways. Conclusion: REV1 plays different roles in different tumor types, drug susceptibility, and related biological events. REV1 expression is significantly correlated with different prognosis in colorectal, ovarian, lung, breast, and gastric cancer. REV1 expression can be used as predictive marker for various drugs of various pathways in different tumors.

Comprehensive Analysis of the Brain-Expressed X-Link Protein Family in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common, malignant, and deadly primary brain tumor in adults. Brain-expressed X-link (BEX) protein family is involved in tumorigenesis. Here, we have explored the biological function and the prognostic value of the BEX family in GBM. Differentially expressed BEX genes between GBM and normal tissue were screened by using The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analyses identified the prognosis-related genes BEX1, BEX2, and BEX4, which were involved in the regulation of immune response. The results of correlation analysis and protein-protein interaction network (PPI network) showed that there was a significant correlation between the BEX family and TCEAL family in GBM. Furthermore, the expression of transcription elongation factor A (SII)-like (TCEAL) family is generally decreased in GBM and related to poor prognosis. With the use of the least absolute shrinkage and selection operator (LASSO) Cox regression, a prognostic model including the BEX family and TCEAL family was built to accurately predict the likelihood of overall survival (OS) in GBM patients. Therefore, we demonstrated that the BEX family and TCEAL family possessed great potential as therapeutic targets and prognostic biomarkers in GBM. Further investigations in large-scale, multicenter, and prospective clinical cohorts are needed to confirm the prognostic model developed in our study.

Development and validation of a novel prognostic nomogram including tumor deposits could better predict survival for colorectal cancer: a population-based study.

BACKGROUND: The number of tumor deposits (TDs) in colorectal cancer (CRC) prognosis remains debated. We evaluated whether the number of TDs affects prognosis in stage III CRC patients. METHODS: Univariate and multivariate analyses were performed with Cox proportional hazards models. The Kaplan-Meier method was used to estimate survival curves. The best cutoff was determined using X-Tile. Patients were 1:1 randomly divided into the training set or the testing set. Prognostic nomogram was established for stage III CRC patients. Concordance index (C-index) and calibration plot were used to assess Nomogram models. RESULTS: In total, 18,043 (84.69%) CRC patients without TDs and 3,263 (15.31%) patients with TDs were analyzed. Patients with TDs had significantly worse cancer-specific survival (CSS) rates (P<0.001). The number of TDs is an independent factor for the CSS of stage III CRC patients. CSS nomogram of stage III CRC patients was constructed based on race, age at diagnosis, tumor location, histological grade, pathological type, T, N, TDs, chemotherapy. In training set, C-index for CSS nomogram 0.762 (95% CI: 0.752-0.772). In testing set, the C-index for CSS nomogram 0.759 (95% CI: 0.749-0.768). The quality of calibration plots of nomogram models was high. CONCLUSIONS: The presence of TDs is an independent risk prognostic factor for stage III CRC. The number of TDs had a high proportion of prognostic impact.

A truncated protein product of the germline variant of the DUOX2 gene leads to adenomatous polyposis.

Objective: In some patients with adenomatous polyposis, an identifiable pathogenic variant of known associated genes cannot be found. Researchers have studied this for decades; however, few new genes have been identified. Methods: Adenomatous polyposis coli (APC) negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification. Then, whole-exome sequencing (WES) was used to determine candidate genes harboring pathogenic variants. Functional experiments were performed to explore their effects. Subsequently, using Sanger sequencing, we found other polyposis patients carrying variants of the DUOX2 gene, encoding dual oxidase 2, and analyzed them. Results: From 88 patients with suspected familial adenomatous polyposis, 25 unrelated APC negative polyposis patients were identified. Based on the WES results of 3 patients and 2 healthy relatives from a family, the germline nonsense variant (c.1588A>T; p.K530X) of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis. During functional experiments, we observed that the truncated protein, hDuox2 K530, was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant, causing abnormal cell proliferation through endoplasmic reticulum (ER) retention. In addition, we found two unrelated APC negative patients carrying DUOX2 missense variants (c.3329G>A, p.R1110Q; c.4027C>T, p.L1343F). Given the results of the in silico analysis, these two missense variants might exert a negative influence on the function of hDuox2. Conclusions: To our knowledge, this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis. With an autosomal dominant inheritance, it causes ER retention, inducing an unfolded protein response.

Cancer-Associated Fibroblasts Suppress Cancer Development: The Other Side of the Coin.

Cancer-associated fibroblasts (CAFs) are the main stromal components of cancer, representing a group of heterogeneous cells. Many studies indicate that CAFs promote tumor development. Besides, evidence of the tumor suppression effects of CAFs keeps on merging. In the tumor microenvironment, multiple stimuli can activate fibroblasts. Notably, this does not necessarily mean the activated CAFs become strong tumor promoters immediately. The varying degree of CAFs activation makes quiescent CAFs, tumor-restraining CAFs, and tumor-promoting CAFs. Quiescent CAFs and tumor-restraining CAFs are more present in early-stage cancer, while comparatively, more tumor-promoting CAFs present in advanced-stage cancer. The underlying mechanism that balances tumor promotion or tumor inhibition effects of CAFs is mostly unknown. This review focus on the inhibitory effects of CAFs on cancer development. We describe the heterogeneous origin, markers, and metabolism in the CAFs population. Transgenetic mouse models that deplete CAFs or deplete CAFs activation signaling in the tumor stroma present direct evidence of CAFs protective effects against cancer. Moreover, we outline CAFs subpopulation and CAFs derived soluble factors that act as a tumor suppressor. Single-cell RNA-sequencing on CAFs population provides us new insight to classify CAFs subsets. Understanding the full picture of CAFs will help translate CAFs biology from bench to bedside and develop new strategies to improve precision cancer therapy.

Clinical Characteristics, Treatment, and Prognostic Factors of Patients With Primary Extramammary Paget's Disease (EMPD): A Retrospective Analysis of 44 Patients From a Single Center and an Analysis of Data From the Surveillance, Epidemiology, and End Results (SEER) Database.

Objective: Primary extramammary Paget's disease (EMPD) is a rare cutaneous malignancy. The aim of this article is to analyze clinical characteristics, evidence of the prognosis, and share treatment experience of primary EMPD. Methods: We extracted 771 patients' data from the Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2013 to investigate the characteristics and prognosis of patients with EMPD. In addition, 44 patients with primary EMPD in our hospital were retrospectively reviewed for 10 years. Results: Compared with patients younger than 65 years, patients diagnosed at 65-74 years [hazard ratio (HR), 2.453] and 75 years or older (HR, 5.750) had shorter survival. Patients with a primary site in the truncal skin (HR, 0.367) or scrotum (HR, 0.246) had better survival compared to those with a primary site in the perianal area. Compared with localized EMPD, EMPD with distant (HR, 18.821) and regional (HR, 2.180) metastases was associated with a worse prognosis. Patients who received radiotherapy had decreased survival, with an HR of 2.039. Patients with a higher N stage, M stage, and American Joint Committee on Cancer (AJCC) stage had a decreased prognosis (p < 0.001). Conclusions: Older age at diagnosis, primary site in the perianal area, distant metastasis, radiotherapy, and higher N stage, M stage, and AJCC stage may result in decreased survival.

Silencing of brain-expressed X-linked 2 (BEX2) promotes colorectal cancer metastasis through the Hedgehog signaling pathway.

The incidence of colorectal cancer is increasing, and cancer metastasis is one of the major causes of poor outcomes. BEX2 has been reported to be involved in tumor development in several types of cancer, but its role in metastatic colorectal cancer remains largely undefined. Herein, we demonstrated that BEX2 knockout resulted in enhanced migratory and metastatic potential in colorectal cancer cells both in vitro and in vivo, and re-expression of BEX2 in knockout cells could reverse the enhanced migratory capacity. RNA-Seq results indicated that the hedgehog signaling pathway was activated after BEX2 knockout; moreover, the hedgehog signaling inhibitors, GANT61 and GDC-0449 could reverse the migratory enhancement of BEX2-/- colorectal cancer cells. We also demonstrated that the nuclear translocation of Zic2 after BEX2 silencing could activate the hedgehog signaling pathway, while Zic2 knockdown abrogated the migratory enhancement of BEX2-/- cells and inhibited the hedgehog signaling pathway. In summary, our findings suggest that BEX2 negatively modulates the hedgehog signaling pathway by retaining Zic2 in the cytoplasm in colorectal cancer cells, thereby inhibiting migration and metastasis of colorectal cancer cells.

A Competing Nomogram to Predict Survival Outcomes in Invasive Micropapillary Breast Cancer.

Background: Although it is widely accepted that invasive micropapillary carcinoma (IMPC) presents more aggressive behavior and has a higher aggressive behavior, the prognosis of IMPC compared with invasive ductal carcinoma (IDC) remains controversial. We conducted this study to explore gene expression profiles of IMPC and establish a competing nomogram that predicts the survival outcomes across these two groups of patients. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database were reviewed. Propensity score matching (PSM) was used to adjust for potential baseline confounding between IMPC and IDC group. The Kaplan-Meier method was used to calculate the occurrence of overall mortality. The Gray method was used to estimate the rate of breast cancer specific death (BCSD). A competing regression model was used to evaluate factors associated with BCSD. A nomogram based on the competing risk regression model was established to predict individual outcomes. IMPC-specific gene expression profiles were explored using microarrays data from the Gene Expression Omnibus (GEO) database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed. Results: In this study, 330786 (99.62%) patients with IDC 1247 (0.38%) patients with IMPC were included. Patients with IMPC had more lymph node involvement and a larger tumor size compared with those with IDC. After PSM, many distributional differences were eliminated, showing that the IMPC and IDC group were more similar. Patients with IMPC had a favorable prognosis with statistical significance compared with patients with IDC (overall mortality HR = 0.68; 95%CI, 0.53-0.86; P = 0.002). Based on Gray method, patients with IMPC had a favorable prognosis with significant statistical significance compared with patients with IDC (BCSD SHR = 0.64; 95%CI, 0.47-0.88; P = 0.006). Multivariate analysis based on competing risk model demonstrated that IMPC was a favorable independent factor for BCSD. The nomogram could accurately predict BCSD with a high internal and external validated C-index (0.835, 0.818 respectively). A total of 53 upregulated differentially expressed genes (DEGs) and 40 downregulated DEGs of IMPC was identified. The GO analysis results showed that downregulated DEGs were significantly enriched in extracellular structure organization, extracellular matrix, cell-substrate adhesion junction. KEGG analysis of selective gene sets shows that downregulated DEGs significantly enriched for processes related to carbon metabolism, Rap1 signaling pathway. Conclusion: In the current study, IMPC accounted for 0.38% of the entire cohort. IMPC was found to be a favorable independent prognostic factor. The present study identified gene expression profiles and signal pathways of IMPC. The developed nomogram can help the oncologists to predict individual outcomes more accurately.

Accuracy of Magnetic Resonance Imaging in Staging Rectal Cancer with Multidisciplinary Team: A Single-Center Experience.

Purpose: To investigate the accuracy of magnetic resonance imaging (MRI) in preoperative staging diagnosis for rectal cancer with multidisciplinary team (MDT) discussion. Methods: The retrospective study included 377 patients of rectal cancer with preoperative MRI staging from February 2015 to April 2018, in which 137 patients (36 received MDT discussion) received neoadjuvant therapy, 240 did not (97 received MDT discussion) and direct surgery was given. With postoperative pathological stage as the standard, the accuracy of MRI in preoperative staging for rectal cancer with MDT discussion was compared with non-MDT. Results: For direct surgery group, 21 out 97 (21.6%) patients changed their therapy strategy due to the change of the stage assessment after MDT. The accuracy of MRI for the diagnosis of preoperative N stage with MDT was significantly higher than those without MDT (56.2% vs. 42.1%, P=0.021). And for those without lymph node metastasis, the accuracy of MRI was higher after MDT (61.2% vs. 37.8%, P=0.009). For neoadjuvant therapy group, 7 out of 36 (19.4%) patients altered their therapy after MDT because of the changed stage. MDT improved the accuracy of restaging N stage with MRI (70.0% vs. 33.3%, P=0.003). The accuracy of MRI in staging T stage seemed not improved after MDT in both groups. Conclusions: In conclusion, MDT discussion increased the accuracy of MRI in preoperative staging diagnosis for rectal cancer. This mode could give a more accurate clinical stage of patients, which was in favor of choosing a preferable therapy strategy.

Glioma SOX2 expression decreased after adjuvant therapy.

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.

Predictors and Risk Factors of Pathologic Complete Response Following Neoadjuvant Chemoradiotherapy for Rectal Cancer: A Population-Based Analysis.

Background: Patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) may have a better prognosis and may be eligible for non-operative management. The aim of this research was to identify variables for predicting pCR in rectal cancer patients after nCRT and to define clinical risk factors for poor outcome after pCR to nCRT and radical resection in rectal cancer patients. Methods: A retrospective review was performed using the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2013. Non-metastatic rectal cancer patients who received radical resection after neoadjuvant chemoradiotherapy were included in this study. Multivariate analysis of the association between clinicopathological characteristics and pCR was performed, and a logistic regression model was used to identify independent predictors for pCR. A nomogram based on the multivariate logistics regression was built with decision curve analyses to evaluate the clinical usefulness. Results: A total of 6,555 patients were included in this study. The proportion of patients with pCR was 20.5% (n = 1,342). The nomogram based on multivariate logistic regression analysis showed that clinical T4 and N2 stages were the most significant independent clinical predictors for not achieving pCR, followed by mucinous adenocarcinoma and positive pre-treatment serum CEA results. The 3-year overall survival rate was 92.4% for those with pCR and 88.2% for those without pCR. Among all the pCR patients, mucinous adenocarcinoma patients had the worst survival, with a 3-year overall survival rate of 67.5%, whereas patients with common adenocarcinoma had an overall survival rate of 93.8% (P < 0.001). Univariate and multivariate analyses showed that histology and clinical N2 stage were independent risk factors. Conclusion: Mucinous adenocarcinoma, positive pre-treatment serum CEA results, and clinical T4 and N2 stages may impart difficulty for patients to achieve pCR. Mucinous adenocarcinoma and clinical N2 stage might be indicative of a prognostically unfavorable biological tumor profile with a greater propensity for local or distant recurrence and decreased survival.

Cancer-associated fibroblasts in radiotherapy: challenges and new opportunities.

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.

A 10-year Population-based Study of the Differences between NECs and Carcinomas of the Esophagus in Terms of Clinicopathology and Survival.

Purpose: The prevalence of esophageal NECs is rising, but to date, no studies have compared its clinicopathological characteristics to those of esophageal ACs and SCCs from the same period. Patients and methods: A 10-year population-based retrospective cohort study was conducted with the Surveillance, Epidemiology, and End Results Program database. Statistical analyses were performed using Intercooled Stata 12.0 software. Results: A total of 17,196 eligible patients with esophageal tumors, including 246 NECs, 6,102 SCCs and 10,848 ACs, were analyzed. ACs showed an obviously higher prevalence than the other two tumor types, and the prevalence of NECs was increasing. NECs were associated with an obviously worse survival than ACs (log-rank test, P<0.01). Most NECs were poorly differentiated and had an obviously higher percentage of metastasis. NECs and ACs often metastasized to the liver (29.41% and 23.11%, respectively), while SCCs typically metastasized to the lung (15.84%) and distant lymph nodes (15.37%). We divided the patients into two groups for further analysis according to the metastasis status. For NECs, no benefit was obtained by surgery in metastatic disease. For SCCs and ACs, surgery of the primary sites produced survival benefits in both groups, but the benefits of lymphadenectomy and metastasis dissection need further study. Conclusion: NECs of the esophagus have the worst prognosis compared to SCCs and ACs from the same period. Radical surgery provides limited benefits to patients diagnosed with NECs, so systemic treatments should be considered instead of surgical procedures. A unique guideline with a new staging and grading system for esophageal NECs is urgently needed.

Deguelin induces apoptosis in colorectal cancer cells by activating the p38 MAPK pathway.

OBJECTIVES: Deguelin, a rotenoid extracted from Mundulea sericea (Leguminosae), exhibits antitumor effects on several types of human cancers. Due to the limited studies of deguelin on colorectal cancer (CRC), the present study was designed to investigate the antitumor effect of deguelin and to explore the underlying mechanism in CRC. MATERIALS AND METHODS: Cell viability was assessed by the cell counting kit-8 (CCK-8) assay, and cell apoptosis was determined by the annexin v-propidium iodide staining using flow cytometry and Western blot in CRC cell lines after incubation with deguelin. The antitumor effect of deguelin was further evaluated in tumor xenograft models. Moreover, SB203580, a specific inhibitor of p38 MAPK, was used to confirm the involvement of p38 MAPK pathway in deguelin-induced apoptosis. RESULTS: Deguelin significantly inhibited cell proliferation and induced apoptosis in CRC cell lines (SW620 and RKO) in a time-dependent and dose-dependent manner. Western blot analysis also showed that the expression of proapoptotic proteins (cleaved caspase 3 and cleaved PARP) was upregulated, while that of antiapoptotic proteins (Bcl-2 and survivin) was downregulated after deguelin treatment in CRC cell lines. Moreover, oral administration of deguelin significantly suppressed tumor growth and induced apoptosis in subcutaneous xenograft mouse models without obvious toxicity. Additionally, Western blot revealed that deguelin-induced apoptosis might be regulated by the p38 MAPK pathway and inhibition of p38 MAPK could attenuate deguelin-induced proliferative inhibition and apoptosis in CRC cells. CONCLUSION: Collectively, these results demonstrated that deguelin inhibited CRC cell growth by inducing apoptosis via activation of p38 MAPK pathway.

Pattern and risk factors for distant metastases in gastrointestinal neuroendocrine neoplasms: a population-based study.

An increased incidence of gastrointestinal neuroendocrine neoplasms (GI-NENs) has been reported worldwide, and metastasis is the leading cause of GI-NEN-related death. Studies of different metastatic patterns in patients with different primary sites are limited. A population-based retrospective cohort study was conducted with the Surveillance, Epidemiology, and End Results (SEER) database. Patients with a GI-NEN diagnosis between 2010 and 2014 were included. All statistical analyses were performed using Intercooled Stata 12.0 software. There were 12,501 patients eligible for analysis. The metastatic status, primary sites, and histology types affected the patients' overall survival. The liver was the most common metastasis site (65.21% of patients with metastases). Esophageal NENs had the highest risk of metastasis (49.35%), whereas appendiceal NENs had the lowest risk of metastasis (2.79%). Neuroendocrine carcinomas (NECs) were more likely to develop metastatic disease than were neuroendocrine tumors (NETs); 7.12% of patients with NET and 30.20% of patients with NEC developed metastatic disease. The metastatic patterns varied according to the different primary sites and histology types. NECs had a higher potential to develop extrahepatic metastasis at all primary sites than did NETs. Regarding the choice of treatment, surgical resection of primary lesions lowered the risk of tumor-specific death (HR = 0.37, CI: 0.30-0.46, P < 0.01), but surgical resection of metastatic sites did not confer an extra survival benefit (HR = 0.82, CI: 0.63-1.06, P = 0.14). Different primary sites and histology types of GI-NENs have different metastatic patterns and survival. This knowledge could help clinicians to identify patients who require extra surveillance, provide insight for future studies on the mechanisms of metastasis, and establish a prognostic prediction model.