Radical chemoradiotherapy for superficial esophageal cancer complicated with liver cirrhosis.

Background: Although chemoradiotherapy is an effective treatment for esophageal cancer, its feasibility in esophageal cancer with cirrhosis remains largely unclear. Methods: We retrospectively studied 11 patients with superficial esophageal cancer with liver cirrhosis (Child-Pugh score ≤8) who underwent radical chemoradiotherapy from four centers, and the overall survival rate, local control rate and adverse events at 1 and 3 years were explored. Results: The median age of the included patients was 67 years (Inter-Quartile Range 60-75 years). Complete response was observed in most patients (n = 10, 90.9%), and the remaining patient was unevaluable. The 1- and 3-year overall survival and local control rates were 90.9% and 90.9%, and 72.7% and 63.6%, respectively. Hematotoxicity was a common adverse reaction, and seven patients developed radiation esophagitis, with grade 3-4 observed in two cases. All cases of radiation dermatitis (n = 4) and radiation pneumonia (n = 2) were grade 1-2. Gastrointestinal bleeding occurred in two patients, including one with grade 1-2 bleeding, and one died. Conclusion: Radical chemoradiotherapy is a potential treatment option for patients with superficial esophageal cancer complicated with cirrhosis. However, it can increase the risk of bleeding, which warrants prompt recognition and intervention.

Navigating the labyrinth of long non-coding RNAs in colorectal cancer: From chemoresistance to autophagy.

Long non-coding RNAs (lncRNAs), with transcript lengths exceeding 200 nucleotides and little or no protein-coding capacity, have been found to impact colorectal cancer (CRC) through various biological processes. LncRNA expression can regulate autophagy, which plays dual roles in the initiation and progression of cancers, including CRC. Abnormal expression of lncRNAs is associated with the emergence of chemoresistance. Moreover, it has been confirmed that targeting autophagy through lncRNA regulation could be a viable approach for combating chemoresistance. Two recent studies titled "Human ß-defensin-1 affects the mammalian target of rapamycin pathway and autophagy in colon cancer cells through long non-coding RNA TCONS_00014506" and "Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription" revealed novel insights into lncRNAs associated with autophagy and oxaliplatin resistance in CRC, respectively. In this editorial, we particularly focus on the regulatory role of lncRNAs in CRC-related autophagy and chemoresistance since the regulation of chemotherapeutic sensitivity by intervening with the lncRNAs involved in the autophagy process has become a promising new approach for cancer treatment.

Prognostic models for immunotherapy in non-small cell lung cancer: A comprehensive review.

The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of lung cancer. Given the limited clinical benefits of immunotherapy in patients with non-small cell lung cancer (NSCLC), various predictors have been shown to significantly influence prognosis. However, no single predictor is adequate to forecast patients' survival benefit. Therefore, it's imperative to develop a prognostic model that integrates multiple predictors. This model would be instrumental in identifying patients who might benefit from ICIs. Retrospective analysis and small case series have demonstrated the potential role of these models in prognostic prediction, though further prospective investigation is required to evaluate more rigorously their application in these contexts. This article presents and summarizes the latest research advancements on immunotherapy prognostic models for NSCLC from multiple omics perspectives and discuss emerging strategies being developed to enhance the domain.

Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS.

The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis, but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking. To address this gap, we conducted a study aiming to investigate this association and identify relevant biomarkers. We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment, biological activity, and the immune microenvironment. Additionally, we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies (GWASs) involving both East Asian (7062 cases and 195745 controls) and European (24476 cases and 23073 controls) populations. We employed mediation analysis to infer the causal pathway, and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells. Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1 ( FEN1) gene were significantly enriched in colorectal tumor tissues, compared with normal tissues. Moreover, a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer (odds ratio = 0.94, 95% confidence interval: 0.90-0.97, P meta = 4.70 × 10 -9). Importantly, we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors, and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication. In conclusion, this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity, expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

Unraveling the multifaceted role of EpCAM in colorectal cancer: an integrated review of its function and interplay with non-coding RNAs.

The epithelial cell adhesion molecule (EpCAM) is a critical glycoprotein involved in cell cycle progression, proliferation, differentiation, migration, and immune evasion. Its role as a target for bispecific antibodies has shown promise in annihilating cancer cells. EpCAM's potential as a biomarker for tumor-initiating cells, characterized by self-renewal and tumorigenic capabilities, underscores its value in early cancer detection, immunotherapy, and targeted drug delivery. While EpCAM monotherapies have been met with limited success, bispecific antibodies targeting both EpCAM and other proteins have exhibited encouraging results in colorectal cancer (CRC) research. The integration of EpCAM-directed nanotechnology in drug delivery systems has emerged as a pivotal innovation in CRC treatment. Moreover, developing chimeric antigen receptor (CAR) T-cell and CAR natural killer (NK) cell therapies opens promising therapeutic avenues for EpCAM-positive CRC patients. Although preliminary, this review sets the stage for future advances. Additionally, this study advances our understanding of the role of non-coding RNAs in CRC, which may be pivotal in gene regulation and could provide insights into the molecular underpinning. The findings suggest that lncRNA, miRNA, and circRNA could serve as novel therapeutic targets or biomarkers, further enriching the landscape of CRC diagnostics and therapeutics.

The Association of Waist Circumference with the Prevalence and Survival of Digestive Tract Cancer in US Adults: A Population Study Based on Machine Learning Methods.

Aims: This paper aims to investigate the relationship of waist circumference (WC) with digestive tract cancer morbidity and mortality. Methods: Based on the data from a nationally representative US population survey, we summarized the prevalence of digestive tract cancer and all-cause mortality of cancer patients across WC quartiles. Adjusted logistic regression and restricted spline curve were used to analyze WC and the prevalence of digestive tract cancer. Moreover, Cox regression and the Kaplan-Meier curve were applied to investigate the association of WC with all-cause mortality. We also attempted to make a model to predict cancer happening. Results: This paper included a total of 34,041 participants, with digestive tract cancer observed in 265 (0.7%) individuals. WC was positively associated with digestive tract cancer morbidity after full adjustment of covariates (OR: 1.72 and 95% CI: 1.41-2.10). Also, individuals in the highest WC group had a higher risk of digestive tract cancer (Q4, OR: 2.71 and 95% CI: 1.48-5.00). Moreover, no significant association was observed in upper digestive cancer, and WC was associated with a longer survival time once diagnosed (hazard ratio (HR): 0.50 and 95% CI: 0.28-0.92). Finally, the model we made proved to be effective. Conclusion: High WC is a risk factor for digestive tract cancer with or without adjusting for body mass index, especially those located in the lower digestive tract. However, once digestive tract cancer has been diagnosed, patients with higher WC showed better survival outcomes. Moreover, machine learning methods can be used to predict digestive tract cancer risk in the future.

Exosomal circLPAR1 functions in colorectal cancer diagnosis and tumorigenesis through suppressing BRD4 via METTL3-eIF3h interaction.

BACKGROUND: Exosomes have emerged as vital biomarkers of multiple cancers and contain abundant circular RNAs (circRNAs). However, the potential for exosomal circRNAs to be used in diagnostics and their molecular mechanism of action in colorectal cancer (CRC) remain unclear. METHODS: CRC-specific exosomal circRNAs were identified by RNA sequencing, exoRBase database and a tissue microarray. The diagnostic performance of plasma exosomal circRNAs was evaluated among cancer-free controls, precancer individuals, CRC patients, and patients with other types of cancer. The corresponding biological functions were mainly assessed using circRNA pull-down, proteomic analysis, and RNA immunoprecipitation assay underlying cellular and mouse models. RESULTS: CircLPAR1 was encapsulated in exosomes with high stability and detectability, and its expression in plasma exosomes was remarkably decreased during CRC development but recovered after surgery. Exosomal circLPAR1 showed cancer specificity in CRC diagnosis and increased the diagnostic performance to an area under the receiver operating characteristic curve of 0.875, as determined by analysing its performance in combination with common clinical biomarkers CEA and CA19-9. Additionally, circLPAR1 was downregulated in CRC tissues and was associated with overall survival. Mechanistically, exosomal circLPAR1 was internalized by CRC cells, and it suppressed tumor growth, likely because exosomal circLPAR1 directly bound with eIF3h specifically suppressed the METTL3-eIF3h interaction, decreasing the translation of oncogene BRD4. CONCLUSIONS: This comprehensive study highlights plasma exosomal circLPAR1 as a promising predictor in CRC diagnosis and describes its biological regulation of colorectal tumorigenesis. This study provides a new perspective on early diagnosis in the clinic and pathogenesis in disease development.

High-density lipoprotein, low-density lipoprotein and triglyceride levels and upper gastrointestinal cancers risk: a trans-ancestry Mendelian randomization study.

OBJECTIVE: This study was conducted to explore the causal associations of high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglyceride (TG) with the risk of upper gastrointestinal cancers (esophageal cancer [EC] and gastric cancer [GC]). METHODS: A total of 5623 Chinese and 4133 Europeans afforded the individual-level genotyping data, and 203,608 Japanese from Biobank Japan project and 393,926 Europeans from UK Biobank supported summary statistics of cancer genetic associations. Mendelian randomization (MR) analyses, including weighted genetic risk scores (wGRSs), inverse-variance weighted (IVW), weighted median and Egger-regression, were utilized to evaluate the causal effects of three blood lipids on upper gastrointestinal cancers risk. RESULTS: There was no significantly causal relationships between three blood lipids and EC or GC risk among Chinese or Europeans but a potential causal association between TG and GC risk among Japanese (IVW: odds ratio [OR] = 1.11, P = 0.034; Phet = 0.679). In stratified subgroups, higher genetically predicted TG levels were causally associated with an increased risk of GC among Chinese males (wGRS: OR = 1.61, P = 0.021; IVW: OR = 1.57, P = 0.009; Phet = 0.653) and Japanese females (IVW: OR = 1.33, P = 0.024; Phet = 0.378). CONCLUSION: This trans-ancestry MR study suggested null significant causality between serum HDL, LDL or TG and the risk of upper gastrointestinal cancers among Chinese and Europeans, but provided evidence for a causal role of TG involved in GC etiology in Japanese (especially females), which would support a prevention guide for high-risk groups of GC. Further research with more comprehensive information is needed to explore the underlying mechanism.

3D Lightweight Network for Simultaneous Registration and Segmentation of Organs-at-Risk in CT Images of Head and Neck Cancer.

Image-guided radiation therapy (IGRT) is the most effective treatment for head and neck cancer. The successful implementation of IGRT requires accurate delineation of organ-at-risk (OAR) in the computed tomography (CT) images. In routine clinical practice, OARs are manually segmented by oncologists, which is time-consuming, laborious, and subjective. To assist oncologists in OAR contouring, we proposed a three-dimensional (3D) lightweight framework for simultaneous OAR registration and segmentation. The registration network was designed to align a selected OAR template to a new image volume for OAR localization. A region of interest (ROI) selection layer then generated ROIs of OARs from the registration results, which were fed into a multiview segmentation network for accurate OAR segmentation. To improve the performance of registration and segmentation networks, a centre distance loss was designed for the registration network, an ROI classification branch was employed for the segmentation network, and further, context information was incorporated to iteratively promote both networks' performance. The segmentation results were further refined with shape information for final delineation. We evaluated registration and segmentation performances of the proposed framework using three datasets. On the internal dataset, the Dice similarity coefficient (DSC) of registration and segmentation was 69.7% and 79.6%, respectively. In addition, our framework was evaluated on two external datasets and gained satisfactory performance. These results showed that the 3D lightweight framework achieved fast, accurate and robust registration and segmentation of OARs in head and neck cancer. The proposed framework has the potential of assisting oncologists in OAR delineation.

Coexistence of a novel NBEA-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report.

OBJECTIVES: The echinoderm microtubule-associated protein-like 4 gene (EML4) and anaplastic lymphoma kinase gene (ALK) fusion is the most common ALK rearrangements in non-small cell lung cancer (NSCLC). Herein, we firstly report that coexistence of a novel Neurobeachin (NBEA)-ALK, EML4-ALK double-fusion is sensitive to alectinib. MATERIALS AND METHODS: Hematoxylin-eosin staining (HE), fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS) was performed on the biopsy sample. RESULTS: The patient responded to alectinib as a second-line treatment and achieved stable disease for 11 months, without significant symptoms of toxicity. Significantly, the liquid biopsy also validated clinical benefit, with the disappearance of NBEA-ALK and EML4-ALK fusion variants. We also provided a comprehensive review of all 50 ALK fusion genes in NSCLC. CONCLUSION: This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect.

Influence of Clinical and Tumor Factors on Interfraction Setup Errors With Rotation Correction for Vacuum Cushion in Lung Stereotactic Body Radiation Therapy.

PURPOSE: To explore the influence of clinical and tumor factors over interfraction setup errors with rotation correction for non-small cell lung cancer (NSCLC) stereotactic body radiation therapy (SBRT) patients immobilized in vacuum cushion (VC) to better understand whether patient re-setup could further be optimized with these parameters. MATERIALS AND METHODS: This retrospective study was conducted on 142 NSCLC patients treated with SBRT between November 2017 to July 2019 in the local institute. Translation and rotation setup errors were analyzed in 732 cone-beam computed tomography (CBCT) scans before treatment. Differences between groups were analyzed using independent sample t-test. Logistic regression test was used to analyze possible correlations between patient re-setup and clinical and tumor factors. RESULTS: Mean setup errors were the largest in anterior-posterior (AP) direction (3.2 ± 2.4 mm) compared with superior-inferior (SI) (2.8 ± 2.1 mm) and left-right (LR) (2.5 ± 2.0 mm) directions. The mean values were similar in pitch, roll, and rtn directions. Of the fractions, 83.7%, 90.3%, and 86.6% satisfied setup error tolerance limits in AP, SI, and LR directions, whereas 95% had rotation setup errors of <2° in the pitch, roll, or rtn directions. Setup errors were significantly different in the LR direction when age, body mass index (BMI), and "right vs. left" location parameters were divided into groups. Both univariate and multivariable model analyses showed that age (p = 0.006) and BMI (p = 0.002) were associated with patient re-setup. CONCLUSIONS: Age and BMI, as clinical factors, significantly influenced patient re-setup in the current study, whereas all other clinical and tumor factors were not correlated with patient re-setup. The current study recommends that more attention be paid to setup for elderly patients and patients with larger BMI when immobilized using VC, especially in the left-right direction.

Afatinib combined with anlotinib in the treatment of lung adenocarcinoma patient with novel HER2 mutation: a case report and review of the literature.

BACKGROUND: HER2 is a member of the ERBB family of receptor tyrosine kinases, and HER2 mutations occur in 1-4% of non-small cell lung cancer (NSCLC) as an oncogenic driver mutation. We found a rare mutation of HER2 p.Asp769Tyr in NSCLC. CASE PRESENTATION: We presented a case of a 68-year-old nonsmoking male patient with brain metastasis from lung adenocarcinoma harboring a rare mutation of HER2 p.Asp769Tyr. After multiple lines of treatment, he obtained a durable response (10 months) to afatinib and anlotinib. CONCLUSION: We reported for the first time that afatinib and anlotinib have successfully treated lung adenocarcinoma with HER2 p.Asp769Tyr mutation. This finding can provide an insight into the optimal treatment of lung adenocarcinoma patients with novel mutations. Additionally, we summarized the efficacy of targeted therapy for HER2 mutant lung cancer in this article.

A methylation-based prognostic model predicts survival in patients with colorectal cancer.

BACKGROUND: To construct a model that could effectively predict the prognosis of colorectal cancer (CRC) by searching for methylated-differentially expressed genes (MDEGs). METHODS: We identified MDEGs through four databases from Gene Expression Omnibus (GEO) and annotated their functions via bioinformatics analysis. Subsequently, after adjusting for gender, age, and grading, multivariate Cox hazard analysis was utilized to select MDEGs interrelated with the prognosis of CRC, and LASSO analysis was utilized to fit the prediction model in the training set. Furthermore, another independent dataset was harnessed to verify the effectiveness of the model in predicting prognosis. RESULTS: In total, 252 hypomethylated and up-regulated genes and 132 hypermethylated and down-regulated genes were identified, 27 of which were correlated with the prognosis of CRC, and a 10-gene prognostic model was established after LASSO analysis. The overall survival rate could be effectively grouped into different risks by the median score of this model in the training set [risk ratio (HR) =2.27, confidence interval (95% CI), 1.69-3.13, P=8.15×10-8], and the validity of its effect in predicting prognosis in CRC was verified in the validation dataset (HR =1.75, 95% CI, 1.15-2.70, P=9.32×10-3). CONCLUSIONS: Our model could effectively predict the overall survival rate of patients with CRC and provides potential application guidelines for its clinically personalized treatment.

Circular RNAs in body fluids as cancer biomarkers: the new frontier of liquid biopsies.

Cancer is a leading cause of death worldwide, particularly because of its high mortality rate in patients who are diagnosed at late stages. Conventional biomarkers originating from blood are widely used for cancer diagnosis, but their low sensitivity and specificity limit their widespread application in cancer screening among the general population. Currently, emerging studies are exploiting novel, highly-accurate biomarkers in human body fluids that are obtainable through minimally invasive techniques, which is defined as liquid biopsy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs generated mainly by pre-mRNA splicing. Following the rapid development of high-throughput transcriptome analysis techniques, numerous circRNAs have been recognized to exist stably and at high levels in body fluids, including plasma, serum, exosomes, and urine. CircRNA expression patterns exhibit distinctly differences between patients with cancer and healthy controls, suggesting that circRNAs in body fluids potentially represent novel biomarkers for monitoring cancer development and progression. In this study, we summarized the expression of circRNAs in body fluids in a pan-cancer dataset and characterized their clinical applications in liquid biopsy for cancer diagnosis and prognosis. In addition, a user-friendly web interface was developed to visualize each circRNA in fluids ( https://mulongdu.shinyapps.io/circrnas_in_fluids/ ).

Acupuncture for Cancer Pain - An Adjuvant Therapy for Cancer Pain Relief.

As current pain management methods cannot effectively control pain among cancer patients, acupuncture has developed as an adjuvant therapy for cancer pain relief. However, the efficacy of acupuncture in treating cancer pain remains controversial. Here, we briefly introduced the development of pain management, analgesic mechanisms, and acupuncture methods. Meanwhile, a comprehensive overview of acupuncture programs was provided in terms of different cancer types, sources, and degrees. Interestingly, acupuncture can treat both tumor-induced pain and therapy-induced pain well among cancer patients. We preliminarily summarized frequently-used acupoints for different types of cancer pain and found that needle retention time was mostly 30 min, and treatment cycle was two weeks. Additionally, clinicians consistently selected Ashi acupoint or bilateral Zusanli acupoint and combined multiple acupuncture methods for different degrees of cancer pain.

A novel TJP1-ROS1 fusion in malignant peripheral nerve sheath tumor responding to crizotinib: A case report.

RATIONALE: Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma. Owing to the lack of specific histological criteria, immunohistochemical, and molecular diagnostic markers, several differential diagnoses must be considered. Advances in molecular testing can provide significant insights for management of rare tumor. PATIENT CONCERNS: The patient was a 50-year-old man with a history of lumpectomy on the right back 30 years ago. He felt a stabbing pain at the right iliac fossa and went to the local hospital. DIAGNOSIS: By immunohistochemistry, the tumor cells stained positively for S-100 (focal +), CD34 (strong +++) and Ki-67 (20%), and negatively for smooth muscle actin, pan-cytokeratin, neurofilament, pan-cytokeratin-L, GFAP, CD31, STAT6, ERG, myogenin, and MyoD1. Combined with the histopathology and immunohistochemistry results, our initial diagnosis was solitary fibrous tumor (SFT) or MPNST. The tissue biopsy was sent for next-generation sequencing. neurofibromatosis type 1 Q1395Hfs*22 somatic mutation, neurofibromatosis type 1 D483Tfs*15 germline mutation, and amplifications of BTK, MDM2, ATF1, BMPR1A, EBHA2, GNA13, PTPN11, RAD52, RPTOR, and SOX9, as well as TJP1-ROS1 fusion, CDKN2A-IL1RAPL2 fusion and CDKN2A/UBAP1 rearrangement were identified. Given that NAB2-STAT6 fusion, a specific biomarker of SFT, was not identified in our patient's tumor, the SFT was excluded by through genetic testing results. Therefore, our finally diagnosis was a MPNST by 2 or more pathologists. INTERVENTIONS AND OUTCOMES: Subsequently, the patient received crizotinib therapy for 2 months and showed stable disease. However, after crizotinib continued treatment for 4 months, the patient's disease progressed. Soon after, the patient stopped crizotinib treatment and died in home. LESSONS: To our knowledge, this is the first report of the TJP1-ROS1 fusion, which expands the list of gene fusions and highlights new targets for targeted therapy. Also, our case underlines the value of multi-gene panel next-generation sequencing for diagnosis of MPNST.

The prognostic value of prognostic nutritional index (PNI) and neutrophil to lymphocyte ratio (NLR) for advanced non-small cell lung cancer treated with platinum-based chemotherapeutics.

BACKGROUND: The present study aimed to investigate the relationship between prognostic nutritional index (PNI) and peripheral blood neutrophil to lymphocyte ratio (NLR), and the prognosis of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based therapeutics. METHODS: The data of 99 advanced NSCLC patients treated with platinum chemotherapeutics between January 2011 and June 2019 were retrospectively analyzed. The association between PNI and NLR and the clinicopathological characteristics of the patients was examined. The patients were randomized into high or low groups according to PNI and NLR. The predictive value of PNI and NLR for overall survival (OS) was evaluated by receiver operating characteristic (ROC) curve analysis. Univariate and multivariate Cox proportional hazards regression analyses were performed to investigate the prognostic factors of advanced NSCLC patients treated with platinum-based chemotherapeutics. The association between PNI and NLR and progression-free survival (PFS) or OS was determined using the Kaplan-Meier method and compared between groups using the log-rank test. RESULTS: The ROC curve analysis determined the optimal cut-off values of PNI and NLR for predicting OS to be 52.525 and 3.525, respectively. Univariate analysis indicated that low Karnofsky performance scale (KPS) score (P=0.005), poor tumor differentiation (P=0.022), brain metastasis (P<0.001), and low PNI (P=0.001) were independent risk factors for PFS in patients with advanced NSCLC; however, there was no significant correlation observed between NLR (P=0.082) and PFS in patients with advanced NSCLC. Low KPS score (P=0.003), poor tumor differentiation (P=0.001), brain metastasis (P<0.001), low PNI (P<0.001), and high NLR (P=0.046) were significantly associated with shorter OS. Furthermore, Cox multivariate analysis revealed that brain metastasis (P=0.005) and low PNI (P=0.008) were significant independent prognostic factors for PFS, while brain metastasis (P=0.003) and low PNI (P=0.028) were also found to be significant independent risk factors for poor OS. CONCLUSIONS: PNI is a reliable, simple, easily available, and inexpensive biomarker for predicting the prognosis of advanced NSCLC patients treated with platinum-based chemotherapeutics in routine clinical practice. Furthermore, PNI is superior to NLR in as a prognostic indicator for advanced NSCLC patients treated with platinum-based chemotherapeutics.

A phase I study investigation of metabolism, and disposition of [14C]-anlotinib after an oral administration in patients with advanced refractory solid tumors.

PURPOSE: Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/ß, c-kit, and Ret. It shows antitumor effect in patients with advanced refractory solid tumors. The detailed absorption, metabolism, and excretion pathways of anlotinib have not yet been fully investigated. METHODS: Six male patients were enrolled and divided into two groups. Group A (containing two patients) received 14.15 mg/80 µCi/subject [14C]-anlotinib hydrochloride. Group B (containing four patients) received 14.15 mg/120 µCi/subject [14C]-anlotinib hydrochloride. The blood, urine, and feces of all the six patients after orally administration of [14C]-anlotinib were collected. The absorption, metabolism, and excretion of [14C]-anlotinib were investigated, and the efficacy and safety of anlotinib were evaluated. RESULTS: In plasma, the average time to peak concentration (Tmax) of total radioactivity was 4.42 h and the average peak concentration (Cmax) of total radioactivity was 18.80 ng Eq./g. The average values of AUC0-last, AUC0-∞, and MRT0-t were 4071 h.ng Eq./g, 13,555 h.ng Eq./g, and 125 h, respectively. The average recovery of total radioactivity (TRA) in urine and feces was 62.03%, accounting for 48.52% and 13.51% in feces and urine of the total dosage, respectively. The parent drug, a carboxylic metabolite (M30), and mono-oxidation products (M46/M66) were major drug-related components in human plasma. Oxidative metabolism played the major role in drug clearance in human. The major metabolic pathways include oxidative deamination to M2, mono-oxidation to M1, and the formation of M30. Adverse events occurred in five patients and severe adverse events (SAE) occurred in one. Tumor response were evaluated as stable disease (SD) in three, partial response (PR) in one, and progressive disease (PD) in one of the patients, respectively. CONCLUSIONS: Anlotinib had a good pharmacokinetic profile with rapid absorption, long half-life, and extensive hepatic metabolism. The adverse events and efficacy were as expected.

NFE2L2/KEAP1 Mutations Correlate with Higher Tumor Mutational Burden Value/PD-L1 Expression and Potentiate Improved Clinical Outcome with Immunotherapy.

BACKGROUND: Abnormalities in the KEPA1-NRF2 pathway have a role in cancer progression, metastasis, and resistance to chemo- and radiotherapies. Persistent activation of NRF2 associates with poor prognosis across different cancer types. However, the beneficial therapeutic strategy to harness this pathway in cancer remains unclear. This study aimed to investigate the clinical outcome with immunotherapy in NFE2L2/KEAP1 mutant population. MATERIALS AND METHODS: We investigated the correlation between NFE2L2/KEAP1 mutations and tumor mutational burden (TMB) and programmed death-ligand 1 (PD-L1) expression status to identify the therapeutic vulnerability. For this purpose, relevance analysis with TMB value was performed in 9,040 patients with cancer, and relevance analysis with PD-L1 expression was performed in 3,457 patients. The Memorial Sloan Kettering Cancer Center (MSKCC) database and real-world evidence were used to assess the immunotherapy response in NFE2L2/KEAP1 mutant subsets. RESULTS: NFE2L2/KEAP1 mutations occurred in various cancers, and the highest mutation incidences occurred in lung squamous cell carcinoma (LUSC) at 19.16% (NFE2L2) and 10.31% (KEAP1). We confirmed that higher TMB value and PD-L1 expression were associated with NFE2L2/KEAP1 mutations compared with wild-type, especially in non-small lung cancer. MSKCC database analysis showed the improved survival of patients with NFE2L2/KEAP1 mutant with immunotherapy compared with other treatments (median overall survival 22.52 VS 12.89, p = .0034). Real-world evidence further confirmed the efficacy of immunotherapy in the mutant population. CONCLUSION: Our study revealed that patients with NFE2L2/KEAP1 mutant could achieve improved outcomes from immunotherapy than the other treatments. These findings may broaden the application of immune checkpoint blockade to patients harboring NFE2L2/KEAP1 mutations. IMPLICATIONS FOR PRACTICE: NFE2L2/KEAP1 alterations occur frequently in multiple cancer types and are associated with poor prognosis; however, the efficacious strategy to inhibit this pathway in cancer is poorly understood. This study was designed to analyze the mutational characteristics of NFE2L2/KEAP1 alterations in 9,243 Chinese patients. The highest mutation incidences occurred in lung squamous cell carcinoma at 19.16% (NFE2L2) and 10.31% (KEAP1). Relevance analysis showed the NFE2L2/KEAP1 mutant subsets were associated with higher tumor mutational burden value and programmed death-ligand 1 expression. Clinical data further confirmed NFE2L2/KEAP1 mutations correlate with improved outcome with immunotherapy. These findings suggest the clinical application of immunotherapy in the NFE2L2/KEAP1 mutant population.

Genetic variants in circTUBB interacting with smoking can enhance colorectal cancer risk.

Circular RNAs (circRNAs) are an intriguing class of regulatory RNAs involved in the tumorigenesis of many cancers, including colorectal cancer. Mechanistically, circRNAs sponge microRNAs (miRNAs) with specific miRNA response elements (MREs) and compete for regulatory target genes downstream. However, the genetic effects of MREs on colorectal cancer susceptibility remain unclear. The MREs of colorectal cancer-associated circRNAs (CRC-circRNAs) and corresponding single nucleotide polymorphisms (SNPs) were identified by the transcriptome of cancer cells and the 1000 Genomes Project. The association between candidate SNPs and colorectal cancer risk was evaluated in a Chinese population (1150 cases and 1342 controls) and two European populations (9023 cases and 386,896 controls) using logistic regression analysis. Among the 197 candidate SNPs within MREs of 186 CRC-circRNAs, rs25497 in circTUBB was significantly associated with colorectal cancer risk in a Chinese population after false discovery rate (FDR) correction [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.44-2.21, P = 1.42 × 10-7, PFDR = 2.80 × 10-5] and even reached significance in a genome-wide association study (GWAS) under the dominant model (P = 1.28 × 10-8). Similar results were found in the European populations (ORmeta = 1.30, 95% CI = 1.10-1.53). Both stratification and interaction analyses revealed that rs25497 interacting with smoking affected the colorectal cancer risk (Pinteraction = 1.48 × 10-2). Here, we first comprehensively identified genetic variants in MREs of CRC-circRNAs and evaluated their effects on colorectal cancer risk in both Chinese and European populations. These findings provide basis for a comprehensive understanding of colorectal cancer etiology.