MACC: a visual interactive knowledgebase of metabolite-associated cell communications.

Metabolite-associated cell communications play critical roles in maintaining the normal biological function of human through coordinating cells, organs and physiological systems. Though substantial information of MACCs has been continuously reported, no relevant database has become available so far. To address this gap, we here developed the first knowledgebase (MACC), to comprehensively describe human metabolite-associated cell communications through curation of experimental literatures. MACC currently contains: (a) 4206 carefully curated metabolite-associated cell communications pairs involving 244 human endogenous metabolites and reported biological effects in vivo and in vitro; (b) 226 comprehensive cell subtypes and 296 disease states, such as cancers, autoimmune diseases, and pathogenic infections; (c) 4508 metabolite-related enzymes and transporters, involving 542 pathways; (d) an interactive tool with user-friendly interface to visualize networks of multiple metabolite-cell interactions. (e) overall expression landscape of metabolite-associated gene sets derived from over 1500 single-cell expression profiles to infer metabolites variations across different cells in the sample. Also, MACC enables cross-links to well-known databases, such as HMDB, DrugBank, TTD and PubMed etc. In complement to ligand-receptor databases, MACC may give new perspectives of alternative communication between cells via metabolite secretion and adsorption, together with the resulting biological functions. MACC is publicly accessible at: http://macc.badd-cao.net/.

ALOX5 deficiency contributes to bladder cancer progression by mediating ferroptosis escape.

Ferroptosis is an iron-dependent form of regulated cell death driven by the lethal lipid peroxides. Previous studies have demonstrated that inducing ferroptosis holds great potential in cancer therapy, especially for patients with traditional therapy failure. However, cancer cells can acquire ferroptosis evasion during progression. To date, the therapeutic potential of inducing ferroptosis in bladder cancer (BCa) remains unclear, and whether a ferroptosis escape mechanism exists in BCa needs further investigation. This study verified that low pathological stage BCa cells were highly sensitive to RSL3-induced ferroptosis, whereas high pathological stage BCa cells exhibited obviously ferroptosis resistance. RNA-seq, RNAi-mediated loss-of-function, and CRISPR/Cas9 experiments demonstrated that ALOX5 deficiency was the crucial factor of BCa resistance to ferroptosis in vitro and in vivo. Mechanistically, we found that ALOX5 deficiency was regulated by EGR1 at the transcriptional level. Clinically, ALOX5 expression was decreased in BCa tissues, and its low expression was associated with poor survival. Collectively, this study uncovers a novel mechanism for BCa ferroptosis escape and proposes that ALOX5 may be a valuable therapeutic target and prognostic biomarker in BCa treatment.

A multi-omics study to investigate the progression of the Correa pathway in gastric mucosa in the context of cirrhosis.

BACKGROUND: Patients with liver cirrhosis (LC) are prone to gastric mucosa damage. We investigated the alterations of gastric mucosa in LC patients and their possible mechanisms through multi-omics. RESULTS: We observed significant gastric mucosa microbial dysbiosis in LC subjects. Gastric mucosal microbiomes of LC patients contained a higher relative abundance of Streptococcus, Neisseria, Prevotella, Veillonella, and Porphyromonas, as well as a decreased abundance in Helicobacter and Achromobacter, than control subjects. The LC patients had higher levels of bile acids (BAs) and long-chain acylcarnitines (long-chain ACs) in serum. The gastric mucosal microbiomes were associated with serum levels of BAs and long-chain ACs. Transcriptome analyses of gastric mucosa revealed an upregulation of endothelial cell specific molecule 1, serpin family E member 1, mucin 2, caudal type homeobox 2, retinol binding protein 2, and defensin alpha 5 in LC group. Besides, the bile secretion signaling pathway was significantly upregulated in the LC group. CONCLUSIONS: The alterations in the gastric mucosal microbiome and transcriptome of LC patients were identified. The impaired energy metabolism in gastric mucosal cells and bile acids might aggravate the inflammation of gastric mucosa and even exacerbate the Correa's cascade process. The gastric mucosal cells might reduce bile acid toxicity by bile acid efflux and detoxification. TRIAL REGISTRATION: ChiCTR2100051070.

Prediction of immune infiltration and prognosis for patients with urothelial bladder cancer based on the DNA damage repair-related genes signature.

Objectives: To analyze the correlations between the expression and effect of DNA damage repair genes and the immune status and clinical outcomes of urothelial bladder cancer (BLCA) patients. In addition, we evaluate the efficacy and value of utilizing the DNA damage repair genes signature as a prognosis model for BLCA. Methods: Two subtype groups (C1 and C2) were produced based on the varied expression of DNA damage repair genes. Significantly differentiated genes and predicted enriched gene pathways were obtained between the two subtypes. Seven key genes were obtained from the DNA damage repair-related genes and a 7-gene signature prognosis model was established based on the key genes. The efficacy and accuracy of this model in prognosis prediction was evaluated and verified in two independent databases. Also, the difference in biological functions, drug sensitivity, immune infiltration and affinity between the high-risk group and low-risk group was analyzed. Results: The DNA damage repair gene signature could significantly differentiate the BLCA into two molecular subgroups with varied genetic expression and enriched gene pathways. Seven key genes were screened out from the 232 candidate genes for prognosis prediction and a 7-gene signature prognosis model was established based on them. Two independent patient cohorts (TCGA cohort and GEO cohort) were utilized to validate the efficacy of the prognosis model, which demonstrated an effective capability to differentiate and predict the overall survival of BLCA patients. Also, the high-risk group and low-risk group derived from the 7-gene model exhibited significantly differences in drug sensitivity, immune infiltration status and biological pathways enrichment. Conclusions: Our established 7-gene signature model based on the DNA damage repair genes could serve as a novel prognosis predictive tool for BLCA. The differentiation of BLCA patients based on the 7-gene signature model may be of great value for the appropriate selection of specific chemotherapy agents and immune-checkpoint blockade therapy administration.

Preoperative US Integrated Random Forest Model for Predicting Delphian Lymph Node Metastasis in Patients with Papillary Thyroid Cancer.

BACKGROUND: Delphian lymph node (DLN) has been considered to be a gate that predicts widespread lymph node involvement, higher recurrence and mortality rates of head and neck cancer. OBJECTIVE: This study aimed to establish a preoperative ultrasonography integrated machine learning prediction model to predict Delphian lymph node metastasis (DLNM) in patients with diagnosed papillary thyroid carcinoma (PTC). METHODS: Ultrasonographic and clinicopathologic variables of PTC patients from 2014 to 2021 were retrospectively analyzed. The risk factors associated with DLNM were identified and validated through a developed random forest (RF) algorithm model based on machine learning and a logistic regression (LR) model. RESULTS: A total of 316 patients with 402 thyroid lesions were enrolled for the training dataset and 280 patients with 341 lesions for the validation dataset, with 170 (28.52%) patients developed DLNM. The elastography score of ultrasonography, central lymph node metastasis, lateral lymph node metastasis, and serum calcitonin were predictive factors for DLNM in both models. The RF model has better predictive performance in the training dataset and validation dataset (AUC: 0.957 vs. 0.890) than that in the LR model (AUC: 0.908 vs. 0.833). CONCLUSION: The preoperative ultrasonography integrated RF model constructed in this study could accurately predict DLNM in PTC patients, which may provide clinicians with more personalized clinical decision-making recommendations preoperatively. Machine learning technology has the potential to improve the development of DLNM prediction models in PTC patients.

Antifungal immunity mediated by C-type lectin receptors may be a novel target in immunotherapy for urothelial bladder cancer.

Immunotherapies, such as immune-checkpoint blockade and adoptive T-cell therapy, offer novel treatment options with good efficacy for patients with urothelial bladder cancer. However, heterogeneity and therapeutic resistance have limited the use of immunotherapy. Further research into immune-regulatory mechanisms in bladder cancer is urgently required. Emerging evidence demonstrates that the commensal microbiota and its interactions with host immunity play pivotal roles in a variety of physiological and pathological processes, including in cancer. The gut microbiota has been identified as a potentially effective target of treatment that can be synergized with immunotherapy. The urothelial tract is also a key site for multiple microbes, although the immune-regulatory role of the urinary microbiome in the process of carcinogenesis of bladder cancer remains to be elucidated. We performed a comprehensive analysis of the expression and biological functions of C-type lectin receptors (CLRs), which have been recognized as innate pathogen-associated receptors for fungal microbiota, in bladder cancer. In line with previous research on fungal colonization of the urothelial tract, we found that CLRs, including Dectin-1, Dectin-2, Dectin-3, and macrophage-inducible Ca2+-dependent lectin receptor (Mincle), had a significant association with immune infiltration in bladder cancer. Multiple innate and adaptive pathways are positively correlated with the upregulation of CLRs. In addition, we found a significant correlation between the expression of CLRs and a range of immune-checkpoint proteins in bladder cancer. Based on previous studies and our findings, we hypothesize that the urinary mycobiome plays a key role in the pathogenesis of bladder cancer and call for more research on CLR-mediated anti-fungal immunity against bladder cancer as a novel target for immunotherapy in urothelial bladder cancer.

Evaluating adipose-derived stem cell exosomes as miRNA drug delivery systems for the treatment of bladder cancer.

OBJECTIVES: Exosomes are essential mediators of intercellular communication as they transport proteins and RNAs between cells. Owing to their tumor-targeting capacity, immune compatibility, low toxicity, and long half-life, mesenchymal stem cell-derived exosomes have great potential for the development of novel antitumor strategies. In this context, the role of exosomes produced by adipose-derived mesenchymal stem cells (ADSCs) for the treatment of bladder cancer (BC) remains unclear. Here, we investigated the use of ADSCs as a source of therapeutic exosomes, as well as their efficacy in delivering the tumor suppressor miR-138-5p in BC. METHODS: ADSCs stably expressing miR-138-5p were established using Lentivirus infection, and ADSC-derived miR-138-5p exosomes (Exo-miR-138-5p) were isolated from the cell culture medium. The effect of Exo-miR-138-5p on BC cell migration, invasion, and proliferation was evaluated in vitro using wound healing, transwell invasion, and proliferation assays. The in vivo effect of Exo-miR-138-5p was investigated using a subcutaneous xenograft mouse model. RESULTS: Exo-miR-138-5p prevented the migration, invasion, and proliferation of BC cells in vitro. Moreover, ADSC-derived exosomes could penetrate tumor tissues and successfully deliver miR-138-5p to suppress the growth of xenograft tumors in vivo. CONCLUSIONS: The present results reveal that ADSC-derived exosomes are an effective delivery vehicle for small molecule drugs in vivo, and exosome-delivered miR-138-5p is a promising therapeutic agent for BC treatment.

The Lymph Node Microenvironment May Invigorate Cancer Cells With Enhanced Metastatic Capacities.

Cancer metastasis, a typical malignant biological behavior involving the distant migration of tumor cells from the primary site to other organs, contributed majorly to cancer-related deaths of patients. Although constant efforts have been paid by researchers to elucidate the mechanisms of cancer metastasis, we are still far away from the definite answer. Recently, emerging evidence demonstrated that cancer metastasis is a continuous coevolutionary process mediated by the interactions between tumor cells and the host organ microenvironment, and epigenetic reprogramming of metastatic cancer cells may confer them with stronger metastatic capacities. The lymph node served as the first metastatic niche for many types of cancer, and the appearance of lymph node metastasis predicted poor prognosis. Importantly, multiple immune cells and stromal cells station and linger in the lymph nodes, which constitutes the complexity of the lymph node microenvironment. The active cross talk between cancer cells and immune cells could happen unceasingly within the metastatic environment of lymph nodes. Of note, diverse immune cells have been found to participate in the formation of malignant properties of tumor, including stemness and immune escape. Based on these available evidence and data, we hypothesize that the metastatic microenvironment of lymph nodes could drive cancer cells to metastasize to further organs through epigenetic mechanisms.

The molecular mechanism of kinesin family member 2A (KIF2A) underlying non-small cell lung cancer: the effect of its knockdown on malignant behaviors, stemness, chemosensitivity, and potential regulated signaling pathways.

Kinesin family member 2A (KIF2A) represents an oncogene in several cancers, however, its involvement in non-small cell lung cancer (NSCLC) is limitedly investigated. Therefore, the present study aimed to explore potential molecular mechanism of KIF2A knockdown in repressing NSCLC malignant behaviors. The effect of KIF2A knockdown on cell proliferation, apoptosis, invasion, epithelial-mesenchymal transition (EMT) markers, stemness, chemosensitivity was detected after transfecting KIF2A short hairpin RNA (ShRNA) plasmids into A549 and NCI-H1975 cells. Moreover, KIF2A knockdown mediated signaling pathways were analyzed by RNA sequencing (RNA-seq), and then validated by western blot assay. Both KIF2A mRNA and protein expressions were increased in A549, NCI-H650, NCI-H358, NCI-H2106, NCI-H1299, NCI-H1650 and NCI-H1975 cells compared with BEAS-2B cells. KIF2A knockdown inhibited proliferation, invasion, EMT, stemness, but enhanced chemosensitivity to cisplatin and paclitaxel in both A549 and NCI-H1975 cells. Meanwhile, it only promoted apoptosis in NCI-H1975 cells but not in A549 cells. Moreover, after KIF2A knocking down, RNA-seq data indicated that 356 accordant differentially expressed genes (DEGs) in both A549 and NCI-H1975 cells, and these DEGs were enriched in PI3K-Akt, Wnt and Notch signaling pathways. Further western blot disclosed that KIF2A knockdown indeed inactivated PI3K-Akt, Wnt and Notch signaling pathways in both A549 and NCI-H1975 cells. In conclusion, KIF2A knockdown suppresses NSCLC cell malignant behaviors, EMT and stemness, but enhances chemosensitivity via inactivating PI3K-Akt, Wnt, and Notch signaling pathways, which proposes it as a potential therapeutic target for NSCLC treatment.

BarH-like homeobox 2 represses the transcription of keratin 16 and affects Ras signaling pathway to suppress nasopharyngeal carcinoma progression.

Nasopharyngeal carcinoma (NPC) refers to a malignancy initiating from the superior mucosal epithelium of the nasopharynx. Optimal therapies for NPC are still needed. In this investigation, we attempted to explore whether BarH-like homeobox 2 (BARX2), a well-known tumor suppressor, had anti-cancer properties on NPC, and the possible mechanisms. After searching for NPC-related databases, we determined BARX2 as one of the core genes in NPC. The results of RT-qPCR and immunohistochemistry or Western blot demonstrated that BARX2 was reduced in NPC patients and cells. Ectopic expression of BARX2 reverted the malignant phenotype of NPC cells. Mechanistically, BARX2 bound to the keratin 16 (KRT16) promoter to downregulate its expression. In addition, BARX2 was found to reduce the phosphorylation levels of MEK and ERK. Further KRT16 upregulation in cells overexpressing BARX2 promoted malignant aggressiveness of C666-1 and HNE3 cells and activated the Ras signaling pathway. BARX2 inhibited the growth and metastasis of tumors and suppressed the Ras signaling pathway in vivo. In conclusion, our findings indicate that BARX2 reverts malignant phenotypes of NPC cells by downregulating KRT16 in a Ras-dependent fashion. BARX2 might act as a possible therapeutic regulator for NPC.

Ocular findings in two Chinese children with Loeys-Dietz syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a type of connective tissue disease with systemic symptoms similar to Marfan syndrome. Ocular findings are rarely reported especially fundus and extraocular muscles. CASE PRESENTATION: A 6-month old boy with systemic skeletal development delay was found peripheral non-perfusion and neovascularization in the both eyes, and gaven intravitreal injection of ranibizumab and laser. Fundus examination revealed a mild straightening of the temporal vessel in the both eyes. A 22-month old girl with confirmed connective tissue disorder presented to our hospital for strabismus and showed congenital hypoplasia of extraocular muscles. She also had arteriovenous anastomosis in the retinal. The diagnosis of LDS was supported by the genetic DNA examination. CONCLUSION: His is the first report of LDS with congenital hypoplasia of extraocular muscles, meanwhile, ocular examination especially fundus should be paid attention to.

The abnormal expression of chromosomal region maintenance 1 (CRM1)-survivin axis in ovarian cancer and its related mechanisms regulating proliferation and apoptosis of ovarian cancer cells.

Ovarian cancer (OC) is the main type of cancer that affects the female reproductive system and has a high morbidity and mortality rate. This study aimed to explore the regulatory effect of the chromosomal region maintenance 1 (CRM1)-survivin axis on the progression of OC. Ovarian cancer cells were transfected with pcDNA3.1-survivin and short hairpin RNA (sh)-CRM1. Cell proliferation was analyzed by cell counting kit-8 (CCK8), 5-ethynyl-2´-deoxyuridine (EdU) staining, and colony formation assays. Apoptosis was detected using flow cytometry. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to analyze the expression of RNA and protein, respectively. qRT-PCR and prognostic correlation analyses revealed that CRM1 is highly expressed in OC cells and related to survival. The results of qRT-PCR, CCK8, colony formation test, EdU staining, flow cytometry, and Western blotting showed that CRM1 silencing inhibited the proliferation and colony formation of OVCAR 3 and SKOV3 cells and promoted cell apoptosis by promoting Caspase-3 activation. Survivin was positively regulated by CRM1 and promoted the development of OC. The results of the rescue experiment showed that overexpression of survivin reversed the inhibitory effect of CRM1 knockdown on the proliferation of ovarian cancer cells and its inhibitory effect on apoptosis. Our findings confirm the role of the CRM1-survivin signal transduction axis in OC by regulating the proliferation and apoptosis of OC cells, and may thus serve as a potential therapeutic target for OC.

A Comparative Analysis of the Gene Expression Profiles of Small Cell Esophageal Carcinoma, Small Cell Lung Cancer, and Esophageal Adeno/Squamous Carcinoma.

Purpose/objectives: Primary small cell esophageal carcinoma (SCEC) is a rare malignancy without an established treatment strategy. This study investigated the gene expression profile of SCEC and compared it with the expression profiles of small cell lung cancer (SCLC) and esophageal adeno/squamous carcinoma (EAC/ESCC). Materials/methods: All patients with SCEC, SCLC, and EAC/ESCC in the Surveillance, Epidemiology, and End Results (SEER) database 1973-2014 were included. Overall survival (OS) and prognostic analysis were conducted. De novo expression array analysis was performed on three pairs of frozen primary SCEC tissues and the corresponding normal samples from the institutional tissue bank using the Affymetrix HG U133 plus 2.0 Array. These data were complemented with public domain expression data sets from the Gene Expression Omnibus (GEO) repository using the same working platforms, which included primary SCLC, EAC/ESCC, and normal lung/esophagus specimens (series GSE30219 and GSE26886). After individual normalization, the primary tumors were submitted to statistical analysis (GeneSpring GX 13.0) to identify the differentially expressed genes (DEGs) relative to their paired normal tissues. Enrichments of genes categorized by function and gene interactions were analyzed by DAVID 6.8 and STRING 11.0, respectively. Results: The clinical outcomes of the patients with SCEC were significantly more worse than those with EAC/ESCC and SCLC in the SEER database. SCEC had more DEGs in common with SCLC than EAC/ESCC [829 vs. 450; false discovery rate (FDR) < 0.01; and fold change ≥2], leading to a stronger correlation between SCEC and SCLC (Pearson's correlation coefficient was 0.60 for SCEC vs. SCLC, 0.51 or 0.45 for SCEC vs. ESCC or EAC, and the coefficient was 0.73 for ESCC vs. EAC). Similar findings were obtained by principal component analysis (PCA) using all DEGs retrieved from these four groups. Functional annotation showed that a higher proportion of pathways and biological processes were common between SCEC and SCLC and were associated with the cell cycle (mitosis), DNA replication, telomere maintenance, DNA repair, and P53 and RB pathways (Benjamini p < 0.05). Compared with EAC/ESCC, SCEC shared more co-upregulated DEGs coding for the aforementioned common pathways with SCLC (584 vs. 155). In addition, SCEC and SCLC were found to have possessed overlapping gene-interactive networks, with centromere protein F (CENPF), never in mitosis gene A-related kinase 2 ( NEK2), kinesin family member 11 (KIF11), thymopoietin (TMPO), and forkhead box protein M1 (FOXM1) as common skeletons centered by gene regulatory network (NUF2). Conclusions: This study is the first attempt to examine the genomic signatures of SCEC at the transcriptomic level and compare the expression profiles between SCEC, SCLC, and EAC/ESCC. Our preliminary data indicate that SCEC and SCLC display notably similar patterns of gene expression for mitosis and DNA repair. Further validation studies are warranted.

Identification of a EML4-ALK exon 19 fusion variant in lung adenocarcinoma and alectinib resistance.

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown a high response rate and long progression-free survival in primary treatment of ALK-positive non-small-cell lung cancer (NSCLC). De novo resistance or refractory subtype is rare event. Herein, we identify the first case with serial next-generation sequencing (NGS) results that harboured a rare echinoderm microtubule associated protein like 4 gene (EML4) -ALK (breaking site at exon 19) fusion in a lung adenocarcinoma (LUAD) patient who acquired alectinib resistance rapidly (less than 3 months), followed by multi-drug resistance and short survival time.

Circular RNA circZNF292 regulates H2 O2 -induced injury in human lens epithelial HLE-B3 cells depending on the regulation of the miR-222-3p/E2F3 axis.

Circular RNAs (circRNAs) play important roles in the pathogenesis of age-related cataract (ARC). CircRNA zinc finger protein 292 (circZNF292, hsa_circ_0004058) is downregulated in ARC lens capsules. Here, we focused on its precise roles in oxidative stress underlying the pathogenesis of ARC. CircZNF292, microRNA (miR)-222-3p, and E2F transcription factor 3 (E2F3) were quantified by quantitative real-time polymerase chain reaction or western blot. Cell viability was assessed by the cell counting kit-8 assay. Cell cycle distribution and apoptosis were detected by flow cytometry. The activities of superoxide dismutase, catalase, and malondialdehyde were measured using the corresponding assay kit. Targeted correlations among circZNF292, miR-222-3p, and E2F3 were verified by the dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Our data showed that circZNF292 was downregulated in ARC tissues and H2 O2 -treated human lens epithelial B3 (HLE-B3) cells. Increased expression of circZNF292 alleviated H2 O2 -induced cell viability suppression, apoptosis promotion, and oxidative stress enhancement. Mechanistically, circZNF292 directly targeted miR-222-3p, and circZNF292 regulated E2F3 expression through miR-222-3p. MiR-222-3p was a functional mediator of circZNF292 in modulating H2 O2 -induced injury in HLE-B3 cells. Furthermore, reduced level of miR-222-3p ameliorated H2 O2 -induced HLE-B3 cell damage by upregulating E2F3. Our present study demonstrated that increased expression of circZNF292 ameliorated H2 O2 -induced injury in HLE-B3 cells at least in part through the miR-222-3p/E2F3 axis, highlighting a novel insight into the involvement of circRNAs in the pathogenesis of ARC.

Metastasis Patterns and Prognosis of Octogenarians with NSCLC: A Population-based Study.

Non-small cell lung cancer (NSCLC) is the most common cancer and the leading cause of cancer-related deaths worldwide. Age at diagnosis of advanced NSCLC is much older, but studies describing the practice patterns for octogenarians with distant metastasis NSCLC are limited. A retrospective, population-based study using national representative data from the Surveillance, Epidemiology, and End Results (SEER) program was conducted to evaluate 34 882 NSCLC patients with extrathoracic metastases from 2010 to 2013. Patients were classified into three groups (older group: ≥80 yrs, middle-aged group: 60-79 yrs, and younger group: ≤59 yrs). The role of different age at diagnosis of NSCLC in metastasis patterns was investigated, and survival of different age groups of metastatic NSCLC was assessed. The analysis revealed that older patients were more likely to only have bone or liver metastasis (p< 0.001), but less likely to have brain only metastasis (p<0.001) and multiple metastatic sites (p< 0.001) than other two groups. Age at diagnosis was an independent risk factor for different metastasis types. Older group had the worst overall survival (p<0.001) and cancer-specific survival (p<0.001). Furthermore, older age patients with only bone metastasis had the best cancer specific survival (p<0.05) while younger patients with only brain metastasis had the best prognosis (p<0.001). Over 60% octogenarians with metastatic NSCLC did not receive anti-cancer therapy and had the highest rate of cancer deaths among all patients. Our results may help clinicians make positive decisions regarding personalized treatment of metastatic NSCLC in the elderly.

A case report of exceptional clinical response to chemoradiotherapy and tyrosine kinase inhibitors in a patient with EML4-ALK fusion variant 1 non-small cell lung cancer.

Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion occurs in approximately 5% of non-small cell lung cancer (NSCLC) cases. Variants 1 and 3a/b are the most common EML4-ALK variants. Emerging evidence indicates that patients with variant 1 and those with variant 3a/b exhibit differential therapeutic responses. However, the National Comprehensive Cancer Network guidelines have not included the EML4-ALK fusion subtype in treatment decision-making to date. Herein, we report the case of a non-smoking 36-year-old female patient who was diagnosed with right lung adenocarcinoma in 2005 (cT1N3M0, IIIB) and received definitive chemoradiotherapy. The patient achieved a partial response, and her disease remained under control for 8 years. However, in May 2013, the patient was diagnosed with brain metastasis and underwent subsequent surgical resection, followed by postoperative brain radiotherapy and chemotherapy. Postoperative pathology confirmed ALK gene rearrangement, and next-generation sequencing performed in 2020 identified the EML4-ALK variant as variant 1. After progression-free survival lasting 4 years, new metastatic lesions were found in the patient's right lung, and she was administered crizotinib for 20 months. Due to a suspicious recurrence in the intracranial surgical margin area, as well as an unbearable gastrointestinal reaction to crizotinib, alectinib was later adopted. At the 7-month follow-up, positron emission tomography/computed tomography revealed a clinical complete response. This case of an NSCLC patient with EML4-ALK fusion variant 1 who exhibited an exceptional response to chemoradiotherapy and ALK inhibitors might broaden horizons in efforts to reveal the molecular mechanism of radiosensitivity in ALK-positive NSCLC and provide reference for further research regarding the optimal radiotherapy delivery dose and tyrosine kinase inhibitor selection.

The Eighth Edition of the American Joint Committee on Cancer Distant Metastases Stage Classification for Metastatic Pancreatic Neuroendocrine Tumors Might Be Feasible for Metastatic Pancreatic Ductal Adenocarcinomas.

BACKGROUND: Significant modifications have been made to the 8th edition of the American Joint Committee on Cancer (AJCC) distant metastases (M) stage classification for metastatic pancreatic neuroendocrine tumors (PanNETs). We aimed to validate this revised classification among metastatic PanNET patients using the Surveillance, Epidemiology, and End Results database. We further sought to evaluate the feasibility of applying this classification to metastatic pancreatic neuroendocrine carcinoma (PanNEC) and pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: Stage IV pancreatic neuroendocrine neoplasm (PanNEN, including G1/G2 PanNET and G3 PanNEC classified according to the World Health Organization [WHO] 2010 grading scheme) and PDAC patients with metastatic disease diagnosed between 2010 and 2015 were identified and restaged according to the revised M stage classification for PanNET. Overall survival (OS) was compared using Kaplan-Meier analysis and log-rank test. Uni- and multivariate Cox regression models were utilized to identify prognostic factors. RESULTS: A total of 1,371 stage IV PanNEN and 634 PDAC patients were included. Among PanNEN patients, liver (75.0%) was the most common metastatic site, followed by distant lymph nodes (8.5%), lung (8.4%), bone (7.3%), and brain (1.0%). The 5-year OS for PanNET patients with M1a, M1b, and M1c stage was 44.15, 53.32, and 19.70%, respectively. However, survival comparison showed no significant difference between M1a and M1b stages among PanNET patients. Similar findings were noted after applying this classification to PanNEC patients. Multivariate analysis showed that the age at diagnosis and the number of distant metastatic sites were independent prognostic factors for metastatic PanNEN patients. Interestingly, excellent survival discrimination by M stage among stage IV PDAC patients was noted (M1a vs. M1b vs. M1c, 5-year OS: 5.42, 2.46, and 0%, respectively). CONCLUSION: Our study is the first large sample-based validation of the AJCC 8th M stage classification for PanNET. The revised classification did not effectively stratify metastatic PanNEN patients. However, further study is warranted to validate this classification for PanNET patients according to the WHO 2017 classification. Interestingly, the revised M stage classification might be feasible for PDAC patients with metastatic disease.

Assessment of a Radiomic Signature Developed in a General NSCLC Cohort for Predicting Overall Survival of ALK-Positive Patients With Different Treatment Types.

BACKGROUND: The purpose of the study was to investigate the potential of a radiomic signature developed in a general non-small-cell lung cancer (NSCLC) cohort for predicting the overall survival of anaplastic lymphoma kinase (ALK)-positive (ALK+) patients with different treatment types. MATERIALS AND METHODS: After test-retest in the Reference Image Database to Evaluate Therapy Response data set, 132 features (intraclass correlation coefficient > 0.9) were selected in the least absolute shrinkage and selection operator Cox regression model with a leave-one-out cross-validation. The NSCLC radiomics collection from The Cancer Imaging Archive was randomly divided into a training set (n = 254) and a validation set (n = 63) to develop a general radiomic signature for NSCLC. In our ALK+ set, 35 patients received targeted therapy and 19 patients received nontargeted therapy. The developed signature was tested later in this ALK+ set. Performance of the signature was evaluated with the concordance index (C-index) and stratification analysis. RESULTS: The general signature had good performance (C-index > 0.6; log rank P < .05) in the NSCLC radiomics collection. It includes 5 features: Geom_va_ratio, W_GLCM_Std, W_GLCM_DV, W_GLCM_IM2, and W_his_mean. Its accuracy of predicting overall survival in the ALK+ set achieved 0.649 (95% confidence interval [CI], 0.640-0.658). Nonetheless, impaired performance was observed in the targeted therapy group (C-index = 0.573; 95% CI, 0.556-0.589) whereas significantly improved performance was observed in the nontargeted therapy group (C-index = 0.832; 95% CI, 0.832-0.852). Stratification analysis also showed that the general signature could only identify high- and low-risk patients in the nontargeted therapy group (log rank P = .00028). CONCLUSION: This preliminary study suggests that the applicability of a general signature to ALK+ patients is limited. The general radiomic signature seems to be only applicable to ALK+ patients who had received nontargeted therapy, which indicates that developing special radiomics signatures for patients treated with tyrosine kinase inhibitors might be necessary.