Objective To investigate the inhibitory effect of the natural polyphenol Agrimol B on pancreatic ductal adenocarcinoma (PDAC) and its underlying molecular mechanisms.Methods The effects of Agrimol B on PDAC cell proliferation and apoptosis were assessed using Cell Counting Kit-8, colony formation, and flow cytometry assays. An in vivo PDAC xenograft mouse model was established for evaluation. Label-free quantitative proteomics, western blotting, immunofluorescence, and transmission electron microscopy were employed to analyze mitochondrial function, autophagy, and related signaling pathways. A patient-derived organoid model was used to evaluate the synergistic effects of Agrimol B with first-line chemotherapy drugs.Results Agrimol B significantly inhibited PDAC growth and induced apoptosis both in vitro and in vivo. Mechanistically, Agrimol B downregulated the expression of mitochondrial transcription termination factor 3, and promoted the accumulation of PTEN induced kinase 1 (PINK1) in mitochondria and Parkin translocation, thereby excessively activating PINK1/Parkin-dependent mitophagy. Concurrently, Agrimol B blocked lysosome biogenesis, leading to autophagosome accumulation and impaired autophagic flux. This dysfunctional autophagy ultimately mediated the anti-PDAC effect of Agrimol B. Furthermore, in PDAC patient-derived organoids, Agrimol B exhibited synergistic effects with first-line chemotherapy drugs such as gemcitabine and nab-paclitaxel.Conclusion Agrimol B exerts its anti-PDAC effects by downregulating mitochondrial transcription termination factor 3, hyperactivating PINK1/Parkin-mediated mitophagy, and obstructing autophagic flux. Its synergistic effect with chemotherapy drugs provides experimental evidence supporting its potential clinical translation.

Dysregulation of Speckle-type POZ protein (SPOP) and cargo receptor p62/SQSTM1 impairs homologous recombination (HR)-mediated DNA repair by destabilizing RAD51 and FLNA, yet their mechanistic interplay in genomic stability and oncogenesis remains unclear. In this study, we found that the interaction between SPOP and p62/SQSTM1 is obviously enhanced in nucleus in response to DNA damage. Moreover, the nuclear ubiquitination of p62/SQSTM1 at lysine 7 by SPOP led to its degradation, resulting in upregulation of RAD51 and FLNA, RAD51 foci formation, and HR efficiency. In addition, patients-derived p62/SQSTM1 mutations in SPOP-binding consensus (SBC) motif (S276Y/S277G/S277I) increased radiotherapy sensitivity in vitro and in vivo, which attributes to HR deficiency caused by increased degradation of RAD51 and FLNA proteins, and decreased RAD51 and γ-H2AX foci formation. Our finding provides insight into the regulation of HR by SPOP and p62/SQSTM1, and disrupting the interaction between SPOP, p62/SQSTM1 and nuclear ubiquitination may be a potential approach for overcoming radiotherapy resistance in cancer.

Translational reprogramming enables cancer cells to drive tumour progression and metastasis. eIF3i is a core component of the translational regulatory machinery, but the underlying mechanisms through which it promotes tumour metastasis remain unclear. Proteomic analysis identified eIF3i-regulated targets. Functional validation utilised in vitro and in vivo models, including migration/invasion assays, polysome profiling, RNA-binding assays (RIP and RNA pull-down), and mouse metastatic models. Clinical relevance was assessed in CRC patients with liver metastases. eIF3i was significantly overexpressed in metastatic CRC. Its knockdown inhibited cell migration, invasion, epithelial-mesenchymal transition (EMT), invadopodia formation in vitro, and lung metastasis in vivo. NELFCD was identified as a key downstream target, whose translation is directly promoted by eIF3i binding to its mRNA, independent of transcription. NELFCD knockdown phenocopied the anti-metastatic effects of eIF3i depletion. Crucially, the pro-metastatic capacity of eIF3i overexpression was abolished by concurrent NELFCD knockdown. eIF3i and NELFCD protein levels showed a significant positive correlation in clinical CRC metastases. The eIF3i-NELFCD axis drives CRC metastasis by directly upregulating NELFCD translation, thereby facilitating EMT and invadopodia formation. This pathway represents a promising therapeutic target for inhibiting metastatic progression in CRC.

Chromosomal instability (CIN) is a hallmark of cancer, closely associated with tumor evolution, metastasis, immune evasion, and resistance to treatment. CIN is driven by persistent chromosome missegregation, resulting in abnormal chromosomal copy numbers and promoting tumor progression through mitotic errors, faulty chromosome segregation, and the formation of micronuclei or chromosome bridges. Previous studies have demonstrated that p62 localizes to micronuclei, where it interacts with mitochondria, enhancing reactive oxygen species-mediated cysteine oxidation and promoting p62 homo-oligomerization. This disrupts repair by recruiting CHMP7 and other ESCRT-III components, impairing their function in restoring the micronuclear envelope. Notably, we observed a time-dependent increase in nuclear p62 levels following radiation therapy, which correlated with enhanced chromatin fragmentation and chromothripsis. While p62 inhibits homologous recombination repair and promotes non-homologous end joining, we hypothesize that radiation-induced nuclear p62 accumulation impairs nuclear envelope resealing by inhibiting ESCRT-III components, thereby contributing to chromosomal fragmentation and chromothripsis. These chromosomal alterations may play a significant role in tumor evolution and treatment resistance. Our findings suggest that irradiation-induced p62 accumulation is crucial for chromothripsis and may affect nuclear repair processes, impacting chromosomal stability. Future research will focus on elucidating how p62 contributes to these abnormalities and their implications for tumor progression and treatment resistance.

Despite significant progress in characterizing the omics landscape of head and neck squamous cell carcinoma (HNSCC), the development of precision therapies remains limited. One key factor contributing to this challenge is the marked molecular heterogeneity of HNSCC. Further investigation of molecular profiles within HNSCC may facilitate the improvement in more effective precision treatments. Here, we focus on the dysregulation of PDZ and LIM domain protein 3 (PDLIM3) in HNSCC. The expression levels of PDLIM3 were analyzed using public datasets to assess its potential role in tumor progression. We found that PDLIM3 was downregulated in pan-cancer and HNSCC. The prognostic significance of PDLIM3 was evaluated through tissue microarray, and the downregulation of PDLIM3 was correlated with poor HNSCC prognosis. Investigating the implications of PDLIM3 for tumor metastatic ability in vitro, we found that PDLIM3 suppressed the migration and invasion of HNSCC, accompanied by partially impeding the process of epithelial-mesenchymal transition (EMT). Furthermore, PDLIM3 inhibited the transcriptional activity of Yes-associated protein (YAP), suggesting that YAP may be involved in the PDLIM3-mediated suppression of HNSCC metastatic ability. Our findings identify a potential signaling axis wherein PDLIM3 regulates YAP-EMT, thereby influencing tumor metastatic ability, and suggest the potential role of PDLIM3 as a tumor suppressor and prognostic biomarker for HNSCC.

Introduction:The majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an intermediate stage, and current treatment options are associated with unfavourable overall prognosis. This study aimed to evaluate the efficacy of conversion therapy before resection compared with direct resection or comprehensive therapy alone in patients with intermediate-stage HCC, with a focus on pathological responses and long-term outcomes. Methods:In this multicentre study, 248 patients diagnosed with intermediate-stage HCC between January 2020 and December 2023 were enrolled. Of these, 56 patients received preoperative conversion therapy followed by resection (conversion resection group), 162 underwent direct resection (direct resection group), and 30 received comprehensive therapy alone and did not undergo surgical resection (comprehensive therapy group). Propensity score matching was performed to balance the baseline characteristics, and pathological responses were systematically evaluated. Results:Among conversion resection group, 13 patients (23.2%) achieved a pathological complete response, and 29 (51.8%) achieved a major pathological response. The conversion resection group exhibited significantly lower microvascular invasion rates (17.9% vs. 58.6%, p < 0.001) and higher tumour differentiation grades (p < 0.001). The median recurrence-free survival (RFS) was markedly improved in the conversion resection group (not reached vs. 12.3 months, p < 0.001), with 3-year overall survival (OS) rates of 94.7% vs. 77.6% vs. 43.9% being observed in the conversion resection group, direct resection group and comprehensive therapy group, respectively (p < 0.001). Multivariate analysis identified conversion therapy as an independent prognostic factor for both RFS (HR: 0.241, p < 0.001) and OS (HR: 0.179, p = 0.006). Conclusions:Preoperative conversion therapy could significantly improve pathological responses and long-term survival outcomes in intermediate-stage HCC patients.

OBJECTIVE:To summarize and assess the existing evidence on the effectiveness and safety of immune checkpoint inhibitors (ICIs) treatments in patients diagnosed with hepatocellular carcinoma (HCC). DESIGN:An umbrella review encompassing current meta-analyses reporting clinical effectiveness or safety outcomes of ICIs. DATA SOURCES:PubMed, Web of Science, Embase, the Cochrane Systematic Reviews Database, and reviewed reference sections of relevant research articles. STUDY SELECTION:We included all systematic reviews with meta-analyses of observational or interventional studies evaluating ICIs in patients with HCC. The patient cohorts comprised adults with HCC, including both those with advanced disease and those receiving neoadjuvant therapy for resectable tumors. RESULTS:Fifty-four meta-analyses (covering 166 direct comparisons and over 35,000 patients) were included. High-quality evidence demonstrated that ICI plus tyrosine kinase inhibitor (TKI) significantly improved overall survival (HR 0.58, 95% CI, 0.49-0.70) and progression-free survival (HR 0.58, 95% CI, 0.51-0.67), and increased objective response rates (OR 3.17, 95% CI, 2.21-4.54), compared with TKI monotherapy. Triple combination therapy (ICI + TKI + locoregional therapy) yielded the largest absolute gains in survival (HR 0.48, 95% CI, 0.36-0.64) and tumor response, but evidence was of moderate quality due to protocol heterogeneity. Subgroup analyses indicated greater benefits in hepatitis B-related HCC and male patients. ICIs demonstrated a manageable safety profile, with increased risks of hypertension and thyroid dysfunction, but no significant excess in most grade ≥3 toxicities. Only 11.1% of meta-analyses were of high methodological quality; just 24.4% of statistically significant outcomes were graded as high quality, and all evidence was class IV by sample size. CONCLUSION:ICI-based regimens, particularly ICI + TKI doublets, offer substantial survival and tumor response benefits for HCC with manageable toxicity. Triple and conversion strategies are promising but require further high-quality randomized trials. Current recommendations are limited by the generally low quality and size of existing meta-analyses, underscoring the need for rigorous primary studies and robust future evidence syntheses.

This study investigates the expression characteristics of RNA binding motif single stranded interacting protein 1 (RBMS1) in gliomas and its associations with clinicopathological features, immune infiltration, and prognosis, aiming to evaluate its potential as a prognostic biomarker. Differentially expressed genes (DEGs) were screened from the GEO datasets GSE43378 and GSE178621 (thresholds: P < 0.05,|logFC|> 1), with RBMS1 validated via the TCGA and GEPIA databases. Correlations between RBMS1 and immune infiltration were assessed using the TISIDB. Correlations between RBMS1 and immune checkpoint molecules, costimulatory genes, and chemokines were also explored using GEPIA. Immunohistochemistry (IHC) was performed on 165 glioma and 62 normal brain tissues to analyze RBMS1 expression and its clinicopathological relevance (WHO grade, distant metastasis). Three-year survival outcomes were evaluated using Kaplan–Meier (K-M) curves and log-rank tests for overall survival (OS) and relapse-free survival (RFS). Additionally, univariate and multivariate Cox regression analyses were conducted to assess independent prognostic factors. Integrated bioinformatic analysis identified RBMS1 as a key DEG, showing significant upregulation in gliomas (TCGA and GEPIA: P < 0.05) and moderate positive correlations with immune cell infiltration (Tregs: r = 0.461; NKTs: r = 0.505; Th1: r = 0.451; all P < 0.001). RBMS1 also showed significant positive correlations with key immune checkpoint molecules (PDCD1, CD274, CTLA4, etc.), costimulatory genes (CD28, TNFRSF9), and chemokines (CXCL9, CXCL10, CCL5), suggesting its potential role in modulating the immune microenvironment. Clinically, RBMS1 positivity was markedly higher in gliomas than controls (59.39

Metastasis remains a primary cause of cancer-related mortality, with its intricate mechanisms continuing to be uncovered through advancing research. Among the various regulatory processes involved, RNA modification has emerged as a critical epitranscriptomic mechanism influencing cancer metastasis. N6-methyladenosine (m6A), recognized as one of the most prevalent and functionally significant RNA modifications, plays a central role in the regulation of RNA metabolism. In this review, we explore the multifaceted role of m6A in the different stages of cancer metastasis, including epithelial–mesenchymal transition, invasion, migration, and colonization. In addition to summarizing the current state of our understanding, we offer insights into how m6A modifications modulate key oncogenic pathways, highlighting the implications of recent discoveries for therapeutic interventions. Furthermore, we critically assess the limitations of previous studies and propose areas for future research, including the potential for targeting m6A as a novel approach in anti-metastatic therapies. Our analysis provides a comprehensive understanding of the regulatory landscape of m6A in metastasis, offering directions for continued exploration in this rapidly evolving field.

Metabolic reprogramming is a common feature in tumor progression and metastasis. Like proteins, lipids can transduce signals through lipid-protein interactions. During tumor initiation and metastasis, dysregulation of the Hippo pathway plays a critical role. Specifically, the inhibition of YAP1 phosphorylation leads to the relocation of YAP1 to the nucleus to activate transcription of genes involved in metastasis. Although recent studies reveal the involvement of phosphatidylethanolamine (PE) synthesis enzyme phosphoethanolamine cytidylyltransferase 2 (PCYT2) in tumor chemoresistance, the effect of PCYT2 on tumor metastasis remains elusive. Here, we show that PCYT2 was significantly downregulated in metastatic colorectal cancer (CRC) and acted as a tumor metastasis suppressor. Mechanistically, PCYT2 increased the interaction between PEBP1 and YAP1-phosphatase PPP2R1A, thus disrupting PPP2R1A-YAP1 association. As a result, phosphorylated YAP1 levels were increased, leading to YAP1 degradation through the ubiquitin protease pathway. YAP1 reduction in the nucleus repressed the transcription of ZEB1 and SNAIL2, eventually resulting in metastasis suppression. Our work provides insight into the role of PE synthesis in regulating metastasis and presents PCYT2 as a potential therapeutic target for CRC.

Cumulative studies have established the significance of transfer RNA-derived small RNA (tsRNA) in tumorigenesis and progression. Nevertheless, its function and mechanism in pancreatic cancer metastasis remain largely unclear. Here, we screened and identified tiRNA-Val-CAC-2 as highly expressed in pancreatic cancer metastasis samples by tsRNA sequencing. We also observed elevated levels of tiRNA-Val-CAC-2 in the serum of pancreatic cancer patients who developed metastasis, and patients with high levels of tiRNA-Val-CAC-2 exhibited a worse prognosis. Additionally, knockdown of tiRNA-Val-CAC-2 inhibited the metastasis of pancreatic cancer in vivo and in vitro, while overexpression of tiRNA-Val-CAC-2 promoted the metastasis of pancreatic cancer. Mechanically, we discovered that tiRNA-Val-CAC-2 interacts with FUBP1, leading to enhanced stability of FUBP1 protein and increased FUBP1 enrichment in the c-MYC promoter region, thereby boosting the transcription of c-MYC. Of note, rescue experiments confirmed that tiRNA-Val-CAC-2 could influence pancreatic cancer metastasis via FUBP1-mediated c-MYC transcription. These findings highlight a potential novel mechanism underlying pancreatic cancer metastasis, and suggest that both tiRNA-Val-CAC-2 and FUBP1 could serve as promising prognostic biomarkers and potential therapeutic targets for pancreatic cancer.

BACKGROUND:As a member of the Krüppel-like factor (KLFs) family, Krüppel-like factor 6 (KLF6) plays a critical role in regulating key cellular functions. Presently, scholars have proved the important role of KLF6 in the tumorigenesis of certain cancers through a large number of experiments. However, gaps still remain in our knowledge of the role of KLF6 in pancreatic cancer (PAAD). Therefore, this paper mainly investigates the role of KLF6 in the progression of pancreatic cancer.METHODS:The expression pattern of KLF6 in pancreatic cancer was explored in pancreatic cancer tissues and cell lines. Then, we investigated the prognostic value of KLF6 in pancreatic cancer by immunohistochemical assays. Next, Cell Counting Kit-8 (CCK8) and clone information assays were employed to explore the proliferation of PAAD affected by KLF6. The metastasis and epithelial-mesenchymal transition (EMT) abilities affected by KLF6 were identified through transwell invasion as well as migration assays and western blots. Finally, the TRRUST tool was used to analyze the potential targeted genes of KLF6. The results were verified by Quantificational Real-time Polymerase Chain Reaction (qRT-PCR), western blot and rescue assays.RESULTS:KLF6 expresses lowly in pancreatic cancer compared to corresponding normal tissues and relates to poor survival times. Overexpression of KLF6 inhibits the proliferation, metastasis, and EMT progression in pancreatic cancer cells. Further studies suggest that KLF6 could upregulate ATF3 in PAAD.CONCLUSIONS:Our results suggest that KLF6 can be a useful factor in predicting the prognosis of PAAD patients and that it inhibits the progression of pancreatic cancer by upregulating activating transcription factor 3 (ATF3).

Background: Members of the nuclear receptor-binding SET domain (NSD) family of histone H3 lysine 36 methyltransferases comprise NSD1, NSD2 (MMSET/WHSC1), and NSD3 (Wolf-Hirschhorn syndrome candidate 1-like 1, WHSC1L1). While the expression of NSD genes is essential to normal biological processes and cancer, knowledge of their expression levels to prognosticate in cancer remains unclear.Methods: We analyzed the expression patterns for NSD family genes across multiple cancer types and examined their association with clinical features and patient survival profiles. Next, we explored the association between NSD3 expression and described features of the tumor microenvironment (TME) in PAAD, a severe type of pancreatic cancer. In particular, we correlated promoter methylation levels for NSD3 with patient outcomes in PAAD. Finally, we explored the putative oncogenic roles for NSD3 using a series of experiments with pancreatic cancer cells.Results: We report that the expression of NSD family members is correlated with clinical prognosis across multiple types of cancers. Also, we demonstrate that NSD3 variants are most prevalent among NSD genes across cancers we analyzed. Notably, when compared with NSD1 and NSD2, we find that NSD3 is prominently expressed, and its expression is significantly linked with clinical outcome in pancreatic cancer. Furthermore, NSD3 is frequently amplified, exhibits low promoter methylation, and is correlated with immune cell infiltration and enhanced proliferation of pancreatic cancer. Finally, we demonstrate that knockdown of NSD3 alters H3K36me2 methylation, downstream gene expression and EGFR/ERK signaling in pancreatic cancer cells.Conclusions: We find that expression levels, the presence of genetic variants of NSD family genes, as well as their promoter methylation are correlated with clinical outcomes in cancer, including pancreatic cancer. Our in vitro experiments suggest that NSD3 may be relevant to gene expression regulation and growth factor signaling in pancreatic cancer.

Translation is a fundamental process in all living organisms that involves the decoding of genetic information in mRNA by ribosomes and translation factors. The dysregulation of mRNA translation is a common feature of tumorigenesis. Protein expression reflects the total outcome of multiple regulatory mechanisms that change the metabolism of mRNA pathways from synthesis to degradation. Accumulated evidence has clarified the role of an increasing amount of mRNA modifications at each phase of the pathway, resulting in translational output. Translation machinery is directly affected by mRNA modifications, influencing translation initiation, elongation, and termination or altering mRNA abundance and subcellular localization. In this review, we focus on the translation initiation factors associated with cancer as well as several important RNA modifications, for which we describe their association with cancer.

BackgroundClose to one third of colorectal cancer (CRC) patients are diagnosed with metastatic CRC (mCRC). Patients with wild-type RAS and BRAF usually receive anti-EGFR monoclonal antibody therapy containing cetuximab. Overall, 30–50% of mCRC patients are reported to harbor RAS mutations, and RAS mutation status should be assessed when considering EGFR inhibitor treatment according to mCRC biomarker guidelines. Of note, 0.67–2% of patients with CRC harbored a KRAS amplification. Here we reported a case of advanced rectal cancer with wild-type RAS and BRAF in a male patient who harbored a KRAS amplification during anti-EGFR treatment.Case PresentationA 46-year-old man was diagnosed with rectal adenocarcinoma with liver metastases (cT3NxM1a, stage IVA). After receiving first-line irinotecan- fluorouracil chemotherapy (FOLFIRI) plus cetuximab, second-line capecitabine- oxaliplatin chemotherapy (XELOX) plus bevacizumab, and third-line regorafenib, he rechallenged FOLFIRI and cetuximab for seven cycles, achieving a prolonged survival of at least 5 months. The KRAS copy number of circulating tumor DNA (ctDNA) was assessed during treatment. Notably, apart from serum carbohydrate antigen 199 (CA199) and carcinoembryonic antigen (CEA), the change of plasm Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) copy number appeared to strongly correlate with treatment response.ConclusionOur findings suggest that the dynamic change of KRAS copy number on ctDNA during treatment might be a negative predictive biomarker. Additionally, RAS and BRAF wild-type mCRC patients who are resistant to first-line FOLFIRI plus cetuximab therapy may respond well to the FOLFIRI plus cetuximab “rechallenged” strategy.

Triple-negative breast cancer (TNBC) is a type of breast tumor that currently lacks options for targeted therapy. Tremendous effort has been made to identify treatment targets for TNBC. Here, we report that the expression level of anaphase promoting complex (APC) coactivator Cdh1 in TNBC is elevated compared to that in the adjacent healthy tissues, and high levels of Cdh1 expression are correlated with poor prognoses, suggesting that Cdh1 contributes to the progression of TNBC. Interfering with the function of Cdh1 can potentiate the cytotoxic effects of PARP inhibitors against BRCA-deficient and BRCA-proficient TNBC cells through inducing DNA damage, checkpoint activation, cell cycle arrest, and apoptosis. Further investigation reveals that Cdh1 promotes BRCA1 foci formation and prevents untangled DNA entering mitosis in response to PARP inhibition (PARPi) in TNBC cells. Collectively, these results suggest that APC/Cdh1 is a potential molecular target for PARPi-based therapies against TNBCs.

Background Kinesin superfamily of proteins (KIFs) has been broadly reported to play an indispensable role in the biological process. Recently, emerging evidence reveals its oncogenic role in various cancers. However, the prognostic, oncological, and immunological values of KIFs have not been comprehensively explored in pancreatic ductal adenocarcinoma (PDAC) patients. We aimed to illustrate the relationship between KIFs and pancreatic ductal adenocarcinoma by using bioinformatical analysis. Methods We use GEPIA, Oncomine datasets, cBioPortal, LOGpc, TIMER, and STRING bioinformatics tools and web servers to investigate the aberrant expression, prognostic values, and oncogenic role of KIFs. The two-gene prognostic model and the correlation between KIFs and KRAS and TP53 mutation were performed using an R-based computational framework. Results Our results demonstrated that KIFC1/2C/4A/11/14/15/18A/18B/20B/23 (we name it prognosis-related KIFs) were upregulated and associated with unfavorable clinical outcome in pancreatic cancer patients. KIF21B overexpression is associated with better clinical outcome. The KIFC1/2C/4A/11/14/15/18A/18B/20B/23 profiles were significantly increased compared to grade 1 and grade 2/3. Besides, KIFC1/2C/4A/11/14/15/18A/18B/20B/23 was significantly associated with the mutation status of KRAS and TP53.Notably, most prognosis-related KIFs have strong correlations with tumor growth and myeloid-derived suppressor cells infiltration (MDSCs). A prognostic signature based on KIF20B and KIF21B showed a reliable predictive performance. Receiver operating characteristic (ROC) curve was employed to assess the predictive power of two-gene signature. Consequently, the gene set enrichment analysis (GSEA) showed that KIF20B and KIF21B’s overexpression was associated with the immunological and oncogenic pathway activation in pancreatic cancer. Finally, real-time quantitative PCR (RT-qPCR) was utilized to investigate the expression pattern of KIF20B and KIF21B in pancreatic cancer cell lines and normal pancreatic cell. Conclusions Knowledge of the expression level of the KIFs may provide novel therapeutic molecular targets and potential prognostic biomarkers to pancreatic cancer patients.

Purpose Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is the routine treatment for patients with metastatic non-small cell lung cancer (NSCLC) harboring positive EGFR mutations. Patients who undergo such treatment have reported cognitive decline during follow-up. This study, therefore, aimed to evaluate brain structural changes in patients receiving EGFR-TKI to increase understanding of this potential symptom. Method The medical records of 75 patients with metastatic NSCLC (without brain metastasis or other co-morbidities) who received EGFR-TKI therapy from 2010 to 2017 were reviewed. The modified Scheltens Visual Scale and voxel-based morphometry were used to evaluate changes in white matter lesions (WML) and gray matter volume (GMV), respectively. Results The WML scores were higher at the 12-month [8.65 ± 3.86; 95% confidence interval (CI), 1.60–2.35; p < 0.001] and 24-month follow-ups (10.11 ± 3.85; 95% CI, 2.98–3.87; p < 0.001) compared to baseline (6.68 ± 3.64). At the 24-month follow-up, the visual scores were also significantly higher in younger patients (3.89 ± 2.04) than in older patients (3.00 ± 1.78; p = 0.047) and higher in female patients (3.80 ± 2.04) than in male patients (2.73 ± 1.56; p = 0.023). Additionally, significant GMV loss was observed in sub-regions of the right occipital lobe (76.71 voxels; 95% CI, 40.740–112.69 voxels), left occipital lobe (93.48 voxels; 95% CI, 37.48–149.47 voxels), and left basal ganglia (37.57 voxels; 95% CI, 21.58–53.57 voxels) (all p < 0.005; cluster-level false discovery rate < 0.05). Conclusions An increase in WMLs and loss of GMV were observed in patients with metastatic NSCLC undergoing long-term EGFR-TKI treatment. This might reflect an unknown side-effect of EGFR-TKI treatment. Further prospective studies are necessary to confirm our findings.

We report the case of a 90-year-old female patient who was suffering from c-ros oncogene 1 (ros-1) rearrangement adenocarcinoma and breast cancer. After about 14 months of a reduced dose of crizotinib treatment, she had a stable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). This patient's case demonstrates that ros-1 rearrangements are not limited to patients of young age. In addition, this case indicates that crizotinib, as second-line, or even first-line, treatment may be effective and manageable in elderly patients. Furthermore, for elderly patients carrying a ros1 fusion, a reduced dose of crizotinib may be efficacious rather than a resistance factor. Based on our findings, we recommend that elderly patients with advanced lung adenocarcinoma should be considered for inclusion in molecular screening for ros-1 translocation, especially for never-smokers negative for epidermal growth factor receptor (egfr) mutation and the fusion between echinoderm microtubule associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK). This deserves attention because the population is aging, with increasing incidence and morbidity of multiple primary malignant tumors. Neglect of breast nodules at the onset is one of the limitations of our case, as combination of primary lung cancer with breast cancer is common. Above all, use of antiestrogens before and after the diagnosis of non-small-cell lung cancer is related to a reduced risk of lung cancer mortality. Therefore, careful attention should always be paid to these cases.