ABSTRACT
The epithelial‐to‐mesenchymal transition (EMT) is a developmental programme that regulates embryonic morphogenesis and involves significant morphological and molecular changes in cells. ...Experimental models have revealed that EMT also contributes to various malignant features of cancer cells, including motile, invasive, anti‐apoptotic and stem‐like phenotypes. Clinically, correlative studies have indicated that mesenchymal‐like features of tumour cells are associated with poor tumour differentiation as well as worse patient prognosis. Nevertheless, due to its transitory nature, demonstration of an actual occurrence of EMT during human carcinogenesis is challenging, and most of the evidence to date has been limited to breast and colorectal cancers. However, recent studies suggest that EMT may occur during lung cancer development, although such evidence is still limited. We propose three approaches for obtaining direct evidence of EMT in human cancers and use these criteria to review the available data. We suggest that multiple intrinsic and extrinsic factors cooperatively induce EMT in lung cancer. Intrinsic factors include oncogenic genetic changes such as mutant K‐RAS. Extrinsic factors are associated with a tumour microenvironment that is inflammatory and hypoxic. The induction of EMT is primarily mediated by various EMT‐inducing transcription factors that suppress E‐cadherin expression, including SLUG and ZEB1. miR‐200 family expression can reverse EMT by suppressing EMT‐ inducing transcription factors. Obviously, more data demonstrating the clinical relevance of EMT in lung cancer are required, and further elucidation of how EMT is regulated in lung cancer will enable us to develop novel therapeutics that specifically target molecules with critical roles in EMT.
To assess the prevalence of vestibular schwannoma (VS) in patients with sudden sensorineural hearing loss (SSNHL).
This is a retrospective chart review of 861 patients who were diagnosed with or ...treated for SSHNL between January 2008 and February 2017 at our department in a tertiary academic center. We retrospectively analyzed the medical charts and MRI findings of 499 patients who had undergone MRI.
Fifteen (3.0%) of the 499 patients exhibited tumors at the cerebellopontine angle on the same side affected by SSNHL. In one patient, a tumor was incidentally detected in the contralateral ear. The 15 VS lesions were graded using the Koos acoustic neuroma grading system as follows: grade I (intracanalicular tumor), n=8; grade II (up to 2cm), n=6; and grade III (up to 3cm), n=1. Koos grade IV tumors, which are large tumors that displace the trunk or cranial nerves, were not found.
The prevalence of VS in patients with SSNHL was 3.0% in the present study. Considering this high prevalence, clinicians should consider detailed examinations in addition to audiometry for patients with SSNHL.
We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBEC) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic ...changes (p53, KRAS, and MYC) and followed the stepwise transformation of HBECs to full malignancy. This model showed that: (i) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRAS(V12), and c-MYC) is sufficient for full tumorigenic conversion of HBECs; (ii) genetically identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; (iii) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; (iv) high levels of KRAS(V12) are required for full malignant transformation of HBECs, however, prior loss of p53 function is required to prevent oncogene-induced senescence; (v) overexpression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRAS(V12); (vi) growth of parental HBECs in serum-containing medium induces differentiation, whereas growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); (vii) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; (viii) an mRNA signature derived by comparing tumorigenic versus nontumorigenic clones was predictive of outcome in patients with lung cancer. Collectively, our findings show that this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes.
The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) ...interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8–18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.
We investigated the frequency and function of mutations and increased copy number of the PIK3CA gene in lung cancers. PIK3CA mutations are one of the most common gene changes present in human ...cancers. We analyzed the mutational status of exons 9 and 20 and gene copy number of PIK3CA using 86 non-small cell lung cancer (NSCLC) cell lines, 43 small cell lung cancer (SCLC) cell lines, 3 extrapulmonary small cell cancer (ExPuSC) cell lines, and 691 resected NSCLC tumors and studied the relationship between PIK3CA alterations and mutational status of epidermal growth factor receptor (EGFR) signaling pathway genes (EGFR, KRAS, HER2, and BRAF). We also determined PIK3CA expression and activity and correlated the findings with effects on cell growth. We identified mutations in 4.7% of NSCLC cell lines and 1.6% of tumors of all major histologic types. Mutations in cell lines of small cell origin were limited to two ExPuSC cell lines. PIK3CA copy number gains were more frequent in squamous cell carcinoma (33.1%) than in adenocarcinoma (6.2%) or SCLC lines (4.7%). Mutational status of PIK3CA was not mutually exclusive to EGFR or KRAS. PIK3CA alterations were associated with increased phosphatidylinositol 3-kinase activity and phosphorylated Akt expression. RNA interference-mediated knockdown of PIK3CA inhibited colony formation of cell lines with PIK3CA mutations or gains but was not effective in PIK3CA wild-type cells. PIK3CA mutations or gains are present in a subset of lung cancers and are of functional importance.
In cholesteatoma, the prognosis of tympanoplasty has been well discussed in terms of hearing outcomes and residual or recurrent lesions. Postoperative dizziness and vertigo are major complications of ...tympanoplasty; however, few reports are available.
We investigated each condition of cholesteatoma postoperative vestibular risk using the STAM system and staging published by EAONO/JOS, as well as findings on bony destruction.
From April 2010 to March 2021, 156 patients (166 ears) with cholesteatoma who underwent primary microscopic tympanoplasty at our hospital were registered. Subjective vestibular symptoms were recorded the day after surgery.
Postoperative vestibular symptoms were observed in 13.9% of subjects. All of them were stage II and had both attic and mastoid lesions. Attic (p < .05) and mastoid (p < .01) lesions were risk factors. Multivariate analysis showed that significant differences were found in past histories of vestibular symptoms (p < .05) and exposure of the dura mater (p < .01).
In the exposed dura group, the length of the prominence of the lateral semicircular canal to the middle cranial fossa dura was significantly shorter than that of the non-exposed group (p < .01). Narrow working space and downward operation may increase vestibular risk.
Various liquid biopsy methods have been developed for the non-invasive and early detection of diseases. In particular, the detection of circulating tumor cells (CTCs) and cancer-associated ...fibroblasts (CAFs) in blood has been receiving a great deal of attention. We have been developing systems and materials to facilitate such liquid biopsies. In this study, we further developed glass filters (with various patterns of holes, pitches, and non-adhesive coating) that can capture CTCs, but not white blood cells. We optimized the glass filters to capture CTCs, and demonstrated that they could be used to detect CTCs from lung cancer patients. We also used the optimized glass filters for detecting CAFs. Additionally, we further developed a system for visualizing the captured cells on the glass filters. Finally, we demonstrated that we could directly culture the captured cells on the glass filters. Based on these results, our high-performance glass filters appear to be useful for capturing and culturing CTCs and CAFs for further examinations.
Molecular genetic studies of lung cancer have revealed that clinically evident lung cancers have multiple genetic and epigenetic abnormalities, including DNA sequence alterations, copy number ...changes, and aberrant promoter hypermethylation. Together, these abnormalities result in the activation of oncogenes and inactivation of tumor-suppressor genes. In many cases these abnormalities can be found in premalignant lesions and in histologically normal lung bronchial epithelial cells. Findings suggest that lung cancer develops through a stepwise process from normal lung epithelial cells towards frank malignancy, which usually occurs as a result of cigarette smoking. Lung cancer has a high morbidity because it is difficult to detect early and is frequently resistant to available chemotherapy and radiotherapy. New, rationally designed early detection, chemoprevention, and therapeutic strategies based on the growing understanding of the molecular changes important to lung cancer are under investigation. For example, methylated tumor DNA sequences in sputum or blood are being investigated for early detection screening, and new treatments that specifically target molecules such as vascular endothelial growth factor and the epidermal growth factor receptor are becoming available. Meanwhile, global gene expression signatures from individual tumors are showing potential as prognostic and therapeutic indicators, such that molecular typing of individual tumors for therapy selection is not far away. Finally, the recent development of a model system of immortalized human bronchial epithelial cells, along with a paradigm shift in the conception of cancer stem cells, promises to improve the situation for patients with lung cancer. These advances highlight the translation of molecular discoveries on lung cancer pathogenesis from the laboratory to the clinic.
In this article, we report a case with pleuroparenchymal fibroelastosis (PPFE) following hematopoietic stem cell transplantation (HSCT) that developed acute respiratory failure with new bilateral ...ground glass opacity, which could not be explained by either a pulmonary infection, drug toxicity or extraparenchymal causes. Although combination therapy with multiple immunosuppressants was transiently effective, the patient died from a recurrent exacerbation. Autopsied lungs demonstrated diffuse alveolar damage superimposed on PPFE. There was no evidence of any coexisting interstitial pneumonia with the usual interstitial pneumonia (UIP) pattern. Our case suggests that acute exacerbation can occur in patients with post-HSCT PPFE, even when a coexisting UIP pattern is absent.
Glyphosate and its salt formulations are nonselective herbicides that have been extensively used worldwide, both for residential and agricultural purposes. The possible carcinogenicity and ...teratogenicity of glyphosate remain to be elucidated. We developed a sensitive and high-throughput analytical method for urinary glyphosate using liquid chromatography-tandem mass spectrometry with the aim of contributing to glyphosate exposure assessment in epidemiological studies.
After urine dilution (creatinine matching dilution to 0.05 g creatinine/L), glyphosate was extracted using two types of solid phase extraction columns (SCX and NH2) with automated sample preparation instruments. The eluate was dried and dissolved in the mobile phase, followed by liquid chromatography-tandem mass spectrometry analysis. The optimized method was applied to urine samples obtained from 54 Japanese adults and children.
The results from the validation study demonstrated good recoveries (91.0-99.6%), within- and between-run precisions (< 15%), low detection limits (0.1 μg/L), and lower limit of quantification (0.3 μg/L). The detection frequency and median concentration of the urinary glyphosate in Japanese subjects were 59% and 0.25 μg/L (0.34 μg/g creatinine).
Our reliable determination method was successful in measuring urinary glyphosate concentration. Moreover, this is the first biomonitoring report of urinary glyphosate levels in the Japanese general population.
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