The prognostic significance of the relapse interval in patients with resected oral cavity squamous cell carcinoma (OCSCC) is a matter of ongoing debate. In this large-scale, registry-based, ...nationwide study, we examined whether the time interval between surgery and the first disease relapse may affect survival outcomes in Taiwanese patients with OCSCC.
Data made available by the Taiwan Health Promotion Administration as of 2004 were obtained. The study cohort consisted of patients who were included in the registry between 2011 and 2017. Disease staging was performed according to the American Joint Committee on Cancer (AJCC) Staging Manual, Eight Edition. We retrospectively reviewed the clinical records of 13,789 patients with OCSCC who received surgical treatment. A total of 2327 (16.9%) patients experienced a first disease relapse. The optimal cutoff value for the relapse interval was 330 days when both 5-year disease-specific survival (DSS) and overall survival (OS) (≤ 330/>330 days, n = 1630/697) were taken into account. In addition, we undertook a propensity score (PS)-matched analysis of patients (n = 654 each) with early (≤ 330 days) versus late (> 330 days) relapse.
The median follow-up time in the entire study cohort was 702 days (433 and 2001 days in the early and late relapse groups, respectively). Compared with patients who experienced late relapse, those with early relapse showed a higher prevalence of the following adverse prognostic factors: pT4, pN3, pStage IV, poor differentiation, depth of invasion ≥ 10 mm, and extra-nodal extension. Multivariable analysis revealed that early relapse was an independent adverse prognostic factor for both 5-year DSS and OS (average hazard ratios AHRs: 3.24 and 3.91, respectively). In the PS-matched cohort, patients who experienced early relapse showed less favorable 5-year DSS: 58% versus 30%, p < 0.0001 (AHR: 3.10 2.69 - 3.57) and OS: 49% versus 22%, p < 0.0001 (AHR: 3.32 2.89 - 3.81).
After adjustment for potential confounders and PS matching, early relapse was an adverse prognostic factor for survival outcomes in patients with OCSCC. Our findings may have significant implications for risk stratification.
DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and ...radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize cancer cells to DNA damage. In this study, we examined the anti-HCC effects of melatonin and elucidated the regulatory mechanisms. The results of functional assays showed that in addition to inhibiting the proliferation, migration, and invasion abilities of HCC cells, melatonin suppressed their DNA repair capacity, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole-transcriptome and gain- and loss-of-function analyses revealed that melatonin induces expression of the long noncoding RNA RAD51-AS1, which binds to RAD51 mRNA to inhibit its translation, effectively decreasing the DNA repair capacity of HCC cells and increasing their sensitivity to chemotherapy and radiotherapy. Animal models further demonstrated that a combination of melatonin and the chemotherapeutic agent etoposide (VP16) can significantly enhance tumor growth inhibition compared with monotherapy. Our results show that melatonin is a potential adjuvant treatment for chemotherapy and radiotherapy in HCC.
The quality of biological samples greatly affects the accuracy of scientific results. However, RNA in cryopreserved tissues gradually degrades during storage, leading to errors in the results of ...subsequent experiments. A suitable sample preservative solution can prolong storage and enhance the research value of samples. Here, we developed a sample preservative solution using the properties of the ribonucleoside vanadyl complex (RVC) and compared its effects on RNA and DNA quality, protein activity, and tissue morphology with the commercially available and widely used RNAlater® Stabilization Solution. The results showed that both the RVC-based preservative solution and RNAlater can effectively delay RNA degradation in tissue samples stored at 4°C or -80°C compared with samples stored without any preservative solution. In contrast to RNAlater, the RVC-based preservative solution did not result in damage to the tissue morphology or a loss of protein activity. Additionally, the RVC-based preservative solution did not affect the RNA and genomic DNA contents of the tissue samples or the results of subsequent experimental analyses. An RVC-based reagent can be used as a multifunctional yet relatively inexpensive tissue preservative solution to provide a comprehensive and cost-effective method for preserving samples for tissue banks.
Pathologic diagnosis of nasopharyngeal carcinoma (NPC) can be challenging since most cases are nonkeratinizing carcinoma with little differentiation and many admixed lymphocytes. Our aim was to ...evaluate the possibility to identify NPC in nasopharyngeal biopsies using deep learning. A total of 726 nasopharyngeal biopsies were included. Among them, 100 cases were randomly selected as the testing set, 20 cases as the validation set, and all other 606 cases as the training set. All three datasets had equal numbers of NPC cases and benign cases. Manual annotation was performed. Cropped square image patches of 256 × 256 pixels were used for patch-level training, validation, and testing. The final patch-level algorithm effectively identified NPC patches, with an area under the receiver operator characteristic curve (AUC) of 0.9900. Using gradient-weighted class activation mapping, we demonstrated that the identification of NPC patches was based on morphologic features of tumor cells. At the second stage, whole-slide images were sequentially cropped into patches, inferred with the patch-level algorithm, and reconstructed into images with a smaller size for training, validation, and testing. Finally, the AUC was 0.9848 for slide-level identification of NPC. Our result shows for the first time that deep learning algorithms can identify NPC.
Abnormal histone deacetylase (HDAC) expression is closely related to cancer development and progression. Many HDAC inhibitors have been widely used in cancer treatment; however, severe side effects ...often limit their clinical application. In this study, we attempted to identify natural compounds with HDAC inhibitory activity and low physiological toxicity and explored their feasibility and mechanisms of action in liver cancer treatment. A yeast screening system was used to identify natural compounds with HDAC inhibitory activity. Further, western blotting was used to verify inhibitory effects on HDAC in human liver cancer cell lines. Cell functional analysis was used to explore the effects and mechanisms and the
results were verified in BALB/c nude mice. We found that hydroxygenkwanin (HGK), an extract from Daphne genkwa, inhibited class I HDAC expression, and thereby induced expression of tumor suppressor p21 and promoted acetylation and activation of p53 and p65. This resulted in the inhibition of growth, migration, and invasion of liver cancer cells and promoted cell apoptosis. Animal models revealed that HGK inhibited tumor growth in a synergistic manner with sorafenib. HGK inhibited class I HDAC expression and had low physiological toxicity. It has great potential as an adjuvant for liver cancer treatment and may be used in combination with anticancer drugs like sorafenib to improve therapeutic efficacy.
There are limited data on the prevalence and distribution of human papillomavirus (HPV) genotypes in vaginal intraepithelial neoplasia (VAIN). We sought to clarify this issue in a series of 450 VAIN ...cases with a confirmed diagnosis between 1990 and 2006. HPV genotyping was performed using paraffin‐embedded specimens and polymerase chain reaction (PCR)‐based methods. Multiple HPV types were validated by E6 type‐specific PCR and direct sequencing. The HPV genotypes of the vaginal and cervical neoplasms were compared for those with incident VAIN and a history of previous/concomitant cervical neoplasms. Ki‐67 was performed for supporting diagnosis of VAIN. Of these 450 VAIN cases (median age, 59 years; range, 19–93), two with missing paraffin blocks and 54 with poor DNA quality were excluded. HPV was detected in 273/394 (69.3%) VAIN, and multiple infections were found in 17.9% of HPV‐positive samples. The leading types were HPV16 (35.5%), HPV58 (9.9%), HPV52 (9.9%), HPV39 (8.4%), HPV33 (7.3%) and HPV53 (7.0%). Among the 156 cases with a history of previous cervical neoplasia, 29.0% had concordant HPV genotypes, while synchronous VAIN samples (n = 49) were more likely to harbor concordant genotypes (58.7%) with the concomitant cervical neoplasm (p = 0.0003). Whether those HPV types in the incident VAIN lesions had existed in the vaginal epithelium at the time of the previous cervical neoplasia or a new acquisition needs to be clarified in prospective follow‐up studies.
Inflammatory bowel diseases (IBD) include ulcerative colitis (UC) and Crohn's disease (CD). The incidence in children and adolescents has risen since the 21st century globally, including Taiwan. The ...study aimed to disclose the characteristics and outcome of pediatric IBD (pIBD) patients in a tertiary center for the past two decades.
We retrospectively reviewed the charts of pIBD children from 2000 to 2018 in a tertiary center in Northern Taiwan. Demographics, presentations, diagnostic modalities, treatment, and outcomes were analyzed.
A total of 38 cases were enrolled, including 27 CD and 11 UC patients. An almost 3-folds increase in incidence after 2010 was observed. Twelve cases (32%) were early-onset, and six of them (16%) were very-early-onset; four of them were detected with single-gene mutations XIAP, TTC7A (2 siblings), and ZAP70. Eleven CD patients (40.7%) received bowel resection at the onset, and another two (7.4%) had bowel resection years after the diagnosis. Initial bowel resection was associated with fibrostenotic/penetrating behavior, early-onset disease, and growth failure.
This study demonstrated an increased incidence of pIBD in the past two decades in Taiwan, a low-prevalence region. The initial high bowel resection rate in CD was related to the fibrostenotic and/or penetrating behavior, younger age at diagnosis, and growth failure.
We assessed the utility of the dual PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235) as single agent therapy and in combination with conventional chemotherapy for thyroid cancer.
Eight cell lines from four ...types of thyroid cancer (papillary, follicular, anaplastic, medullary) were studied. The cytotoxicity of BEZ235 and five conventional chemotherapeutic agents alone and in combination was measured using LDH assay. Quantitative western blot assessed expression of proteins associated with cell cycle, apoptosis and signaling pathways. Cell cycle distribution and apoptosis were measured by flow cytometry. Murine flank anaplastic thyroid cancers (ATC) were treated with oral BEZ235 daily. We found that BEZ235 effectively inhibited cell proliferation of all cancer lines, with ATC exhibiting the greatest sensitivity. BEZ235 consistently inactivated signaling downstream of mTORC1. BEZ235 generally induced cell cycle arrest at G0/G1 phase, and also caused apoptosis in the most sensitive cell lines. Baseline levels of p-S6 ribosomal protein (Ser235/236) and p27 correlated with BEZ235 sensitivity. Growth of 8505C ATC xenograft tumors was inhibited with BEZ235, without any observed toxicity. Combination therapy of BEZ235 and paclitaxel consistently demonstrated synergistic effects against ATC in vitro.
BEZ235 as a single therapeutic agent inhibits thyroid cancer proliferation and has synergistic effects in combination with paclitaxel in treating ATC. These findings encourage future clinical trials using BEZ235 for patients with this fatal disease.
The aberrant subcellular translocation and distribution of epidermal growth factor receptor (EGFR) represent a major yet currently underappreciated cancer development mechanism in non-small cell lung ...cancer (NSCLC). In this study, we investigated the subcellular interactome of EGFR by using a spectral counting-based approach combined with liquid chromatography-tandem mass spectrometry to understand the associated protein networks involved in the tumorigenesis of NSCLC. A total of 54, 77, and 63 EGFR-interacting proteins were identified specifically in the cytosolic, mitochondrial, and nuclear fractions from a NSCLC cell line, respectively. Pathway analyses of these proteins using the KEGG database shown that the EGFR-interacting proteins of the cytosol and nucleus are involved in the ribosome and spliceosome pathways, respectively, while those of the mitochondria are involved in metabolizing propanoate, fatty acid, valine, leucine, and isoleucine. A selected nuclear EGFR-interacting protein, hnRNP A3, was found to modulate the accumulation of nuclear EGFR. Downregulation of hnRNP A3 reduced the nuclear accumulation of EGFR, and this was accompanied by reduced tumor growth ability in vitro and in vivo. These results indicate that variations in the subcellular translocation and distribution of EGFR within NSCLC cells could affect tumor progression.
The prognostic value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal carcinoma (NPC) is controversial, with previous studies showing conflicting results. Most NPCs in endemic areas ...are Epstein-Barr virus (EBV)-positive. Our aim was to evaluate the clinical significance of PD-L1 expression in EBV-positive NPC. We retrospectively analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs) by immunohistochemistry in 208 EBV-positive NPC patients who underwent radiotherapy (203 with concurrent chemotherapy). The percentages of TCs and ICs expressing PD-L1 were evaluated respectively. There was a strong correlation between local recurrence and low PD-L1 expression on ICs (
= 0.0012), TCs (
= 0.013) or both (
= 0.000044), whereas all clinical parameters had no influence on local recurrence. Using multivariate analysis, low PD-L1 expression on ICs was an independent adverse prognostic factor (
= 0.0080; HR = 1.88; 95% CI = 1.18⁻3.00) for disease-free survival. High PD-L1 expression on both ICs and TCs was an independent favorable prognostic factor (
= 0.022; HR = 0.46; 95% CI = 0.24⁻0.89) for overall survival. We show for the first time that low PD-L1 expression on ICs and TCs strongly correlates with local recurrence in EBV-positive NPC patients after radiation-based therapy. A simple immunohistochemical study for PD-L1 can identify patients prone to local recurrence, and such patients might benefit from more aggressive treatment in future clinical trials.
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