Oral squamous cell carcinoma (SCC) is a prevalent malignant disease worldwide, especially so in Taiwan. Early- or even preclinical-stage detection is critical for reducing morbidity and mortality from oral SCC. Epidemiological and genome association studies are useful for identifying clinicopathological risk factors for preventive, diagnostic, and therapeutic approaches of oral SCC. For advanced oral SCC, effective treatments are critical to prolonging survival and enhancing quality of life. As oral SCC is characteristic of regional invasion with lymph node metastases, understanding the aggressive features of oral SCC, particularly in lymphangiogenesis, is essential for determining effective treatments. Emerging evidence has demonstrated that the tumor microenvironment (TME) plays a pivotal role in tumor growth, invasion, and metastases. Recent clinical successes in immune checkpoint inhibitors either alone or combined with chemotherapy have also supported the therapeutic value of immunotherapy in oral SCC. This review summarizes critical advances in basic knowledge of oral SCC from the perspective of clinicopathological risk factors, molecular tumorigenesis, and the TME. We also highlight our recent investigations on the microbiome, genome association studies, lymphangiogenesis, and immunomodulation in oral SCC. This review may provide new insights for oral SCC treatment by systematically interpreting emerging evidence from various preclinical and clinical studies.
Background The homologous recombination (HR) pathway is involved in DNA damage response (DDR), which is crucial to cancer cell survival after treatment with DNA damage agents. O6-methylguanine DNA methyltransferase (MGMT) is associated with cisplatin (CDDP) resistance in cancer cells; however, the underlying mechanisms remain unclear. Here, we explored the interactions between MGMT and the HR pathway in CDDP-activated DDR and their clinical implications in nasopharyngeal carcinoma (NPC). Methods Human NPC cells were assessed using loss-of-function approaches in vitro. The expression correlations between MGMT and major proteins of the HR pathway were analyzed through Western blotting, quantitative real-time PCR, and bioinformatic analysis by using a public database. The physical interactions between MGMT and HR proteins were studied using co-immunoprecipitation and immunofluorescence analyses. Cell comet tails and γ-H2AX expression levels were examined to evaluate double-strand break (DSB) formation. Established immunofluorescence and reporter analyses were conducted to measure HR activity. Xenograft and cell viability studies were used to assess the therapeutic potential of MGMT inhibition in combination with CDDP and poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Results Among major proteins of the HR pathway, MGMT suppression inhibited CDDP-induced RAD51 expression. Bioinformatic analyses showed a positive correlation between MGMT and RAD51 expression in patients with NPC. Moreover, MGMT physically interacted with BRCA1 and regulated CDDP-induced BRCA1 phosphorylation (ser 988). In functional assays, MGMT inhibition increased CDDP-induced DSB formation through attenuation of HR activity. NPC xenograft studies demonstrated that MGMT inhibition combined with CDDP treatment reduced tumor size and downregulated RAD51 expression and BRCA1 phosphorylation. Furthermore, MGMT suppression increased PARP inhibitor–induced cell death and DSB formation in NPC cells. Conclusion MGMT is crucial in the activation of the HR pathway and regulates DDR in NPC cells treated with CDDP and PARP inhibitor. Thus, MGMT is a promising therapeutic target for cancer treatments involving HR-associated DDR.
High collagen type XI alpha 1 (COL11A1) levels are associated with tumor progression, chemoresistance, and poor patient survival in several cancer types. MicroRNAs (miRNAs) are dysregulated in multiple cancers, including epithelial ovarian carcinoma (EOC); however, the regulation of COL11A1 by miRNAs in EOC remains unclear. We examined the role of miRNAs in regulating COL11A1 expression. We identified miR-509 and miR-335 as the candidate miRNAs through an online database search. EOC cell treatment with miR-335 mimics abrogated COL11A1 expression and suppressed cell proliferation and invasion, besides increasing the sensitivity of EOC cells to cisplatin. Conversely, treatment with miR-335 inhibitors prompted cell growth/invasiveness and chemoresistance of EOC cells. miR-335 inhibited COL11A1 transcription, thus reducing the invasiveness and chemoresistance of EOC cells via the Ets-1/MMP3 and Akt/c/EBPβ/PDK1 axes, respectively. Furthermore, it did not directly regulate PDK1 but increased PDK1 ubiquitination and degradation through COL11A1 inhibition. In vivo findings highlighted significantly decreased miR-335 mRNA expressions in EOC samples. Furthermore, patients with low miR335 levels were susceptible to advanced-stage cancer, poor response to chemotherapy, and early relapse. This study highlighted the importance of miR-335 in downregulating COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival and suggested its potential application as a therapeutic target.
Background and objectives: High-flow nasal cannula (HFNC) can be used as a respiratory support strategy for patients with acute respiratory failure (ARF). However, no clear evidence exists to support or oppose HFNC use in immunocompromised patients. Thus, this meta-analysis aims to assess the effects of HFNC, compared to conventional oxygen therapy (COT) and noninvasive ventilation (NIV), on the outcomes in immunocompromised patients with ARF. The Pubmed, Embase and Cochrane databases were searched up to November 2018. Materials and Methods: Only clinical studies comparing the effect of HFNC with COT or NIV for immunocompromised patients with ARF were included. The outcome included the rate of intubation, mortality and length of stay (LOS). Results: A total of eight studies involving 1433 immunocompromised patients with ARF were enrolled. The pooled analysis showed that HFNC was significantly associated with a reduced intubation rate (risk ratio (RR), 0.83; 95% confidence interval (CI), 0.74–0.94, I2 = 0%). Among subgroup analysis, HFNC was associated with a lower intubation rate than COT (RR, 0.86; 95% CI, 0.75–0.95, I2 = 0%) and NIV (RR, 0.59; 95% CI, 0.40–0.86, I2 = 0%), respectively. However, there was no significant difference between HFNC and control groups in terms of 28-day mortality (RR, 0.78; 95% CI, 0.58–1.04, I2 = 48%), and intensive care unit (ICU) mortality (RR, 0.87; 95% CI, 0.73–1.05, I2 = 57%). The ICU and hospital LOS were similar between HFNC and control groups (ICU LOS: mean difference, 0.49 days; 95% CI, −0.25–1.23, I2 = 69%; hospital LOS: mean difference, −0.12 days; 95% CI, −1.86–1.61, I2 = 64%). Conclusions: Use of HFNC may decrease the intubation rate in immunocompromised patients with ARF compared with the control group, including COT and NIV. However, HFNC could not provide additional survival benefit or shorten the LOS. Further large, randomized controlled trials are needed to confirm these findings.
Anti-epithelial growth factor receptor or anti-vascular endothelial growth factor agents combined with chemotherapy were the standard of treatment for metastatic colorectal cancer (CRC). However, increasing evidence of molecularly stratified treatment makes the complexity of treatment. Anaplastic lymphoma kinase (ALK) gene alternation is one of potential target for biomarker-guided therapy for CRC. We present a case of a 56-year-old man who suffered from advanced ascending colon cancer, harboring echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion gene E21; A20 variant, a rare variant in EML4-ALK fusion gene in lung cancer. We also detected this fusion gene from different tissue types including circulating tumor DNA (ctDNA) and ascites fluid. The patient was offered alectinib, an ALK inhibitor, with partial response in lung, liver, and peritoneal metastasis for 8 months. Tumor heterogeneity, especially in gastrointestinal tract cancer, raise our interest in comprehensive genetic profiling in clinical practice. Convenience and reliability of next-generation sequencing, including using ctDNA, help physicians deal with clinical dilemma. ALK-positive CRC is rare. However, advanced CRC with ALK gene alteration responds to ALK inhibitor. It is reasonable to check ALK gene alteration in clinical practice for CRC.
TPS5595 Background: Women with recurrent/metastatic cervical cancer represent a poor prognostic group with high unmet clinical needs. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor expressed on immune cells and upregulated on T-cells and natural killer cells in multiple solid tumors, inhibiting anticancer immune responses. Ociperlimab (BGB-A1217) is a novel, humanized, monoclonal antibody that binds TIGIT with high specificity and affinity, blocking the interaction with its ligands on tumor cells. Tislelizumab is an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-202 is a Phase 2, randomized, multicenter, open-label study (NCT04693234). Approximately 167 pts with cervical squamous cell or adenosquamous carcinoma or adenocarcinoma, recruited from 100 centers, whose disease progressed on or after ≥ 1 prior line of chemotherapy for recurrent/metastatic disease will be included in this 2-Part study. In Part 1, approximately 80 pts will be randomized (1:1) to either ociperlimab 900 mg intravenously (IV) in combination with tislelizumab 200 mg IV every 3 weeks (Q3W) (Arm 1), or tislelizumab monotherapy 200 mg IV Q3W (Arm 2), until disease progression, unacceptable toxicity, or withdrawal of consent. In Part 2, Arm 1 will be expanded by approximately 87 additional pts whose tumors are evaluable for PD-L1 expression. The primary endpoint is overall response rate (ORR) (RECIST v1.1) assessed by Independent Review Committee (IRC) in Arm 1. Secondary endpoints are investigator-assessed ORR in Arm 2, IRC-assessed and investigator-assessed ORR in Arm 1, IRC-assessed and investigator-assessed duration of response, progression-free survival, time to response, disease control rate, clinical benefit rate and overall survival, cancer-specific health-related quality of life (HRQoL), safety, pharmacokinetics and immunogenicity in Arms 1 and 2. Exploratory endpoints are generic HRQoL and the association of biomarkers with patient prognosis, response or resistance. Clinical trial information: NCT04693234.
Background Lymph node and distant metastasis contribute to poor outcomes in patients with oral squamous cell carcinoma (OSCC). The mechanisms regulating cancer migration and invasion play a key role in OSCC. Methods We determined migration and invasion ability of OSCC by wound-healing assay, two-chamber transwell invasion assay and cell mobility tracking and evaluated tumor metastasis in vivo. Western blot (WB), qRT-PCR, RNA-seq, dual-luciferase reporter assays and nuclear/cytoplasmic fractionation were performed to investigate the potential mechanism. Immunohistochimical (IHC) staining determined vimentin and PDZK1IP1 expression in OSCC tissues. Results and conclusion In this study, we determined that miR-455-5p was associated with lymph node metastasis and clinical invasion, leading to poor outcomes in patients with OSCC. MiR-455-5p promoted oral cancer cell migration and invasion and induced epithelial-to-mesenchymal transition (EMT). We also identified a new biomarker, PDZK1IP1 (MAP17), that was targeted by miR-455-5p. PDZK1IP1 knockdown led to migration, metastasis, EMT, and increased transforming growth factor-β signaling in OSCC. In addition, miR-455-5p overexpression and PDZK1IP1 inhibition promoted collective OSCC cell migration. According to data from the Cancer Genome Atlas database and the NCKU-OrCA-40TN data set, miR-455-5p and PDZK1IP1 are positively and negatively correlated, respectively, with partial EMT score. High miR-455-5p expression was associated with high vimentin levels and low MAP17 H-scores. The patients with low MAP17 expression had higher rates of disease recurrence than did patients with high MAP17 expression, especially for patients with clinical invasion risk factors and low MAP17 expression. These results suggest that miR-455-5p suppresses PDZK1IP1 expression and mediates OSCC progression. MiR-455-5p and PDZK1IP1 may therefore serve as key biomarkers and be involved in regulating partial EMT in OSCC cells. PDZK1IP1 expression may also serve as an independent factor that impacts outcomes in patients with clinical risk factors for recurrence.
Melatonin, a naturally biosynthesized molecule secreted by the pineal gland, exhibits antitumor activities against several different types of cancer. The mechanisms of action of melatonin against tumor progression involve cellular apoptosis, antimetastatic activity, antioxidant and mutagenic effects, antiangiogenic activity, and the restoration of cancer immune surveillance. Melatonin has anticancer activity when administered alone or in combination with standard chemotherapeutic agents, with measurable improvements seen in the clinical endpoints of tumor regression and patient survival. However, scant clinical evidence supports the use of melatonin in bladder cancer treatment. Our study has found that melatonin treatment suppresses the bladder cancer cell migratory ability by inhibiting the epithelial-mesenchymal transition (EMT) process, which appears to be linked to melatonin-induced decreases in bladder cancer cell autophagy. Finally, an evaluation of in vivo melatonin-induced antitumor effects in an orthotopic animal model of bladder cancer indicated that melatonin treatment slightly prolonged the survival of tumor-bearing mice. Our study offers novel insights into the use of melatonin in bladder cancer treatment.
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