Enhancing regional control in p16-negative oropharyngeal cancer: A propensity score-matched analysis of upfront neck dissection and definitive chemoradiotherapy.

BACKGROUND: The presence of p16 and neck disease is important predictors of prognosis for oropharyngeal squamous cell carcinoma (OPSCC). Patients who are p16-negative and have clinically node-positive (cN+) disease generally have worse oncologic outcomes. This study aimed to investigate whether upfront neck dissection (UFND) could provide potential benefits for patients with cN+ p16-negative OPSCC. METHODS: Through this retrospective study, 76 patients with cN+ p16-negative OPSCC were analyzed, those who received either definite concurrent chemoradiotherapy (CCRT group) or UFND followed by chemoradiotherapy (UFND group). The primary endpoints were regional recurrence-free survival (RRFS), disease-specific survival (DSS), and overall survival (OS). Factors associated with survival were evaluated by univariate and multivariate analysis. Survival between the two groups was compared by propensity score-matched analysis. RESULTS: Matched 23 patients in each group through propensity analysis, the UFND group showed a significantly better 5-year RRFS (94.1% vs 61.0%, p = 0.011) compared to the CCRT group. Univariate analysis revealed that UFND was the sole factor associated with regional control (hazard ratio [HR] = 0.110; 95% CI, 0.014-0.879; p = 0.037). Furthermore, the study found that the CCRT group was associated with a higher dose of radiotherapy and exhibited a significantly higher risk of mortality due to pneumonia. CONCLUSION: The study indicated that UFND followed by CCRT may be a potential treatment option for patients with cN+ p16-negative OPSCC, as it can reduce the risk of regional recurrence. Additionally, the study highlights that definite CCRT is connected to a larger dose of radiotherapy and a higher risk of fatal pneumonia. These findings could be beneficial in informing clinical decision-making and improving treatment outcomes for patients with OPSCC.

Extracellular Vesicular Analysis of Glypican 1 mRNA and Protein for Pancreatic Cancer Diagnosis and Prognosis.

Detecting pancreatic duct adenocarcinoma (PDAC) in its early stages and predicting late-stage patient prognosis undergoing chemotherapy is challenging. This work shows that the activation of specific oncogenes leads to elevated expression of mRNAs and their corresponding proteins in extracellular vesicles (EVs) circulating in blood. Utilizing an immune lipoplex nanoparticle (ILN) biochip assay, these findings demonstrate that glypican 1 (GPC1) mRNA expression in the exosomes-rich (Exo) EV subpopulation and GPC1 membrane protein (mProtein) expression in the microvesicles-rich (MV) EV subpopulation, particularly the tumor associated microvesicles (tMV), served as a viable biomarker for PDAC. A combined analysis effectively discriminated early-stage PDAC patients from benign pancreatic diseases and healthy donors in sizable clinical from multiple hospitals. Furthermore, among late-stage PDAC patients undergoing chemotherapy, lower GPC1 tMV-mProtein and Exo-mRNA expression before treatment correlated significantly with prolonged overall survival. These findings underscore the potential of vesicular GPC1 expression for early PDAC screenings and chemotherapy prognosis.

Identifying essential genes in genome-scale metabolic models of consensus molecular subtypes of colorectal cancer.

Identifying essential targets in the genome-scale metabolic networks of cancer cells is a time-consuming process. The present study proposed a fuzzy hierarchical optimization framework for identifying essential genes, metabolites and reactions. On the basis of four objectives, the present study developed a framework for identifying essential targets that lead to cancer cell death and evaluating metabolic flux perturbations in normal cells that have been caused by cancer treatment. Through fuzzy set theory, a multiobjective optimization problem was converted into a trilevel maximizing decision-making (MDM) problem. We applied nested hybrid differential evolution to solve the trilevel MDM problem to identify essential targets in genome-scale metabolic models for five consensus molecular subtypes (CMSs) of colorectal cancer. We used various media to identify essential targets for each CMS and discovered that most targets affected all five CMSs and that some genes were CMS-specific. We obtained experimental data on the lethality of cancer cell lines from the DepMap database to validate the identified essential genes. The results reveal that most of the identified essential genes were compatible with the colorectal cancer cell lines obtained from DepMap and that these genes, with the exception of EBP, LSS, and SLC7A6, could generate a high level of cell death when knocked out. The identified essential genes were mostly involved in cholesterol biosynthesis, nucleotide metabolisms, and the glycerophospholipid biosynthetic pathway. The genes involved in the cholesterol biosynthetic pathway were also revealed to be determinable, if a cholesterol uptake reaction was not induced when the cells were in the culture medium. However, the genes involved in the cholesterol biosynthetic pathway became non-essential if such a reaction was induced. Furthermore, the essential gene CRLS1 was revealed as a medium-independent target for all CMSs.

A generational comparison for unfavorable cancer of unknown primary in a single institute over 20 years.

BACKGROUND: The prognosis of unfavorable cancer of unknown primary is extremely poor. This is the first report to compared the treatment results between generations of CUP and examined prognostic factors. METHODS: This retrospective single-center cohort study enrolled 68 patients with newly diagnosed unfavorable cancer of unknown primary at Taipei Veteran General Hospital from 2017 to 2020 as study cohort and 167 patients from 2000 to 2009 as historical cohort. RESULTS: The median overall survival was 4.3 months in the study cohort (95% CI, 2.7-6.2 months) and 4.5 months in the historical cohort (95% CI, 3.0-5.5 months; p = 0.858). Eleven patients in the study cohort received immunotherapy. The disease control rates were 45%. Multivariate analysis showed that an Eastern Cooperative Oncology Group score > 1 and a C-reactive protein level > 1 correlated with poor survival. A new prognostic stratification model was constructed by using Eastern Cooperative Oncology Group score and C-reactive protein values. The good-, intermediate-, and poor-risk groups had distinct median overall survival of 18.3, 7.0 and 1.2 months, respectively (area under the curve, 0.817; p < 0.001). CONCLUSION: The outcome of unfavorable cancer of unknown primary has not changed much over the last 20 years. The application of a new prognostic stratification model can further stratify unfavorable cancer of unknown primary.

BMX, a specific HDAC8 inhibitor, with TMZ for advanced CRC therapy: a novel synergic effect to elicit p53-, ß-catenin- and MGMT-dependent apoptotic cell death.

BACKGROUND: Despite advances in treatment, patients with refractory colorectal cancer (CRC) still have poor long-term survival, so there is a need for more effective therapeutic options. METHODS: To evaluate the HDAC8 inhibition efficacy as a CRC treatment, we examined the effects of various HDAC8 inhibitors (HDAC8i), including BMX (NBM-T-L-BMX-OS01) in combination with temozolomide (TMZ) or other standard CRC drugs on p53 mutated HT29 cells, as well as wild-type p53 HCT116 and RKO cells. RESULTS: We showed that HDAC8i with TMZ cotreatment resulted in HT29 arrest in the S and G2/M phase, whereas HCT116 and RKO arrest in the G0/G1 phase was accompanied by high sub-G1. Subsequently, this combination approach upregulated p53-mediated MGMT inhibition, leading to apoptosis. Furthermore, we observed the cotreatment also enabled triggering of cell senescence and decreased expression of stem cell biomarkers. Mechanistically, we found down-expression levels of ß-catenin, cyclin D1 and c-Myc via GSK3ß/ß-catenin signaling. Intriguingly, autophagy also contributes to cell death under the opposite status of ß-catenin/p62 axis, suggesting that there exists a negative feedback regulation between Wnt/ß-catenin and autophagy. Consistently, the Gene Set Enrichment Analysis (GSEA) indicated both apoptotic and autophagy biomarkers in HT29 and RKO were upregulated after treating with BMX. CONCLUSIONS: BMX may act as a HDAC8 eraser and in combination with reframed-TMZ generates a remarkable synergic effect, providing a novel therapeutic target for various CRCs. Video Abstract.

Treatment outcomes of cetuximab-containing regimen in locoregional recurrent and distant metastatic head and neck squamous cell carcinoma.

BACKGROUND: Recurrent/ metastatic squamous cell carcinoma of head and neck (R/M SCCNH) is still a difficult-to-treat disease with poor clinical outcomes and limited treatment choices. In view of locoregional recurrent versus distant metastatic SCCHN, the therapeutic efficacy of cetuximab-containing regimen and relevant prognostic factors for these two groups may be different. Thus, the aim of this study was to explore the treatment outcomes of cetuximab-containing regimen in locoregional recurrent and distant metastatic SCCHN groups, and to identify clinical factors correlated with better survival outcomes. METHODS: From 2016 to 2020, patients with R/M SCCHN who received cetuximab-containing regimen in our institute were enrolled in this study. Clinical outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated in both locoregional recurrence and distant metastasis groups. Exploratory analysis were conducted to investigate major clinical features associated with better outcomes. RESULTS: A total of 107 patients with locoregional recurrent SCCHN (N = 66) and distant metastatic SCCNH (N = 41) who received cetuximab-containing regimen were enrolled in this retrospective study. Patients with oral cavity cancer and patients with disease recurrence within 6 months after radiation therapy were significantly increased in locoregional recurrence group. The median OS (15.6 vs. 9.7 months, P = 0.004) and PFS (5.8 months vs. 4.2 months, P = 0.008) were longer in locoregional recurrence group than in distant metastasis group. In multivariate analysis of clinical features, locoregional recurrence was still an important risk factor associated with better OS (Hazzard ratio (HR) 0.64, p = 0.06) and PFS (HR 0.67, p = 0.075). In addition, a trend of favorable disease control rate (DCR; 62.5% vs. 45.0%, p = 0.056) was noted in locoregional recurrence group. In locoregional recurrence group, prior salvage surgery was associated with longer OS (HR = 0.24, P = 0.008) and PFS (HR = 0.30, P = 0.005). CONCLUSION: SCCHN with locoregional recurrence is associated with better disease control and survival outcomes comparing to distant metastatic SCCHN when treated with cetuximab-containing regimen. Salvage surgery for locoregional recurrence may further improves clinical outcome.

Dehydroepiandrosterone (DHEA) Sensitizes Irinotecan to Suppress Head and Neck Cancer Stem-Like Cells by Downregulation of WNT Signaling.

Purpose: Current treatment options for head and neck squamous cell carcinoma (HNSCC) are limited, especially for cases with cancer stem cell-induced chemoresistance and recurrence. The WNT signaling pathway contributes to maintenance of stemness via translocation of ß-catenin into the nucleus, and represents a promising druggable target in HNSCC. Dehydroepiandrosterone (DHEA), a steroid hormone, has potential as an anticancer drug. However, the potential anticancer mechanisms of DHEA including inhibition of stemness, and its therapeutic applications in HNSCC remain unclear. Methods: Firstly, SRB assay and sphere formation assay were used to examine cellular viability and cancer stem cell-like phenotype, respectively. The expressions of stemness related factors were measured by RT-qPCR and western blotting. The luciferase reporter assay was applied to evaluate transcriptional potential of stemness related pathways. The alternations of WNT signaling pathway were measured by nuclear translocation of ß-catenin, RT-qPCR and western blotting. Furthermore, to investigate the effect of drugs in vivo, both HNSCC orthotopic and subcutaneous xenograft mouse models were applied. Results: We found that DHEA reduced HNSCC cell viability, suppressed sphere formation, and inhibited the expression of cancer-stemness markers, such as BMI-1 and Nestin. Moreover, DHEA repressed the transcriptional activity of stemness-related pathways. In the WNT pathway, DHEA reduced the nuclear translocation of the active form of ß-catenin and reduced the protein expression of the downstream targets, CCND1 and CD44. Furthermore, when combined with the chemotherapeutic drug, irinotecan (IRN), DHEA enhanced the sensitivity of HNSCC cells to IRN as revealed by reduced cell viability, sphere formation, expression of stemness markers, and activation of the WNT pathway. Additionally, this combination reduced in vivo tumor growth in both orthotopic and subcutaneous xenograft mouse models. Conclusion: These findings indicate that DHEA has anti-stemness potential in HNSCC and serves as a promising anticancer agent. The combination of DHEA and IRN may provide a potential therapeutic strategy for patients with advanced HNSCC.

Efficacy of cetuximab-containing regimens in the treatment of recurrent/metastatic head and neck cancer after progression to immune checkpoint inhibitors.

BACKGROUND: The antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab and immune checkpoint inhibitors (ICIs) are the current front-line treatment for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, understanding of the efficacy of cetuximab-containing regimens in patients who fail ICI treatments is limited. In this study, we present the efficacy of cetuximab-based regimens in heavily pretreated R/M HNSCC patients after progression to ICIs. METHODS: This was a retrospective study that analyzed patients diagnosed with R/M HNSCC who progressed after ICIs and then received their first-time cetuximab-based regimens at Taipei Veterans General Hospital from January 2017 to December 2020. The response rate, overall survival, and progression-free survival were measured. RESULTS: A total of 28 patients were included in this study. Most patients had received pembrolizumab as an ICI. The median duration of cetuximab-based regimens prescribed was 4.5 months. The objective response rate (ORR) was 32.1% (95% confidence interval [CI], 17.9%-50.6%), and the disease control rate (DCR) was 53.6% (95% CI, 42.4%-76.4%). The median overall survival and median progression-free survival were 9.1 months (95% CI, 1.3-16.8) and 2.9 months (95% CI, 2.2-3.5), respectively. The incidence of cetuximab-related adverse events was reported as 39.2%. CONCLUSION: A cetuximab-based regimen is still an effective and tolerable treatment for R/M HNSCC after progression on ICIs. Future prospective studies are needed to identify better treatments for previously ICI-treated or heavily treated R/M HNSCC patients.

FAS receptor regulates NOTCH activity through ERK-JAG1 axis activation and controls oral cancer stemness ability and pulmonary metastasis.

Pulmonary metastasis occurring via the colonization of circulating cancer stem cells is a major cause of oral squamous cell carcinoma (OSCC)-related death. Thus, understanding the mechanism of OSCC pulmonary metastasis may provide a new opportunity for OSCC treatment. FAS, a well-known apoptosis-inducing death receptor, has multiple nonapoptotic, protumorigenic functions. Previously, we found that SAS OSCC cells with FAS receptor knockout did not affect orthotopic tumor growth or cervical lymph node metastasis. However, FAS knockout cells could not colonize in distant organs to form metastases upon intravenous injection, which hinted at the cancer stemness function of the FAS receptor. Immunohistochemistry staining indicated that the FAS receptor serves as a poor prognosis marker in OSCC patients. FAS knockout inhibited in vitro cancer spheroid formation, migration and invasion, and prevented mesenchymal transition in OSCC cells and inhibited OSCC pulmonary metastasis in vivo. To determine the regulatory mechanism by which the FAS receptor exerts its oncogenic function, we utilized cDNA microarrays and phosphoprotein arrays to discover key candidate genes and signaling pathway regulators. JAG1 expression and NOTCH pathway activation were controlled by the FAS receptor through ERK phosphorylation. Both JAG1 and NOTCH1 silencing decreased in vitro cancer spheroid formation. In OSCC cells, FAS ligand or JAG1 protein treatment increased NOTCH pathway activity, which could be abolished by FAS receptor knockout. In FAS knockout cells, restoring the NOTCH1 intracellular domain stimulated cancer spheroid formation. Both JAG1 and NOTCH1 silencing decreased in vivo OSCC growth. In conclusion, we found a novel FAS-ERK-JAG1-NOTCH1 axis that may contribute to OSCC stemness and pulmonary metastasis.

Tongue conservation treatment for oral tongue squamous cell carcinoma with induction chemotherapy, surgery, and risk-adapted adjuvant therapy: A phase II trial.

BACKGROUND: To assess the feasibility of tongue conservation treatment with induction chemotherapy (ICT), tongue conservation surgery, and risk-adapted postoperative adjuvant therapy in oral tongue squamous cell carcinoma (OTSCC). METHODS: Patients with newly diagnosed OTSCC cT2-4 N0-2 M0 were recruited. The ICT with a regimen of docetaxel, cisplatin, and oral tegafur/uracil (DCU) was administrated every 21 days. After the first cycle of ICT (DCU1), patients with a more than 30% decrease in the longest diameter of primary tumor underwent a second cycle of ICT (DCU2). Tongue conservation surgery was performed after ICT, and risk-adapted adjuvant therapy was organized based on pathological features. RESULTS: From July 2011 to December 2015, a total of 23 patients were enrolled, 87% of whom were classified as stage III-IV. Clinical responders to DCU1 and DCU2 were determined in 90.5% (19/21) and 88.2% (15/17) of patients. Tongue conservation surgery was performed in 16 responders to ICT. Only one patient had a positive margin (6.3%), and a complete pathologic response was achieved in eight patients (50%). Only one patient developed local recurrence after a median follow-up of 58.6 months (range, 7.9-105.2). The 5-year overall survival (0% vs. 87.5%, P = 0.001) and disease-specific survival (0% vs. 93.3%, P = 0.000) were significantly different between the DCU1 nonresponders and responders. CONCLUSION: Tongue conservation treatment with ICT, followed by conservation surgery and risk-adapted adjuvant therapy, is feasible for patients with OTSCC who are good responders to ICT. However, the outcomes of nonresponders are dismal. Further study in a larger patient population is warranted.

Computer-Aided Design for Identifying Anticancer Targets in Genome-Scale Metabolic Models of Colon Cancer.

The efficient discovery of anticancer targets with minimal side effects is a major challenge in drug discovery and development. Early prediction of side effects is key for reducing development costs, increasing drug efficacy, and increasing drug safety. This study developed a fuzzy optimization framework for Identifying AntiCancer Targets (IACT) using constraint-based models. Four objectives were established to evaluate the mortality of treated cancer cells and to minimize side effects causing toxicity-induced tumorigenesis on normal cells and smaller metabolic perturbations. Fuzzy set theory was applied to evaluate potential side effects and investigate the magnitude of metabolic deviations in perturbed cells compared with their normal counterparts. The framework was applied to identify not only gene regulator targets but also metabolite- and reaction-centric targets. A nested hybrid differential evolution algorithm with a hierarchical fitness function was applied to solve multilevel IACT problems. The results show that the combination of a carbon metabolism target and any one-target gene that participates in the sphingolipid, glycerophospholipid, nucleotide, cholesterol biosynthesis, or pentose phosphate pathways is more effective for treatment than one-target inhibition is. A clinical antimetabolite drug 5-fluorouracil (5-FU) has been used to inhibit synthesis of deoxythymidine-5'-triphosphate for treatment of colorectal cancer. The computational results reveal that a two-target combination of 5-FU and a folate supplement can improve cell viability, reduce metabolic deviation, and reduce side effects of normal cells.

Ruxolitinib Combined with Gemcitabine against Cholangiocarcinoma Growth via the JAK2/STAT1/3/ALDH1A3 Pathway.

Cholangiocarcinoma is the most common primary malignant tumor of the bile duct. The current standard first-line treatment for advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin. However, few effective treatment choices exist for refractory cholangiocarcinoma, and additional therapeutic drugs are urgently required. Our previous work demonstrated that the ALDH isoform 1A3 plays a vital role in the malignant behavior of cholangiocarcinoma and may serve as a new therapeutic target. In this study, we found a positive correlation between ALDH1A3 protein expression levels and the cell migration abilities of three cholangiocarcinoma cell lines, which was verified using ALDH1A3-overexpressing and ALDH1A3-knockdown clones. We also used ALDH1A3-high and ALDH1A3-low populations of cholangiocarcinoma cell lines from the library of integrated network-based cellular signatures (LINCS) program and assessed the effects of ruxolitinib, a commercially available JAK2 inhibitor. Ruxolitinib had a higher cytotoxic effect when combined with gemcitabine. Furthermore, the nuclear translocation STAT1 and STAT3 heterodimers were markedly diminished by ruxolitinib treatment, possibly resulting in decreased ALDH1A3 activation. Notably, ruxolitinib alone or combined with gemcitabine led to significantly reduced tumor size and weight. Collectively, our studies suggest that ruxolitinib might suppress the ALDH1A3 activation through the JAK2/STAT1/3 pathway in cholangiocarcinoma, and trials should be undertaken to evaluate its efficacy in clinical therapy.

Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. FINDINGS: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). INTERPRETATION: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.

ALDH2 deficiency induces atrial fibrillation through dysregulated cardiac sodium channel and mitochondrial bioenergetics: A multi-omics analysis.

Point mutation in alcohol dehydrogenase 2 (ALDH2), ALDH2*2 results in decreased catalytic enzyme activity and has been found to be associated with different human pathologies. Whether ALDH2*2 would induce cardiac remodeling and increase the attack of atrial fibrillation (AF) remains poorly understood. The present study evaluated the effect of ALDH2*2 mutation on AF susceptibility and unravelled the underlying mechanisms using a multi-omics approach including whole-genome gene expression and proteomics analysis. The in-vivo electrophysiological study showed an increase in the incidence and reduction in the threshold of AF for the mutant mice heterozygous for ALDH2*2 as compared to the wild type littermates. The microarray analysis revealed a reduction in the retinoic acid signals which was accompanied by a downstream reduction in the expression of voltage-gated Na+ channels (SCN5A). The treatment of an antagonist for retinoic acid receptor resulted in a decrease in SCN5A transcript levels. The integrated analysis of the transcriptome and proteome data showed a dysregulation of fatty acid ß-oxidation, adenosine triphosphate synthesis via electron transport chain, and activated oxidative responses in the mitochondria. Oral administration of Coenzyme Q10, an essential co-factor known to meliorate mitochondrial oxidative stress and preserve bioenergetics, conferred a protection against AF attack in the mutant ALDH2*2 mice. The multi-omics approach showed the unique pathophysiology mechanisms of concurrent dysregulated SCN5A channel and mitochondrial bioenergetics in AF. This inspired the development of a personalized therapeutic agent, Coenzyme Q10, to protect against AF attack in humans characterized by ALDH2*2 genotype.

Combination of pembrolizumab and lenvatinib is a potential treatment option for heavily pretreated recurrent and metastatic head and neck cancer.

BACKGROUND: Immunotherapy has become the current standard of care for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). One potential approach to improve immunotherapy efficacy is to combine pembrolizumab, an anti-PD-1 agent, with lenvatinib, a potent multikinase inhibitor. In this study, we presented our up-to-date experience with pembrolizumab/lenvatinib combination therapy in heavily pretreated R/M HNSCC. METHODS: Patients who had R/M HNSCC, were ineligible for curative treatment, progressed after at least two lines of systemic treatment and had received pembrolizumab/lenvatinib combination therapy were enrolled in this study. The primary endpoint was the objective response rate. The secondary endpoints included the disease control rate, overall survival, progression-free survival, and the duration of response. RESULTS: A total of 14 patients were enrolled in this study. All the patients had received at least two lines of systemic treatment and radiation therapy, and 71% of patients had failed previous anti-PD-1 treatment. The objective response rate of pembrolizumab/lenvatinib combination therapy was 28.6% (95% confidence interval [CI], 5.0%-52.2%). The disease control rate was 42.9% (95% CI, 17.0%-68.8%). The overall survival and progression-free survival were 6.2 months (95% CI, 2.9-9.6) and 4.6 months (95% CI, 0.05-0.9.2), respectively. Of those who had failed previous anti-PD-1 therapy, partial responses were observed in two patients. All the patients with partial responses were in the tumor proportion score <50 and combined positive score 1 to 19 groups. CONCLUSION: Our study provided up-to-date evidence that pembrolizumab/lenvatinib combination therapy achieved objective responses in both heavily pretreated and anti-PD-1 refractory R/M HNSCC patients. This study supported the use of pembrolizumab/lenvatinib combination therapy in R/M HNSCC patients without standard of care.

Aldolase A and Phospholipase D1 Synergistically Resist Alkylating Agents and Radiation in Lung Cancer.

Exposure to alkylating agents and radiation may cause damage and apoptosis in cancer cells. Meanwhile, this exposure involves resistance and leads to metabolic reprogramming to benefit cancer cells. At present, the detailed mechanism is still unclear. Based on the profiles of several transcriptomes, we found that the activity of phospholipase D (PLD) and the production of specific metabolites are related to these events. Comparing several particular inhibitors, we determined that phospholipase D1 (PLD1) plays a dominant role over other PLD members. Using the existing metabolomics platform, we demonstrated that lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) are the most critical metabolites, and are highly dependent on aldolase A (ALDOA). We further demonstrated that ALDOA could modulate total PLD enzyme activity and phosphatidic acid products. Particularly after exposure to alkylating agents and radiation, the proliferation of lung cancer cells, autophagy, and DNA repair capabilities are enhanced. The above phenotypes are closely related to the performance of the ALDOA/PLD1 axis. Moreover, we found that ALDOA inhibited PLD2 activity and enzyme function through direct protein-protein interaction (PPI) with PLD2 to enhance PLD1 and additional carcinogenic features. Most importantly, the combination of ALDOA and PLD1 can be used as an independent prognostic factor and is correlated with several clinical parameters in lung cancer. These findings indicate that, based on the PPI status between ALDOA and PLD2, a combination of radiation and/or alkylating agents with regulating ALDOA-PLD1 may be considered as a new lung cancer treatment option.

Predictors of early progression after curative resection followed by platinum-based adjuvant chemoradiotherapy in oral cavity squamous cell carcinoma.

OBJECTIVES: Early progression, defined as a disease-free interval (DFI) of less than 6 months after completion of adjuvant platinum-based chemoradiotherapy (CRT), leads to poor outcomes in locally advanced oral cavity squamous cell carcinoma (OCSCC). However, appropriate biomarkers for predicting early progression remain unknown. METHODS: In this study, 346 patients with OCSCC, who underwent curative surgical resection and platinum-based adjuvant CRT at the Taipei Veterans General Hospital (202 patients, training cohort) and Chung Shan Medical University Hospital (144 patients, validation cohort) were enrolled. The clinical-pathological variables were compared using the χ2 test. Cox proportional-hazards analyses were performed for DFIs. Survival was estimated using the Kaplan-Meier method and log-rank tests, and a scoring system for predicting early progression was established. RESULTS: One-fifth (20.5%, 71/346) of all patients experienced progression within 6 months. Each of the independent factors for the DFI in the training cohort, including pT3-4, extracapsular spread, and perineural invasion, were assigned a score of one point to establish a scoring system. The 6-month DFIs of the low-risk (score 0-1), intermediate-risk (score 2), and high-risk (score 3) groups were 97.8%, 78.7%, and 35.7% and 88.2%, 77.6%, and 42.1% in the training and validation cohorts, respectively. If the cutoff level was ≥2 or <2, the sensitivity/specificity/area under the curve for the training and validation cohorts were 94.4%/56.1%/0.837, and 73.3%/56.6%/0.703, respectively. CONCLUSIONS: The established scoring system effectively predicted early progression after adjuvant CRT for locally advanced OCSCC.

Clinical Perspective of FDA Approved Drugs With P-Glycoprotein Inhibition Activities for Potential Cancer Therapeutics.

P-glycoprotein (also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) plays a crucial role in determining response against medications, including cancer therapeutics. It is now well established that p-glycoprotein acts as an ATP dependent pump that pumps out small molecules from cells. Ample evidence exist that show p-glycoprotein expression levels correlate with drug efficacy, which suggests the rationale for developing p-glycoprotein inhibitors for treatment against cancer. Preclinical and clinical studies have investigated this possibility, but mostly were limited by substantial toxicities. Repurposing FDA-approved drugs that have p-glycoprotein inhibition activities is therefore a potential alternative approach. In this review, we searched the Drugbank Database (https://www.drugbank.ca/drugs) and identified 98 FDA-approved small molecules that possess p-glycoprotein inhibition properties. Focusing on the small molecules approved with indications against non-cancer diseases, we query the scientific literature for studies that specifically investigate these therapeutics as cancer treatment. In light of this analysis, potential development opportunities will then be thoroughly investigated for future efforts in repositioning of non-cancer p-glycoprotein inhibitors in single use or in combination therapy for clinical oncology treatment.