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Background:Cutaneous melanoma is the most serious skin malignancy and new therapeutic strategies are needed for advanced melanoma. TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma. Here, we investigated the WIP1 inhibitor, GSK2830371, and MDM2-p53 binding antagonists (nutlin-3, RG7388 and HDM201) alone and in combination treatment in cutaneous melanoma cell lines and explored the mechanistic basis of these responses in relation to the genotype and induced gene expression profile of the cells.Methods:A panel of three p53WT (A375, WM35 and C8161) and three p53MUT (WM164, WM35-R and CHL-1) melanoma cell lines were used. The effects of MDM2 and WIP1 inhibition were evaluated by growth inhibition and clonogenic assays, immunoblotting, qRT-PCR gene expression profiling and flow cytometry.Results:GSK2830371, at doses ([els]10 μM) that alone had no growth-inhibitory or cytotoxic effects on the cells, nevertheless significantly potentiated the growth-inhibitory and clonogenic cell killing effects of MDM2 inhibitors in p53WT but not p53MUT melanoma cells, indicating the potentiation worked in a p53-dependent manner. The siRNA-mediated knockdown of p53 provided further evidence to support the p53 dependence. GSK2830371 increased p53 stabilisation through Ser15 phosphorylation and consequent Lys382 acetylation, and decreased ubiquitination and proteasome-dependent degradation when it was combined with MDM2 inhibitors. These changes were at least partly ATM mediated, shown by reversal with the ATM inhibitor (KU55933). GSK2830371 enhanced the induction of p53 transcriptional target genes, cell cycle arrest and apoptosis.Conclusions:GSK2830371, a WIP1 inhibitor, at doses with no growth-inhibitory activity alone, potentiated the growth-inhibitory and cytotoxic activity of MDM2 inhibitors by increasing phosphorylation, acetylation and stabilisation of p53 in cutaneous melanoma cells in a functional p53-dependent manner.

Brain metastases (BM) significantly impact prognosis and healthcare utilization but remain underrepresented in economic evaluations. The IMpower133 trial demonstrated the efficacy of atezolizumab plus chemotherapy (carboplatin and etoposide), particularly among patients without baseline BM, leading to its approval for extensive-stage small-cell lung cancer (EX-SCLC) in several countries. As previous studies did not incorporate BM status, we addressed this gap by including BM in the cost-effectiveness analysis of atezolizumab for EX-SCLC. A four-state Markov model was constructed with the following health states: progression-free, progressive disease (PD) without brain metastases, PD with brain metastases, and death, over a 15-year time horizon. Time-varying efficacy and utility were derived from IMpower133; direct medical costs were estimated using population-based databases. Both deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty in input parameters. Adding atezolizumab to chemotherapy increased QALYs by 0.721 at an incremental cost of NT$2,111,359, yielding an incremental net monetary benefit of NT$68,264, and a 53.22% probability of cost-effectiveness. Key sources of uncertainty include efficacy, cost of atezolizumab, time horizon, and utility. In conclusion, adding atezolizumab to chemotherapy is cost-effective for patients with EX-SCLC without baseline BM. Incorporating BM status into CEA could support more nuanced policy recommendations.

Background Afatinib is one of the standard treatments for patients with epidermal growth factor receptor ( EGFR )-mutated non-small-cell lung cancer (NSCLC). However, data on the use of afatinib in patients with poor performance status (PS ≥ 2) are limited. This study aimed to retrospectively review the clinical outcomes and safety of afatinib treatment in EGFR -mutation-positive (EGFRm+) NSCLC patients with PS ≥ 2. Methods The data for 62 patients who were treated at Linkou Chang Gung Memorial Hospital from January 2010 to August 2019 were retrospectively reviewed. Patients’ clinicopathological features were obtained, and univariate and multivariate analyses were performed to identify possible prognostic factors. Data on adverse events were collected to evaluate general tolerance for afatinib therapy. Results Until February 2020, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 58.1% (36/62), 69.4% (43/62), 8.8 months, and 12.9 months, respectively. The absence of liver metastasis (PFS: p  = 0.044; OS: p  = 0.061) and good disease control ( p  < 0.001 for PFS and OS) were independent favorable prognostic factors for PFS and OS. Bone metastasis ( p  = 0.036) and dose modification (reduction/interruption, p  = 0.021) were predictors of disease control. Conclusion Afatinib demonstrated acceptable efficacy and safety in the current cohort. This study provided evidence to support the use of afatinib as a first-line treatment in EGFRm+ NSCLC patients with poor PS.

Gemcitabine-based chemotherapy is the current standard treatment for biliary tract cancers (BTCs) and resistance to gemcitabine remains the clinical challenge. TP53 mutation has been shown to be associated with poor clinicopathologic characteristics and survival in patients with BTCs, indicating that p53 plays an important role in the treatment of these cancers. Herein, we comprehensively reviewed previous BTC preclinical research and early clinical trials in terms of p53, as well as novel p53-targeted treatment, alone or in combination with either chemotherapy or other targeted therapies in BTCs. Preclinical studies have demonstrated that p53 mutations in BTCs are associated with enhanced gemcitabine resistance, therefore targeting p53 may be a novel therapeutic strategy for treatment of BTCs. Directly targeting mutant p53 by p53 activators, or indirectly by targeting cell cycle checkpoint proteins (Chk1, ataxia telangiectasia related (ATR), and Wee1) leading to synthetic lethality, may be potential future strategies for gemcitabine-resistant p53 mutated BTCs. In contrast, for wild-type p53 BTCs, activation of p53 by inhibition of its negative regulators (MDM2 and wild-type p53-induced phosphatase 1 (WIP1)) may be alternative options. Combination therapies consisting of standard cytotoxic drugs and novel small molecules targeting p53 and related signaling pathways may be the future key standard approach to beat cancer.

Background Chemotherapy with gemcitabine and cisplatin has been the standard of care in first-line chemotherapy for advanced biliary tract cancer (BTC) since the trial ABC-02 was published in 2010. We aimed to investigate the prognostic and predictive factors of this regimen in a cohort of Taiwanese patients with advanced BTC. Methods A total of 118 patients with histologically confirmed BTC treated at Chang Gung Memorial Hospital at Linkou from 2012 to 2017 were retrospectively reviewed. Results The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 8.4 months, respectively. In the multivariate analysis, neutrophil to lymphocyte ratio (NLR) > 7.45, biliary drainage requiring both percutaneous transhepatic cholangiography drainage (PTCD) and internal stenting, and tumor responses with progressive diseases and not assessed were independent poor prognostic factors for PFS. Male sex, NLR > 7.45, alkaline phosphatase> 94 U/L, biliary drainage requiring both PTCD and internal stenting, and tumor responses with stable disease, progressive diseases and not assessed were independent poor prognostic factors for OS. Monocyte to lymphocyte ratio (MLR) ≤ 0.28 was the only significant predictive factor for the tumor response. Patients with complete response/partial response had significantly lower MLR than patients with other tumor responses. Conclusion We identified three important prognostic factors, namely tumor response, NLR, and biliary drainage requiring both PTCD and internal stenting for both PFS and OS. MLR was the only significant predictive factor for the tumor response. These findings could provide physicians with more information to justify the clinical outcomes in patients with advanced BTC in real-world practice.

Background The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. Methods We retrospectively reviewed 49 melanoma patients undergoing therapy with ICIs (anti-PD-1 monotherapy), and analyzed the correlation between irAEs and clinical outcomes including progression-free survival (PFS) and overall survival (OS). Results: Overall, the patients who experienced grade 1–2 irAEs had longer PFS (median PFS, 4.6 vs. 2.5 months; HR, 0.52; 95% CI: 0.27–0.98; p  = 0.042) and OS (median OS, 15.2 vs. 5.7 months; HR, 0.50; 95% CI: 0.24–1.02; p  = 0.058) than the patients who did not experience irAEs. Regarding the type of irAE, the patients with either skin/vitiligo or endocrine irAEs showed better PFS (median PFS, 6.1 vs. 2.7 months; HR, 0.40, 95% CI: 0.21–0.74; p  = 0.003) and OS (median OS, 18.7 vs. 4.5 months; HR, 0.34, 95% CI: 0.17–0.69, p = 0.003) than patients without any of these irAEs. Conclusions Melanoma patients undergoing anti-PD-1 monotherapy and experiencing mild-to-moderate irAEs (grade 1–2), particularly skin (vitiligo)/endocrine irAEs had favorable survival outcomes. Therefore, the association between irAEs and the clinical outcomes in melanoma patients undergoing anti-PD-1 ICIs may be severity and type dependent.

Background Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. This study aimed to evaluate the efficacy of EGFR‐TKIs and prognostic factors for patients with NSCLC harboring uncommon EGFR mutations, which account for 10% of EGFR mutations. Methods A total of 230 treatment‐naive patients with NSCLC harboring uncommon EGFR mutations treated with first‐line EGFR‐TKIs between 2011 and 2018 at four hospitals (belonging to four institutions, Linkou, Kaohsiung, Keelung, and Chiayi, of the Chang Gung Memorial Hospital) in Taiwan were retrospectively reviewed. Their clinicopathological characteristics, adverse events (AEs), objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and overall survival (OS) were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors for PFS. Results Overall, patients who received afatinib (n = 62) had better PFS (median: 6.4 vs. 5.9 months, p = 0.022) and OS (median: 13.4 vs. 13.0 months, p = 0.008) than those who received gefitinib/erlotinib (n = 124), although no significant differences were observed for ORR (46.8% vs. 35.5%, p = 0.137) or DCR (59.7% vs. 58.9%, p = 0.916). Patients who received afatinib showed significantly higher ORR (58.3% vs. 31.3%, p = 0.027) but not DCR compared with gefitinib/erlotinib for major uncommon mutations. Afatinib trended toward better PFS and OS for major uncommon mutations and compound mutations. No EGFR‐TKIs were effective for most NSCLC patients with exon 20 insertions. Performance status, metastasis of the liver and pleura, and dose reduction were independent prognostic factors for PFS. Conclusion Afatinib demonstrated better survival outcomes than gefitinib/erlotinib for NSCLC patients harboring major EGFR uncommon mutations and compound mutations. Performance status and metastatic sites may be useful for predicting PFS for major uncommon mutations and compound mutations. NSCLC patients with uncommon mutations treated with afatinib demonstrated higher survival than those given gefitinib/erlotinib. The independent predictors of progression‐free survival include dose reduction, metastases to the liver and pleura. The severity of paronychia is associated with progression‐free survival, particularly in patients with uncommon mutations. Afatinib is superior to gefitinib/erlotinib in terms of progression‐free survival and overall survival of NSCLC patients with uncommon mutations. Afatinib may represent one possible option for treatment of patients with exon 20 insertions, particularly if specific inhibitors are unavailable in daily practice.

Cholangiocarcinoma (CCA) is the second most common primary liver malignancy and carries a dismal prognosis due to difficulties in achieving an optimal resection, and poor response to current standard-of-care systemic therapies. We previously devised a CTLA4-PD-L1 DNA cancer vaccine (DNA vaccine) and demonstrated its therapeutic effects on reducing tumor growth in a thioacetamide (TAA)-induced rat intrahepatic CCA (iCCA) model. Here, we developed a CTLA4-PD-L1 chimeric protein vaccine (Protein vaccine), and examined its effects in the rat iCCA model. In a therapeutic setting, iCCA-bearing rats received either DNA plus Protein vaccines or Protein vaccine alone, resulting in increased PD-L1 and CTLA-4 antibody titers, and reduced iCCA tumor burden as verified by animal positron emission tomography (PET) scans. Treating iCCA-bearing rats with Protein vaccine alone led to the increase of CTAL4 antibody titers that correlated with the decrease of tumor SUV ratio, indicating regressed tumor burden, along with increased CD8 and granzyme A ( GZMA ) expression, and decreased PD-L1 expression on tumor cells. In a preventive setting, DNA or Protein vaccines were injected in rats before the induction of iCCA by TAA. Protein vaccines induced a more sustained PD-L1 and CTLA-4 antibody titers compared with DNA vaccines, and was more potent in preventing iCCA tumorigenesis. Correspondingly, Protein vaccines, but not DNA vaccines, downregulated PD-L1 gene expression and hindered the carcinogenesis of iCCA. Taken together, the CTLA4-PD-L1 chimeric protein vaccine may function both as a therapeutic cancer vaccine and as a preventive cancer vaccine in the TAA-induced iCCA rat model.

Esophageal cancer (EC) is a major cause of cancer-related mortality in Taiwan and globally. Patients with EC are highly prone to malnutrition, which adversely affects their prognosis. While Chinese herbal medicine (CHM) is commonly used alongside conventional anti-cancer treatments, its long-term impact on EC patients with malnutrition remains unclear. This study utilized a multi-center cohort from the Chang Gung Research Database, focusing on the long-term outcomes of CHM in EC patients with malnutrition between 1 January 2001, and 31 December 2018. Patients were monitored for up to 5 years or until death. Overall survival (OS) rates were calculated using the Kaplan-Meier method. Overlap weighting and landmark analysis were employed to address confounding and immortal time biases. Additionally, the study analyzed prescription data using a CHM network to identify key CHMs for EC with malnutrition, and potential molecular pathways were investigated using the Reactome database. EC patients with malnutrition who used CHM had a higher 5-year OS compared with nonusers (22.5% vs. 9% without overlap weighting; 24.3% vs. 13.3% with overlap weighting; log-rank test: = 0.006 and 0.016, respectively). The median OS of CHM users was significantly longer than that of nonusers (19.8 vs. 12.9 months, respectively). Hazard ratio (HR) analysis showed a 31% reduction in all-cause mortality risk for CHM users compared with nonusers (HR: 0.69, 95% confidence interval: 0.50-0.94, = 0.019). We also examined 665 prescriptions involving 306 CHM, with Willd. exhibiting the highest frequency of use. A CHM network was created to determine the primary CHMs and their combinations. The identified CHMs were associated with the regulation of immune and metabolic pathways, particularly in areas related to immune modulation, anti-cancer cachexia, promotion of digestion, and anti-tumor activity. The results of this study suggest a correlation between CHM use and improved clinical outcomes in EC patients with malnutrition. The analysis identified core CHMs and combinations of formulations that play a crucial role in immunomodulation and metabolic regulation. These findings lay the groundwork for more extensive research on the use of CHM for the management of malnutrition in patients with EC.

Background This study investigated the relationship between inflammatory biomarkers (lymphocyte ratio [NLR], monocyte‐to‐lymphocyte ratio [MLR], and platelet‐to‐lymphocyte ratio [PLR]) and the treatment outcomes of patients with non‐small cell lung cancer (NSCLC) treated with afatinib. Methods The patients with NSCLC treated with afatinib between June 2014 and February 2018 were retrospectively reviewed. Their inflammatory biomarkers and clinical outcomes (progression‐free survival [PFS] and tumor response) were explored using univariate and multivariate analyses. Results Among 325 patients, those with an NLR >2.18, MLR >0.19, and PLR >177.73 had significantly worse PFS than those with lower values. After adjusting for performance status, stage, and liver metastasis, the PFS was still unfavorable for a baseline NLR >2.18, MLR >0.19, or PLR > 177.73. Among 188 patients with paired inflammatory values, those whose NLR decreased by >29.5%, MLR decreased by >57.9%, and PLR increased by <18.8% had significantly better PFS. After adjusting for performance status, stage, and liver metastasis, the PFS was significantly unfavorable for an NLR decrease of <29.5% and MLR decrease of <57.9%. Among the patients with tumor response, NLR, MLR, and PLR significantly decreased after treatment (all p < 0.05). Conclusions Our study presented the NLR, MLR, and PLR as prognostic factors for patients with NSCLC treated with afatinib. Further investigation into these markers representing the tumor microenvironment and their association with cancer status is crucial for evaluating prognosis and clinical outcomes in patients with NSCLC. EGFRm NSCLC patients (n = 325). EGFRm NSCLC patients (n = 188). Afatinib for 1–3 months. Unfavorable prognostic factors for PFS. Baseline inflammatory values. NLR >2.18, MLR >0.19. PLR >177.73. Changes of inflammatory values. NLR decrease of <29.5%. MLR decrease of <57.9%.