Lung adenocarcinoma promotion by air pollutants.

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 µm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1ß. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for  PM2.5 air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

Long-term use and risk of major adverse cardiac events: Comparing enzalutamide and abiraterone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

This is a retrospective cohort study by analyzing a multi-institutional electronic medical records database in Taiwan to compare long-term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate-specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63-1.17) and OS (0.68: 0.41-1.14) between the use of ENZ and AA in chemotherapy-naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07-0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy-naïve mCRPC patients with high CV risk profile.

Therapeutic Potential of Regorafenib in Cisplatin-Resistant Bladder Cancer with High Epithelial-Mesenchymal Transition and Stemness Properties.

Bladder cancer is becoming one of the most common malignancies across the world. Although treatment strategy has been continuously improved, which has led to cisplatin-based chemotherapy becoming the standard medication, cancer recurrence and metastasis still occur in a high proportion of patients because of drug resistance. The high efficacy of regorafenib, a broad-spectrum kinase inhibitor, has been evidenced in treating a variety of advanced cancers. Hence, this study investigated whether regorafenib could also effectively antagonize the survival of cisplatin-resistant bladder cancer and elucidate the underlying mechanism. Two types of cisplatin-resistant bladder cancer cells, T24R1 and T24R2, were isolated from T24 cisplatin-sensitive bladder cancer cells. These cells were characterized, and T24R1- and T24R2-xenografted tumor mice were created to examine the therapeutic efficacy of regorafenib. T24R1 and T24R2 cells exhibited higher expression levels of epithelial-mesenchymal transition (EMT) and stemness markers compared to the T24 cells, and regorafenib could simultaneously inhibit the viability and the expression of EMT/stemness markers of both T24R1 and T24R2 cells. Moreover, regorafenib could efficiently arrest the cell cycle, promote apoptosis, and block the transmigration/migration capabilities of both types of cells. Finally, regorafenib could significantly antagonize the growth of T24R1- and T24R2-xenografted tumors in mice. These results demonstrated the therapeutic efficacy of regorafenib in cisplatin-resistant bladder cancers. This study, thus, provides more insights into the mechanism of action of regorafenib and demonstrates its great potential in the future treatment of cisplatin-resistant advanced bladder cancer patients.

Real-world evidence of the safety and effectiveness of regorafenib in Taiwanese patients with metastatic colorectal cancer: CORRELATE Taiwan.

BACKGROUND/PURPOSE: This analysis reports safety and effectiveness data from the Taiwanese cohort of the CORRELATE study. METHODS: CORRELATE was a prospective, observational study to assess the safety and effectiveness of regorafenib for the treatment of metastatic colorectal cancer (CRC) in real-world clinical practice that was conducted in 13 different countries in Asia, Europe and Latin America. The primary endpoint of the study was incidence of all treatment-emergent AEs (TEAEs), and secondary endpoints included overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). RESULTS: The global study population (N = 1037) included 128 Taiwanese patients with a median age of 64 years, median weight of 62.02 kg and 66.41% were male. Reduced initiating doses of regorafenib and dose interruptions were common in Taiwanese patients (71.87% and 50.00%, respectively). The safety profile of regorafenib was consistent with that seen in Asian patients in the clinical development trials, including the CORRECT and CONCUR studies, with hand-foot-skin reactions (HFSR) of any grade occurring in 33.59% of patients. Median OS was 11.64 months in the Taiwanese patients (95% confidence interval [CI], 8.36-13.82) and median PFS was 2.17 months (95% CI, 1.97-2.89). CONCLUSION: The safety and effectiveness of regorafenib in this real-world study was generally consistent with the known efficacy and safety profile in Asian patients in clinical trials. TRIAL REGISTRATION: NCT02042144.

Prognostic Significance of Neoadjuvant Rectal Scores in Preoperative Short-Course Radiotherapy and Long-Course Concurrent Chemoradiotherapy for Patients with Locally Advanced Rectal Cancer.

BACKGROUND: This study aimed to investigate the prognostic factors and the utility of the neoadjuvant rectal (NAR) score for patients who have locally advanced rectal cancer (LARC) treated with preoperative short-course radiotherapy (SRT) or long-course concurrent chemoradiotherapy (CRT). METHODS: Of 314 consecutive stage 2 or 3 rectal cancer patients enrolled from January 2006 to December 2017, 205 underwent preoperative SRT (2500 cGy/5 fractions), and 109 underwent preoperative CRT (4200-5080 cGy/21-28 fractions) after total mesorectal excision (TME). The study calculated NAR scores using the following equation: [5 pN - 3(cT - pT) + 12]2/9.61. RESULTS: The multivariate analysis showed that age above 65 years, pT4, pN2, NAR scores higher than 16, and distance from anal verges (< 8 cm) were significant prognostic factors for overall survival (OS), whereas, pN2, NAR scores lower than 16, and distance from anal verges (< 8 cm) were significant prognostic factors for disease-free survival (DFS) and distant metastasis (DM). The patients with an NAR score higher than 16, had a 5-year OS rate of 67.6%, a DFS rate of 56.9%, a locoregional recurrence (LRR) rate of 7.7%, and a DM rate of 35% compared with corresponding rates of 87.6%, 76.7%, 5.4%, and 7.2% for the patients with an NAR score of 16 or lower (p < 0.001 for OS, < 0.001 for DFS, 0.25 for LRR, and < 0.001 for DM). CONCLUSIONS: For patients who undergo SRT or CRT for LARC, a higher NAR score is associated with worse OS and DFS and higher DM rates at 5 years. The NAR score could be used as a short-term surrogate end point after neoadjuvant therapy for LARC.

Accelerated Risk of Premature Ischemic Stroke in 5-Year Survivors of Nasopharyngeal Carcinoma.

BACKGROUND: Research on cancer survivorship associated with nasopharyngeal carcinoma (NPC) is rare. We aimed to elucidate the risk of ischemic stroke in 5-year survivors of NPC following radiotherapy (RT) or concurrent chemoradiation therapy (CCRT). SUBJECTS, MATERIALS, AND METHODS: NPC survivors, defined as those who survived longer than 5 years after diagnosis, were identified and matched at a 1:5 ratio with normal controls from the Longitudinal Health Insurance Database 2005 of Taiwan. The stratified Cox regression models were used to access the risk of ischemic stroke, with adjustment for age, treatment modality, comorbidities, and socioeconomic characteristics. RESULTS: From 2000 to 2005, a total of 3,016 NPC survivors who had received RT (n = 959) or CCRT (n = 2,057) and 15,080 controls were matched for age, sex, income, and urbanization level. The risk of ischemic stroke was significantly higher in the NPC survivor cohort than in the control cohort. Stroke was positively related to death. Moreover, the age onset of stroke for NPC survivors was 10 years earlier than that for the general population. CONCLUSION: Not only was the stroke risk in NPC survivors higher than that in the general population, but the onset age was also 10 years earlier. Future survivorship care should include ischemic stroke as a late complication, for its proper prevention and management. IMPLICATIONS FOR PRACTICE: Nasopharyngeal carcinoma (NPC) is endemic in Taiwan, and its 5-year survival is 65.2%. With the increased 5-year cancer survivors, survivorship has become an important issue. However, research on NPC survivorship is very rare. To the authors' knowledge, this is the first population-based study on long-term NPC survivors. This study's results indicated that not only was the risk of ischemic stroke in NPC survivors at least triple that of the general population, but the onset age was also 10 years earlier. These results may provide solid evidence that survivorship care guidelines should include stroke as a late complication in 5-year NPC survivors, for its proper prevention and management.

The Predictive Value of Pretreatment Neutrophil-To-Lymphocyte Ratio in Esophageal Squamous Cell Carcinoma.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has been reported to be both a prognostic biomarker for cancer and associated with inflammation, but its predictive role in tumor immunity is not clear. The present study examined the correlations of the NLR and immune suppression with the prognoses in patients with esophageal squamous cell carcinoma (ESCC). METHODS: We performed a retrospective review of 1168 patients who were newly diagnosed with stage T1N(+) and T2-T4 ESCC at our hospital. The NLR of each ESCC patient prior to treatment was calculated, and the associations of the NLR with various clinicopathological parameters and prognoses were then examined. In addition, correlations of the proportion of myeloid-derived suppressor cells (MDSCs) and level of interleukin (IL)-6 with the NLR were assessed in 242 ESCC patients. RESULTS: An elevated NLR was significantly correlated with advanced-stage disease and reduced overall survival (OS) of ESCC patients. Furthermore, the levels of IL-6 in tumors and MDSCs in the peripheral circulation were significantly correlated with the prognoses of ESCC, and the NLR was positively correlated with MDSC levels in the circulation and IL-6 staining intensity in tumor specimens. Moreover, a high NLR was significantly associated with reduced OS in the 926 patients treated with concomitant chemoradiotherapy, but not in the 242 patients who underwent surgical intervention. CONCLUSION: The NLR may represent a clinically useful biomarker to guide ESCC treatment decisions. Patients with a higher NLR may be an optimal subgroup for IL-6- and MDSC-targeted therapy.

Baseline circulating stem-like cells predict survival in patients with metastatic breast Cancer.

BACKGROUND: Circulating tumor cells (CTCs) are associated with breast cancer prognosis. Research is limited regarding the role of circulating cancer stem-like cells (cCSCs) considering the treatment response and survival among patients with metastatic breast cancer. Accordingly, we performed this prospective study to clarify the prognostic significance of baseline cCSCs for metastatic breast cancer in terms of first-line chemotherapy. METHODS: Between April 2014 and January 2016, we prospectively enrolled 48 patients with stage IV breast invasive ductal carcinoma who underwent first-line chemotherapy. We identified and analyzed CTCs and cCSCs by using a protocol based on negative selection and flow cytometry before chemotherapy. CTCs were identified as EpCAM+Hoechst+CD45- cells and cCSCs as CD133+EpCAM+Hoechst+CD45- cells. cCSCs were expressed as a percentage of CTCs. The associations between CTCs, cCSCs, and the clinicopathological variables that were predictive of the treatment response and survival outcome were analyzed using univariate and multivariate analyses. RESULTS: We identified CTCs in all the enrolled patients, with a median number of 33.9/mL CTCs. CSCs were isolated in 97.9% of the patients; the median percentage of cCSCs was 14.7%. A high baseline level of cCSCs was correlated with an inferior tumor response rate (54.2% vs. 95.8%, p < 0.001), overall survival (OS; median: 27.7 months vs. not reached, p < 0.001), and progression-free survival (PFS; median: 5.7 vs. 18.0 months, p < 0.001). Multivariate analysis revealed that along with other clinical variables, baseline cCSCs remained an independent prognostic factor for OS and PFS. CONCLUSIONS: Baseline cCSCs predict the treatment response as well as survival in patients with metastatic breast cancer undergoing first-line chemotherapy. Therefore, the measurement of cCSCs may assist in identifying early cancer treatment response and prognosis.

Antrodia cinnamomea extract inhibits the proliferation of tamoxifen-resistant breast cancer cells through apoptosis and skp2/microRNAs pathway.

BACKGROUND: Breast cancer is the most common cancer in women and affects 1.38 million women worldwide per year. Antiestrogens such as tamoxifen, a selective estrogen receptor (ER) modulator, are widely used in clinics to treat ER-positive breast tumors. However, remissions of breast cancer are often followed by resistance to tamoxifen and disease relapse. Despite the increasing understanding of the resistance mechanisms, effective regimens for treating tamoxifen-resistant breast cancer are limited. Antrodia cinnamomea is a traditional medicinal mushroom native only to Taiwan. In this study, we aimed to examine in vitro effect of antrodia cinnamomea in the tamoxifen-resistant cancer. METHODS: Antrodia cinnamomea was studied for its biological activity against proliferation of tamoxifen-resistant breast cancer by XTT assay. Next, the underlying mechanism was studied by flow cytometry, qPCR and Western's blotting assay. RESULTS: Our results revealed that the ethanol extract of antrodia cinnamomea (AC) can inhibit the growth of breast cancer cells, including MCF-7 cell and tamoxifen-resistant MCF-7 cell lines. Combination treatment with AC and 10- 6 M tamoxifen have the better inhibitory effect on the proliferation of tamoxifen-resistant MCF-7 cells than only AC did. AC can induce apoptosis in these breast cancer cells. Moreover, it can suppress the mRNA expression of skp2 (S-phase kinase-associated protein 2) by increasing the expressions of miR-21-5p, miR-26-5p, and miR-30-5p in MCF-7 and tamoxifen-resistant MCF-7 cells. CONCLUSIONS: These results suggest that the ethanol extract of antrodia cinnamomea could be a novel anticancer agent in the armamentarium of tamoxifen-resistant breast cancer management. Moreover, we hope to identify additional pure compounds that could serve as promising anti-breast cancer candidates for further clinical trials.

MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis.

Chondrosarcoma, a heterogeneous malignant bone tumor, commonly produces cartilage matrix, which generally has no response to conventional therapies. Studies have reported that MLN4924, a NEDD8-activating enzyme inhibitor, achieves antitumor effects against numerous malignancies. In this study, the suppressive effects of MLN4924 on human chondrosarcoma cell lines were investigated using in vitro and in vivo assays, which involved measuring cell viability, cytotoxicity, apoptosis, proliferation, cell cycles, molecule-associated cell cycles, apoptosis, endoplasmic reticulum (ER) stress, and tumor growth in a xenograft mouse model. Our results demonstrated that MLN4924 significantly suppressed cell viability, exhibited cytotoxicity, and stimulated apoptosis through the activation of caspase-3 and caspase-7 in chondrosarcoma cell lines. Furthermore, MLN4924 significantly inhibited cell proliferation by diminishing the phosphorylation of histone H3 to cause G2/M cell cycle arrest. In addition, MLN4924 activated ER stress⁻related apoptosis by upregulating the phosphorylation of c-Jun N-terminal kinase (JNK), enhancing the expression of GRP78 and CCAAT-enhancer-binding protein homologous protein (CHOP, an inducer of endoplasmic ER stress⁻related apoptosis) and activating the cleavage of caspase-4. Moreover, MLN4924 considerably inhibited the growth of chondrosarcoma tumors in a xenograft mouse model. Finally, MLN4924-mediated antichondrosarcoma properties can be accompanied by the stimulation of ER stress⁻related apoptosis, implying that targeting neddylation by MLN4924 is a novel therapeutic strategy for treating chondrosarcoma.

The survival impact of delayed surgery and adjuvant chemotherapy on stage II/III rectal cancer with pathological complete response after neoadjuvant chemoradiation.

Neoadjuvant concurrent chemoradiation (CCRT) is standard treatment for clinical stage II/III rectal cancers. However, whether patients with pathological complete response (pT0N0, pCR) should receive adjuvant chemotherapy and whether delayed surgery will influence the pCR rate remains controversial. A nationwide population study was conducted using the Taiwan Cancer Registry Database from January 2007 to December 2013. Kaplan-Meier survival analysis was performed. Cox proportional hazards models were used to estimate multivariate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). Of the 1,914 patients who received neoadjuvant CCRT, 259 (13.6%) achieved pCR and had better survival (adjusted HR: 0.37, 95% CI: 0.24-0.58; p < 0.001). The cumulative rate of pCR rose up to 83.4% in the 9th week and slowly reached a plateau after the 11th week. Among the patients with pCR, those who received adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy (adjusted HR: 0.72, 95 CI: 0.27-1.93; p = 0.52). By subgroup analysis, those younger than 70-year old and received adjuvant chemotherapy had better survival benefit than those without adjuvant chemotherapy (adjusted HR: 0.19, 95% CI: 0.04-0.97; p = 0.046). Delayed surgery by 9-12 weeks after the end of neoadjuvant CCRT can maximize the pCR rate, which is correlated with better survival. Adjuvant chemotherapy may be considered in patients with pCR and aged <70-year old, but further prospectively randomized controlled trials are warranted to validate these findings.

Glasgow prognostic score after concurrent chemoradiotherapy is a prognostic factor in advanced head and neck cancer.

OBJECTIVE: This study aims to evaluate the impact and potential prognostic roles of the pre- and post-treatment Glasgow prognostic score (GPS) and the change thereof in patients with advanced head and neck cancer undergoing concurrent chemoradiotherapy (CCRT). METHODS: We collected GPS and clinicopathological data of 139 stage III, IVA, and IVB head and neck cancer patients who underwent CCRT between 2008 and 2011. Their GPSs pre- and post-CCRT and the change thereof were analyzed for correlations with recurrence and survival. RESULTS: The GPS changed in 72 (51.8%) patients, with worse scores observed post-CCRT in 65 (90.3%) of the GPS changed patients. Patients in the improved GPS group showed a tendency toward better survival. From the multivariate analysis, the post-CCRT GPS level was an independent prognostic factor in addition to tumor stage. CONCLUSIONS: After CCRT, a high GPS was revealed to be an important predictor of survival for advanced head and neck cancer.

Overall survival benefits of first-line EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancers: a systematic review and meta-analysis.

BACKGROUND: Accumulating data shows that exon 19 deletions and L858R, both activating epidermal growth factor receptor mutations in non-small-cell lung cancers (NSCLCs), are just two different entities in terms of prognosis and treatment response to tyrosine kinase inhibitors (TKIs). METHODS: A systematic review and meta-analysis of randomized controlled trials comparing TKIs with conventional chemotherapy was performed. Eight trials of 1498 patients and five trials of 1279 patients with either exon 19 deletions or L858R were included in the meta-analysis. RESULTS: TKI treatment demonstrated progression-free survival benefit in patients with exon 19 deletions (hazard ratio (HR): 0.27, 95% confidence interval (CI): 0.21-0.35) and L858R (HR: 0.45, 95% CI: 0.35-0.58). Patients with exon 19 deletions had significant overall survival (OS) benefit under TKI treatment (HR: 0.72, 95% CI: 0.60-0.88). Subgroup analyses showed that irreversible TKIs, but not reversible TKIs, had statistically significant OS benefit in these patients (irreversible TKIs, HR: 0.59, 95% CI: 0.47-0.73; reversible TKIs, HR: 0.84, 95% CI: 0.69-1.02). Patients with L858R demonstrated no OS benefit under first-line TKI use (HR: 1.15, 95% CI: 0.95-1.39). CONCLUSIONS: In patients with advanced NSCLC harbouring exon 19 deletions, TKIs are associated with better OS compared with conventional chemotherapy. Future clinical trials should take exon 19 deletions and L858R as distinct disease entities and evaluate the treatment efficacy separately.

Incidence and risk factors for central venous access port-related infection in Chinese cancer patients.

BACKGROUND/PURPOSE: Cytotoxic chemotherapy via central venous access ports is an important part of the standard treatment for most cancers, but it is accompanied with the risk of infections. This study aimed to analyze the incidence and risk factors for central venous access port-related infection (CPI) among Chinese patients receiving cytotoxic chemotherapy. METHODS: Between January 1, 2002 and December 31, 2005 a total of 1391 cancer patients with 1449 totally implantable central venous access ports were evaluated. The log-rank test and Cox proportional hazards model were used for the analyses of risk factors. RESULTS: The overall CPI incidence rate was 0.21 per 1000 catheter-days. Hematological malignancies and head and neck cancer were associated with an increased risk of CPI (hazard ratio 4.00 and 4.11, respectively, both p < 0.001) and less infection-free catheter longevity (p < 0.001) compared with other cancer types. Chemotherapy in an adjuvant setting was associated with a lower risk of infection than for patients in a nonadjuvant setting (p < 0.001). The most common pathogens isolated from CPI were Pseudomonas aeruginosa and Candida. CONCLUSION: Infection remains to be a challenging issue for totally implantable central venous ports. Implementation of an insertion bundle for the prevention of central line-associated bloodstream infections is warranted, especially for those patients with hematological and head and neck cancers, as well as for patients receiving chemotherapy in the metastatic settings.

Modulation of mitochondrial apoptosis by ß2-adrenergic receptor blockage in colorectal cancer after radiotherapy: an in-vivo and in-vitro study.

Colorectal cancer (CRC) is one of the leading causes of malignancy-related deaths worldwide. Radiotherapy is often combined with surgery to treat patients with more advanced CRC. Despite impressive initial clinical responses, radiotherapy resistance is the main reason for most treatment failures in colorectal cancer. The G protein-coupled adrenergic receptor (AR) has shown to involve in the development and radiotherapy resistance of CRC. The ß2-AR blockage (ICI-118,551) can use to inhibit the progression of CRC through downregulating EGFR-Akt-ERK1/2 signaling. Since catecholamines-activated the G protein-coupled AR activation has been shown to result in radioresistant, co-treatment with both ß2-AR blockage and radiation may be improved the clinical outcome of CRC. We demonstrated that selective ß2-AR blockage, but not selective ß1-AR blockage, significantly enhanced radiation-induced apoptosis in CRC cells with wild-type p53 in vitro. The molecular mechanism of the apoptotic pathway was possibly triggered by a change in the mitochondrial membrane permeability and release of cytosolic cytochrome C through phospho-P53 mitochondrial translocation. We also found that a P53 knockout in the HCT116 cells was correlated with reversing ß2-AR blockage-mediated apoptosis induction after radiation treatment. Furthermore, the ß2-AR blockage significantly inhibited CRC cell-xenograft growth in vivo. Our study suggests that ß2-AR blockage may be used as adjunct agent for improving the clinical outcomes of CRC following radiotherapy by inducing apoptosis in CRC cells.

The impact of sarcopenia on overall survival in patients with pan-RAS wild-type colorectal liver metastasis receiving hepatectomy.

Sarcopenia has been associated with conventional chemotherapy-related toxicity, postoperative complications and poor overall survival in patients with genotype-unselected metastatic colorectal cancer (mCRC). This study aimed to evaluate the prognostic implications of sarcopenia and its change after perioperative cetuximab plus doublet chemotherapy and hepatectomy in patients with RAS wild-type colorectal liver metastasis (CRLM). Patients with CRLM from 2007 to 2018 in Chang Gung Research Database were retrospectively analyzed. Baseline characteristics as well as skeletal muscle index (SMI) at baseline and dynamic changes after interventions were collected. A multivariate Cox proportional hazard model was used to evaluate the effect of each parameter on overall survival (OS), and the Kaplan-Meier method was used to establish survival curves. A two-sided p value < 0.05 was considered statistically significance. Of 214 RAS wild-type mCRC patients who received both cetuximab and doublet chemotherapy, 77 who received upfront or subsequent hepatectomy were included in this study. The median follow-up time was 2.3 years. The rate of sarcopenia was higher in the patients who received neoadjuvant cetuximab-containing regimens than in those who received upfront hepatectomy (95% versus 63%, p = 0.001). Increased SMI after perioperative systemic therapy remained independently associated with better OS in multivariate analysis [hazard ratio (HR) = 0.27/10% increase, p = 0.013). The patients with sarcopenia had a trend of worse OS than those without sarcopenia (median OS: 4.5 versus 3.6 years, log-rank p = 0.282). Improvement in sarcopenia ([SMI after intervention - initial SMI]/initial SMI × 100%) is an important prognostic factor for OS. Future research is warranted to investigate direct interventions for sarcopenia and the impact on OS.

Efficacy and Safety of a Parenteral Nutrition Program for Patients with RAS Wild-Type Metastatic Colorectal Cancer Administered First-Line Cetuximab Plus Chemotherapy: A Propensity Score Matching Study.

Malnutrition is a common problem in patients with metastatic colorectal cancer (mCRC) receiving targeted therapy plus chemotherapy, resulting in severe toxicity and decreased survival rates. This retrospective study employing propensity score matching (PSM) examined the efficacy and safety of a supplemental home parenteral nutrition (HPN) program for patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy. This retrospective nationwide registry study included data from 14 medical centers/hospitals across Taiwan, and the data period ranged from November 2016 to December 2020. Patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy as their first-line therapy were included and divided into HPN and non-HPN program groups. HPN was initiated based on patient-specific factors, such as baseline nutritional status, treatment-related toxicities, and comorbidities. Clinical outcomes were evaluated using response to therapy, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). This study recruited 758 patients, of whom 110 and 648 were included in the HPN and non-HPN program groups, respectively. After 1:3 PSM, the data of 109 and 327 patients from the HPN and non-HPN program groups were analyzed, respectively. The HPN program group had a higher metastasectomy rate (33.9% vs. 20.2%, p = 0.005), and longer duration of treatment and DoR than the non-HPN program group (13.6 vs. 10.3 and 13.6 vs. 9.9 months, p = 0.001 and < 0.001, respectively). The HPN program group tended to have a longer median PFS (18.2 vs. 13.9 months, p = 0.102). Moreover, we noted a significant improvement in the median OS in the same group (53.4 vs. 34.6 months, p = 0.002). Supplemental HPN programs may be recommended for select patients with mCRC receiving targeted therapy plus chemotherapy to improve oncological outcomes.

Survival benefit of metastasectomy in first-line cetuximab therapy in patients with RAS wild-type metastatic colorectal cancer: a nationwide registry.

This multicenter study aimed to explore the survival benefit of metastasectomy by first-line cetuximab-based chemotherapy in real-world patients with RAS wild-type metastatic colorectal cancer (mCRC). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and metastasectomy rate. The exploratory endpoint was the optimal treatment cycle for better OS and PFS. Receiver operating characteristic curve with the area under curve (AUC) was used to identify the optimal cut-off cycle for survival outcomes. A total of 758 mCRC patients were enrolled in this study, with a median OS of 35.1 months, median PFS of 14.6 months, and metastasectomy rate of 21.4%. Left-sided mCRC had a significantly higher DCR (88.9% vs. 73.1%, P<0.001) and better OS (36.4 vs. 19.6 months, P<0.001). There were no significant differences in PFS and metastasectomy rate between left-sided and right-sided mCRC. However, mCRC patients who underwent metastasectomy over the course of treatment had better OS (54.9 vs. 28.6 months, P<0.001) and PFS (21.0 vs. 13.1 months, P<0.001) than those who did not. Notably, right-sided mCRC who benefited from first-line cetuximab-based chemotherapy to underwent metastasectomy also had favorable outcomes, on a par with left-sided mCRC. The optimal treatment cycle was 14 cycles (AUC: 0.779, P<0.001). Patients who received ≥14 cycles had higher metastasectomy rates (27.5% vs. 13.5%, P<0.001), favorable OS (42.6 vs. 23.4 months, P<0.001) and PFS (18.1 vs. 8.6 months, P<0.001), and, importantly, had comparable adverse events compared with patients who received <14 cycles of treatment. Patients who underwent metastasectomy after or during first-line cetuximab therapy have an improved OS in both left-sided and right-sided mCRC. Furthermore, patients receive ≥14 cycles of treatment whenever possible to achieve a higher likelihood of metastasectomy was associated with favorable survival outcomes.

The cancer stemness inhibitor napabucasin suppresses small cell lung cancer growth through SOX2 expression.

Small cell lung cancer (SCLC) is a high-grade malignancy of neuroendocrine origin characterized by aggressive cell growth and a poor survival rate of patients. Currently, the treatment options for SCLC remain limited despite platinum-based chemotherapy. Systemic chemotherapy is effective for SCLC, but most patients eventually acquire drug resistance, which leads to treatment failure. Stemness-high cancer cells show characteristics of advanced tumorigenesis and metastasis and have high potential in promoting treatment resistance and disease relapse. Napabucasin (BBI608), a novel small-molecule drug targeting on signal transducer and activator of transcription 3 (STAT3), was shown to suppress the progression and metastasis of stemness-high cancer stem cells in various cancers. Here, we demonstrated that napabucasin significantly decreased viability and colony formation and induced the arrest of S-phase cell cycle and apoptosis in cisplatin-resistant SCLC cells. Findings from mechanistic studies further indicated that napabucasin directly downregulated the expression of SOX2 in cisplatin-resistant SCLC cells; however, dysfunctional SOX2 expression in SCLC cells was associated with interference in the napabucasin-mediated reduction of cell viability. In contrast, napabucasin-induced viability reduction was restored in these cells when SOX2 expression was upregulated. Furthermore, napabucasin significantly inhibited cisplatin-resistant SCLC cell xenograft growth in vivo by downregulating SOX2 and inducing apoptosis. These data demonstrate that napabucasin may be a novel drug for the clinical treatment of cisplatin-resistant SCLC.

Association of early changes of circulating cancer stem-like cells with survival among patients with metastatic breast cancer.

Background: This study aimed to investigate the role of circulating tumor cells (CTCs) and circulating cancer stem-like cells (cCSCs) before and after one cycle of chemotherapy and assessed the effects of early changes in CTCs and cCSCs on the outcomes of patients with metastatic breast cancer. Methods: Patients with stage IV invasive ductal carcinoma of the breast who received first-line chemotherapy between April 2014 and January 2016 were enrolled. CTCs and cCSCs were measured before the first cycle of chemotherapy (baseline) and on day 21, before the second cycle of chemotherapy commenced; a negative selection strategy and flow cytometry protocol were employed. Results: CTC and cCSC counts declined in 68.8 and 45.5% of patients, respectively. Declines in CTCs and cCSCs following the first chemotherapy cycle were associated with superior chemotherapy responses, longer progression-free survival (PFS), and longer overall survival (OS). An early decline in cCSCs remained an independent prognostic indicator for OS and PFS in multivariate analysis. Conclusions: A cCSC decline after one cycle of chemotherapy for metastatic breast cancer is predictive of a superior chemotherapy response and longer PFS and OS, implying that cCSC dynamic monitoring may be helpful in early prediction of treatment response and prognosis.