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Background: The poor prognosis of anaplastic thyroid cancer (ATC) patients is associated with limited effective therapeutic strategies. Multiple antiangiogenesis tyrosine kinase inhibitors (TKIs) have been applied in later-line treatment of ATC; however, the results reported in clinical trials were controversial. In this study, we reconstructed the patient-level data to pooled-analyze the survival data, responses, and adverse events., Methods: Online databases (PubMed, Web of Science, Embase, and Cochrane CENTRAL) were searched on September 03, 2023. R software combined with the "metaSurvival" and "meta" packages were used to reconstruct the survival curves and summarize the response rates. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were survival rate, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events., Results: Six prospective clinical trials involving 140 ATC patients were enrolled. Four types of TKIs (imatinib, pazopanib, sorafenib, and lenvatinib) were included. When advanced ATC patients were treated with the TKIs, the median OS was 4.8 months and the median PFS was 2.6 months. The pooled ORR and DCR were 9% and 53%. Hypertension, decreased appetite, rash, and lymphopenia were the most common grade ≥ 3 treatment-related adverse events., Conclusion: Mono-anitangiogenesis TKI therapy showed limited improvements in treating advanced ATC patients. Combining antiangiogenesis TKI therapy with chemotherapy, radiotherapy, or immunotherapy could be the direction of future studies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively., Methods: For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs)., Results: Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1-9.7), and the median PFS was 3.2 months (95% CI 1.9-6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%-27%) and 64% (95% CI 55%-72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%-86%)., Conclusion: Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Lin, Kuang and Cao.)

Background: Immunotherapy has revolutionized the treatment of hepatocellular carcinoma (HCC). However, whether adding immunotherapy to antiangiogenic therapy benefits patients with unresectable HCC (uHCC) more in the first-line setting remains controversial., Objective: In this analysis, we compared the clinical outcomes of lenvatinib monotherapy with atezolizumab plus bevacizumab combination therapy in advanced uHCC in real-world clinical practice., Methods: The MEDLINE, Embase, and Cochrane CENTRAL databases were systematically searched on 23 April 2023. The "metaSurvival" and "meta" packages of the R software (version 4.2.2) were used to summarize the survival curves and meta-analyze the survival data. Overall survival (OS) and progression-free survival (PFS) were defined as dual primary endpoints. Secondary endpoints included the objective response rate (ORR) and disease control rate (DCR)., Results: Overall, the pooled median OS was 18.4 months in the lenvatinib group versus 18.5 months in the atezolizumab plus bevacizumab group; the pooled median PFS was 6.9 months in the lenvatinib group versus 7.3 months in the atezolizumab plus bevacizumab group. Lenvatinib therapy showed similar OS [hazard ratio (HR): 0.91, 95% confidence interval (CI): 0.55-1.52, p = 0.72] and PFS (HR: 0.79, 95% CI: 0.56-1.12, p = 0.19) compared with atezolizumab plus bevacizumab therapy. In addition, a comparable ORR [odds ratio (OR): 0.89, 95% CI: 0.65-1.20, p = 0.44) was observed between lenvatinib and atezolizumab plus bevacizumab., Conclusions: Comprehensive analysis suggested that lenvatinib monotherapy exhibited survival outcomes comparable to those of atezolizumab plus bevacizumab combination therapy, which may provide useful insights for clinicians in future clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Tyrosine kinase inhibitors (TKIs) contribute to the treatment of patients with anaplastic thyroid cancer (ATC). Although prospective clinical studies of TKIs exhibit limited efficacy, whether ATC patients benefit from TKI treatment in real-world clinical practice may enlighten future explorations. Therefore, we conducted this effective analysis based on real-world retrospective studies to illustrate the efficacy of TKI treatment in ATC patients., Methods: We systematically searched the online databases on September 03, 2023. Survival curves were collected and reconstructed to summarize the pooled curves. Responses were analyzed by using the "meta" package. The primary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR)., Results: 12 studies involving 227 patients were enrolled in the study. Therapeutic strategies included: anlotinib, lenvatinib, dabrafenib plus trametinib, vemurafenib, pembrolizumab plus dabrafenib and trametinib, pembrolizumab plus lenvatinib, pembrolizumab plus trametinib, and sorafenib. The pooled median OS and PFS were 6.37 months (95% CI 4.19-10.33) and 5.50 months (95% CI 2.17-12.03). The integrated ORR and DCR were 32% (95% CI 23%-41%) and 40% (95% CI 12%-74%)., Conclusion: In real-world clinical practice, ATC patients could benefit from TKI therapy. In future studies, more basic experiments and clinical explorations are needed to enhance the effects of TKIs in the treatment of patients with ATC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kuang, Zhang, Lin, Fu, Cao and Wang.)

Background: Novel-fosfamides (NFOs) belong to active metabolites of ifosfamide that bypass the generation of toxic byproducts. In this analysis, we aimed to comprehensively assess the benefits and risks of NFO monotherapy or in combination with doxorubicin (DOX) versus single-drug DOX in previously untreated patients with advanced soft-tissue sarcoma (ASTS)., Methods: Online PubMed, Web of Science, Embase, and Cochrane CENTRAL databases were systematically searched on April 26, 2022. Objective response rate and disease control rate were primary outcomes. Overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events were secondary outcomes., Results: In all, 3 randomized clinical trials with a total of 1207 ASTS patients were eligible. DOX plus NFO combination therapy showed higher risk ratios of objective response rate (1.50, 95% CI 1.20-1.68, P = .0003) and disease control rate (1.15, 95% CI 1.05-1.27, P = .0030) compared with DOX monotherapy. Nevertheless, NFO-based monotherapy and combination therapy were found no improvements on OS (hazard ratio 0.93, 95% CI 0.52-1.65, P = .8050) and PFS (hazard ratio 0.88, 95% CI 0.54-1.43, P = .6088) against DOX. More incidences of grade 3 or worse anemia, thrombocytopenia, stomatitis, diarrhea, constipation, and febrile neutropenia were observed in NFO-based treatments., Conclusion: Adding NFO to DOX as first-line therapy improved the responses in ASTS patients but did not prolong OS and PFS. Grade 3 or worse treatment-related adverse events should be treated with caution during the NFO-based therapies., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Sacituzumab govitecan (SG) is an antibody-drug conjugate that targets the human trophoblast cell-surface antigen 2 to deliver SN-38 to cancer cells. In this study, we assessed the efficacy and safety of SG in patients with relapsed or refractory metastatic triple-negative breast cancer (RM-TNBC)., Methods: For this integrated analysis, from inception to January 2, 2023, we searched PubMed, Web of Science, Embase, and Cochrane library databases for prospective studies that evaluated SC in RM-TNBC patients. Primary endpoints were survival outcomes and responses. Secondary endpoints were all grade and grade ≥ 3 toxicities., Results: Six hundred potentially relevant records were screened. Our analysis included 3 trials (412 patients). Median overall survival was 12.9 months (95% confidence interval [CI], 11.5-14.4), progression-free survival was 5.7 months (5% CI, 5.1-6.3), and duration of objective response was 7.4 months (5% CI, 5.8-9.0). The objective response rate was 34%, and the disease control rate was 71%. Key grade ≥ 3 toxicities (in over 10% of the patients) included neutropenia (46%), leukopenia (12%), febrile neutropenia (11%), diarrhea (11%), and anemia (10%). Four treatment-related deaths were reported., Conclusion: SG was associated with effectiveness in patients with RM-TNBC. Myelosuppression and diarrhea were the primary treatment-related adverse events., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Taxane chemotherapy represents the standard of care in the second-line setting for non-small cell lung cancer (NSCLC) patients, but immunotherapy agents pose great challenges. Whether immunotherapy/chemotherapy alone or combination therapy has more benefits remains controversial. In this study, we provided comparisons to integrate the efficacy of immunotherapy and taxane chemotherapy as second- or later-line treatments in advanced NSCLC., Methods: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to September 1, 2020. Randomized controlled trials comparing immunotherapy and taxane chemotherapy were enrolled in the Bayesian network analysis. Overall survival (OS) and progression-free survival (PFS) with hazard ratios (HRs) were investigated., Results: Eight trials in 13 studies with 4398 patients comparing seven treatments were identified. Pembrolizumab 10 mg/kg was associated with the best improved OS, with significant differences versus docetaxel (HR 0.81, 95% credible interval [CrI] 0.74-0.88), avelumab (HR 0.84, 95% CrI 0.75-0.95), and pembrolizumab 200 mg plus docetaxel (HR 0.75, 95% CrI 0.56-1.00). Although pembrolizumab 200 mg plus docetaxel ranked the last in terms of OS, the combination therapy showed the most favorable PFS. Additionally, the anti-programmed death-ligand 1 (PD-L1) agent, avelumab, was associated with the least improvement in PFS., Conclusion: As second- or later-line therapeutic strategies, pembrolizumab 10 mg/kg provided the largest OS benefits and pembrolizumab 200 mg plus docetaxel improved PFS to the greatest extent. Considering that immunotherapy has been recommended to the first-line setting of NSCLC, advanced patients who have not received immunotherapy previously might be the suitable population for our findings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Non-small-cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) exon 20 mutant occurs in 3% of NSCLCs. Targeted agents for this population remain an unmet need. In this analysis, we pooled-analyzed the efficacy and safety of poziotinib, a novel tyrosine kinase inhibitor, in HER2 exon 20 mutant NSCLC., Methods: PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were systematically searched on March 9, 2022. The primary endpoints were objective response rate (ORR) and disease control rate. The secondary endpoint was treatment-related adverse events., Results: Three prospective clinical trials, involving 126 patients, were identified. The pooled ORR and disease control rate of poziotinib in HER2 exon 20 mutant NSCLC were 27% (95% CI, 19-35) and 72% (95% CI, 64-80), respectively. Patients with G778_P780dupGSP had the highest ORR (88%; 95% CI, 33-100; n = 12), followed by Y772_A775dupYVMA (20%; 95% CI, 12-30; n = 88) and G776delinsVC (19%; 95% CI, 0-50; n = 13). The most common grade 3 to 4 treatment-related adverse events were skin rash (36%), diarrhea (23%), and oral mucositis (13%)., Conclusion: Poziotinib demonstrates moderate antitumor activity in previously treated HER2 exon 20 mutant NSCLC patients with a manageable safety profile. In addition, different subgroup mutations show various benefits of poziotinib treatment. Large-scale and multiarm clinical trials are warranted to confirm a suitable population and therapeutic strategies., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) monotherapy is the standard of care in treating advanced non-small cell lung cancer (NSCLC). Nevertheless, whether adding pemetrexed-based chemotherapy to EGFR-TKI targeted therapy furtherly prolongs survival outcomes and improves responses remains controversial. Therefore, we conducted this pooled analysis to compare the efficacy and tolerability between gefitinib plus pemetrexed-based chemotherapy and gefitinib alone in the first-line treatment of advanced NSCLC patients with mutated EGFR., Methods: We systematically searched PubMed, Web of Science, Embase, and Cochrane CENTRAL on June 23, 2022. Eligible studies were registered randomized clinical trials comparing gefitinib plus pemetrexed-based chemotherapy with gefitinib alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR), disease control rate (DCR), and discontinuation rate (DR) were explored as secondary outcomes., Results: Eight studies within five randomized clinical trials were eligible. Gefitinib combined with pemetrexed-based chemotherapy significantly prolonged OS (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.37-0.89, p = 0.0125) and PFS (HR 0.52, 95% CI 0.39-0.70, p < 0.0001) versus gefitinib alone. In subgroup analysis, patients with EGFR exon 19 deletion and exon 21 L858R could benefit from the addition of pemetrexed-based chemotherapy to gefitinib in terms of PFS (EGFR exon 19 deletion: HR 0.50, 95% CI 0.34-0.75, p = 0.0008; EGFR exon 21 L858R: HR 0.46, 95% CI 0.26-0.82, p = 0.0079) but not OS. In addition, ORR was improved after the administration of gefitinib plus pemetrexed-based chemotherapy against gefitinib (odds ratio [OR] 1.91, 95% CI 1.44-2.55, p < 0.0001). Both strategies showed comparable DCRs (OR 1.46, 95% CI 0.94-2.26, p = 0.0952) and DRs (risk ratio [RR] 2.80, 95% CI 0.69-11.44, p = 0.1509)., Conclusion: Compared with gefitinib alone, combining pemetrexed-based chemotherapy with gefitinib significantly improved OS and PFS in advanced EGFR-mutant NSCLC patients with acceptable tolerability. However, the accurate sub-population who could have OS benefits requires further validation., Competing Interests: The authors have declared that no competing interests exist.

Background: Immunotherapy has revolutionized the treatment of advanced lung cancer. Nevertheless, it remains unclear whether adding stereotactic body radiotherapy (SBRT) to immunotherapy (IT) further improves responses and survival outcomes. Therefore, in this pooled analysis, we comprehensively compared IT plus SBRT with IT alone in patients with advanced lung cancer., Methods: Online databases, including PubMed, Web of Science, Embase, and Cochrane CENTRAL, were systematically searched on April 24, 2022. Eligible studies were randomized clinical trials comparing IT plus SBRT to IT. The primary outcomes were the objective response rate (ORR) and disease control rate (DCR). Progression-free survival (PFS) and overall survival (OS) were explored as secondary outcomes., Results: Overall, three phase 2 randomized clinical trials with a total of 146 previously treated lung cancer patients were enrolled. The median PFS and OS were 3.8 months and 9.5 months for IT plus SBRT versus 2.4 months and 6.1 months for IT. Comparing IT plus SBRT with IT alone, pooled risk ratios for ORR and DCR were 1.95 (95% confidence interval 1.07-3.53, p  = 0.03) and 1.28 (0.94-1.73, p  = 0.12). While pooled hazard ratios were 0.77 (0.25-2.42, p  = 0.66) for PFS and 0.71 (0.16-3.21, p  = 0.65) for OS, respectively. No publication bias was found across the trials., Conclusion: Compared to IT alone, the addition of SBRT improved the best response but failed to prolong the survival outcomes in treating advanced lung cancer patients. Future studies are necessary to explore new modalities of the combination of IT and SBRT., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Bi-Cheng Wang et al.)

Cemiplimab has been widely recommended by international guidelines to treat patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). In this study, we conducted a comparative analysis to integrate the efficacy and safety data in the published prospective and retrospective studies for better understanding the application of cemiplimab. The online databases (PubMed, Cochrane CENTRAL, Web of Science, and EMBASE) were searched to find out eligible studies from inception to November 4, 2021. The "R" software and the "meta" package were used to synthesize the objective response rates (ORRs), disease control rates (DCRs), and the incidences of treatment-related adverse events (TRAEs). Overall, three retrospective studies with 398 patients and three prospective studies with 219 patients were enrolled. The pooled ORR and DCR were 53% (95% confidence interval [CI] 46-59) and 70% (95% CI 57-82) for retrospective studies versus 45% (95% CI 39-52) and 68% (95% CI 56-79) for prospective studies. In regard of toxicities, prospective studies reported much higher incidences of any grade (99% vs. 47%) and grade 3-4 TRAEs (43% vs. 15%) against retrospective studies. The most reported TRAE was fatigue, followed by diarrhea and pruritus. In addition, nine treatment-related deaths (four in retrospective studies vs. five in prospective studies) were documented. In both retrospective and prospective clinical practices, cemiplimab could be an effective regimen for locally advanced or metastatic CSCC patients, but toxicities during the treatment deserve further attention., (© 2022 Wiley Periodicals LLC.)

Background: Ubiquitin-like with PHD and ring-finger domain 1 (UHRF1) has been defined as an oncogene in tumor cells. However, the role of UHRF1 in mediating metastasis in thyroid cancer remains unexplored. In this study, we aimed to investigate the metastatic function and the potential mechanisms of UHRF1 in thyroid cancer., Methods: Transwell assays were used to detect the metastatic capability of thyroid cancer. Dual-luciferase reporter assays were applied to examine the activation of transcription factors. Coimmunoprecipitation assays and immunofluorescence staining assays were used to elucidate the potential mechanisms of UHRF1 in promoting the metastasis of thyroid cancer., Results: In this study, we found that overexpression of UHRF1 promoted the metastasis of papillary thyroid cancer cells, and suppression of UHRF1 decreased the metastasis of anaplastic thyroid cancer cells. Regarding the signaling pathway in regulating metastasis, UHRF1 directly combined and activated the transcription factor c-Jun/AP-1 in the nucleus, subsequently increasing the transcription of IL-6 and MIF., Conclusion: Our results suggest that UHRF1 could induce the metastasis of thyroid cancer, and the potential signaling pathway might be that UHRF1 activates c-Jun/AP-1 to increase the expression of IL-6 and MIF. These findings provide a novel mechanism of UHRF1 and illustrate that UHRF1/AP-1 complex could be a potential therapeutic target for patients with thyroid cancer., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Bo-Hua Kuang et al.)

Background: Adding induction chemotherapy to concurrent platinum-based chemoradiotherapy has significantly prolonged the survival time of patients with locoregionally advanced nasopharyngeal carcinoma. In this study, we intend to evaluate the survival outcomes, responses, and incidences of toxicities of induction chemotherapy and the differences between different strategies., Methods: A comprehensive search was conducted in PubMed, Embase, Web of Science, and Cochrane CENTRAL on August 10, 2021. Single-arm or multi-arm prospective clinical trials on induction chemotherapy without targeted therapies or immune checkpoint inhibitors were included. Primary outcomes included survival outcomes, objective response rate, and disease control rate, and the secondary outcome was the rates of grade 3 or higher treatment-related adverse events., Results: The 39 studies included in the systematic review and meta-analysis comprised 36 clinical trials and 5389 patients. The estimates for 3-year overall and fail-free survival rates were 87% and 77%. The estimates for 5-year rates of overall and fail-free survival were 81% and 73%. Gemcitabine plus platinum and docetaxel combined with 5-fluorouracil plus platinum strategies were associated with the highest rates of 3-year and 5-year overall survival. The objective response and disease control rates were 85% and 98% after the completion of induction chemotherapy. Neutropenia (27%) and nausea/vomiting (7%) were the most common grade 3 or higher treatment-related hematological and non-hematological adverse events during the induction phase., Conclusions: Different induction chemotherapeutic strategies appear to have varying effects and risks; a comprehensive summary of the survival outcomes, responses, and toxicities in clinical trials may provide a crucial guide for clinicians., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Kuang, Liu, Lin and Liu.)

Background: The prognosis of patients with relapsed Ewing sarcoma is poor. In this study, we aimed to pooled-analyze the efficacy and safety of the combination of irinotecan and temozolomide in treating patients with relapsed Ewing sarcoma., Methods: PubMed, Cochrane CENTRAL, Web of Science, and EMBASE were systematically searched on September 27, 2021. The primary outcomes were rates of objective response and disease control, and the secondary outcomes were toxicities., Results: Six retrospective studies with 184 patients were enrolled in the analysis. The median age ranged from 14 to 21. The integrated rates were 44% (95% confidence interval [CI] 31-58) for objective response and 66% (55-77) for disease control. Grade 3-4 neutropenia, thrombocytopenia, and diarrhea occurred in 8% (3-16), 7% (3-11), and 8% (5-10) of chemotherapeutic cycles, respectively. 18% (7-32) and 6% (2-11) of patients suffered grade 3-4 neutropenia and thrombocytopenia after irinotecan plus temozolomide treatment., Conclusion: Irinotecan plus temozolomide combination chemotherapy showed antitumor activity and an acceptable safety profile in patients with relapsed Ewing sarcoma. More future prospective studies are needed to confirm the retrospective results., (© 2022. The Author(s).)

Background: The major aim of this Bayesian network analysis was to determine the optimal treatment strategy for locoregionally advanced nasopharyngeal carcinoma (LANPC)., Method: We systematically searched databases and extracted data from randomized clinical trials involving LANPC patients randomly assigned to receive induction chemotherapy followed by concurrent chemoradiotherapy (IC+CCRT), CCRT followed by adjuvant chemotherapy (CCRT+AC), or CCRT., Results: In the network analysis, IC+CCRT was significantly better than CCRT alone for 5-year FFS (odds ratio [OR]: 1.63, 95% credible interval [CrI] 1.16-2.29), DMFS (OR: 1.56, 95% CrI 1.08-2.22), and LFRS (OR: 1.62, 95% CrI 1.02-2.59), but not OS (OR: 1.35, 95% CrI 0.92-2.00). Rank probabilities showed that IC+CCRT was ranked the best followed by CCRT+AC and CCRT for all 5-year outcomes. Although compared to IC+CCRT and CCRT, CCRT+AC did not significantly improve survival but had the highest 5-year survival rates., Conclusions: IC+CCRT could be recommended as a front-preferred primary definitive therapy for patients with LANPC., Competing Interests: The authors have declared that no competing interests exist.

Purpose: As an antipsychotic agent that targets multiple neurotransmitter receptors, olanzapine has been added to antiemetic therapies. For better understanding the application of olanzapine in antiemetic strategies for breast cancer patients who suffered anthracycline plus cyclophosphamide-induced nausea and vomiting, we comprehensively reviewed the antiemetic researches related to olanzapine and pooled-analyzed the results to confirm the efficacy and safety of olanzapine in breast cancer., Methods: PubMed, Web of Science, EMBASE, and Cochrane CENTRAL databases were searched from inception through Sep 15, 2021. Both prospective and retrospective studies were eligible. The primary outcomes were complete response (defined as no vomiting and no use of rescue medications) and no nausea rate, and the secondary outcome was treatment-related adverse events., Results: Four studies with 466 breast cancer patients were identified in the pooled analysis. In the acute period (0-24 h), the olanzapine group had significantly higher rates of complete response (71.3% vs 48.1%, odds ratio [OR]: 2.66, 95% confidence interval [CI] 1.39-5.11, p = 0.003) and no nausea (70.0% vs 43.0%, OR: 3.55, 95% CI 1.76-7.18, p = 0.04) than the placebo group, while in the delayed period, the olanzapine group was also superior to the placebo group in terms of the complete response (82.5% vs 63.3%, OR: 3.81, 95% CI 1.58-9.15, p = 0.003) and no nausea (66.3% vs 51.9%, OR: 2.08, 95% CI 1.03-4.21, p = 0.04) rates. During the overall period in prospective studies, the proportions of complete response (50.0% vs 34.2%, OR: 1.93, p = 0.04) and no nausea (51.3% vs 25.3%, OR: 3.40, p = 0.0006) in the olanzapine group were higher than those in the placebo group., Conclusion: Highly emetogenic chemotherapy breast patients could benefit from olanzapine-contained antiemetic therapy. Furthermore, since the cost is low, olanzapine is worth further clinical application and promotion., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Doxorubicin/Adriamycin (ADM) alone or combined with ifosfamide (IFO) (AI) is available for previously untreated advanced soft tissue sarcoma (ASTS). However, the clinical choice between them remains controversial. In this pooled analysis, we comprehensively compared the efficacy and tolerability of AI versus ADM in patients with ASTS., Methods: PubMed, Web of Science, EMBASE, and Cochrane Library were systematically searched from inception to April 14, 2021. Eligible studies were randomized clinical trials comparing AI to ADM. The primary outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Discontinuation rate (DR) and toxic death (TD) were explored as secondary outcomes., Results: Overall, three open-label randomized phase 2/3 clinical trials with a total of 1108 newly diagnosed ASTS patients were enrolled. Between AI and ADM, pooled hazard ratios were 0.93 (95% confidence interval 0.58-1.50, p = 0.78) for OS and 0.85 (0.57-1.25, p = 0.41) for PFS. While pooled risk ratios for ORR, DR, and TD were 1.37 (0.94-1.99, p = 0.10), 1.04 (0.74-1.46, p = 0.82), and 0.68 (0.19-2.36, p = 0.54) respectively. No publication bias was observed across the studies., Conclusion: In the first-line setting, adding IFO to ADM failed to benefit ASTS patients against ADM alone, even with comparable tolerability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Kuang, Xiao and Lin.)

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to improve the anti-cancer effects in combination with radiotherapy. However, the tolerability and safety of adding GM-CSF to radiotherapy in thoracic cancer patients need to be further explored., Methods: Between June 2020 and Sep 2020, seven patients with thoracic cancer were treated with concurrent radiotherapy and GM-CSF (200 µg subcutaneously injected q.o.d during the radiotherapy). The primary endpoint was adverse event., Results: Of seven enrolled patients, four were non-small cell lung cancer, two were small cell lung cancer, and the other one patient was thymic carcinoma. The total dose of GM-CSF that each patient received was at least 3000 µg. All patients had finished the radiotherapy and GM-CSF injection and suffered one or more any grade adverse events. Only one patient had a grade ≥3 hematological adverse event (lymphocytopenia). Grade ≥3 non-hematological toxicities were not observed during the combination treatment. The highest cell counts of white blood cell, neutrophile granulocyte, and monocyte across the treatment were 22.38×109/L,18.65×109/L, and 1.28×109/L respectively., Conclusions: The combination therapy of radiotherapy and GM-CSF (200 µg subcutaneously q.o.d) is tolerable and safe. Further studies are warranted to confirm the effects and optimal total GM-CSF injection doses in the combination of radiotherapy in thoracic cancer patients.

Background: Adjuvant trastuzumab improves survival outcomes of human epidermal receptor 2 positive early breast cancer patients. Currently, administration of 12 months adjuvant trastuzumab is the standard therapy. However, whether 6 months treatment is non-inferior to the standard 12 months treatment remains controversial., Methods: Relevant records were searched in PubMed, Cochrane Library, Web of Science, and EMBASE through Jan 14, 2020. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were meta-analyzed. The primary endpoint was DFS with a non-inferiority hazard margin of 1.2 and the second was OS with 1.43., Results: Three randomized clinical studies met the inclusion criteria, including 3974 patients in 6 months group and 3976 in 12 months group. HR for DFS was 1.18 (95% CI 0.97-1.44, P = .09), with the non-inferiority margin comprised in the 95% CI. HR for OS was 1.14 (95% CI 0.98-1.32, P= .08), whereas the upper limit of 95% CI did not exceed the non-inferiority hazard margin., Conclusion: Our analysis failed to show that 6 months treatment was non-inferior to 12 months treatment in improving the DFS. Although the non-inferiority of the 6-month adjuvant trastuzumab treatment was found for OS, considering that breast cancer patients should receive additional systematic therapies when disease progression or relapse happens, we suggest that 12 months adjuvant trastuzumab treatment should remain the standard therapeutic strategy for patients with early human epidermal receptor 2 positive breast cancer., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The prognosis of patients with extensive-stage small cell lung cancer (SCLC) is poor. Adding an immune checkpoint inhibitor (ICI) to chemotherapy may exert a synergistic effect and improve survival outcomes. However, for treatment-naive extensive-stage SCLC patients, the efficacy of immunotherapy in combination with cytotoxic chemotherapy remains controversial., Objective: To evaluate the benefits and risks of the combination of immunotherapy and chemotherapy and to assess the comparative effectiveness of different first-line treatment strategies for extensive-stage SCLC., Methods: PubMed, Web of Science, EMBASE, and Cochrane Library were searched for randomized clinical trials studying different immunotherapeutics for patients with previously untreated extensive-stage SCLC up to Feb 16, 2020. The primary outcomes were overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were objective response rate (ORR), disease control rate (DCR), and adverse events., Results: We identified 141 published records, and 4 studies (comprising 2202 patients) were included in the analysis. Immunotherapy (including ipilimumab, atezolizumab, and durvalumab) plus chemotherapy was associated with better OS (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.75-0.93; risk ratio (RR) 0.90, 95% CI 0.81-1.00) and PFS (HR: 0.81, 95% CI 0.74-0.88; RR 0.96, 95% CI 0.93-0.99) than placebo plus chemotherapy. The addition of immunotherapy to chemotherapy showed similar improvement in ORR, DCR, and adverse events versus placebo plus chemotherapy. On the surface under the cumulative ranking (SUCRA) analysis, the anti-PD-L1 agent, atezolizumab, had the highest likelihood of achieving improved OS (93.4%) and PFS (95.0%)., Conclusion: In the first-line setting, combining immunotherapy with chemotherapy is better than standard chemotherapy in terms of OS and PFS. Across the eligible studies, PD-L1 inhibitors might be preferred. Further explorations of more ICIs in the first-line treatment for extensive-stage SCLC patients should be needed., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Bi-Cheng Wang et al.)

Background: The combination of durvalumab and tremelimumab results in clinical benefit, with a tolerable safety profile in patients with solid tumors., Objective: To evaluate the efficacy and safety of durvalumab in combination with tremelimumab compared with either drug alone., Methods: The online databases (PubMed, Web of Science, EMBASE, and Cochrane Library) were searched for potential clinical studies up to Nov 26, 2019. Eligible studies were prospective and registered clinical trials. Pooled odds ratios for objective response rate and disease control rate and pooled risk ratios for treatment-related adverse events were meta-analyzed. A random-effect model was used due to the synthesis of different cancer types., Results: Overall, 5 studies were eligible for systematic review, 3 of which were further meta-analyzed. Durvalumab plus tremelimumab was superior to tremelimumab monotherapy in improving disease control rate in head and neck squamous cell carcinoma. However, there were no significant differences between dual immunotherapy and mono-immunotherapy in pancreatic ductal adenocarcinoma and gastric and gastroesophageal junction adenocarcinoma. Additionally, pooled analyses illustrated that no significant differences in treatment-related adverse events were displayed between the 2 groups., Conclusion: Durvalumab and tremelimumab combination therapy had a good safety profile and resulted in clinical benefit in head and neck squamous cell carcinoma. Future explorations are needed to further confirm the application of durvalumab plus tremelimumab.

Background: Gemcitabine combined the oral fluoropyrimidine capecitabine (GemCap) is an active antitumor therapy in the treatment of advanced or metastatic pancreatic cancer, and has been shown potential synergistic activity in previous clinical trials. In this study, we sought to systematically review and synthesize the efficacy and safety of GemCap in the treatment of advanced or metastatic pancreatic cancer., Methods: A systematic review was performed through PubMed, Cochrane Library, EMBASE, and Web of Science databases up to Jul 10, 2019 to identify clinical trials that included advanced or metastatic pancreatic cancer patients treated with GemCap. Data of overall survival (OS), progression-free survival (PFS), 1-year survival rate, objective response rate (ORR), disease control rate (DCR) and adverse events were extracted and meta-analyzed., Results: Fifteen studies were identified for systematic review, of which 13 were included in the metaanalysis. In comparison with Gem monotherapy, the pooled hazard ratios (HR) of GemCap treatment for OS and PFS were 0.85 (95% CI: 0.75-0.95, P=0.007) and 0.80 (95% CI: 0.72-1.04, P=0.0002). The pooled 1-year survival rate, ORR and DCR of GemCap were, respectively, 33.1% (95% CI: 28.7-37.5), 22.9% (95% CI: 17.6-28.3) and 65.7% (95% CI: 56.7-74.8). GemCap combination therapy showed significantly higher ORR (OR: 1.98, 95% CI: 1.34-2.67, P=0.0003) and DCR (OR: 1.41, 95% CI: 1.05- 1.88, P=0.02) compared to Gem monotherapy. The most common grade ≥3 hematological toxicities in patients treated with GemCap combination therapy were neutropenia (19.7%), leucocytopenia (7.9%) and anemia (4.9%). The most common grade ≥3 non-hematological toxicities were hand-foot syndrome (6.3%), fatigue (5.7%) and nausea (4.8%)., Conclusions: GemCap combination therapy had an encouraging activity and might be a better treatment strategy compared with Gem alone in the first-line treatment for patients with advanced or metastatic pancreatic cancer.

Background: Immune checkpoint inhibition has been increasingly used in breast cancer therapy. Understanding the benefit and risk of programmed cell death 1 ( PD-1 ) and programmed cell death ligand 1 ( PD-L1 ) inhibitors is critical for clinical practice. This study aims to determine the objective response, disease control and adverse events of breast cancer patients treated with PD-1 / PD-L1 inhibitors., Methods: PubMed, Cochrane Library, Web of Science and EMBASE databases were searched up to Aug 1, 2019. Both nonrandomized and randomized studies were included. Pooled objective response rate (ORR), disease control rate (DCR) and adverse events were pooled analyzed., Results: A total of nine clinical studies were identified. Triple-negative breast cancer (TNBC) showed the highest estimates of ORR [overall population: 49.7%, 95% confidence interval (CI): 33.9-65.5%; PD-L1 positive population: 55.8%, 95% CI: 42.9-68.8%] and DCR (overall population: 67.5%, 95% CI: 38.6-96.4%; PD-L1 positive population: 83.4%, 95% CI: 72.2-94.5%) post-anti- PD-L1 plus nab-paclitaxel treatment. With respect to grade ≥3 treatment related adverse events, the pooled estimates ranged from 12.0% to 50.9% for anti- PD-1 / PD-L1 monotherapy. The pooled estimates percentages of grade ≥3 treatment related adverse events in TNBC patients treated with anti- PD-L1 plus nab-paclitaxel were 59.6% (95% CI: 36.1-83.0)., Conclusions: We presented the aggregate estimates of ORR, DCR, and treatment related adverse events for breast cancer patients receiving anti- PD-1 / PD-L1 treatment. However, these results were largely derived from single-arm studies, and randomized studies with head-to-head comparison of PD-1 / PD-L1 inhibitors and chemotherapy are lacking. Additionally, the incidence of varying treatment related adverse events should be also carefully monitored., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-19-3020). The authors have no conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

Background: Induction chemotherapy (IC) combined with concurrent chemoradiotherapy (CCRT) has been recommended as the first-line therapy for locoregional nasopharyngeal carcinoma (NPC). Due to the different chemotherapeutic drugs used in the IC and CCRT, the results remain controversial., Methods: PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically retrieved to search potentially eligible clinical trials up to Sep 11, 2019. Eligible studies were registered and prospective randomized controlled clinical trials., Results: From 526 records, nine articles including seven randomized controlled clinical trials were eligible, with a total of 2311 locoregional advanced NPC patients. IC + CCRT had significantly lower risks of death (3-year hazard ratio [HR]: 0.70, 95% confidence interval [CI] 0.55-0.89, p = 0.003; 5-year HR: 0.77, 95% CI 0.62-0.94, p = 0.01), disease progression (3-year HR: 0.67, 95% CI 0.55-0.80, p < 0.001; 5-year HR: 0.70, 95% CI 0.58-0.83, p < 0.0001), distant metastasis (3-year HR: 0.58, 95% CI 0.45-0.74, p < 0.0001; 5-year HR: 0.69, 95% CI 0.55-0.87, p = 0.001) and locoregional relapse (3-year HR: 0.69, 95% CI 0.50-0.95, p = 0.02; 5-year HR: 0.66, 95% CI 0.51-0.86, p = 0.002) than CCRT. Compared with CCRT, IC + CCRT showed higher relative risks of grade 3 or more neutropenia, thrombocytopenia, nausea, vomiting and hepatotoxicity throughout the course of treatment, and higher relative risks of grade ≥ 3 thrombocytopenia and vomiting during CCRT., Conclusion: IC combined with CCRT significantly improved the survival in locoregional advanced NPC patients. Moreover, toxicities were well tolerated during IC and CCRT. Further clinical trials are warranted to confirm the optimal induction chemotherapeutic regimen in the future.

Objectives: There is currently no effective salvage therapeutic modality that improves the survival outcomes of patients with recurrent or metastatic nasopharyngeal carcinoma. However, the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors may provide clinical benefit for these advanced patients., Materials and Methods: The databases, including PubMed, Web of Science, EMBASE and Cochrane Library, were systematically searched up to Nov 5, 2019. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) rate, overall survival (OS) rate, and drug-related adverse events were extracted and pooled meta-analyzed., Results: From 71 search records, eight studies were included in the systematic review, of which three were eligible for final meta-analysis. In recurrent or metastatic nasopharyngeal carcinoma patients treated with anti-PD-1 therapy, the pooled ORR was 27% (95% confidence interval [CI] 19-36%), DCR was 63% (95% CI 50-75%), 6 months PFS rate was 49% (95% CI 40-58%), 1-year PFS rate was 25% (95% CI 19-32%), 1-year OS rate was 61% (95% CI 49-72%). The pooled incidences of any grade and grade ≥ 3 drug-related adverse events were 94% and 20% respectively., Conclusion: We present the aggregate response rates, survival rates and incidences of drug-related adverse events for recurrent or metastatic nasopharyngeal carcinoma patients receiving PD-1/PD-L1 blockage treatment, which could provide useful information for future design of clinical studies. There is a need for more randomized controlled studies with head-to-head comparison of PD-1/PD-L1 inhibitors and traditional chemotherapeutic strategies to enable better recommendations for optimal advanced nasopharyngeal carcinoma treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Anaplastic thyroid cancer (ATC), an undifferentiated subtype of thyroid cancer, is one of the most malignant endocrine cancer with low survival rate, and resistant to chemotherapy and radiation therapy. Here we found that UHRF1 was highly expressed in human ATC compared with normal tissue and papillary thyroid cancer (PTC). Knockdown of UHRF1 inhibited proliferation of ATC in vitro and in vivo . Consistently, overexpression of UHRF1 promoted the proliferation of thyroid cancer cells. Moreover, UHRF1 suppression induced differentiation of three-dimensional (3D) cultured ATC cells and down-regulated the expression of dedifferentiation marker (CD97). The stem cell markers (Sox2, Oct4 and Nanog) were suppressed simultaneously. In addition, UHRF1 knockdown reduced the transcription of cytokines (IL-8, TGF-α and TNF-α), which might relieve the inflammatory reaction in ATC patients. This study demonstrated a role of UHRF1 in ATC proliferation, dedifferentiation and inflammatory reaction, presenting UHRF1 as a potential target in ATC therapy., Competing Interests: CONFLICTS OF INTEREST The authors declare that there is no potential conflicts of interest.

Cytokine-induced killer (CIK) cell therapy has recently been used as an adjuvant setting following resection of hepatocellular carcinoma (HCC), while its benefit remains unclear. This study aimed to evaluate the efficacy of adjuvant CIK application in solitary HCC patients undergoing curative resection with stratification of microvascular invasion (MVI).In total, specimens and data from 307 solitary HCC patients undergoing curative resection between January 2007 and December 2010 were included. Of these, 102 patients received CIK treatment after surgery (CIK group), whereas 205 patients did not (control group). Pathological evaluation was used to retrospectively determine MVI status. The CIK group had 60 MVI-negative and 42 MVI-positive patients, while the numbers in control group were 124 and 81. Kaplan-Meier and Cox regression analyses were used to validate possible effects of CIK treatment on disease free survival (DFS) and overall survival (OS) as appropriate.For all patients, the CIK group exhibited significantly higher OS than the control group (log-rank test; PDFS = 0.055, POS = 0.020). Further analysis based on MVI stratification showed that for patients with MVI, DFS and OS did not differ between the 2 groups (PDFS = 0.439, POS = 0.374). For patients without MVI, the CIK group exhibited better DFS and OS than the control group (PDFS = 0.042, POS = 0.007), and multivariate analyses demonstrated that CIK treatment was an independent prognostic factor both for DFS and OS.For solitary HCC, CIK cell therapy after curative resection improves DFS and OS for patients without MVI, but has no statistically significant survival benefit for patients with MVI.

Background: The clinical significance of microRNAs (miRNAs) in intrahepatic cholangiocarcinoma (ICC) is unclear. The objective of this study is to examine the miRNA expression profiles and identify a miRNA signature for the prognosis of ICC., Methods: Using a custom microarray containing 1,094 probes, the miRNA expression profiles of 63 human ICCs and nine normal intrahepatic bile ducts (NIBD) were assessed. The miRNA signatures were established and their clinical significances in ICC were analyzed. The expression levels of some miRNAs were verified by quantitative real-time RT-PCR (qRT-PCR)., Results: Expression profile analysis showed 158 differentially expressed miRNAs between ICC and NIBD, with 77 up-regulated and 81 down-regulated miRNAs. From the 158 differentially expressed miRNAs, a 30-miRNA signature consisting of 10 up-regulated and 20 down-regulated miRNAs in ICC was established for distinguishing ICC from NIBD with 100% accuracy. A separate 3-miRNA signature was identified for predicting prognosis in ICC. Based on the 3-miRNA signature, a formula was constructed to compute a risk score for each patient. The patients with high-risk had significantly lower overall survival and disease-free survival than those with low-risk. The expression level of these three miRNAs detected by microarray was verified by qRT-PCR. Multivariate analysis indicated that the 3-miRNA signature was an independent prognostic predictor., Conclusions: In this study, a 30-miRNA signature for distinguishing ICC from NIBD, and a 3-miRNA signature for evaluating prognosis of ICC were established, which might be able to serve as biomarkers for prognosis of ICC. Further studies focusing on these miRNAs may shed light on the mechanisms associated with ICC pathogenesis and progression.

Background and Objective: There are few studies about origins of regulatory T (Treg) cells increased in primary hepatocellular carcinoma (HCC) tissue. Studies showed that Treg cells could be induced by transforming growth factor-beta1 (TGF-beta1), but the relation between TGF-beta1 expression and Treg cell infiltration is unclear in HCC tissue. This study was to investigate the expression of TGF-beta1 and correlations with the amount of Treg cells in HCC, and to evaluate their clinical values in predicting the prognosis of HCC., Methods: Envision immunohistochemistry was used to detect the expression of TGF-beta1 and Foxp3 in 102 specimens of HCC tissue and paired adjacent non-tumor liver tissue., Results: Of the 102 specimens of HCC, 41 showed low TGF-beta1 expression and 61 (59.8%) showed high expression; of the 102 specimens of adjacent non-tumor tissue, 22 showed low TGF-beta1 expression and 80 (78.4%) showed high expression. The high expression rate of TGF-beta1 was significantly lower in HCC than in adjacent non-tumor tissues (P = 0.001). Average Foxp3+ cell density in HCC was 2.98 cells/HP, but there was very few or no expression of Foxp3 in adjacent non-tumor liver tissue. Expression of TGF-beta1 was positively correlated with expression of Foxp3 in HCC tissues (r = 0.228, P = 0.021). The expression of TGF-beta1 was significantly higher in HCC tissues with high preoperative AFP concentration than in those with low preoperative AFP concentration (P = 0.023). TGF-beta1 and Foxp3 expression had no correlations with tumor diameter, tumor capsule, liver cirrhosis, and so on. The 5-year survival rate was not different between HCC tissues with high and low TGF-beta1 expression (P = 0.790); however, it was significantly lower in HCC tissues with high Treg cell infiltration than in those low infiltration (25% vs. 44%, P = 0.007). Cox multivariate analysis showed that the number of Treg cells and tumor capsule were independent prognostic factors (P = 0.021, P = 0.001)., Conclusions: Expression of TGF-beta1 may relate to the infiltration of Treg cells in HCC tissues, but the relation need to be further investigated. The number of Treg cells in HCC tissues could be used as a potential immunological prognostic indicator for HCC patients after resection.