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Xylan is one of the major hemicelluloses in plant cell walls and its xylosyl backbone is often decorated at O-2 with glucuronic acid (GlcA) and/or methylglucuronic acid (MeGlcA) residues. The GlcA/MeGlcA side chains may be further substituted with 2-O-arabinopyranose (Arap) or 2-O-galactopyranose (Gal) residues in some plant species, but the enzymes responsible for these substitutions remain unknown. During our endeavor to investigate the enzymatic activities of Arabidopsis MUR3-clade members of the GT47 glycosyltransferase family, we found that one of them was able to transfer Arap from UDP-Arap onto O-2 of GlcA side chains of xylan, and thus it was named xylan 2-O-arabinopyranosyltransferase 1 (AtXAPT1). The function of AtXAPT1 was verified in planta by its T-DNA knockout mutation showing a loss of the Arap substitution on xylan GlcA side chains. Further biochemical characterization of XAPT close homologs from other plant species demonstrated that while the poplar ones had the same catalytic activity as AtXAPT1, those from Eucalyptus, lemon-scented gum, sea apple, 'Ohi'a lehua, duckweed and purple yam were capable of catalyzing both 2-O-Arap and 2-O-Gal substitutions of xylan GlcA side chains albeit with differential activities. Sequential reactions with XAPTs and glucuronoxylan methyltransferase 3 (GXM3) showed that XAPTs acted poorly on MeGlcA side chains, whereas GXM3 could efficiently methylate arabinosylated or galactosylated GlcA side chains of xylan. Furthermore, molecular docking and site-directed mutagenesis analyses of Eucalyptus XAPT1 revealed critical roles of several amino acid residues at the putative active site in its activity. Together, these findings establish that XAPTs residing in the MUR3 clade of family GT47 are responsible for 2-O-arabinopyranosylation and 2-O-galactosylation of GlcA side chains of xylan.
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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 gradeâ ≥â 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.
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Inhibidores de la Angiogénesis , Inhibidores de Proteínas Quinasas , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Neoplasias de la Tiroides/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Prospectivos , Sorafenib/uso terapéutico , Sorafenib/efectos adversos , Indazoles/uso terapéutico , Indazoles/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Supervivencia sin Progresión , Pirimidinas , Quinolinas , SulfonamidasRESUMEN
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.
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Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Prospectivos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/mortalidadRESUMEN
MAIN CONCLUSION: A member of the rice GT61 clade B is capable of transferring both 2-O-xylosyl and 2-O-arabinosyl residues onto xylan and another member specifically catalyses addition of 2-O-xylosyl residue onto xylan. Grass xylan is substituted predominantly with 3-O-arabinofuranose (Araf) as well as with some minor side chains, such as 2-O-Araf and 2-O-(methyl)glucuronic acid [(Me)GlcA]. 3-O-Arabinosylation of grass xylan has been shown to be catalysed by grass-expanded clade A members of the glycosyltransferase family 61. However, glycosyltransferases mediating 2-O-arabinosylation of grass xylan remain elusive. Here, we performed biochemical studies of two rice GT61 clade B members and found that one of them was capable of transferring both xylosyl (Xyl) and Araf residues from UDP-Xyl and UDP-Araf, respectively, onto xylooligomer acceptors, whereas the other specifically catalysed Xyl transfer onto xylooligomers, indicating that the former is a xylan xylosyl/arabinosyl transferase (named OsXXAT1 herein) and the latter is a xylan xylosyltransferase (named OsXYXT2). Structural analysis of the OsXXAT1- and OsXYXT2-catalysed reaction products revealed that the Xyl and Araf residues were transferred onto O-2 positions of xylooligomers. Furthermore, we demonstrated that OsXXAT1 and OsXYXT2 were able to substitute acetylated xylooligomers, but only OsXXAT1 could xylosylate GlcA-substituted xylooligomers. OsXXAT1 and OsXYXT2 were predicted to adopt a GT-B fold structure and molecular docking revealed candidate amino acid residues at the predicted active site involved in binding of the nucleotide sugar donor and the xylohexaose acceptor substrates. Together, our results establish that OsXXAT1 is a xylan 2-O-xylosyl/2-O-arabinosyl transferase and OsXYXT2 is a xylan 2-O-xylosyltransferase, which expands our knowledge of roles of the GT61 family in grass xylan synthesis.
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Arabidopsis , Oryza , Glicosiltransferasas/análisis , Oryza/metabolismo , Xilanos/metabolismo , Arabidopsis/metabolismo , Simulación del Acoplamiento Molecular , UDP Xilosa Proteína Xilosiltransferasa , Poaceae/metabolismo , Pared Celular/metabolismoRESUMEN
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.
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Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Supervivencia sin Progresión , Estudios Retrospectivos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/mortalidad , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/mortalidad , /uso terapéuticoRESUMEN
As a novel tyrosine kinase inhibitor (TKI), pyrotinib can irreversibly block dual pan-ErbB receptors and has been used in the treatment of advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, there are limited data on the use of pyrotinib in early breast cancer. Therefore, the present meta-analysis was conducted to evaluate the safety and efficacy of pyrotinib in the neoadjuvant setting for patients with early-stage or locally advanced HER2-positive breast cancer. Online databases (Pubmed, Web of Science, Embase and Cochrane Library) were comprehensively searched for eligible prospective clinical trials on August 17, 2023. The primary endpoint was the treatment-related adverse events (TRAEs), and the secondary endpoint was pathological complete response (pCR) rate. In total, seven trials with a total enrolment of 407 patients were included. A total of seven studies evaluated pyrotinib in combination with trastuzumab and chemotherapy in the neoadjuvant setting. The median age ranged from 47-50 years. The most common TRAEs were diarrhea [98% of patients; 95% confidence interval (CI): 92-100%], followed by anemia (71%; 95% CI: 55-89%), vomiting (69%; 95% CI: 55-82%), and leucopenia (66%; 95% CI: 35-91%). No treatment-related deaths occurred. The pooled pCR rate was 57% (95% CI: 47-68%). It was concluded that pyrotinib-containing neoadjuvant therapy could be an effective treatment strategy in patients with early-stage or locally advanced HER2-positive breast cancer; however, the management of adverse events should be a key consideration. The management of adverse events should be paid great attention to, during pyrotinib therapy, although pyrotinib-contained neoadjuvant therapy could be an effective treatment for patients with early-stage or locally advanced HER2-positive breast cancer. Head-to-head randomized clinical trials are warranted to further confirm the benefits and risks associated with pyrotinib therapy in patients with breast cancer.
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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.
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Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Humanos , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
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.
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Sarcoma , Neoplasias de los Tejidos Blandos , Trombocitopenia , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Doxorrubicina/efectos adversos , Sarcoma/tratamiento farmacológicoRESUMEN
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 gradeâ ≥â 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 gradeâ ≥â 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.
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Inmunoconjugados , Neoplasias de la Mama Triple Negativas , Humanos , Antígenos de Neoplasias , Camptotecina/efectos adversos , Diarrea/inducido químicamente , Inmunoconjugados/efectos adversos , Estudios Prospectivos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Radiation-related nasopharyngeal necrosis (RRNN) is a rare and often fatal complication in patients with nasopharyngeal carcinoma (NPC). Currently, no standard treatments are recommended for RRNN. The effects of traditional conservative treatments are suboptimal, and surgery for RRNN cannot be performed by inexperienced doctors. In the present study, the use of Endostar in two patients with RRNN was evaluated. Two patients with RRNN were treated at the Department of Oncology, Panyu Central Hospital (Guangzhou, China). Endostar was administrated (15 mg/day from day 1 to day 7, every three weeks) intravenously for four and seven cycles in a male and a female patient, respectively. The effects of Endostar were assessed using magnetic resonance imaging (MRI) and a nasopharyngoscope. The symptoms of RRNN in both patients were relieved after treatment with Endostar. MRI and nasopharyngoscope analysis revealed that necrosis of the nasopharynx was substantially decreased and nasopharyngeal ulcers were healed. Endostar has the potential to be a novel, effective therapy for the treatment of patients with RRNN. However, clinical trials are required to confirm the results of the present study.
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Background: Adebrelimab showed excellent efficacy in the first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC). However, whether adebrelimab is superior to durvalumab and atezolizumab remains unclear. Therefore, we, in this study, aimed to compare the survival data of adebrelimab (CAPSTONE-1 trial) with durvalumab (CASPIAN trial) and atezolizumab (IMpower133 trial) in the first-line setting of ES-SCLC patients. Methods: Online databases, including PubMed, Embase, Web of Science, and Cochrane CENTRAL, were systematically searched on December 2, 2022. The metaSurvival and IPDfromKM methods were used to analyze the summary survival curves and the reconstructed patient-level data. The main endpoints were median overall survival (OS) and progression-free survival (PFS). Results: In this analysis, survival data in the CASPIAN, IMpower133, and CAPSTONE-1 trials were collected from five published studies. The pooled median OS and PFS were 14.0 months (95% CI 11.2-16.6) and 5.6 months (95% CI 4.7-6.7) when ES-SCLC patients received chemotherapy (etoposide and cisplatin/carboplatin) and anti-PD-L1 therapy. Based on the reconstructed patient-level data, adebrelimab significantly prolonged survival outcomes against atezolizumab (OS: Hazard ratio [HR]0.76, 95% CI 0.60-0.95; PFS: HR 0.67, 95% CI 0.54-0.83) and durvalumab (OS: HR 0.75, 95% CI 0.60-0.92). Conclusion: For previously untreated ES-SCLC patients, longer survival time might be benefited from adding adebrelimab to etoposide-platinum chemotherapy. In future studies, further real-world evidence or head-to-head clinical trials are warranted to confirm the differences between the PD-L1 inhibitors.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antineoplásicos/uso terapéutico , Análisis de Supervivencia , Supervivencia sin Progresión , Ensayos Clínicos como AsuntoRESUMEN
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.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/etiología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/etiología , Docetaxel/uso terapéutico , Teorema de Bayes , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , InmunoterapiaRESUMEN
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; nâ =â 12), followed by Y772_A775dupYVMA (20%; 95% CI, 12-30; nâ =â 88) and G776delinsVC (19%; 95% CI, 0-50; nâ =â 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.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inducido químicamente , Exones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inducido químicamente , Mutación , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
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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.
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Carcinoma de Pulmón de Células no Pequeñas , Gefitinib , Neoplasias Pulmonares , Pemetrexed , Inhibidores de Proteínas Quinasas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB , Gefitinib/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Pemetrexed/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
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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.
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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.
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Carcinoma de Células Escamosas , Neoplasias Cutáneas , Anticuerpos Monoclonales Humanizados , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Humanos , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
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.
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Neutropenia , Sarcoma de Ewing , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina , Dacarbazina/efectos adversos , Humanos , Irinotecán/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Retrospectivos , Sarcoma de Ewing/tratamiento farmacológico , Temozolomida/uso terapéuticoRESUMEN
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.