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Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .
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BACKGROUND: The recent usage of immunotherapy combined with chemoradiotherapy has improved survival in advanced non-small cell lung cancer (NSCLC) patients. However, determining the most effective therapy combination remains a topic of debate. Research suggests immune checkpoint inhibitors (ICIs) post-chemoradiotherapy enhance survival, but the impact of concurrent ICIs during chemoradiotherapy on rapid disease progression is unclear. This meta-analysis aims to assess the effectiveness and safety of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced non-small cell lung cancer. METHODS: We searched PubMed, Embase, the Cochrane Library, and Web of Science for relevant studies, extracting data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). RESULTS: The analysis included ten studies with 490 participants. Stage III NSCLC ORR was 81.8%, while Stage IV ORR was 39.9%. One-year PFS and OS for Stage III were 68.2% and 82.6%, compared to 27.9% and 72.2% for Stage IV. Common adverse events included anemia (46.6%), nausea (47.6%), rash (36.4%), and radiation pneumonitis (36.3%). CONCLUSIONS: Our meta-analysis shows concurrent ICIs with chemoradiotherapy are effective and safe in advanced NSCLC, particularly in stage III patients at risk of progression before starting ICIs after chemoradiotherapy. The findings support further phase III trials. The review protocol was registered on PROSPERO (CRD42023493685) and is detailed on the NIHR HTA programme website.
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Carcinoma de Pulmón de Células no Pequeñas , Quimioradioterapia , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
BACKGROUND: Penpulimab, a new-generation antiprogrammed cell death-1 immunoglobulin G1 monoclonal antibody, was engineered to optimize receptor occupancy and eliminate fragment crystallizable γ-mediated effector function. In this multicenter, phase 1b/2, multicohort study, the objective was to investigate the efficacy, safety, and immunogenicity of penpulimab in advanced solid tumors. METHODS: Patients who had unresectable, advanced solid tumors were enrolled from six centers and received 200 mg penpulimab on day 1 every 2 weeks for up to 24 months. The primary end point was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, version criteria 1.1. RESULTS: Between September 2, 2019, and January 1, 2020, 65 patients were enrolled and received penpulimab. At the time of data cutoff (May 11, 2022), the median follow-up was 12.6 months (range, 1.1-28.6 months). The ORR was 12.3 (95% confidence interval [CI], 5.5%-22.8%), with three (4.6%) complete responses and five (7.7%) partial responses. Twelve patients (18.5%) achieved stable disease, resulting in a disease control rate of 30.8% (95% CI, 19.9%-43.4%). The median duration of response was not reached (95% CI, 6.70 months to not estimable). In all cohorts, the median progression-free survival was 1.74 months (95% CI, 1.41-2.69 months), and the median overall survival was 16.59 months (95% CI, 7.82-22.18 months). Grade 3 or greater treatment-related adverse events and immune-related adverse events occurred in 9.2% and 27.7% of patients, respectively. Positive antidrug antibody responses to penpulimab were observed in one patient (1.8%). CONCLUSIONS: Penpulimab showed promising antitumor activity with an acceptable safety profile, offering a potential new treatment approach for solid tumors. These findings supported the evaluation of penpulimab's durable activity and safety, as monotherapy or in combination therapy, in specific malignancies.
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Neoplasias , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/inmunología , Adulto , Anciano de 80 o más Años , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Inmunoglobulina G/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Metástasis de la NeoplasiaRESUMEN
Many tissues and organ systems have intrinsic regeneration capabilities that are largely driven and maintained by tissue-resident stem cell populations. In recent years, growing evidence has demonstrated that cellular metabolic homeostasis plays a central role in mediating stem cell fate, tissue regeneration, and homeostasis. Thus, a thorough understanding of the mechanisms that regulate metabolic homeostasis in stem cells may contribute to our knowledge on how tissue homeostasis is maintained and provide novel insights for disease management. In this review, we summarize the known relationship between the regulation of metabolic homeostasis and molecular pathways in stem cells. We also discuss potential targets of metabolic homeostasis in disease therapy and describe the current limitations and future directions in the development of these novel therapeutic targets.
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Células Madre , Células Madre/metabolismo , Homeostasis/fisiología , Diferenciación Celular/fisiologíaRESUMEN
Lenvatinib, an FDA-approved first-line oral multi-kinase inhibitor for advanced hepatocellular carcinoma (aHCC), has demonstrated promise for treatment. Nevertheless, findings from the Leap-002 study suggest that the addition of anti-vascular drugs to Lenvatinib may not yield significant improvements in survival rate. This meta-analysis aims to comprehensively assess the effectiveness of Lenvatinib, both as a standalone treatment and in combination with immune checkpoint inhibitors (ICIs), in managing advanced aHCC patients. We retrieved relevant studies published up to March 1, 2023, from databases such as PubMed, the Cochrane Library, Web of Science, and Embase. Subsequently, we conducted an analysis using REVMAN 5.3 and Stata MP 14.0 software, following quality assessment and data extraction procedures. A random effects model was employed to calculate the risk ratio (HR) using a 95% confidence interval (CI). The initial literature search yielded 921 results. However, after multiple rounds of exclusion and the removal of unrelated studies, 26 papers met the screening criteria. After a thorough examination of the full texts, we found that 8 studies met the analysis criteria. The combination of Lenvatinib with ICIs demonstrated significant improvement in overall survival (OS) (HR=1.53, 95% CI: 1.34-1.74; P<0.001) and progression-free survival (PFS) (HR=1.51, 95% CI: 1.34-1.72; P<0.001). Furthermore, subgroup analysis, categorized by the duration of follow-up, revealed that for the 3-year combined OS (HR=2.21, 95% CI: 1.79-2.73; Z=7.40, P<0.05), the combination therapy significantly outperformed monotherapy, leading to a 2.21-fold increase in OS for patients during the 3-year follow-up period. Nevertheless, for non-3-year combinations (HR=1.206, 95% CI: 1.020-1.425; Z=2.19, P<0.05), there was merely a 1.206-fold increase in effectiveness compared to single therapy for follow-ups of both longer and shorter durations. This might be attributed to the insufficient representation of HBV-related aHCC cases and the Asian population in the study, along with the increased availability of second-line treatment options for advanced cancer, which can influence the observed effectiveness of immunotherapy.
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Immunotherapy has become one of the most promising approaches in tumor therapy, and there are numerous associated clinical trials in China. As an immunosuppressive tumor, head and neck squamous cell carcinoma (HNSCC) carries a high mutation burden, making immune checkpoint inhibitors promising candidates in this field due to their unique mechanism of action. The present review outlines a comprehensive multidisciplinary cancer treatment approach and elaborates on how combining immunochemotherapy and immunoradiotherapy guidelines could enhance clinical efficacy in patients with HNSCC. Furthermore, the present review explores the immunology of HNSCC, current immunotherapeutic strategies to enhance antitumor activity, ongoing clinical trials and the future direction of the current immune landscape in HNSCC. Advanced-stage HNSCC presents with a poor prognosis, low survival rates and minimal improvement in patient survival trends over time. Understanding the potential of immunotherapy and ways to combine it with surgery, chemotherapy and radiotherapy confers good prospects for the management of human papillomavirus (HPV)-positive HNSCC, as well as other HPV-positive malignancies. Understanding the immune system and its effect on HNSCC progression and metastasis will help to uncover novel biomarkers for the selection of patients and to enhance the efficacy of treatments. Further research on why current immune checkpoint inhibitors and targeted drugs are only effective for some patients in the clinic is needed; therefore, further research is required to improve the overall survival of affected patients.
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BACKGROUND: The role of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKIs) in improving the prognostic outcome of non-small cell lung cancer (NSCLC) cases harboring EGFR mutation following radical surgery is still controversial. This work focused on comparing EGFR-TKIs and adjuvant chemotherapy (ACT) or placebo in treating NSCLC cases, specifically on those with EGFR-mutant, being in the stage of IB-IIIA and possibly gained benefits from the above treatment after radical resection. METHODS: The Cochrane Library, MEDLINE, and Embase databases were searched to identify eligible clinical trials; two authors were responsible for screening the results. The primary outcomes were evaluated by disease-free survival (DFS) and overall survival (OS) based on hazard ratios (HRs) and a relevant 95% confidence interval (CI). RESULTS: The literature search yielded twelve eligible studies, including four retrospective cohort studies and eight randomized controlled trials (RCTs) that enrolled 1694 cases and were of acceptable quality. In patients receiving adjuvant EGFR-TKIs compared with ACT or placebo treatment, HR regarding DFS was 0.47 (95% CI: 0.40, 0.55), whereas the OS rate was 0.74 (95% CI: 0.58, 0.95). For patients who received adjuvant EGFR-TKIs in combination with conventional chemotherapy compared to chemotherapy, the efficiency was significantly enhanced, with the HR for DFS being 0.29 (95% CI: 0.15, 0.58) and that for OS being 0.51 (95% CI: 0.25, 1.04), separately. CONCLUSION: For NSCLC cases who had EGFR mutations and surgery, adjuvant EGFR-TKI combined with chemotherapy achieved superior effect over chemotherapy or placebo with reference to DFS and may prolong the OS up to some extent.
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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/cirugía , Adyuvantes Farmacéuticos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adyuvantes Inmunológicos , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , MutaciónRESUMEN
Superhydrophobic coatings on iron surface have a wide application potential in medical instruments, chemical industrial equipment, and house construction. In this work, we developed a multi-functional superhydrophobic coating on iron surface with a high air/water contact angle of 162.3° and a low sliding angle of 2.4°. The construction of superhydrophobic coating involves physical friction processing to fabricate micropatterns and structures, followed by annealing treatment and surface chemical modification with 1H,1H,2H,2H-tridecafluoro-n-octyltrimethoxysilane. The obtained organic-inorganic composite material exhibited considerable optimization potential to anti-condensation performance. The low surface energy of the superhydrophobic coating also leads to poor adhesion of water, dust, and blood platelets, which is beneficial for applications in medical devices. The electrochemical and impedance test results demonstrated that the superhydrophobic surface provided effective corrosion protection for the iron substrate, with an 84.63% increase in corrosion protection efficiency. The experimental results showed that the anti-bacterial ratios reached 90% for E. coli and 85% for S. epidermidis, while the anti-bacterial ratios of ordinary iron were only 8% for E. coli and 15% for S. epidermidis, respectively.
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Sarcomatoid carcinoma is a rare tumor that is composed of a mixture of malignant epithelial cells and mesenchymal cells. Many studies have reported that sarcomatoid carcinoma occurs in multiple organs including the liver. Sarcomatoid intrahepatic cholangiocarcinoma (S-iCCA) is an extremely rare tumor that primarily occurs in the liver. This case occurred in a middle-aged man who was admitted to our hospital with abdominal pain. Enhanced computed tomography of the abdomen showed a low-density mass in the upper right posterior lobe of the liver with enhancement in the periphery. Histological and immunohistochemical examination indicated that the tumor was malignant, with both cancer and sarcoma components, and was positive for cytokeratin and vimentin. The patient was diagnosed with S-iCCA. Metastases appeared in the liver and lung 4 months after surgery. Two cycles of chemotherapy were administered. Because of enlargement of the tumor, anti-angiogenic agents combined with immunotherapy were subsequently given to achieve disease control. To the best of our knowledge, this is the first reported case of a programmed cell death-1 inhibitor used in a S-iCCA patient. The purpose of this case report and literature review is to enhance clinician understanding of S-iCCA and to explore safe and effective treatment methods.
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BACKGROUND: The safety and anti-tumor activity of penpulimab in patients with advanced upper gastrointestinal (UGI) cancers were evaluated in this study. METHODS: Patients with advanced UGI cancers naive to immune checkpoint inhibitors were enrolled in two trials of penpulimab. In the Phase Ia/Ib trial in Australia, patients received penpulimab intravenous infusion of 1, 3 and 10 mg/kg every 2 weeks in dose-escalation phase and 200 mg every 2 weeks in dose-expansion phase. In the phase Ib/II trial conducted in China, patients received 200 mg penpulimab every 2 weeks. Primary endpoints were safety and tolerability for the phase Ia/Ib trial and the objective response rate for the phase Ib/II trial. The safety and efficacy of penpulimab in patients with UGI cancers in these two trials were evaluated. RESULTS: A total of 67 patients with UGI cancers from Australia and China were enrolled in these two trials and had received penpulimab with a median of 6 (1-64) doses. 44.8% of patients experienced at least one treatment-related adverse event (TRAE), and 7.5% of patients experienced a grade ≥3 TRAE. Among 60 patients evaluable for response, the confirmed objective response rates ranged between 11.1 and 26.3% across cohorts for pancreatic cancer, cholangiocarcinoma, gastric or Gastroesophageal junction carcinoma (Gastric/GEJ), and hepatocellular carcinoma. 11/13 (85.0%) responders had ongoing responses at data cutoff date. CONCLUSIONS: Penpulimab monotherapy demonstrated an acceptable safety and encouraged anti-tumor activity in patients with advanced UGI cancers. Further exploration in a large cohort of patients is warranted. TRIAL REGISTRATION: Phase Ia/Ib trial in Australia (NCT03352531) and phase Ib/II trial in China (NCT04172506).
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Anticuerpos Monoclonales , Neoplasias Gastrointestinales , Inhibidores de Puntos de Control Inmunológico , Anticuerpos Monoclonales/efectos adversos , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoglobulina GRESUMEN
BACKGROUND: A substantial proportion of patients with unresectable stage III non-small-cell lung cancer (NSCLC) cannot either tolerate or access concurrent chemoradiotherapy, so sequential chemoradiotherapy is commonly used. We assessed the efficacy and safety of sugemalimab, an anti-PD-L1 antibody, in patients with stage III NSCLC whose disease had not progressed after concurrent or sequential chemoradiotherapy. METHODS: GEMSTONE-301 is a randomised, double-blind, placebo-controlled, phase 3 trial in patients with locally advanced, unresectable, stage III NSCLC, done at 50 hospitals or academic research centres in China. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had not progressed after concurrent or sequential chemoradiotherapy. We randomly assigned patients (2:1, using an interactive voice-web response system) to receive sugemalimab 1200 mg or matching placebo, intravenously every 3 weeks for up to 24 months. Stratification factors were ECOG performance status, previous chemoradiotherapy, and total radiotherapy dose. The investigators, trial coordination staff, patients, and study sponsor were masked to treatment allocation. The primary endpoint was progression-free survival as assessed by blinded independent central review (BICR) in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of assigned study treatment. The study has completed enrolment and the results of a preplanned analysis of the primary endpoint are reported here. The trial is registered with ClinicalTrials.gov, NCT03728556. FINDINGS: Between Aug 30, 2018 and Dec 30, 2020, we screened 564 patients of whom 381 were eligible. Study treatment was received by all patients randomly assigned to sugemalimab (n=255) and to placebo (n=126). At data cutoff (March 8, 2021), median follow-up was 14·3 months (IQR 6·4-19·4) for patients in the sugemalimab group and 13·7 months (7·1-18·4) for patients in the placebo group. Progression-free survival assessed by BICR was significantly longer with sugemalimab than with placebo (median 9·0 months [95% CI 8·1-14·1] vs 5·8 months [95% CI 4·2-6·6]; stratified hazard ratio 0·64 [95% CI 0·48-0·85], p=0·0026). Grade 3 or 4 treatment-related adverse events occurred in 22 (9%) of 255 patients in the sugemalimab group versus seven (6%) of 126 patients in the placebo group, the most common being pneumonitis or immune-mediated pneumonitis (seven [3%] of 255 patients in the sugemalimab group vs one [<1%] of 126 in the placebo group). Treatment-related serious adverse events occurred in 38 (15%) patients in the sugemalimab group and 12 (10%) in the placebo group. Treatment-related deaths were reported in four (2%) of 255 patients (pneumonia in two patients, pneumonia with immune-mediated pneumonitis in one patient, and acute hepatic failure in one patient) in the sugemalimab group and none in the placebo group. INTERPRETATION: Sugemalimab after definitive concurrent or sequential chemoradiotherapy could be an effective consolidation therapy for patients with stage III NSCLC whose disease has not progressed after sequential or concurrent chemoradiotherapy. Longer follow-up is needed to confirm this conclusion. FUNDING: CStone Pharmaceuticals and the National Key Research and Development Program of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Carcinoma de Pulmón de Células no Pequeñas , Quimioradioterapia , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Método Doble Ciego , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Estadificación de NeoplasiasRESUMEN
BACKGROUND: We compared the efficacy, safety, and immunogenicity of MIL60 with reference bevacizumab as first-line treatment in patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) in this phase 3, randomized, double-blind study. METHODS: Patients with untreated advanced or recurrent NSCLC were randomized (1:1 ratio) to receive either MIL60 or bevacizumab in combination with paclitaxel/carboplatin. Patients with non-progressive disease continued maintenance single-agent MIL60 until disease progression, or intolerable toxicity. The primary endpoint was the 12-week objective response rates (ORR12) by independent review committee (IRC) using RECIST 1.1. Bioequivalence was established if the ORR ratio located between 0.75 and 1/0.75. The trial was registered with clinicaltrials.gov (NCT03196986). FINDINGS: Between Aug 23, 2017, and May 8, 2019, 517 patients were randomly assigned to MIL60 group (n=257) and bevacizumab group (n=260). In the full analysis set (FAS) population including all randomized and evaluable patients who received at least one dose of MIL60 or bevacizumab, the ORR12 in MIL60 group and bevacizumab group were 48.6% and 43.1%, respectively. The ORR ratio of these two groups were 1.14 (90% CI 0.97-1.33), which fell within the pre-specified equivalence boundaries (0.75-1/0.75). The median DOR was 5.7 months (95% CI 4.5-6.2) for MIL60 and 5.6 months (95% CI 4.3-6.4) for bevacizumab. No significant difference was noted in median PFS (7.2 vs. 8.1 months; HR 1.01, 95% CI 0.78-1.30, p=0.9606) and OS (19.3 vs. 16.3 months; HR 0.81, 95% CI 0.64-1.02, p=0.0755). Safety and tolerability profiles were similar between the two groups. No patient detected positive for Anti-drug antibody (ADA). INTERPRETATION: The efficacy, safety and immunogenicity of MIL60 were similar with bevacizumab, providing an alternative treatment option for advanced or recurrent non-squamous NSCLC. FUNDING: This study was sponsored by Betta Pharmaceutical Co., Ltd.
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Pulmonary large cell neuroendocrine carcinoma (LCNEC), which accounts for approximately 1% of all lung cancers, is a rare and highly aggressive malignancy with a poor prognosis. Therefore, it is important to devise an effective treatment strategy. In the treatment of locally advanced complex LCNEC, it is unique to first administer radiotherapy combined with albumin-bound paclitaxel plus carboplatin, followed by durvalumab for immune maintenance treatment after concurrent radiotherapy and chemotherapy to achieve complete remission. We report a 54-year-old man who smoked and who felt chest tightness for 2 weeks and was diagnosed as having combined pulmonary LCNEC. For patients with locally advanced pulmonary LCNEC, chemoradiotherapy increases overall survival. After surgical resection and chemoradiotherapy, our patient achieved complete remission. Durvalumab was then started to consolidate the treatment. After six courses of immune maintenance therapy, the patient developed grade 2 immune-related pneumonitis and took prednisone orally until the symptoms resolved, and then reached complete remission again. The patient achieved complete remission, which was a challenge with this rare carcinoma, through albumin-bound paclitaxel plus platinum-based chemotherapy combined with radiotherapy and durvalumab for immune maintenance therapy. This approach may provide a treatment option for locally advanced combined pulmonary LCNEC.
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Carcinoma de Células Grandes , Carcinoma Neuroendocrino , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma Neuroendocrino/tratamiento farmacológico , Quimioradioterapia , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. METHODS: Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. RESULTS: A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation. CONCLUSIONS: Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL. TRIAL REGISTRATION: NCT02824458.
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Neoplasias Pulmonares , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Enfermedad , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Gefitinib/farmacología , Gefitinib/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas , Quinazolinas/uso terapéutico , Factor A de Crecimiento Endotelial VascularRESUMEN
This study aimed to develop an effective therapy against M2 macrophages and to investigate the effects of imidazole and mannose modified carboxymethyl chitosan-nanoparticles (MIC-NPs) on tumor growth and antitumor immune responses. MIC-NPs were constructed and analyzed through 1H NMR, nano-laser particle size analyzer, and transmission electron microscopy. The nanoparticles were mainly distributed in 75-85 nm, and zeta potential was 1.5 mV. Cytotoxicity studies in vitro and in vivo indicated that MIC-NPs were safe. The targeting effect of MIC-NPs on M2 macrophages was observed through fluorescence microscope and microplate system. The results demonstrated the uptake of a large amount of FITC-loaded MIC-NPs by M2. Cell growth inhibition experiments showed that MIC-NPs significantly inhibited M2 through cell apoptosis. The evaluation of anti-tumor activity in vivo showed that MIC-NPs could accumulate in the tumor site to exert an anti-tumor effect. Flow cytometry showed that the proportion of M2 macrophages at the tumor site in the experimental group was significantly lower than that in the control group, while the Treg cells and cytotoxic T cells (CTL) were found to be increased. PCR detection showed that the cDNA of FIZZ, MR, TGF-ß, and arginase, closely related to M2 macrophages, in the experimental group, was significantly lower than that in the control group, but there was no significant difference in the cDNA of Treg cell characteristic Foxp3 between the two groups. These results suggest that MIC-NPs are expected to provide a new and effective treatment for tumor.
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Quitosano/análogos & derivados , Portadores de Fármacos/química , Macrófagos/efectos de los fármacos , Nanopartículas/química , Animales , Supervivencia Celular , Química Farmacéutica , Quitosano/administración & dosificación , Quitosano/farmacocinética , Quitosano/farmacología , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , Fibroblastos/efectos de los fármacos , Humanos , Imidazoles/química , Masculino , Manosa/química , Ratones , Microscopía Electrónica de Transmisión , Tamaño de la Partícula , Propiedades de Superficie , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Reguladores/metabolismo , Células U937 , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. AIM: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. METHODS: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. RESULTS: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. CONCLUSION: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Inmunoglobulina G/inmunología , Linfoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Linfoma/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: The outbreak of COVID-19 has resulted in serious concerns in China and abroad. To investigate clinical features of confirmed and suspected patients with COVID-19 in west China, and to examine differences between severe versus non-severe patients. METHODS: Patients admitted for COVID-19 between January 21 and February 11 from fifteen hospitals in Sichuan Province, China were included. Experienced clinicians trained with methods abstracted data from medical records using pre-defined, pilot-tested forms. Clinical characteristics between severe and non-severe patients were compared. RESULTS: Of the 169 patients included, 147 were laboratory-confirmed, 22 were suspected. For confirmed cases, the most common symptoms from onset to admission were cough (70·7%), fever (70·5%) and sputum (33·3%), and the most common chest CT patterns were patchy or stripes shadowing (78·0%); throughout the course of disease, 19·0% had no fever, and 12·4% had no radiologic abnormality; twelve (8·2%) received mechanical ventilation, four (2·7%) were transferred to ICU, and no death occurred. Compared to non-severe cases, severe ones were more likely to have underlying comorbidities (62·5% vs 26·2%, P = 0·001), to present with cough (92·0% vs 66·4%, P = 0·02), sputum (60·0% vs 27·9%, P = 0·004) and shortness of breath (40·0% vs 8·2%, P < 0·0001), and to have more frequent lymphopenia (79·2% vs 43·7%, P = 0·003) and eosinopenia (84·2% vs 57·0%, P = 0·046). CONCLUSIONS: The symptoms of patients in west China were relatively mild, and an appreciable proportion of infected cases had no fever, warranting special attention.
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COVID-19/fisiopatología , Adulto , Anciano , COVID-19/diagnóstico , Preescolar , China , Comorbilidad , Tos , Brotes de Enfermedades , Femenino , Fiebre , Hospitalización , Humanos , Lactante , Pulmón/diagnóstico por imagen , Linfopenia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos XRESUMEN
The biological functions of circular RNAs in liver tumorigenesis have been well demonstrated by a number of studies. Nevertheless, to the best of our knowledge, the role and mechanism of action of hsa_circ_0008537 (circ_0008537) in liver cancer pathogenesis remain undetermined. In the present study, circ_0008537 expression was associated with the GLI3 gene and was markedly increased in liver cancer tissue specimens and cells. High expression levels of circ_0008537 exhibited a poor prognosis. In addition, circ_0008537 overexpression resulted in an increased proliferation, migration and invasion of liver cancer cells, whereas circ_0008537 knockdown exhibited opposite effects. circ_0008537 acted as a sponge of microRNA1533p (miR1533p), and a negative correlation was observed between circ_0008537 and miR1533p expression in liver cancer. Transfection with miR1533p further abolished the effects of circ_0008537 on the malignant behavior of liver cancer cells. Furthermore, circ_0008537 indirectly affected the expression levels of prosurvival protein myeloid cell leukemia 1 (MCL1) and snail family zinc finger 1 (Snail1) via miR1533p in liver cancer cells. In conclusion, the data indicated that circ_0008537 facilitated liver carcinogenesis by indirectly regulating miR1533p and leading to the release of MCL1 and Snail1.
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Neoplasias Hepáticas/genética , MicroARNs/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , ARN Circular/metabolismo , Factores de Transcripción de la Familia Snail/genética , Adulto , Anciano , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Hepatectomía , Humanos , Estimación de Kaplan-Meier , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Activación Transcripcional , Regulación hacia ArribaRESUMEN
BACKGROUND: In China, platinum-based doublet chemotherapy is the standard treatment for patients who have unresectable stage III non-small cell lung cancer (NSCLC), administered with radiotherapy on either a concurrent or sequential basis. However, NSCLC patients who undergo this treatment can expect poor median progression-free survival (PFS) of around 8-10 months and a dismal 5-year overall survival (OS) rate of about 15%. In the recent PACIFIC trial, durvalumab was demonstrated to hold significant clinical benefit for patients with locally advanced/unresectable NSCLC who experienced no disease progression after definitive concurrent chemoradiotherapy (cCRT). CS1001 is the first full-length, fully human immunoglobin G4 (IgG4) monoclonal antibody (mAb) that targets programmed death ligand-1 (PD-L1) created through the OMT transgenic rat platform. The phase Ia/Ib study indicated CS1001 was well tolerated and exhibited anti-tumor potential with a range of tumors. GEMSTONE-301 is a phase III randomized, double-blind, study to explore the efficacy and safety of CS1001 compared with a placebo as consolidation therapy for stage III unresectable NSCLC patients. METHODS: In this trial, eligible patients will be randomized to receive CS1001 1,200 mg or placebo, every 3 weeks (Q3W). The primary endpoint will be investigator-assessed PFS, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints will include OS, PFS assessment based on Blinded Independent Center Review (BICR), objective response rate (ORR), other efficacy measurements, safety, and tolerability. DISCUSSION: This phase III trial will determine the efficacy and safety of CS1001 as consolidation therapy in patients with locally advanced/unresectable (stage III) NSCLC who did not have disease progression after prior concurrent/sequential chemoradiotherapy (cCRT or sCRT), and is the first phase III trial on an anti-PD-L1 mAb initiated in China for this indication. PROTOCOL VERSION: Version 3.0/September 12, 2019.