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BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.
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Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Cetuximab , Neoplasias Colorrectales , Fluorouracilo , Leucovorina , Neoplasias Hepáticas , Compuestos Organoplatinos , Proteínas Proto-Oncogénicas B-raf , Humanos , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Femenino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/administración & dosificación , Proteínas Proto-Oncogénicas B-raf/genética , Anciano , Adulto , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/administración & dosificación , Resultado del Tratamiento , Proteínas ras/genéticaRESUMEN
OBJECTIVES: Immune checkpoint inhibitor (ICI)-associated myocarditis is a potentially fatal complication. Sparse published researches evaluated the prognostic value of cardiovascular magnetic resonance feature tracking (CMR-FT) for ICI-associated myocarditis. METHODS: In the single-center retrospective study, 52 patients with ICI-associated myocarditis and CMR were included from August 2018 to July 2021. The ICI-associated myocarditis was diagnosed by using the clinical criteria of the European Society of Cardiology guidelines. Major adverse cardiovascular events (MACE) were comprised of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. RESULTS: During a median follow-up of 171 days, 14 (27%) patients developed MACE. For patients with MACE, the global circumferential strain (GCS), global radial strain (GRS), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF) were significantly worse and native T1 values and late gadolinium enhancement (LGE) extent were significantly increased, compared with patients without MACE (p < 0.05). The GLS remained the independent factor associated with a higher risk of MACE (hazard ratio (HR): 2.115; 95% confidence interval (CI): 1.379-3.246; p = 0.001) when adjusting for LVEF, LGE extent, age, sex, body mass index, steroid treatment, and prior cardiotoxic chemotherapy or radiation. After adjustment for LVEF, the GLS remained the independent risk factor associated with a higher rate of MACE among patients with a preserved LVEF (HR: 1.358; 95% CI: 1.007-1.830; p = 0.045). CONCLUSIONS: GLS could provide independent prognostic value over GCS, GRS, traditional CMR features, and clinical features in patients with ICI-associated myocarditis. KEY POINTS: ⢠The global circumferential strain (GCS), global radial strain (GRS), and global longitudinal strain (GLS) by cardiovascular magnetic resonance feature tracking were significantly impaired in patients with an immune checkpoint inhibitor (ICI)-associated myocarditis. ⢠GLS was still significantly impaired in patients with preserved left ventricular ejection fraction. ⢠The worse GLS was an independent risk factor over GCS, GRS, traditional CMR features, and clinical features for predicting major adverse cardiovascular events in patients with ICI-associated myocarditis.
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Miocarditis , Función Ventricular Izquierda , Humanos , Volumen Sistólico , Miocarditis/inducido químicamente , Miocarditis/diagnóstico por imagen , Imagen por Resonancia Cinemagnética , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Pronóstico , Estudios Retrospectivos , Medios de Contraste/efectos adversos , Gadolinio , Valor Predictivo de las Pruebas , MiocardioRESUMEN
This study aimed at the efficacy of sequential treatment of bone marrow-derived mesenchymal stem cell secretion for busulfan-treated azoospermia in mice. The conditioned media (CM) was obtained from bone marrow mesenchymal stem cells (MSCs) or 293 cells. Chemically induced azoospermia mice received 200 µl MSC-CM or 293-CM twice a week intravenously for three consecutive weeks. The histological assessment of spermatogenic recovery quantifying the expression of meiosis-associated genes, and Sertoli cell barrier functional factors were assessed. The characteristics of TM4 cells (Sertoli cell line) after pre-incubation of MSC-CM in vitro were also obtained. The MSC-CM group had the most spermatogenic colonies among the three groups (p < .05), but no spermatids were seen. Expressions of the meiosis-associated genes Dazl, Vasa, Miwi, Stra8, CyclinA1, Pgk2 and Scp3 in MSC-CM testis were remarkably higher compared with 293-CM and busulfan groups respectively (p < .05). The levels of Sertoli cell barrier functional factors, for example ICAM-1 and N-cadherin, were significantly increased during MSC-CM treatment (p < .05). Moreover, pre-incubation of MSC-CM particularly accelerated the CD54 (ICAM-1) and CD44 expressions of TM4 cells and promoted cell inherent adhesion. MSC-CM treatment can significantly improve the short-term restoration of spermatogonial structures of chemically induced azoospermia related to facilitating Sertoli cell adhesion integrity.
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Azoospermia , Células Madre Mesenquimatosas , Animales , Azoospermia/inducido químicamente , Azoospermia/terapia , Busulfano/toxicidad , Humanos , Masculino , Ratones , Células de Sertoli , EspermatogénesisRESUMEN
OBJECTIVE: To investigate the potential mechanism of the effect of metabolic syndrome (MetS) on prostate volume (PV) and the risk of benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) and the relationships of MetS and the major pathogenic factors of MetS with the clinical progression of BPH/LUTS in older Chinese men. SUBJECTS AND METHODS: We analyzed clinical data obtained from 506 ostensibly healthy men who underwent routine health check-ups and recruited 415 subjects from a group of previously studied men after 4 years. We evaluated the associations of major pathological factors of MetS, including insulin resistance, subclinical inflammatory state, and sex hormone changes, with PV, the risk of BPH and the clinical progression of BPH/LUTS by using multiple linear regression and logistic regression. RESULTS: After adjustment for age, insulin, HOMA (homeostatic model assessment) index, leptin, resistin, adiponectin, C-reactive protein, tumor necrosis factor-α (TNF-α), sex hormone-binding globulin, and testosterone levels were significantly associated with PV (all P < .05), and in the age-adjusted logistic regression model, positive associations of resistin and TNF-α with BPH/LUTS were found (OR, 1.662, P = .007 and OR, 1.044, P < .001, respectively). Predictors of BPH/LUTS clinical progression were significantly correlated with MetS and TNF-α. The group with higher TNF-α levels had a higher rate of newly diagnosed BPH (9.5% vs 19.1%, P = .006) and a greater increase in PV levels (0.61 ± 0.08 vs 1.09 ± 0.35 cm3 , P <.001) after 4 years. CONCLUSIONS: MetS and its pathological factors were associated with an increased PV and an increased risk of BPH/LUTS that is more prone to clinical progression. TNF-α may serve as an early biological indicator to identify which patients with BPH/LUTS are at higher risk of unfavorable outcomes.
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Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Anciano , Presión Sanguínea/fisiología , Humanos , Modelos Logísticos , Masculino , Próstata/metabolismo , Próstata/patología , Circunferencia de la Cintura/fisiologíaRESUMEN
BACKGROUND: Due to the phenotypic and molecular diversity of hepatocellular carcinomas (HCC), it is still a challenge to determine patients' prognosis. We aim to identify new prognostic markers for resected HCC patients. METHODS: 274 patients were retrospectively identified and samples collected from Zhongshan hospital, Fudan University. We analyzed the gene expression patterns of tumors and compared expression patterns with patient survival times. We identified a "9-gene signature" associated with survival by using the coefficient and regression formula of multivariate Cox model. This molecular signature was then validated in three patients cohorts from internal cohort (n = 69), TCGA (n = 369) and GEO dataset (n = 80). RESULTS: We identified 9-gene signature consisting of ZC2HC1A, MARCKSL1, PTGS1, CDKN2B, CLEC10A, PRDX3, PRKCH, MPEG1 and LMO2. The 9-gene signature was used, combined with clinical parameters, to fit a multivariable Cox model to the training cohort (concordance index, ci = 0.85), which was successfully validated (ci = 0.86 for internal cohort; ci = 0.78 for in silico cohort). The signature showed improved performance compared with clinical parameters alone (ci = 0.70). Furthermore, the signature predicted patient prognosis than previous gene signatures more accurately. It was also used to stratify early-stage, HBV or HCV-infected patients into low and high-risk groups, leading to significant differences in survival in training and validation (P < 0.001). CONCLUSIONS: The 9-gene signature, in which four were upregulated (ZC2HC1A, MARCKSL1, PTGS1, CDKN2B) and five (CLEC10A, PRDX3, PRKCH, MPEG1, LMO2) were downregulated in HCC with poor prognosis, stratified HCC patients into low and high risk group significantly in different clinical settings, including receiving adjuvant transarterial chemoembolization and especially in early stage disease. This new signature should be validated in prospective studies to stratify patients in clinical decisions.
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Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/diagnóstico , Transformación Celular Viral/genética , Hepacivirus/fisiología , Virus de la Hepatitis B/fisiología , Neoplasias Hepáticas/diagnóstico , Transcriptoma , Adulto , Anciano , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/virología , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Hepacivirus/patogenicidad , Hepatitis B/complicaciones , Hepatitis B/diagnóstico , Hepatitis B/genética , Hepatitis B/cirugía , Virus de la Hepatitis B/patogenicidad , Hepatitis C/complicaciones , Hepatitis C/diagnóstico , Hepatitis C/genética , Hepatitis C/cirugía , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: To compare the efficacy of oxaliplatin-based and oxaliplatin-free adjuvant chemotherapies in patients with different Lauren type gastric cancers after D2 gastrectomy. METHODS: From our established gastric cancer database, patients with pathological stage II and III gastric cancer who received adjuvant chemotherapy after D2 gastrectomy at Zhongshan Hospital of Fudan University were analyzed. Patients who received different adjuvant chemotherapy regimens were divided into two subgroups: oxaliplatin-based and oxaliplatin-free subgroup. Clinical outcomes were analyzed according to pathological stage and different Lauren types. RESULTS: From Jan 2010 to June 2017, a total of 580 patients met all the eligibility criteria and were enrolled. The median DFS for all the patients was 24.37 months and the median OS was 56.70 months. In patients with intestinal type gastric cancer, the median DFS of the oxaliplatin-based subgroup was significantly longer than that of oxaliplatin-free subgroup (48.73 vs. 18.33 months, P < 0.001). The median OS was not reached in the oxaliplatin-based subgroup and 54.33 months in the oxaliplatin-free subgroup (P = 0.006). In patients with diffuse type gastric cancer, neither DFS nor OS differed significantly between two subgroups. In multivariate analysis, oxaliplatin-based adjuvant chemotherapy was independent positive predictor of DFS (HR 0.40; 95% CI 0.28-0.59; P < 0.001) and OS (HR 0.35; 95% CI 0.20-0.62; P < 0.001) in patients with intestinal type gastric cancer. CONCLUSIONS: The results of our study suggested that oxaliplatin-based adjuvant chemotherapy was more effective in patients with intestinal type gastric cancer after D2 gastrectomy but showed no more survival benefit in patients with diffuse type.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gastrectomía/métodos , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Capecitabina/administración & dosificación , Quimioterapia Adyuvante , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Oxaliplatino/administración & dosificación , Cuidados Posoperatorios , Pronóstico , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Tasa de SupervivenciaRESUMEN
BACKGROUND: Metabolic syndrome (MetS) and serum prostate-specific antigen (PSA) levels are correlated. To investigate the underlying effect of MetS on PSA levels, the relationship between the major pathogenic factors of MetS and serum PSA levels was studied. METHODS: A total of 506 ostensibly healthy men who underwent routine health check-ups were recruited to this study. We evaluated the effect of the major pathogenic factors of MetS, which included insulin resistance, a subclinical inflammatory state and sexual hormone changes, on serum PSA levels by using linear regression analysis and multivariate analysis after adjusting for age, BMI and prostate volume. RESULTS: When simultaneously adjusting for age, BMI, prostate volume and high-density lipoprotein cholesterol, serum insulin levels and SHBG levels were inversely correlated with serum PSA levels (P = 0.049 and P = 0.004, respectively), and testosterone levels were positively correlated with serum PSA levels (P = 0.039). In multivariate regression models, serum insulin levels and serum SHBG levels were significantly associated with serum PSA levels (both P < 0.001). CONCLUSIONS: Among the major pathogenic factors of metabolic syndrome, insulin resistance and sexual hormone changes may be the most significant contributors to the decline in serum PSA levels.
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Síndrome Metabólico/sangre , Síndrome Metabólico/etiología , Antígeno Prostático Específico/sangre , Anciano , Correlación de Datos , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Factores de RiesgoRESUMEN
The present study was designed to investigate the therapeutic effect of bone marrow MSC-derived factors on gonadotropic toxicity induced by busulfan in vivo. The conditioned media (CM) was obtained from MSCs in serum-free incubation for 48 hr and concentrated ~25-fold by ultrafiltration. The CM of HEK 293 cells was treated as control (293-CM). MSC-CM was injected into busulfan mice via caudal veins after 1 day of busulfan treatment for 2 weeks (200 µl per dose/twice weeklyï¼. Compared to the 293-CM group, testicular injury was delayed in MSC-CM group, including reduced vacuolations of cells in the basal compartment of the seminiferous epithelium and detachment of cells from basement membrane. Apoptotic spermatogenic cells were significantly decreased in MSC-CM group (p ï¼ 0.05). Interesting N-cadherinï¼ICAM-1 and P-cadherin expressions significantly increased in MSC-CM group, while occludin, ZO-1 and connexin 43 expressions showed no difference among MSC-CM, 293-CM and busulfan groups. Present results suggest MSC-secreted factors protect spermatogenesis impairment after busulfan treatment by reducing the apoptosis of spermatogenic cells and enhancing intercellular adhesion molecule expressions.
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Barrera Hematotesticular/efectos de los fármacos , Busulfano/toxicidad , Medios de Cultivo Condicionados/farmacología , Infertilidad Masculina/tratamiento farmacológico , Células Madre Mesenquimatosas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Barrera Hematotesticular/citología , Barrera Hematotesticular/patología , Cadherinas/metabolismo , Adhesión Celular/efectos de los fármacos , Medios de Cultivo Condicionados/metabolismo , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/patología , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Ratones , Espermatogénesis/efectos de los fármacosRESUMEN
BACKGROUND: The aim of this study was to compare the efficacies of the XELOX and DOS regimens as preoperative chemotherapy in patients with locally advanced gastric cancer. METHODS: All cases of locally advanced gastric cancer treated with the XELOX or DOS regimen were reviewed retrospectively. Propensity score matching (PSM) was carried out to reduce selection bias based on age, gender, location, Lauren type, carcinoembryonic antigen level, clinical tumor stage, and clinical node stage. RESULTS: From January 2010 to December 2016, 248 patients were matched; 159 of them received the XELOX regimen and 89 the DOS regimen. The response rates in the XELOX and DOS groups were 34.5 and 38.1%, respectively (P = 0.823). After four cycles of chemotherapy, 111 patients (69.8%) in the XELOX group and 65 patients (73.0%) in the DOS group underwent radical surgery (P = 0.485). The median progression-free survival (33.0 months vs. 18.7 months, P = 0.0356) and the median overall survival (43.8 months vs. 29.1 months, P = 0.0003) were longer for patients who received the DOS regimen than for those who received the XELOX regimen. The occurrence of grade 3 to 4 toxicity was similar in the two groups. CONCLUSIONS: For locally advanced gastric cancer patients, the DOS regimen showed more benefit than the XELOX regimen as preoperative chemotherapy, without any added toxicity effects.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Puntaje de Propensión , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Quimioterapia Adyuvante , Desoxicitidina/uso terapéutico , Docetaxel/administración & dosificación , Combinación de Medicamentos , Femenino , Fluorouracilo/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Oxaliplatino/administración & dosificación , Oxaloacetatos , Ácido Oxónico/administración & dosificación , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Tegafur/administración & dosificaciónRESUMEN
Alterations of the autophagy-lysosomal pathway (ALP) and autophagy have been involved in lung ischemia-reperfusion (I/R) injury. However, dynamic imaging of ALP function under lung I/R injury particularly is not fully understood. Here we depicted the live-cell fluorescence imaging of autophagosome to monitor ALP activation and autophagy function. The pAsRed2-N1-LC3 vectors were transfected into CRL-2192 NR8383 (an alveolar macrophage cell line) and CCL149 (an alveolar epithelial cell line) successfully. 0-h, 2-h, 4-h, and 6-h hypoxia/0-h, 2-h, 4-h, and 6-h reoxygenation were then induced with an ALP inhibitor (3-MA) or activator (rapamycin) in the culture of transfected cells separately. ALP activation was conformed by up-regulating AMPK and beclin1 expression. Apoptosis was not obvious in 2-h hypoxia/2-h reoxygenation. pAsRed2-N1-LC3 CCL149 and pAsRed2-N1-LC3 NR8383 cells revealed gradually enhanced AsRed2 from 2-h to 6-h hypoxia/reoxygenation. AsRed2 varied sensitively to 3-MA and rapamycin interventions during 2-h hypoxia/reoxygenation. Our data provides a simple method of autophagosome imaging to monitor ALP activation and autophagy function in lung I/R injury.
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Autofagia , Hipoxia/fisiopatología , Pulmón/fisiopatología , Lisosomas/fisiología , Terapia por Inhalación de Oxígeno , Animales , Secuencia de Bases , Cartilla de ADN , Técnicas In Vitro , Ratas , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
INTRODUCTION: Right-sided colon cancer (RSCC) and left-sided colorectal cancer (LSCRC) differ with respect to their biology and genomic patterns. This study aimed to examine whether the primary tumor location is associated with the response to cetuximab in patients with metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC treated with cetuximab and standard chemotherapy as first- or second-line treatments were compared with randomly chosen patients who were treated with chemotherapy alone between 2005 and 2013. The main outcome measures were the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). The differences in the outcome were analyzed by using the chi-squared test, Student's t test, and Kaplan-Meier method. RESULTS: The treatment results of 206 patients with mCRC treated with cetuximab and standard chemotherapy as first- or second-line treatments were compared with those of 210 patients who were treated with chemotherapy alone. As a first-line treatment, cetuximab with chemotherapy was associated with a significantly higher ORR (49.4 % vs. 28.6 %, P = 0.005) as well as longer PFS (9.1 vs. 6.2 months, P = 0.002) and OS (28.9 vs. 20.1 months, P = 0.036) than chemotherapy alone in patients with LSCRC. However, cetuximab neither improved the ORR (36.4 % vs. 26.2 %, P = 0.349) nor prolonged PFS (5.6 vs. 5.7 months, P = 0.904) or OS (25.1 vs. 19.8 months, P = 0.553) in patients with RSCC. As a second-line treatment, cetuximab exhibited a tendency to improve the ORR (23.5 % vs. 10.2 %, P = 0.087) and prolong PFS (4.9 vs. 3.5 months, P = 0.064), and it significantly prolonged OS (17.1 vs. 12.4 months, P = 0.047) compared with chemotherapy alone in the patients with LSCRC. In contrast, as a second-line treatment, cetuximab neither improved the ORR (7.1 % vs. 11.4 %, P = 0.698) nor prolonged PFS (3.3 vs. 4.2 months, P = 0.761) or OS (13.4 vs. 13.0 months, P = 0.652) in patients with RSCC. CONCLUSIONS: The addition of cetuximab to chemotherapy in both first- and second-line treatments of mCRC may only benefit patients with primary LSCRC.
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Cetuximab , Neoplasias del Colon , Neoplasias Colorrectales , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Enfermedad , Humanos , Estudios RetrospectivosRESUMEN
The monoclonal antibody trastuzumab has brought survival benefit to patients with advanced gastric cancer (AGC) that have human epidermal growth factor receptor 2 (HER2) over expression or amplification. This study was designed to compare the clinical outcomes of HER2-negative and HER2-positive AGC patients with or without trastuzumab treatment. There were three groups of patients enrolled for analysis. Group A was 51 HER2-positive AGC patients treated with trastuzumab and chemotherapy; group B was a matched control group of 47 HER2-positive patients who received chemotherapy only; group C was a matched group of 251 HER2-negative patients who received chemotherapy. All the patients were enrolled at Sun Yat-sen University Cancer Center or Zhongshan Hospital, Fudan University between January 2010 and December 2012. The primary endpoint was overall survival (OS). The Kaplan-Meier method and log-rank test were used for survival analysis. The median duration of follow-up was 13.5 months (range 5-18.6 months). The median OS of these three groups of patients was 14.8 months, 11.3 months and 14.4 months respectively (p < 0.001). The survival difference between group A and B was significant, p < 0.001. Similarly, there was significant difference between group B and C, p < 0.001. Moreover the survival between group A and C was comparable, p = 0.281. The median progression-free survival for these three groups was 7.4, 6.0 and 7.2 months. Multivariate analysis confirmed that trastuzumab treatment was an independent prognostic factor in group A and B patients (p = 0.017). HER2 positive was an independent adverse prognostic factor in group B and C patients (p = 0.013).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Pronóstico , Estudios Prospectivos , Receptor ErbB-2/genética , Receptor ErbB-2/inmunología , Neoplasias Gástricas/metabolismo , Trastuzumab , Resultado del Tratamiento , Vómitos/inducido químicamente , Adulto JovenRESUMEN
The interaction between cancer cells and immune cells plays critical roles in gastric cancer (GC) progression and immune evasion. Forced legumain (LGMN) is one of the characteristics correlated with poor prognosis in gastric cancer patients. However, the role of gastric-cancer-secreted LGMN (sLGMN) in modulating the tumor immune microenvironment and the biological effect on the immune evasion of gastric cancer remains unclear. In this study, we found that forced expression of sLGMN in gastric cancer serum correlates with increased M2 macrophage infiltration in GC tissues and predicted resistance to anti-PD-1 immunotherapy. Mechanistically, gastric cancer cells secrete LGMN via binding to cell surface Integrin αvß3, then activate Integrin αvß3/PI3K (Phosphatidylinositol-4,5-bisphosphate3-kinase)/AKT (serine/threonine kinase)/mTORC2 (mammalian target of rapamycin complex 2) signaling, promote metabolic reprogramming, and polarize macrophages from the M1 to the M2 phenotype. Either blocking LGMN, Integrin αv, or knocking out Integrin αv expression and abolishing the LGMN/Integrin αvß3 interaction significantly inhibits metabolic reprogramming and polarizes macrophages from the M1 to the M2 phenotype. This study reveals a critical molecular crosstalk between gastric cancer cells and macrophages through the sLGMN/Integrinαvß3/PI3K/AKT/mTORC2 axis in promoting gastric cancer immune evasion and resistance to anti-PD-1 immunotherapy, indicating that the sLGMN/Integrinαvß3/PI3K/AKT/mTORC2 axis may act as a promising therapeutic target.
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OBJECTIVE: To describe the treatment patterns and survival status of advanced gastric cancer (AGC) in China in the past two decades, and objectively evaluate the impact of standardized Chinese medicine (CM) treatment on the survival of AGC patients. METHODS: This multicenter registry designed and propensity score analysis study described the diagnosis characteristics, treatment-pattern development and survival status of AGC from 10 hospitals in China between January 1, 2000 and July 31, 2021. Overall survival (OS) was evaluated between non-CM cohort (standard medical treatment) and CM cohort (integrated standard CM treatment ≥3 months). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to adjust any difference in average outcomes for bias. RESULTS: A total of 2,001 patients histologically confirmed locally advanced and/or metastasis stomach and gastroesophageal junction adenocarcinoma were enrolled. Among them, 1,607 received systemic chemotherapy, 215 (10.74%) accepted molecular targeted therapy, 44 (2.2%) received checkpoint inhibitor therapy, and 769 (38.43%) received CM. Two-drug regimen was the main choice for first-line treatment, with fluoropyrimidine plus platinum as the most common regimen (530 cases, 60.09%). While 45.71% (16 cases) of patients with HER2 amplification received trastuzumab in first-line. The application of apatinib increased (33.33%) in third-line. The application of checkpoint inhibitors has increased since 2020. COX analysis showed that Lauren mixed type (P=0.017), cycles of first-line treatment >6 (P=0.000), CM (P=0.000), palliative gastrectomy (P=0.000), trastuzumab (P=0.011), and apatinib (P=0.008) were independent prognostic factors for the OS of AGC. After PSM and IPTW, the median OS of CM cohort and non-CM cohort was 18.17 and 12.45 months, respectively (P<0.001). CONCLUSIONS: In real-world practice for AGC in China, therapy choices consisted with guidelines. Two-drug regimen was the main first-line choice. Standardized CM treatment was an independent prognostic factor and could prolong the OS of Chinese patients with AGC. (Registration No. NCT02781285).
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Medicina Tradicional China , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Masculino , Femenino , Persona de Mediana Edad , Análisis de Supervivencia , Medicina Tradicional China/métodos , Anciano , China/epidemiología , Puntaje de Propensión , AdultoRESUMEN
The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Oncología Médica , Inmunoterapia , Terapia Neoadyuvante , ChinaRESUMEN
OBJECTIVE: To assess the efficacy and safety of bevacizumab (BEV) plus chemotherapeutic agents in the treatment of metastatic colorectal cancer (mCRC). METHODS: Seventy-seven mCRC patients received BEV plus 5-Fu type, oxaliplatin or irinotecan-based chemotherapy. The clinical efficacy and bevacizumab-related adverse reactions were observed. The efficacy assessment was conducted after at least 2 cycles of BEV therapy. The adverse reactions were recorded in each therapy cycle. Among the 77 cases, 64 patients had finished the efficacy assessment. The adverse reactions in all patients were assessed. RESULTS: The overall response rate (ORR) of BEV plus chemotherapy regimen was 18.75% (12/64), and the disease control rate (DCR) was 75.0% (48/64). In 27 patients who received the regimen as first-line treatment, the ORR reached 37.0% (10/27), while the DCR was 85.2%. Four patients with potentially resectable lesions became resectable after the regimen and received R0 resection of the liver metastases successfully. Twenty-five patients who received the regimen as second line therapy had poor result with ORR 8.0% and DCR 76.0%. Hypertension was observed in 12 cases, with 8 cases of grade 1, 3 cases of grade 2, 1 case of grade 3. Various bleedings occurred in 24/77 cases (31.2%), all were of grade 1-2, including 17 cases of epistaxis, grade 1 hemorrhoid bleeding in one case, hematuria in 3 case (2 of grade 1, 1 of grade 2), GI bleeding in 2 cases, hemoptysis in 1 case (grade 2), and proteinuria in 4 cases (grade 1). Intestinal perforation occurred in 1 case (0.3%). In two patients who had incomplete intestinal obstruction history appeared exacerbated intestinal obstruction symptoms after the application of BEV plus CPT11 regimen. CONCLUSIONS: BEV plus chemotherapy regimen as first-line treatment can improve the ORR and DCR of mCRC patients. When it was used as second- or later-line therapy, it may display satisfied DCR, although with a poor efficacy. The bevacizumab-related toxicity is mild and can be well tolerated.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Capecitabina , Neoplasias del Colon/patología , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Hemorragia/inducido químicamente , Humanos , Hipertensión/inducido químicamente , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Oxaloacetatos , Proteinuria/inducido químicamente , Neoplasias del Recto/patología , Inducción de Remisión , Adulto JovenRESUMEN
Background: Trastuzumab (TRA) shows significant efficacy in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). While TRA can help treat HER2-positive breast cancer, TRA resistance is a key clinical challenge. Nestin reportedly regulates the cellular redox homeostasis in lung cancer. This study aimed at identifying the functions of Nestin on the TRA sensitivity of HER2-positive GC cells. Methods: Real-time polymerase chain reaction (PCR) and Western blotting (WB) were performed to explore the association between the mRNA and protein expression profiles, respectively, of Nestin and the Keap1-Nrf2 pathway. The influence of Nestin overexpression on the in vitro sensitivity of GC cells to TRA was explored by Cell Counting Kit-8 (CCK-8) assay, colony formation assay, reactive oxygen species (ROS) detection, and flow cytometry. Results: TRA treatment caused Nestin downregulation in two HER2-positive GC cell lines (MKN45 and NCI-N87). Nestin overexpression reduced the sensitivity of GC cells to TRA. The expression and activity of Nrf2 and relevant downstream antioxidant genes were increased by Nestin overexpression. Nestin overexpression also significantly suppressed TRA-induced apoptosis and ROS generation. In vivo tumor growth experiment with female BALB/c nude mice indicated that Nestin upregulation restored the tumor growth rate which was inhibited by TRA treatment. Conclusions: Collectively, the inhibitory effect of Nestin on the TRA sensitivity of cells to TRA was confirmed in this study. These results imply that the antioxidant Nestin-Nrf2 axis may play a role in the mechanism underlying the resistance of GC cells to TRA.
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Coiled-Coil Domain-Containing (CCDC) is a large class of structural proteins containing left-handed supercoiled structure. The clinical value and the functional implication of CCDC in colorectal cancer (CRC) remain unknown. Based on the genetic, transcriptional, and clinical data from The Cancer Genome Atlas, five of thirty-six CCDC proteins were differentially expressed in the CRC and associated with the survival of patients with CRC. A CCDC-score model was established to evaluate the prognosis of patients. The potential function of Coiled-Coil Domain-Containing 154 (CCDC154) was investigated using bioinformatical methods, which unveiled that high expression of CCDC154 indicates poor survival for patients with CRC and correlates with low infiltration of CD8+ T cells and high infiltration of neutrophils, indicating that CCDC154 enhances tumor growth and metastasis. CCDC154 interacts with Minichromosome Maintenance Complex Component 2 (MCM2) protein and promotes malignant phenotype via MCM2. We validated the expression level and survival prediction value of CCDC154 in clinical samples, and analyzed its co-expression of MCM2, Ki-67 and p53. This work discloses the role of CCDC in clinical setting and CCDC154 functions in CRC.
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Proteínas de Ciclo Celular , Neoplasias Colorrectales , Humanos , Linfocitos T CD8-positivos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Componente 2 del Complejo de Mantenimiento de Minicromosoma/genética , Componente 2 del Complejo de Mantenimiento de Minicromosoma/metabolismo , PronósticoRESUMEN
BACKGROUND: Stereotactic body radiotherapy (SBRT) and programmed cell death 1 inhibitors have shown potential in treating hepatocellular carcinoma (HCC) in retrospective studies. AIM: To evaluate the efficacy of combining SBRT with sintilimab for patients with recurrent or oligometastatic HCC. METHODS: This trial involved patients with recurrent or oligometastatic HCC intravenously treated with SBRT plus sintilimab every 3 wk for 12 mo or until disease progression. The primary endpoint was progression-free survival (PFS). RESULTS: Twenty-five patients were enrolled from August 14, 2019, to August 23, 2021. The median treatment duration was 10.2 (range, 0.7-14.6) months. SBRT was delivered at a median dose of 54 (range, 48-60) Gy in 6 (range, 6-10) fractions. The median follow-up time was 21.9 (range, 10.3-39.7) mo, and 32 targeted lesions among 25 patients were evaluated for treatment response according to the Response Evaluation Criteria in Solid Tumors version 1.1. The median PFS was 19.7 mo [95% confidence interval (CI): 16.9-NA], with PFS rates of 68% (95%CI: 52-89) and 45.3% (95%CI: 28-73.4) at 12 and 24 mo, respectively. The median overall survival (OS) was not reached, with OS rates of 91.5% (95%CI: 80.8-100.0) and 83.2% (95%CI: 66.5-100.0) at 12 and 24 mo, respectively. The 1- and 2-year local control rate were 100% and 90.9% (95%CI: 75.4%-100.0%), respectively. The confirmed objective response rate and disease control rate was 96%, and 96%, respectively. Most adverse events were graded as 1 or 2, and grade 3 adverse events were observed in three patients. CONCLUSION: SBRT plus sintilimab is an effective, well-tolerated treatment regimen for patients with recurrent or oligometastatic HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Radiocirugia , Humanos , Radiocirugia/efectos adversos , Estudios RetrospectivosRESUMEN
Background: Metabolic reprogramming is a feature of cancer. However, colon cancer subtypes based on the glycolysisâcholesterol synthesis axis have not been identified, and little is known about connections between metabolic features and the tumor microenvironment. Methods: Data for 430 colon cancer cases were extracted from The Cancer Genome Atlas, including transcriptome data, clinical information, and survival outcomes. Glycolysis and cholesterol synthesis-related gene sets were obtained from the Molecular Signatures Database for a gene set variation analysis. The relationship between the genomic landscape and immune landscape were investigated among four metabolic subtypes. Hub genes were determined. The clinical significance of candidate hub gene was evaluated in 264 clinical samples and potential functions were validated in vitro and in vivo. Results: Colon cancer cases were clustered into four metabolic subtypes: quiescent, glycolytic, cholesterogenic, and mixed. The metabolic subtypes differed with respect to the immune score, stromal score, and estimate score using the ESTIMATE algorithm, cancer-immunity cycle, immunomodulator signatures, and signatures of immunotherapy responses. Patients in the cholesterogenic group had better survival outcomes than those for other subtypes, especially glycolytic. The glycolytic subtype was related to unfavorable clinical characteristics, including high mutation rates in TTN, APC, and TP53, high mutation burden, vascular invasion, right colon cancer, and low-frequency microsatellite instability. GGH, CACNG4, MME, SLC30A2, CKMT2, SYN3, and SLC22A31 were identified as differentially expressed both in glycolytic-cholesterogenic subgroups as well as between colon cancers and healthy samples, and were involved in glycolysisâcholesterol synthesis. GGH was upregulated in colon cancer; its high expression was correlated with CD4+ T cell infiltration and longer overall survival and it was identified as a favorable independent prognostic factor. The overexpression of GGH in colon cancer-derived cell lines (SW48 and SW480) inhibited PKM, GLUT1, and LDHA expression and decreased the extracellular lactate content and intracellular ATP level. The opposite effects were obtained by GGH silencing. The phenotype associated with GGH was also validated in a xenograft nude mouse model. Conclusions: Our results provide insight into the connection between metabolism and the tumor microenvironment in colon cancer and provides preliminary evidence for the role of GGH, providing a basis for subsequent studies.