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The efficacy of immune checkpoint inhibitors (ICI) in the treatment of hepatocellular carcinoma (HCC) remains limited, highlighting the need for further investigation into the underlying mechanisms. Accumulating evidence indicates that tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) are implicated in immune evasion and treatment resistance. This study aimed to explore the contribution of TAMs in the HCC TME. Our findings reveal the critical involvement of CX3C motif chemokine receptor 1 (CX3CR1)-positive TAMs in inducing T cell exhaustion through interleukin-27 (IL-27) secretion, providing valuable insights into the mechanisms underlying the suboptimal efficacy of anti-PD-1 therapy in HCC. Moreover, we identified prostaglandin E2 (PGE2), released by immune-attacked tumor cells, as a key regulator of CX3CR1+ TAM phenotype transition. To augment the therapeutic response to current anti-PD-1 therapy, we propose an innovative treatment strategy that incorporates targeting CX3CR1+ TAMs in addition to anti-PD-1 therapy. In conclusion, our study contributes to the understanding of TAMs' role in cancer immunotherapy and highlights potential clinical implications for HCC treatment. The combination of targeting CX3CR1+ TAMs with anti-PD-1 therapy holds promise for enhancing the efficacy of immunotherapeutic interventions in HCC patients.
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Immune checkpoint inhibitors (ICI) have dramatically transformed the treatment landscape for metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) or high microsatellite instability (MSI-H). Envafolimab, a novel programmed death-1 ligand 1 (PD-L1) inhibitor, has been reported to be efficient and safe for the management of advanced MSI-H/dMMR solid tumors. Here, we report the case of a 35-year-old female patient with MSI-H/dMMR mCRC who was treated with envafolimab following mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) plus bevacizumab. While suffering from interstitial pneumonia after chemotherapy, the patient achieved a complete clinical response with the use of envafolimab without additional adverse events. Thus, PD-L1 inhibitors may be potential candidates for treating patients with MSI-H/dMMR mCRC.
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OBJECTIVE: This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. BACKGROUND: Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries. METHODS: In this ongoing, multicenter, single-arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3-week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee. RESULTS: As of January 29, 2021, 31 patients were enrolled. The median follow-up was 5.1 months (range, 1.5-9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval [CI], 31.3-68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4-100). The median time to response was 1.4 months (95% CI, 1.3-1.4), the median duration of response was not reached, and the median progression-free survival was 6.3 months (95% CI, 4.9-not estimable [NE]). Eight (25.8%) of 31 patients had ≥grade 3 treatment-emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly Asunto(s)
Antineoplásicos
, Neoplasias de los Conductos Biliares
, Colangiocarcinoma
, Adulto
, Humanos
, Antineoplásicos/efectos adversos
, Antineoplásicos/uso terapéutico
, Neoplasias de los Conductos Biliares/tratamiento farmacológico
, Neoplasias de los Conductos Biliares/genética
, Conductos Biliares Intrahepáticos/patología
, Colangiocarcinoma/tratamiento farmacológico
, Colangiocarcinoma/genética
, Pueblos del Este de Asia
, Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética
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BACKGROUND: Cells of the immune system can inhibit tumor growth and progression; however, immune cells can also promote tumor cell growth, survival, and angiogenesis as a result of the immunosuppressive microenvironments. In the last decade, a growing number of new therapeutic strategies focused on reversing the immunosuppressive status of tumor microenvironments (TMEs), to reprogram the TME to be normal, and to further activate the antitumor functions of immune cells. Most of the "hot tumors" are encompassed with M2 macrophages promoting tumor growth, and the accumulation of M2 macrophages into tumor islets leads to poor prognosis in a wide variety of tumors. SUMMARY: Therefore, how to uncover more immunosuppressive signals and to reverse the M2 tumor-associated macrophages (TAMs) to M1-type macrophages is essential for reversing the immunosuppressive state. Except for reeducation of TAMs in the cancer immunotherapy, macrophages as central effectors and regulators of the innate immune system have the capacity of phagocytosis and immune modulation in macrophage-based cell therapies. KEY MESSAGES: We review the current macrophage-based cell therapies that use genetic engineering to augment macrophage functionalities with antitumor activity for the application of novel genetically engineered immune cell therapeutics. A combination of TAM reeducation and macrophage-based cell strategy may bring us closer to achieving the original goals of curing cancer. In this review, we describe the characteristics, immune status, and tumor immunotherapy strategies of macrophages to provide clues and evidences for future macrophage-based immune cell therapies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Anticuerpos Monoclonales Humanizados , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/efectos adversos , Terapia RecuperativaRESUMEN
Advanced or recurrent mucinous carcinoma of the ovary minimally responds to current cytotoxic treatments and has a poor prognosis. Despite multimodal treatment with chemotherapy and surgery, most patients ultimately progress and require palliative systemic therapy. Anti-HER2 therapy has been demonstrated to be an effective strategy for the treatment of HER2-positive breast cancer. However, the role of anti-HER2 therapy in ovarian cancer remains largely unknown. Here, we report the case of a young woman with FIGO Stage IIIc recurrent mucinous ovarian carcinoma (MOC) who developed trastuzumab resistance and disease progression following cross-treatment with trastuzumab combined with pertuzumab. HER2 amplification was discovered using next-generation sequencing (NGS). The patient then received bevacizumab, and pyrotinib (an irreversible HER2 antagonist) plus capecitabine treatment, and achieved a long-term clinical benefit for 22 months. Pyrotinib combined with bevacizumab is a potential treatment for MOC patients who are heavily pretreated and harbor a HER2 amplification. Our case may provide valuable treatment information for patients with advanced or recurrent MOC.
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OBJECTIVE: The specific purpose of this study is to investigate the impact exosomes from adipose-derived mesenchymal stem cell (AMSC) has on non-small cell lung carcinoma (NSCLC) and the relative applications. METHODS: circ_100395, miR-141-3p, and LATS2 were expressed and detected in NSCLC and paracancerous tissues as well as NSCLC cell lines. Pearson correlation analysis, Dual-Luciferase Reporter Assay and RNA pull-down assay were used to validate their expression and interaction, respectively. After isolation and culture of AMSCs, exosomes were extracted and identified. EdU, epithelial-mesenchymal transition (EMT), and cell colony formation assay were used to distinguish the biological activity of the cells. Expression Hippo/YAP signalling pathway-related proteins were measured by western blotting. Subsequently, tumour volume and weight were confirmed based on xenograft nude mice models, Ki-67 and LATS2 expression was observed by immunohistochemistry. RESULTS: circ_100395 was lowly expressed in NSCLC tissues or cells. The negative correlations and interactions were confirmed between circ_100395 and miR-141-3p, miR-141-3p, and LATS2. AMSC-derived exosomes with overexpression of circ_100395 (exo-circ_100395) significantly inhibited the biological activity as well as EMT of H1650 cells and Hippo/YAP signalling pathway activity. In addition, exo-circ_100395 markedly reduced tumour volume and weight as well as Ki-67 and LASP1 expression in vivo. However, overexpressed miR-141-3p or knocked down LATS2 alleviated the above effects. CONCLUSION: Exo-circ_100395 can increase LATS2 expression by sponging miR-141-3p to regulate Hippo/YAP signalling pathway, thereby inhibiting NSCLC malignant transformation.
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BACKGROUND AND AIM: Programmed cell death-ligand 1 (PD-L1) immunohistochemistry score has been approved as the predictive biomarker for anti-PD1/PD-L1 therapy in several advanced malignancies. Although its predictive role remained inconclusive in hepatocellular carcinoma, ongoing study of anti-PD1/PD-L1 therapy showed promising results. However, less is known about the PD-L1 immunohistochemistry score and factors correlated with it in hepatocellular carcinoma. We investigated PD-L1 immunohistochemistry scores in a large cohort of hepatocellular carcinoma, as well as its correlation with various clinical and genomic factors. METHODS: Immunohistochemistry was performed to detect the expression of PD-L1 protein in 315 hepatocellular carcinoma tissues. All slides were independently reviewed by three senior pathologists. Next-generation YS panel (450 genes) sequencing was performed on 309 patients. RESULTS: Higher PD-L1 expression as measured by combined positive score (CPS) was associated with increased Edmondson-Steiner grade (grade III vs II, P = 0.041) and TP53 mutations (P = 0.021). PD-L1 CPS had no correlation with tumor mutational burden (Spearman's correlation coefficient 0.067). PD-L1 CPS was not significantly associated with hepatitis B virus infection. CONCLUSIONS: Our data indicated that patients with higher Edmondson-Steiner grade (grade III) had significantly higher PD-L1 CPS than patients with lower Edmondson-Steiner grade (grade II). Patients with TP53 mutations had significantly higher PD-L1 expression.
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Antígeno B7-H1 , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/genética , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Femenino , Humanos , Inmunoquímica , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Adulto JovenRESUMEN
INTRODUCTION: The role of postoperative radiation therapy (PORT) for thymoma is under debate, especially in patients aged ≥60 years with an advanced stage (Masaoka stages III and IV). We aimed to evaluate the efficacy of PORT for thymoma in a population-based registry. METHODS: A retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER) database was conducted to compare the outcomes of thymoma patients with or without PORT. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS). Conditional inference tree analyses were performed for risk classification according to the study variables. Cox regression was performed to evaluate the prognostic effect of PORT in the specific subgroups. RESULTS: A total of 2,236 patients were included. The conditional inference tree analysis identified that an age ≥60, a Masaoka stage ≥3, and the year of diagnosis were important factors when classifying patients into prognostic subgroups. PORT was found to be a protective predictor of OS in patients aged ≥60 years, those with a Masaoka stage III-IV, and those diagnosed after 2005. Further subgroup analyses revealed that PORT was significantly associated with a better OS (HR = 0.77) in patients aged ≥60 years, whereas it was not significantly associated with CSS. CONCLUSIONS: An older age (≥60 years) is critical for predicting survival outcomes in thymoma patients. Moreover, patients aged ≥60 years could benefit from PORT in terms of OS.
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Timoma , Neoplasias del Timo , Bases de Datos Factuales , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Timoma/patología , Neoplasias del Timo/patologíaRESUMEN
BACKGROUND: While there have been encouraging preliminary clinical results for immune checkpoint inhibitors (ICIs) in BTCs, it remains a challenge to identify the subset of patients who may benefit. In this study, we evaluated the efficacy of ICI treatment in patients with advanced BTCs, and explored potential biomarkers that are predictive of response. METHODS: The study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with intrahepatic cholangiocarcinoma [ICCs]) who received ICI treatment. Targeted next-generation sequencing (NGS) was performed on tumor tissue samples collected from 17 patients. Clinical and genomic characteristics were assessed for the correlation with clinical outcome. RESULTS: Analysis of the baseline clinical characteristics showed that performance score (PS) of 0 was associated with a better prognosis than PS of 1 (HR = 1.08 × 109 ; 95% CI, 0â¼Inf; P = .002). No significant correlations were found between clinical outcome and inflammation-related indicators. NGS profiling of the available tumor tissues, revealed largely non-overlapping somatic alterations between GCs and ICCs. Mutations in LRP1B (HR = 0.26; 95% CI, 0.06-1.21; P = .067), ERBB2 (HR = 0.15; 95% CI, 0.02-1.19; P = .04), or PKHD1 (HR < 0.01; 95% CI, 0-Inf; P = .04) showed strong association with increased progression-free survival (PFS) benefit. Subsequent analysis showed that alterations in the RTK-RAS pathway were associated with improved outcomes (HR = 0.12; 95% CI, 0.02-0.63; P = .003). Tumor mutation burden (TMB) was higher in patients with GC than those with ICC, and was associated with LRP1B mutations (P = .032). We found that patients with 19q amplification (19q Amp) and 9p deletion (9p Del) had poor PFS outcome (19q Amp, HR = 15.4; 95% CI, 2.7-88.5; P < .001; 9p Del; HR = 4.88 × 109 ; 95% CI, 0-Inf; P < .001), while those with chromosomal instability derived PFS benefit (HR = 0.24; 95% CI, 0.05-1.17; P = .057). CONCLUSION: Our study identified several potential clinical and genomic features that may serve as biomarkers of clinical response to ICIs in advanced BTCs patients. A larger sample size is required for further verification.
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For early-stage upper urothelial carcinoma, total nephroureterectomy combined with bladder sleeve resection is the standard treatment. However, for patients with advanced disease, there is a lack of effective therapeutic strategies. In recent years, with an increased understanding of cancer immunobiology, systemic immunotherapies targeting immune checkpoint inhibition has been explored and clinically used in the area of urothelial carcinoma. The programmed cell death 1 receptor (PD-1) and its ligand (PD-L1) are important negative regulators of immune activity, preventing the destruction of normal tissues and autoimmunity. Nowadays, five immune checkpoint inhibitors blocking PD-1 (pembrolizumab, nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved by the United States Food and Drug Administration (US FDA) for the first- or second-line use in urothelial carcinoma, based on durable response and manageable safety profiles observed in relevant clinical trials. In this study, we present the case of a 64-year-old patient with renal pelvis carcinoma who went on to develop lung metastasis after postoperative chemotherapy. CT scan showed multiple scattered solid small nodule foci in both lungs (considered as metastasis). The patient received immunotherapy with PD-L1 monoclonal antibody (Durvalumab) alone, and achieved complete remission (CR) after 3 cycles of treatment. During the treatment, slight weakness was reported, and no nausea, fever and other adverse events were observed. This case shows that durvalumab could effectively and safely treat a case of renal pelvis carcinoma with lung metastases.
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Neoplasias Pulmonares , Neoplasias de la Vejiga Urinaria , Anticuerpos Monoclonales/uso terapéutico , Humanos , Inmunoterapia , Pelvis Renal , Neoplasias Pulmonares/tratamiento farmacológico , Persona de Mediana EdadAsunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Trasplante de Hígado/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/secundario , Carcinoma Hepatocelular/secundario , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/virología , Quimioembolización Terapéutica , Resultado Fatal , Hepatectomía , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/virología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etiología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidoresRESUMEN
BACKGROUND: Cholangiocarcinoma, or bile duct cancer, is a gastrointestinal cancer with limited therapeutic options and a poor outcome. Studies have revealed that some major driver genes are associated with cholangiocarcinoma, but no targeted therapies have been approved. Immune checkpoint inhibitors, which are represented by inhibitors of programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), have emerged as a potential therapy for multiple types of solid cancers. CASE PRESENTATION: A 53-year-old female presented with postoperative recurrence of PD-L1-positive intrahepatic cholangiocarcinoma with a high tumour mutational burden. This patient exhibited a marked response to the combination of anti-PD-1 immunotherapy and chemotherapy. CONCLUSIONS: As far as we know, this is the first case report on the success of the combination of immunotherapy and chemotherapy for advanced cholangiocarcinoma with PD-L1 positivity and a high tumour mutational burden.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/genética , Biomarcadores de Tumor , Colangiocarcinoma/genética , Colangiocarcinoma/terapia , Inmunoterapia , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/inmunología , Femenino , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Resultado del TratamientoAsunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Receptor ErbB-2/genética , Trastuzumab/uso terapéutico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Neoplasias de los Conductos Biliares/genética , China , Colangiocarcinoma/genética , Femenino , Humanos , Lapatinib/uso terapéutico , Masculino , Retratamiento , Insuficiencia del TratamientoRESUMEN
PURPOSE: The surgery with adjuvant radiation for the treatment of thymoma is still debated. The aim of this study was to examine the efficacy of postoperative radiotherapy (PORT) in a population-based registry of patients with thymoma. MATERIALS AND METHODS: We conducted a retrospective analysis of the Surveillance, Epidemiology, and End Results database to compare the outcomes of patients with thymoma who received surgery with or without PORT. RESULTS: Among the 2234 patients of this study, the surgery with PORT group had a longer mean overall survival (OS) and cancer-specific survival (CSS) than did the surgery without PORT group (OS: 172.3 vs. 155.3 months, p = .005; CSS: 247.3 vs. 241.8 months, p = .04). PORT significantly improved OS and CSS of patients with stage III/IV disease, but decreased CSS for those with stage I/IIA disease. Although the surgery with PORT group had a higher rate of secondary cancers, the between-group difference in the disease-free interval was not significant. CONCLUSIONS: PORT provides a significant benefit for patients with thymoma, particularly those with advanced disease. However, it also increases the risk of a second malignancy. We suggest that treatment guidelines should adopt a more positive stance on the use of PORT.
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Radioterapia Adyuvante , Programa de VERF , Timoma/radioterapia , Neoplasias del Timo/radioterapia , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Timoma/mortalidad , Neoplasias del Timo/mortalidad , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
PURPOSE: Paclitaxel and S-1 are both effective antitumor chemotherapeutic agents for advanced gastric cancer. However, the continuous administration of S-1 for 3 weeks or more can result in unacceptable toxicities, particularly hematological toxicities. Therefore, an alternative treatment schedule (1-week administration followed by 1-week rest) is warrant for testing in order to allow continuation of the therapy. We evaluate the efficacy and safety of biweekly S-1 and paclitaxel (SPA) as first-line chemotherapy in patients with metastatic or advanced gastric cancer. METHODS: Patients with previously untreated advanced or relapsed gastric cancer who had measurable lesion(s) were enrolled. Paclitaxel was administered intravenously at a dose of 120 mg/m(2) on day 1 and oral S-1 was given twice daily (BSA < 1.25 m(2), 80 mg/day; 1.25 ≤ BSA < 1.50 m(2), 100 mg/day; 1.50 m(2) ≤ BSA, 120 mg/day) on days 1-7 followed by a drug-free interval of 1 week every 14-day cycle. RESULTS: Forty-four patients (M/F = 33/11) were enrolled. A total of 277 chemotherapy cycles were administered, with a median of six cycles per patient (range 1-12), and 19 (43.2 %) patients received up to seven cycles. The assessed overall response rate was 38.6 with 38.6 % partial response in 17 patients, 45.4 % stable disease in 20 patients, and 13.6 % progressive disease in six patients. Thirty-four patients (77.3 %) received second-line chemotherapy. The estimated median progression-free survival and median overall survival times were, respectively, 5.2 months (95 % CI 4.08-6.39 months) and 12.2 months (95 % CI 8.81-15.60 months). The major hematological toxicities were included grade 3 leucocytopenia in two patients (4.5 %), grade 3 neutropenia in 14 patients (40.9 %), and grade 4 neutropenia in four patients (9.0 %). Two patients (4.5 %) suffered grade 1 febrile neutropenia. All grade of the non-hematological toxicities, such as nausea, vomiting, alopecia, and diarrhea, held the proportion of 54.5 % (grade 3/4, 4.5 %), 31.8, 95.4, and 18.1 % (grade 3/4, 2.2 %), respectively. CONCLUSIONS: Biweekly S-1 and paclitaxel (SPA regimen) combination therapy had promising activity with acceptable adverse toxicities. SPA regimen was easily implemented, and more patients received second-line chemotherapy. It deserved to conduct a well-designed randomized phase III study to compare this regimen with S-1-based combination treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Estudios Prospectivos , Neoplasias Gástricas/patología , Tegafur/administración & dosificación , Tegafur/efectos adversos , Adulto JovenRESUMEN
Primary Fallopian tube carcinoma (PFTC) is a rare but highly aggressive disease. Currently, treatments are similar to those used in epithelial ovarian carcinoma (EOC), however, there are distinct differences between the two diseases. PFTC tends to recur in the retroperitoneal nodes and distant sites more often than EOC. Limited literature with regard to effective agents in platinum-resistant and -refractory (Pt-R) disease exists, particularly after two lines of consecutive treatment. In this case report, a 47-year-old female with PFTC exhibited recurrence in the liver after postoperative chemotherapy. The patient received paclitaxel and cisplatin combination as first-line chemotherapy and topotecan as a second-line treatment, which is considered platinum-refractory. After the second-line treatment failed, this patient received a gemcitabine plus cisplatin combination as third-line chemotherapy for a total of 6 cycles. The liver metastases regressed rapidly and completely. The patient's progression-free survival (PFS) was 10 months and overall survival (OS) was 45 months. In conclusion, gemcitabine and cisplatin combination is an effective regimen for refractory PFTC even after the failure of two previous lines of consecutive chemotherapy and this warrants further independent investigation.
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BACKGROUND: Cyclooxygenase-2 (COX-2) is believed to be an important enzyme in the pathogenesis of colorectal cancer (CRC). Correlations between the expression of COX-2 with tumor growth and distant metastasis have become an issue; thus, attention has been paid to COX-2 as a prognostic factor. Various studies examined the relationship between COX-2 immunohistochemistry (IHC) overexpression with the clinical outcome in patients with colorectal cancer, but yielded conflicting results. The prognostic significance of COX-2 overexpression in colorectal cancer remains controversial. METHODS: Electronic databases updated to October 2012 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between COX-2 overexpression and survival of patients with colorectal cancer. Survival data were aggregated and quantitatively analyzed. RESULTS: We performed a meta-analysis of 23 studies (n â=â 4567 patients) that evaluated the correlation between COX-2 overexpression detected by IHC and survival in patients with colorectal cancer. Combined hazard ratios suggested that COX-2 overexpression had an unfavorable impact on overall survival (OS) (HR [hazard ratio] â=â 1.193, 95% CI [confidence interval]: 1.02 â¼ 1.37), but not disease free survival (DFS) (HR â=â 1.25, 95% CI: 0.99 â¼ 1.50) in patients with colorectal cancer. CONCLUSIONS: Cox-2 overexpression in colorectal cancer detected by IHC appears to have slightly worse overall survival. However, the prognostic value of COX-2 on survival in colorectal cancer still needs further large-scale prospective trials to be clarified.
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Neoplasias Colorrectales/metabolismo , Ciclooxigenasa 2/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Ciclooxigenasa 2/genética , Expresión Génica , Estudios de Asociación Genética , Humanos , Inmunohistoquímica , Pronóstico , Sesgo de PublicaciónRESUMEN
S-1 is an oral antitumor agent that contains tegafur, which is converted to fluorouracil (5-FU) in the human body. Cytochrome P450 2A6 (CYP2A6) is the principal enzyme responsible for bioconversion of tegafur to 5-FU. A number of CYP2A6 polymorphisms have been associated with variations in enzyme activity in several ethnic populations. The CYP2A6*4C allele leads to deletion of the entire CYP2A6 gene, and is the main finding in patients with reduced CYP2A6 enzymatic activity. Thus, the aim of our study was to evaluate the allele frequencies of CYP2A6 polymorphisms in a population with cancer of the digestive system. We developed a simple screening method, which combined TA cloning and direct-sequencing, to detect CYP2A6 genetic polymorphisms in Chinese patients with cancers of the digestive system. A total of 77 patients with various types of digestive system cancers were screened for CYP2A6 genetic polymorphisms. The allele frequencies of CYP2A6*1A, CYP2A6*1B and CYP2A6*4C in the 77 patients screened were 62, 42 and 13%, respectively. Frequencies of the homozygous genotypes for CYP2A6*1A and CYP2A6*4C were 27 and 12%, respectively. As expected, patients that were determined to be homozygous for CYP2A6*4C exhibited the characteristic chemotherapy efficacy and toxicity profiles. The TA cloning-based direct sequencing method facilitated allele frequency and genotyping determination for CYP2A6*1A, 1B and 4C of cancer patients. The findings indicated that the population carries a high frequency of the CYP2A6*4C homozygous genotype. Thus, the reduced efficacy of standard chemotherapy dosage in Chinese cancer patients may be explained by the lack of CYP2A6-mediated S-1 bioconversion to 5-FU.
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Antimetabolitos Antineoplásicos/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Neoplasias del Sistema Digestivo/tratamiento farmacológico , Neoplasias del Sistema Digestivo/genética , Ácido Oxónico/uso terapéutico , Polimorfismo Genético , Tegafur/uso terapéutico , Adolescente , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Secuencia de Bases , Citocromo P-450 CYP2A6 , Combinación de Medicamentos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Ácido Oxónico/efectos adversos , Tegafur/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Celastrol is a natural compound extracted from the traditional Chinese medicinal herb, Tripterygium wilfordii Hook. It has attracted interests for its potential anti-inflammatory and antitumor effects. However, the molecular mechanisms of celastrol-induced apoptosis in cancer cells remain unclear. In this study, we investigated the effects of celastrol on the human non-small-cell lung cancer (NSCLC) cell line A549 in vitro. Celastrol caused a dose- and time-dependent growth inhibition of A549 cells with an IC(50) of 2.12 µM at 48 h treatment. Celastrol induced A549 cells apoptosis as confirmed by annexin V/propidium iodide staining and DNA fragmentation. Celastrol-induced apoptosis was characterized by cleavage of caspase-9, caspase-8, caspase-3, and PARP protein, increased Fas and FasL expression, and a reduction in the mitochondrial membrane potential. Furthermore, celastrol induced the release of cytochrome c. Celastrol also up-regulated the expression of pro-apoptotic Bax, down-regulated anti-apoptotic Bcl-2, and inhibited Akt phosphorylation. These results demonstrate that celastrol can induce apoptosis of human NSCLC A549 cells through activation of both mitochondria- and FasL-mediated pathways.