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1.
Am J Cancer Res ; 11(9): 4259-4276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659886

RESUMO

BACKGROUND: Sintilimab is a humanized monoclonal antibody against the programmed cell death 1 (PD-L1). We aimed to assess the safety and activity of sintilimab monotherapy or in combination with chemotherapy in advanced solid tumors. METHODS: This phase Ib study included six cohorts. Cohort A-C were sintilimab monotherapy settings, and enrolled pretreated patients (2/3 L cohorts). Cohort D-F were treatment-naïve patients (1 L cohorts), and received sintilimab plus different chemotherapies. The primary endpoints were safety and objective response rate (ORR). Exploratory endpoints were potential biomarkers for the prognosis after treatment, such as tumor mutation burden scores (TMB), PD-L1 and lymphocyte-to-monocyte ratio (LMR). RESULTS: The ORR was 14.6% in the 2/3 L cohorts (n=146), and 73.2% in the 1 L cohorts (n=61). The incidence of grade 3-4 adverse events occurred in 55 patients (37.7%) in 2/3 L cohorts, and in 38 (62.3%) in 1 L cohorts. 157 patients had available TMB scores, and in 2/3 L cohorts, patients in the high TMB groups (TMB≥10) showed a longer progression-free survival (PFS) and overall survival (OS) than those in the low TMB groups (TMB<10). No significant differences in PFS and OS were observed across different PD-L1 groups in both 1 L and 2/3 L cohorts. A high LMR was significantly associated with an improved PFS in 1 L cohorts (P=0.022). CONCLUSION: Sintilimab alone or combined with chemotherapy had a tolerable safety profile in solid tumors. The combination therapy showed a favorable activity with advanced non-small cell lung cancer and gastric or esophagogastric junction adenocarcinoma. LMR might be a prognostic factor for the combination regimen in these patients. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02937116. Registered 18 October 2016.

2.
BMC Surg ; 21(1): 335, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488715

RESUMO

BACKGROUND: The coexistence of primary hyperparathyroidism and papillary thyroid carcinoma (PTC) is common and may be associative with more aggressive PTC, with higher rates of extrathyroidal extension and multicentricity. However, it is unclear whether secondary hyperparathyroidism (SHPT) is associated with more invasive PTC in terms of morbidity, tumor pathological characteristics, and prognosis. The aim of this study was to evaluate the rate and tumor characteristics of PTC in patients with SHPT. METHODS: A total of 531 patients diagnosed with SHPT who underwent surgery from August 2013 to December 2018 at the First Affiliated Hospital of Zhejiang University were evaluated retrospectively. Patient demographics, surgical records, and follow-up information were recorded and analyzed. Control subjects were matched to the enrolled patients in a 1:4 ratio in terms of age, sex and pathological subtype. RESULTS: Among the 531 patients with SHPT who underwent surgery, 34 had coexisting PTC and PTC + SHPT (6.4%). The mean tumor diameter in the PTC + SHPT group was smaller than that in the PTC group (5.57 mm vs 9.00 mm, p < 0.001). The proportion of papillary thyroid micro-carcinoma in the PTC + SHPT group was significantly higher than that in the PTC group (29 [85.29%] vs. 86[63.24%], p = 0.014). There were no statistically significant differences between groups in terms of tumor multicentricity (15 [44.12%] vs 39 [28.68%], p = 0.066), tumor bilaterality (9 [26.47%] vs. 29 [21.32%], p = 0.499), tumor extrathyroidal extension (2 [5.88%] vs. 19 [13.97%], p = 0.255), or lymph node (LN) metastasis rate (12 [35.29%] vs. 49 [36.03%], p = 1.000). However, the PTC + SHPT and PTC groups were significantly different in terms of contralateral thyroidectomy (10 [29.41%] vs. 70 [51.47%], p = 0.023) and lymph node dissection (22 [64.71%] vs. 125 [91.91%], p < 0.001).There was no significant difference between the PTC + SHPT and PTC groups in terms of prognostic staging (33 [97.06%] vs. 122 [89.71%], p = 0.309) or recurrence (mean follow-up time: 36 months vs. 39 months, p = 0.33). CONCLUSIONS: The prevalence of PTC is high in patients with SHPT; compared with PTC in the general population, most papillary thyroid carcinomas with SHPT are occult thyroid carcinomas and present no significant difference in terms of tumor pathological features and prognostic staging. It is necessary for surgeons to perform more adequate preoperative examination and be more careful during surgery to avoid missing the coexistence of PTC in patients with SHPT.


Assuntos
Carcinoma Papilar , Hiperparatireoidismo Secundário , Neoplasias da Glândula Tireoide , Carcinoma Papilar/complicações , Carcinoma Papilar/cirurgia , Humanos , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Câncer Papilífero da Tireoide/complicações , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia
3.
Cancer Med ; 2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34514731

RESUMO

INTRODUCTION: Cytoreductive surgery is one of the recommended treatments for metastatic renal cell carcinoma, while the prognostic information of these patients treated with cytoreductive surgery is limited. In this study, we aimed to investigate the survival profiles based on conditional survival (CS) estimates in metastatic clear cell renal cell carcinoma (mccRCC) patients treated with cytoreductive surgery of primary tumor. METHODS AND MATERIALS: We identified and extracted mccRCC patients from the Surveillance, Epidemiology, and End Results database. We used Kaplan-Meier method to perform CS analyses. A multivariate Cox regression model was applied to explore the changes of well-known prognostic factors. RESULTS: Conditional overall survival (COS) and conditional cancer-specific survival (CCSS) improved increasingly at all periods of survivorships compared to survival estimates at baseline in overall population of mccRCC. The 36-month COS improved by 3.3%-6.4% given per 12 additional months of survivorships and the CCSS improved significantly from 45.1% (95% CI 42.8-47.3) at 12 months to 67.1% (95% CI 62.0-71.7) at 60 months. Much more survival gain was observed in patients with advanced disease. Furthermore, the prognostic significance of age and pathological factors diminished and even disappeared in a long-term survivorship. CONCLUSIONS: Conditional overall survival and CCSS improved with time dynamically in mccRCC patients treated with cytoreductive surgery of primary tumor. Patients with advanced disease achieved significant survival gain and even could harvest a better prognosis given that the time of survivorship exceeds a certain period. Our findings could provide valuable and practical data for patient counseling and surveillance strategy making.

5.
J Int Med Res ; 49(8): 3000605211037422, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34407682

RESUMO

Carcinosarcoma is a rare malignant neoplasm comprising both epithelial and mesenchymal components. Hepatoid adenocarcinoma (HAC) is another rare type of cancer. To date, there are only four reported cases of concurrent carcinosarcomas with HAC across all tumor types, all of which were observed in uterine tumors. Here, we report an unusual case of gastric carcinosarcoma associated with alpha-fetoprotein (AFP)-producing HAC in a 76-year-old woman. Upon admission, the patient had an elevated serum AFP concentration (448 µg/L), a necrotic polypoid tumor of the central gastric cardia revealed by endoscopy, and no evidence of distant metastasis indicated by computed tomography (CT). Owing to malignancy indicated by biopsy, the patient underwent proximal subtotal gastrectomy. The resected tumor was composed of both an HAC component and a sarcoma component, microscopically. The sample was positive for AFP, hepatocyte paraffin (Hep-Par) 1, glypican-3, SALL4, CDX2, cytokeratin (CK) (pan), CK18, desmin, and vimentin staining immunohistochemically. In summary, the tumor was diagnosed as carcinosarcoma of the stomach with AFP-producing HAC. To our knowledge, this is the first report of gastric carcinosarcoma with AFP-producing HAC in the English literature describing gastric tumors.


Assuntos
Adenocarcinoma , Carcinossarcoma , Neoplasias Gástricas , Idoso , Carcinossarcoma/diagnóstico por imagem , Carcinossarcoma/cirurgia , Feminino , Humanos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/cirurgia , alfa-Fetoproteínas
7.
Nat Commun ; 12(1): 3946, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168152

RESUMO

Alpha-fetoprotein producing gastric carcinoma (AFPGC) is a rare and aggressive subtype of gastric cancer. However, little is known about the genomic features of this disease. We perform whole-exome sequencing analysis of AFPGC, and identify 34 significantly mutated genes. Somatic copy number alterations analysis reveals several significant focal amplifications (e.g. 19q12, 17q12) and focal deletions (e.g. 1p36.11, 9p21.3), and some of these negatively affect the patient prognosis. Comparative analyses reveal that AFPGC has distinct genomic features from gastric cancer of The Cancer Genome Atlas as well as four molecular subtypes. Several frequently altered genes with potential as therapeutic targets are identified in AFPGC. Further analysis reveals that AFPGC with amplification of CCNE1 at 19q12 and/or ERBB2 at 17q12 show poorer survival and more aggressive. Subsequently, based on our established patient-derived xenograft models for AFPGC, translational research is performed and the therapeutic value of targeting CCNE1 and ERBB2 is validated. In this work, we provide an understanding of genomic characteristics of AFPGC and propose a platform to explore and validate the genome-guided personalized treatment for this disease.


Assuntos
Mutação , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , alfa-Fetoproteínas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ciclina E/genética , Feminino , Dosagem de Genes , Humanos , Imidazóis/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Proteínas Oncogênicas/genética , Prognóstico , Pirimidinas/farmacologia , Receptor ErbB-2/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Gastric Cancer ; 24(6): 1227-1241, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34095982

RESUMO

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer deaths with high heterogeneity. There is currently a paucity of clinically applicable molecular classification system to guide precise medicine. METHODS: A total of 70 Chinese patients with GC were included in this study and whole-exome sequencing was performed. Unsupervised clustering was undertaken to identify genomic subgroups, based on mutational signature, copy number variation, neoantigen, clonality, and essential genomic alterations. Subgroups were characterized by clinicopathological factors, molecular features, and prognosis. RESULTS: We identified 32 significantly mutated genes (SMGs), including TP53, ARID1A, PIK3CA, CDH1, and RHOA. Of these, PREX2, PIEZO1, and FSIP2 have not been previously reported in GC. Using a novel genome-based classification method that integrated multidimensional genomic features, we categorized GC into four subtypes with distinct clinical phenotypes and prognosis. Subtype 1, which was predominantly Lauren intestinal type, harbored recurrent TP53 mutation and ERBB2 amplification, high tumor mutation burden (TMB)/tumor neoantigen burden (TNB), and intratumoral heterogeneity, with a liver metastasis tendency. Subtype 2 tended to occur at an elder age, accompanying with frequent TP53 and SYNE1 mutations, high TMB/TNB, and was associated with poor prognosis. Subtype 3 and subtype 4 included patients with mainly diffuse/mixed type tumors, high frequency of peritoneal metastasis, and genomical stability, whereas subtype 4 was associated with a favorable prognosis. CONCLUSIONS: By integrating multidimensional genomic characteristics, we proposed a novel genomic classification system of GC associated with clinical phenotypes and provided a new insight to facilitate genome-guided risk stratification and disease management.

9.
Ann Surg Oncol ; 28(11): 6564-6571, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33521903

RESUMO

BACKGROUND: The incidence of papillary thyroid microcarcinoma has been constantly rising in recent decades. The tumor, node, metastasis staging system is designed to predict prognosis in patients with papillary thyroid carcinoma. Recent studies have shown that the American Joint Committee on Cancer (AJCC) 8th edition is superior to the 7th edition for predicting tumor recurrence in PTC patients. To date, whether the 8th edition is also better able to predict recurrence in papillary thyroid microcarcinoma (PTMC) remains unclear. METHOD: We enrolled 1007 cases from our thyroid cancer database in the First Affiliated Hospital, Zhejiang University School of Medicine, from 1997 to 2011. Univariable and multivariate Cox hazard regression analyses were used to identify the association between variables and recurrence. Disease-free survival was calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 1007 PTMC patients were enrolled, with a median follow-up of 67 months. Of 93 (9.2%) patients downstaged by the changes in versions, 49 (52.7%) were downstaged because the age-at-diagnosis cut-off used for staging increased from 45 to 55 years, while 35 (37.6%) were downstaged due to the weakening of the effects of lymph node metastasis. The recurrence rate of PTMC was 4.17%. Univariate Cox hazards regression analyses showed that TNM stage according to the AJCC 8th edition was significantly associated with recurrence, while the recurrence survival curves showed that TNM stage (stage I vs. stage II-IV) according to the AJCC 8th edition, but not the 7th edition, was significantly associated with disease-free survival (p < 0.05). CONCLUSIONS: The AJCC 8th edition has better ability to predict recurrence in PTMC patients than the 7th edition.


Assuntos
Carcinoma Papilar , Neoplasias da Glândula Tireoide , Carcinoma Papilar/patologia , Carcinoma Papilar/cirurgia , Humanos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia
10.
Cancer Immunol Immunother ; 70(3): 857-868, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33070260

RESUMO

Combining chemotherapy with immunotherapy improves the therapeutic outcome for first-line (1L) patients with advance nonsmall-cell lung cancer (NSCLC). Two cohorts of a phase 1b study (NCT02937116) aimed to evaluate the safety and efficacy of sintilimab, a PD-1 inhibitor, plus chemotherapy in 1L patients with nonsquamous and squamous NSCLC (nsqNSCLC/sqNSCLC); and to identify potential biomarkers for treatment response. Treatment-naïve patients with nsqNSCLC were enrolled and intravenously given sintilimab (200 mg), pemetrexed (500 mg/m2), and cisplatin (75 mg/m2), every 3 weeks (Q3W) for 4 cycles in cohort D. Treatment-naïve patients with sqNSCLC were enrolled and intravenously given sintilimab (200 mg), gemcitabine (1250 mg/m2), and cisplatin (75 mg/m2), Q3W, for 6 cycles in cohort E. The primary objective was to evaluate the safety and efficacy of the treatment. The additional objective was to explore biomarkers for the treatment efficacy. Twenty-one patients with nsqNSCLC, and 20 patients with sqNSCLC were enrolled in cohort D and cohort E, respectively. By the data cutoff (April 17, 2019), 8 (38.1%) patients in cohort D and 17 (85.0%) patients in cohort E experienced grade 3-4 adverse events. The median follow-up duration was 16.4 months (14.8-23.0) in cohort D and 15.9 months (11.7-17.7) in cohort E. The objective response rate was 68.4% (95% CI 43.4%, 87.4%) in cohort D and 64.7% (95% CI 38.3%, 85.8%) in cohort E. Neither PD-L1 expression nor tumor mutation burden value was significantly associated with an improved treatment response. Sintilimab plus chemotherapy exhibited manageable toxicity and an encouraging antitumor activity in patients with nsqNSCLC and sqNSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Masculino , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Resultado do Tratamento
11.
Biomed Res Int ; 2020: 8835398, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33313320

RESUMO

Elevated levels of resistin and epidermal growth factor receptor (EGFR) facilitate the development of breast cancer, although there are no reports of any correlation between these proteins. This study analyzed 392 human breast cancer tissue specimens and 42 samples of adjacent normal tissue. Rates of positive and strongly positive resistin expression were significantly higher in breast cancer tissue than in the adjacent nontumor tissue (83.2% vs. 23.8% and 20.9% vs. 0.0%, respectively; P < 0.001 for both comparisons). Positive resistin expression was significantly associated with tumor size, grade, stage, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, and molecular classification; strongly positive resistin expression was associated with tumor grade, ER, PR, HER2 status, and molecular classification. Significantly positive correlations were observed between positive and strongly positive resistin expression and corresponding levels of EGFR expression. Relapse-free and overall survival was worse for patients with high levels of both proteins than for those with high levels of only one protein or normal levels of both proteins. Our evidence suggests that combined high levels of resistin and EGFR expression correlate with survival in patients with breast cancer.


Assuntos
Neoplasias da Mama/genética , Resistina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Intervalo Livre de Doença , Receptores ErbB/genética , Receptor alfa de Estrogênio/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Receptor ErbB-2/genética , Receptores de Progesterona/genética , Recidiva , Resultado do Tratamento , Adulto Jovem
12.
Front Oncol ; 10: 1765, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33014868

RESUMO

Background: Gastric cancer (GC) is the fifth most frequently diagnosed malignancy, and the third leading cause of tumor-related mortalities worldwide. Due to a high heterogeneity in GC, its treatment and prognosis are challenging, necessitating urgent identification of novel prognostic predictors for GC patients. Methods: We downloaded RNA sequence data, from the Cancer Genome Atlas and microarray data from Gene Expression Omnibus database, then identified common differentially-expressed genes (DEGs) between GC and normal gastric tissues across four datasets. We then used a combination of protein-protein interaction (PPI) network and weighted gene co-expression network analysis (WGCNA) to identify key genes with prognostic value in GC. Thereafter, we used quantitative real time polymerase chain reaction (qRT-PCR) to validate expression of the identified key genes in the Zhejiang University (ZJU) cohort. Finally, we evaluated the relationships between gene expression and immune factors, including immune cells and biomarkers of immunotherapy. Results: Among 426 common DEGs screened, 333 and 93 were upregulated and downregulated, respectively. PPI network and WGCNA successfully identified the top 30 hub genes, among which PTPRC, TYROBP, CCR1, CYBB, LCP2, and C1QB were common. Furthermore, TYROBP and C1QB were negatively associated with prognosis of GC patients, implying that they were key GC predictors. Interestingly, TYROBP and C1QB were positively correlated with predictive biomarkers for GC immunotherapy, including PD-L1 expression, CD8+ T cells infiltration, and EBV status. Conclusions: TYROBP and C1QB were identified as two novel key genes with prognostic value in GC by network analysis.

13.
Cancer Cell Int ; 20: 468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005101

RESUMO

Purpose: Increasing evidence has shown that the transcription factor SOX4 is closely associated with the development and progression of many malignant tumors. However, the effect of SOX4 on breast cancer is unclear. In this study, we purposed to investigate the role of SOX4 in the growth and metastasis in breast cancer and the underlying mechanism. Moreover, the effect of SOX4 on cancer cell resistance to chemotherapeutic agents was also evaluated in vitro and in vivo. Methods: We used lentivirus technique to ectopically express SOX4 in MDA-MB-231 and SUM149 cells or knockdown SOX4 in BT474 cells, and examined the effect of these changes on various cellular functions. MTT assay was used to determine the cell viability as well as resistance to chemotherapeutic agents. The regulation of SOX4 on epithelial-mesenchymal transition (EMT)-related genes was analyzed using qRT-PCR. The binding of SOX4 to the CXCR7 gene was demonstrated using chromatin immunoprecipitation assay and dual-luciferase reporter activity assay. The effect of SOX4/CXCR7 axis on metastasis was examined using Transwell migration and Matrigel invasion assays. The expression of SOX4/CXCR7 in primary tumors and metastatic foci in lymph nodes was assessed using immunohistochemistry. Cellular morphology was investigated under phase contrast microscope and transmission electron microscopy. Moreover, the effect of SOX4 on tumor growth, metastasis, and resistance to chemotherapy was also studied in vivo by using bioluminescent imaging. Results: SOX4 increased breast cancer cell viability, migration, and invasion in vitro and enhanced tumor growth and metastasis in vivo. It regulated EMT-related genes and bound to CXCR7 promoter to upregulate CXCR7 transcription. Both SOX4 and CXCR7 were highly expressed in human primary tumors and metastatic foci in lymph nodes. Treatment of breast cancer cells with the CXCR7 inhibitor CCX771 reversed the SOX4 effect on cell migration and invasion. Ectopic expression of SOX4 increased the susceptibility of cells to paclitaxel. Conclusions: SOX4 plays an important role in the growth and metastasis of breast cancer. SOX4/CXCR7 may serve as potential therapeutic targets for the treatment. Paclitaxel may be a good therapeutic option if the expression level of SOX4 is high.

14.
Cancer Manag Res ; 12: 8545-8554, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32982447

RESUMO

Gastric cancer (GC) is a cancer with high prevalence, and is one of the leading causes of cancer death worldwide. Metformin is a widely used hypoglycemic agent for type-2 diabetes mellitus (T2DM). Recently, metformin has drawn increasing attention in the field of cancer research for its emerging anti-cancer roles. However, the efficacy and underlying molecular mechanisms of metformin in the prevention and treatment for GC remain controversial. This review summarized the present clinical and mechanistic studies that investigated the efficacy of metformin in GC. It was found that the majority of clinical studies affirmed protective roles of metformin in both gastric cancer risk and survival rate. In addition, metformin's effects in the prevention and treatment for GC involve multiple pathways mainly via AMPK and IGF-1R. It was concluded that metformin presents a unique opportunity for application against GC, but further clinical and mechanistic investigations are required to solidify the roles of metformin in GC.

15.
Cancer Med ; 9(22): 8498-8518, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32969604

RESUMO

Several biomarkers such as tumor mutation burden (TMB), neoantigen load (NAL), programmed cell-death receptor 1 ligand (PD-L1) expression, and lactate dehydrogenase (LDH) have been developed for predicting response to immune checkpoint inhibitors (ICIs) in melanoma. However, some limitations including the undefined cut-off value, poor uniformity of test platform, and weak reliability of prediction have restricted the broad application in clinical practice. In order to identify a clinically actionable biomarker and explore an effective strategy for prediction, we developed a genetic mutation model named as immunotherapy score (ITS) for predicting response to ICIs therapy in melanoma, based on whole-exome sequencing data from previous studies. We observed that patients with high ITS had better durable clinical benefit and survival outcomes than patients with low ITS in three independent cohorts, as well as in the meta-cohort. Notably, the prediction capability of ITS was more robust than that of TMB. Remarkably, ITS was not only an independent predictor of ICIs therapy, but also combined with TMB or LDH to better predict response to ICIs than any single biomarker. Moreover, patients with high ITS harbored the immunotherapy-sensitive characteristics including high TMB and NAL, ultraviolet light damage, impaired DNA damage repair pathway, arrested cell cycle signaling, and frequent mutations in NF1 and SERPINB3/4. Overall, these findings deserve prospective investigation in the future and may help guide clinical decisions on ICIs therapy for patients with melanoma.

16.
Cancers (Basel) ; 12(8)2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32785164

RESUMO

Gastric cancer (GC) is a leading cause of worldwide cancer-related death. Being a highly heterogeneous disease, the current treatment of GC has been suboptimal due to the lack of subtype-dependent therapies. Peritoneal dissemination (PD) is a common pattern of GC metastasis associated with poor prognosis. Therefore, it is urgently necessary to identify patients at high risk of PD. PD is found to be associated with Lauren diffuse type GC. Molecular profiling of GC, especially diffuse type GC, has been utilized to identify molecular alterations and has given rise to various molecular classifications, shedding light on the underlying mechanism of PD and enabling identification of patients at higher PD risk. In addition, a series of diagnositc and prognostic biomarkers of PD from serum, peritoneal lavages and primary GCs have been reported. This comprehensive review summarizes findings on the multi-omic characteristics of diffuse type GC, the clinical significance of updating molecular classifications of GC in association with PD risk and research advances in PD-associated biomarkers.

17.
BMC Cancer ; 20(1): 760, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795349

RESUMO

BACKGROUND: Sintilimab blocks the interaction between programmed death-1 (PD-1) and its ligands. The safety and efficacy of sintilimab combined with oxaliplatin/capecitabine (CapeOx) as first-line treatment were evaluated in patients with gastric (G)/gastroesophageal junction (GEJ) adenocarcinoma in a phase Ib clinical trial. METHODS: Patients with locally advanced or metastatic G/GEJ adenocarcinoma without previous systemic treatment were enrolled as one cohort of a multi-cohort study. Sintilimab was administered at a dose of 200 mg intravenously (IV) in combination with CapeOx (1000 mg/m2 capecitabine orally, bid, D1-14 and 130 mg/m2 oxaliplatin IV, D1) every 21 days for up to 6 cycles. After combination treatment, patients continued to receive sintilimab (200 mg) at 3 weekly intervals as maintenance therapy until progressive disease (PD), unacceptable toxicity, withdrawal of informed consent, or for up to 24 months. Adverse events (AEs) were monitored to assess safety in terms of their frequency, intensity and causality. The efficacy endpoints included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Tumor mutation burden (TMB) was evaluated for its association with clinical response. RESULTS: A total of 20 patients were enrolled and received sintilimab plus CapeOx. All patients reported treatment-related AEs (TRAEs). Grade 3-4 TRAEs were found in 11 (55.0%) patients. Seventeen patients obtained partial response and the ORR was 85.0% (95% CI: 62.1-96.8%). Three (15.0%) had stable disease and DCR was 100.0% (95% CI: 83.2-100.0%). As data cutoff of May 1, 2019, the median follow-up was 7.8 months. The median PFS was 7.5 months (95% CI: 6.2-9.4) and median OS had not been reached. The OS rates at 6 months and 12 months were 100.0 and 68.0%. No association was observed between TMB and efficacy. CONCLUSIONS: Sintilimab combined with CapeOx as first-line treatment demonstrated acceptable safety and promising efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02937116 . Registered 8 October 2016.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Junção Esofagogástrica/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Intervalo Livre de Progressão , Índice de Gravidade de Doença , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
18.
Oncol Lett ; 20(1): 215-225, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32537023

RESUMO

The present study aimed to identify genes associated with gastric cancer survival and improve risk stratification for patients with gastric cancer. Transcriptomic and clinicopathological data from 443 gastric cancer samples were retrieved from The Cancer Genome Atlas database. The DESeq R package was applied to screen for differentially expressed genes between Tumor-Node-Metastasis (TNM) stage (I vs. IV) and histological grade (G3 vs. G1 and G2). A total of seven genes were common to both comparisons; spondin 1 (SPON1); thrombospondin 4 (THBS4); Sushi, Von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1); prickle planar cell polarity protein 1 (PRICKLE1); ATP binding cassette subfamily A member 8 (ABCA8); Slit guidance ligand 2 (SLIT2); and EGF containing fibulin extracellular matrix protein 1 (EFEMP1), were selected as candidate survival-associated genes for further analysis. The prognostic value of these genes was assessed according to a literature review and Kaplan-Meier survival analysis. In addition, a multivariate Cox regression analysis revealed PRICKLE1 expression to be an independent prognostic factor for patients with gastric cancer. Furthermore, a predictive nomogram was generated using PRICKLE1 expression, patient age and TNM stage to assess overall survival (OS) rate at 1, 3 and 5 years, with an internal concordance index of 0.65. External validation was conducted in an independent cohort of 59 patients with gastric cancer, and high consistency between the predicted and observed results for OS was exhibited. Overall, the current findings suggest that PRICKLE1 expression may serve as an independent prognostic factor that can be integrated with age and TNM stage in a nomogram able to predict OS rate in patients with gastric cancer.

19.
Cancer Manag Res ; 12: 2767-2775, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368151

RESUMO

Purpose: To investigate the prognostic value of combined serum carcinoembryonic antigen (CEA) levels and fibrinogen/albumin ratio (FAR) in patients with resectable gastric cancer (GC). Introduction: This retrospective study evaluated the CEA, fibrinogen, and albumin levels and other clinicopathological features of GC patients. The prognostic significance of these factors for overall survival (OS) was assessed using Kaplan-Meier curves and univariate and multivariate Cox proportional models. Patients and Methods: A total of 267 patients were included. The optimal cutoff values of CEA and FAR were 3.2 ng/mL and 0.086, respectively. Patients were stratified into three groups based on this cutoff value: CEA-FAR=0 (CEA <3.2 ng/mL and FAR <0.086), CEA-FAR=1 (CEA ≥3.2 ng/mL or FAR ≥0.086), and CEA-FAR=2 (CEA ≥3.2 ng/mL and FAR ≥0.086). Results: Higher CEA-FAR was strongly associated with age, tumor size, tumor invasion, lymph node status, and TNM stage (all P<0.05). The OS rates differed significantly between these 3 groups (88.9% vs 65.0% vs 46.9%, P<0.001). Multivariate analysis showed that CEA-FAR was an independent prognostic factor for OS (P<0.001). The area under the curve was larger for CEA-FAR than for either CEA or FAR alone (0.683, 0.644, and 0.669, respectively). Conclusion: Preoperative CEA-FAR could be a potential blood marker for predicting tumor progression and the prognosis of GC patients. Patients with a higher CEA-FAR should undergo extensive follow-up.

20.
Gastroenterol Res Pract ; 2020: 3207345, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184816

RESUMO

Aims: Predicting the prognosis of gastric cancer using tumour-node-metastasis (TNM) staging is difficult as patients with the same TNM stage exhibit different prognoses. Methods: This study investigated the prognostic value of the preoperative fibrinogen/albumin ratio (FAR)-systemic inflammation response index (SIRI) score in resectable gastric cancer (rGC). Results: Clinicopathological features of 231 rGC patients were analysed retrospectively. Patients were divided into three groups: FAR-SIRI score 2 (FAR ≥ 0.071 and SIRI ≥ 0.84), 1 (FAR < 0.071 and SIRI ≥ 0.84), and 0 (SIRI < 0.84). Higher FAR-SIRI scores were associated with larger tumours, poorer differentiation, and advanced TNM stage (P < 0.05). Compared to those with FAR-SIRI scores of 0, patients with scores of 2 had poorer overall survival (OS). The FAR-SIRI score was an independent prognostic factor for OS in rGC. Conclusion: The present data demonstrated that FAR-SIRI scores predicted radical gastric cancer surgical outcomes and may serve as a blood marker for identifying high-risk patients.

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