"Cancer Med"[jour]; +19 new citations

"Cancer Med"[jour]; +19 new citations:

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"Cancer Med"[jour]

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1.
Cancer Med. 2020 Feb 5. doi: 10.1002/cam4.2866. [Epub ahead of print]
Upregulation of hsa_circ_0007874 suppresses the progression of ovarian cancer by regulating the miR-760/SOCS3 pathway.
Li L1, Yu P2, Zhang P3, Wu H4, Chen Q1, Li S5, Wang Y6.

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Abstract


Ovarian cancer (OVA) is a fatal and common malignancy in women worldwide. Circular RNAs (circRNAs) consist of a family of circular endogenous RNAs generated by selective splicing, and they are involved in many diseases. Previous studies reported that hsa_circ_0007874 is aberrantly expressed in cancer and functions in tumorigenesis. While the hsa_circ_0007874 role in OVA is unclear. Here, we detected the hsa_circ_0007874 expression in OVA cell lines using Rt-qPCR. Hsa_circ_0007874 subcellular localization was confirmed by fluorescence in situ hybridization. The relationship between hsa_circ_0007874, microRNAs (miRNAs), and relative protein levels was assessed using the luciferase reporter assays. Results verified that hsa_circ_0007874 is downregulated in OVA cell lines. hsa_circ_0007874 overexpression decreased the OVA cell migration and proliferation in vitro and in vivo. Bioinformatics and luciferase reporter assays confirmed that miR-760 and SOCS3 are the downstream targets of hsa_circ_0007874. Downregulation of SOCS3 or miR-760 overexpression restored the migration and proliferation ability of SKOV3 or A2780 cells overexpressing hsa_circ_0007874. Downregulation of SOCS3 restored the proliferation and migration in miR-760 knockdown SKOV3 and A2780 cells. In summary, the data suggest that hsa_circ_0007874 acts as a tumor suppressor by regulating the miR-760/SOCS3 axis, highlighting its potential as an effective therapeutic target for OVA.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

SOCS3; hsa_circ_0007874; miR-760; ovarian cancer
PMID: 32023009 DOI: 10.1002/cam4.2866
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Select item 320224872.
Cancer Med. 2020 Feb 5. doi: 10.1002/cam4.2901. [Epub ahead of print]
Management and risk factors of recurrent gestational trophoblastic neoplasia: An update from 2004 to 2017.
Kong Y1, Zong L1, Cheng H1, Jiang F1, Wan X1, Feng F1, Ren T1, Zhao J1, Yang J1, Xiang Y1.

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Abstract

OBJECTIVE:

We investigated the clinical characteristics, treatments, and survival of patients with gestational trophoblastic neoplasia (GTN) who experienced recurrence. Factors predictive of recurrence were also investigated.
METHODS:

Patients with GTN who recurred after completing chemotherapy at Peking Union Medical College Hospital Trophoblastic Disease Center were identified between January 2004 and December 2017. Logistic regression analysis was used to identify factors predictive of GTN recurrence.
RESULTS:

A total of 1827 patients with GTN achieved complete remission (CR) at our center, of whom 118 (6.5%) experienced recurrence during follow-up. The recurrence rates for patients initially treated at our center and those referred to us were 2.7% and 14.6%, respectively. The majority of recurrent patients received floxuridine-based multiagent chemotherapy (n = 64). Patients who underwent surgery achieved a significantly higher CR rate than those who did not (88.6% vs 61.1%, P = .001). Although 94.1% of recurrent patients reachieved CR, 33.3% of them recurred for a second time. The 5-year survival rate of the entire cohort was 80.4%. An interval between antecedent pregnancy and chemotherapy >12 months (OR: 6.600, 95% CI [3.217-13.540], P < .001), and an interval from first chemotherapy to achieving β-human chorionic gonadotropin (β-hCG) normalization >14 weeks (OR: 2.226, 95% CI [1.080-4.588], P = .030) were predictors of recurrence.
CONCLUSIONS:

Patients with recurrent GTN are prone to recurring for a second time. Surgery plays a beneficial role in the management of recurrent GTN. An interval between antecedent pregnancy and chemotherapy >12 months, and an interval from first chemotherapy to achieving β-hCG normalization >14 weeks were predictors of recurrence.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

chemotherapy; gestational trophoblastic neoplasia; recurrence; surgery; survival rate
PMID: 32022487 DOI: 10.1002/cam4.2901
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Select item 320224863.
Cancer Med. 2020 Feb 5. doi: 10.1002/cam4.2870. [Epub ahead of print]
Microsatellite instability and its associations with the clinicopathologic characteristics of diffuse large B-cell lymphoma.
Tian T1,2,3, Li J1,2,3, Xue T1,2,3, Yu B1,2,3, Li X1,2,3, Zhou X1,2,3.

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Abstract


Microsatellite instability (MSI) has been investigated as a prognostic and predictive factor for chemotherapy in colorectal cancer and has recently been demonstrated to be predictive of the PD-1/PD-L1 checkpoint blockade response in various solid tumors. However, MSI status in diffuse large B-cell lymphomas (DLBCLs) has not been thoroughly explored. This study investigated MSI status in DLBCLs and analyzed the associations between MSI and clinicopathologic characteristics and clinical outcomes. Ninety-two cases of primary DLBCLs treated with R-CHOP/CHOP chemotherapy between 2009 and 2017 were collected. MSI detection was performed by the Promega MSI Analysis System. The protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry. The associations of MSI-H and MSI-L with progression-free survival (PFS) and overall survival (OS) were assessed by COX models and Kaplan-Meier curves. The correlations of complete response (CR) after R-CHOP/CHOP chemotherapy with MSI-H and MSI-L were examined by univariate and multivariate logistic regression analyses, respectively. 3 of 92 cases (3.2%) were high MSI (MSI-H), and 9 cases (9/92, 9.8%) exhibited low MSI (MSI-L). One case with MSI-H showed negative expression of MSH2 and MSH6. Univariate analysis indicated that MSI-L was correlated with poor response to R-CHOP/CHOP chemotherapy in DLBCLs (OR, 0.178; 95% CI, 0.041-0.776; P = .022). Multivariate analysis showed that MSI-L was an independent predictive factor for non-CR to R-CHOP/CHOP chemotherapy (OR, 0.144; 95% CI, 0.027-0.761; P = .023). Kaplan-Meier curves showed that there was a trend that MSI-H patients had favorable PFS (P = .36) and OS (P = .48), which did not have statistical significance and MSI-L was not significantly correlated with PFS (P = .24) and OS (P = .52).Our study indicated that there existed MSI-H and MSI-L in DLBCLs. MSI-L could be an independent predictive factor for the chemotherapy response in DLBCLs.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

DLBCLs; MSI; chemotherapy response; complete response
PMID: 32022486 DOI: 10.1002/cam4.2870
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Select item 320224774.
Cancer Med. 2020 Feb 5. doi: 10.1002/cam4.2897. [Epub ahead of print]
Impact of somatic mutations on prognosis in resected non-small-cell lung cancer: The Japan Molecular Epidemiology for lung cancer study.
Tamiya A1, Koh Y2, Isa SI1, Kubo A3, Ando M4, Saka H5, Yoshimoto N6, Takeo S7, Adachi H8, Tagawa T9, Kawashima O10, Yamashita M11, Kataoka K12, Takenoyama M13, Takeuchi Y14, Watanabe K15, Matsumura A1, Kawaguchi T16.

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Abstract

BACKGROUND:

To report the follow up data and clinical outcomes of the JME study (UMIN 000008177), a prospective, multicenter, molecular epidemiology examination of 876 surgically resected non-small-cell lung cancer (NSCLC) cases, and the impact of somatic mutations (72 cancer-associated genes) on recurrence-free survival (RFS) and overall survival (OS).
METHODS:

Patients were enrolled between July 2012 and December 2013, with follow up to 30th November 2017. A Cox proportional hazards model was used to assess the impact of gene mutations on RFS and OS, considering sex, smoking history, age, stage, histology, EGFR, KRAS, TP53, and number of coexisting mutations.
RESULTS:

Of 876 patients, 172 had ≥2 somatic mutations. Median follow-up was 48.4 months. On multivariate analysis, number of coexisting mutations (≥2 vs 0 or 1, HR = 2.012, 95% CI: 1.488-2.695), age (≥70 vs <70 years, HR = 1.583, 95% CI: 1.229-2.049), gender (male vs female, HR = 1.503, 95% CI: 1.045-2.170) and pathological stage (II vs I, HR = 3.386, 95% CI: 2.447-4.646; ≥III vs I, HR = 6.307, 95% CI: 4.680-8.476) were significantly associated with RFS, while EGFR mutation (yes vs no, HR = 0.482, 95% CI: 0.309-0.736), number of coexisting mutations (≥2 vs 0 or 1, HR = 1.695, 95% CI: 1.143-2.467), age (≥70 vs <70 years, HR = 1.932, 95% CI: 1.385-2.726), and pathological stage (II vs I, HR = 2.209, 95% CI: 1.431-3.347; ≥III vs I, HR = 5.286, 95% CI: 3.682-7.566) were also significant for OS.
CONCLUSION:

A smaller number of coexisting mutations, earlier stage, and younger age were associated with longer RFS and OS, while EGFR mutations were significantly associated with improved OS.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

next-generation sequencing; non-small cell lung cancer; overall survival; recurrence free survival; somatic mutation
PMID: 32022477 DOI: 10.1002/cam4.2897
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Select item 320224765.
Cancer Med. 2020 Feb 5. doi: 10.1002/cam4.2861. [Epub ahead of print]
Long noncoding RNA DUXAP8 contributes to the progression of hepatocellular carcinoma via regulating miR-422a/PDK2 axis.
Wei F1, Yang L1, Jiang D2, Pan M1, Tang G1, Huang M1, Zhang J1.

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Abstract

BACKGROUND:

Hepatocellular carcinoma (HCC) is one of the most deadly cancer worldwide. Multiple long noncoding RNAs (lncRNAs) are recently identified as crucial oncogenic factors or tumor suppressors. In this study, we explored the functon and mechanism of lncRNA double homeobox A pseudogene 8 (DUXAP8) in the progression of HCC.
METHODS:

Expression levels of DUXAP8 in HCC tissue samples were measured using qRT-PCR. The association between pathological indexes and the expression of DUXAP8 was also analyzed. Human HCC cell lines SMMC-7721 and QSG-7701 were used in in vitro studies. CCK-8 assay was used to assess the effect of DUXAP8 on HCC cell line proliferation. Scratch healing assay and Transwell assay were conducted to detect the effect of DUXAP8 on migration and invasion. Furthermore, dual-luciferase reporter assay was used to confirm targeting relationship between miR-422a and DUXAP8. Additionally, Western blot was used to detect the regulatory function of DUXAP8 on pyruvate dehydrogenase kinase 2 (PDK2).
RESULTS:

DUXAP8 expression HCC clinical samples was significantly increased and this was correlated with unfavorable pathological indexes. High expression of DUXAP8 was associated with shorter overall survival time of patients. Its overexpression remarkably facilitated the proliferation, metastasis, and epithelial-mesenchymal transition of HCC cells. Accordingly, knockdown of it suppressed the malignant phenotypes of HCC cells. Overexpression of DUXAP8 significantly reduced the expression of miR-422a by sponging it, but enhanced the expression of PDK2.
CONCLUSIONS:

DUXAP8 was a sponge of tumor suppressor miR-422a in HCC, enhanced the expression of PDK2 indirectly, and functioned as an oncogenic lncRNA.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

DUXAP8; HCC; PDK2; miR-422a
PMID: 32022476 DOI: 10.1002/cam4.2861
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Select item 320224636.
Cancer Med. 2020 Feb 5. doi: 10.1002/cam4.2814. [Epub ahead of print]
A pediatric regimen for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: Results of the ALLRE08 PETHEMA trial.
Ribera JM1, Morgades M1, Montesinos P2, Tormo M3, Martínez-Carballeira D4, González-Campos J5, Gil C6, Barba P7, García-Boyero R8, Coll R9, Pedreño M10, Ribera J1, Mercadal S11, Vives S1, Novo A12, Genescà E1, Hernández-Rivas JM13, Bergua J14, Amigo ML15, Vall-Llovera F16, Martínez-Sánchez P17, Calbacho M18, García-Cadenas I19, Garcia-Guiñon A20, Sánchez-Sánchez MJ21, Cervera M22, Feliu E1, Orfao A13; PETHEMA Group, Spanish Society of Hematology.

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Abstract

BACKGROUND:

Pediatric-based or -inspired trials have improved the prognosis of adolescents and young adults (AYA) with Philadelphia chromosome-negative (Ph-neg) acute lymphoblastic leukemia (ALL).
METHODS:

This study reports the results of treatment of the ALLRE08 trial, a full pediatric trial for AYA aged 15-30 years with standard-risk (SR) ALL.
RESULTS:

From 2008 to 2018, 89 patients (38 adolescents [15-18 years] and 51 young adults [YA, 19-30 years], median age: 20 [15-29] years) were enrolled in the ALLRE08 trial. The complete response (CR) was 95%. Twenty-two patients were transferred to a high-risk (HR) protocol because of poor marrow response on day 14 (n = 20) or high-level of end-induction minimal residual response (MRD ≥ 0.25%, n = 2). Cumulative incidence of relapse (CIR) at 5 years was 35% (95%CI: 23%-47%), with significant differences between adolescents and YA: 13% (4%-28%) vs 52% (34%-67%), P = .012. No treatment-related mortality was observed in 66/66 patients following the ALLRE08 trial vs 3/23 patients moved to a HR trial. The estimated 5-year overall survival (OS) was 74% (95%CI: 63%-85%), with significantly higher rates for adolescents vs YA: 87% (95%CI: 74%-100%) vs 63% (46%-80%), P = .021. Although CIR or OS were lower in patients who were transferred to a HR trial, the differences were not statistically significant (CIR: 34% [21%-47%] vs 37% [14%-61%]; OS: 78% [66%-90%] vs 61% [31%;91%]).
CONCLUSION:

A full pediatric trial is feasible and effective for AYA with Ph-neg, SR-ALL, with better results for adolescents than for YA. Outcome of patients with poor early response rescued with a HR trial was not significantly inferior.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

acute lymphoblastic leukemia; adolescents and young adults; pediatric treatment
PMID: 32022463 DOI: 10.1002/cam4.2814
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Select item 320224617.
Cancer Med. 2020 Feb 5. doi: 10.1002/cam4.2855. [Epub ahead of print]
Expression of p16 and HPV E4 on biopsy samples and methylation of FAM19A4 and miR124-2 on cervical cytology samples in the classification of cervical squamous intraepithelial lesions.
Leeman A1, Jenkins D1, Del Pino M2, Ordi J3, Torné A2, Doorbar J4, Meijer CJLM5, van Kemenade FJ6, Quint WGV1.

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Abstract


The decision to treat a cervical squamous intraepithelial lesion (SIL) by loop electrosurgical excision procedure (LEEP) relies heavily on a colposcopy-directed biopsy showing high-grade (H)SIL. Diagnosis is often supported by p16, an immunohistochemical (IHC) biomarker of high-risk (hr)HPV E7 gene activity. Additional potential markers include methylation of tumor suppressor genes FAM19A4/miR124-2 in cervical cytology for advanced transforming HSIL and the IHC marker HPV E4 for productive, potentially regressing lesions. In 318 women referred for colposcopy, we investigated the relationship between staining patterns of p16 and E4 IHC in the worst biopsy, and the relation of these to FAM19A4/miR124-2 methylation status in cytology. E4-positive staining decreased with increasing SIL/CIN grade from 41% in LSIL to 3% in HSIL/CIN3. E4 positivity increased with grade of p16 when p16 expression was limited to the lower two third of the epithelium (r = 0.378), but fell with expression over. Loss of E4 expression in the worst lesion was associated with the methylation of FAM19A4/miR124-2. We also examined whether these biomarkers can predict the histological outcome of the LEEP biopsy in a subgroup of 119 who underwent LEEP treatment. About 85% of women with ≥lower two third p16 staining/E4-negative HSIL biopsies and 65% with limited p16 staining/E4-positive HSIL biopsies had ≥HSIL in the LEEP specimen (P = .025). p16 expression in a biopsy is related both to viral production and transformation, while decreased E4 expression relates to methylation, indicating advanced HSIL. p16 expression in ≥2/3 of the epithelium and absent E4 indicate likely HSIL on a subsequent LEEP specimen.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

LEEP; cervical cancer; hrHPV; immunohistochemistry; methylation
PMID: 32022461 DOI: 10.1002/cam4.2855
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Select item 320224598.
Cancer Med. 2020 Feb 5. doi: 10.1002/cam4.2806. [Epub ahead of print]
First-line pembrolizumab for non-small cell lung cancer patients with PD-L1 ≥50% in a multicenter real-life cohort: The PEMBREIZH study.
Amrane K1, Geier M1, Corre R2, Léna H2, Léveiller G3, Gadby F4, Lamy R5, Bizec JL6, Goarant E7, Robinet G1, Gouva S1, Quere G1, Abgral R8, Schick U1, Bernier C9, Chouaid C10, Descourt R1.

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Abstract

BACKGROUND:

The KEYNOTE-024 trial demonstrated that pembrolizumab, a PD-1 inhibitor, significantly improves progression-free survival (PFS) and overall survival (OS) in selected patients with previously untreated advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumor proportion score (TPS) ≥50% and without EGFR/ALK aberrations. The main aim of this study was to report the efficacy and safety profile of pembrolizumab in real-life conditions.
METHOD:

This was a French retrospective multicenter longitudinal study of 108 consecutive patients with advanced NSCLC, a PD-L1 TPS ≥50% and without EGFR/ALK aberrations who were treated by pembrolizumab, in first line. Patient data were obtained from medical files.
RESULTS:

The main characteristics of the cohort were: median age [range] 66.7 [37-87] years, 64.8% male, 23.1% with a performance status (PS) of 2, and 88.9% current or former smokers. Eighty-seven percent had stage IV NSCLC at diagnosis, 9.2% untreated brain metastases at inclusion,. With a median follow-up of 8.2 months, the median PFS was 10.1 months (95% CI, 8.8-11.4). The objective response rate was 57.3% (complete response 2.7%, partial response 54.6%). Disease control rate was 71.1%. At 6 months, the OS rate estimated was 86.2%. Treatment-related adverse events (AE) of grade 3 occurred in 8% of patients. There were no grade 4 or 5 AEs.
CONCLUSION:

In a real-life cohort of advanced NSCLC patients (including PS 2 and untreated brain metastases), with PD-L1 TPS ≥50%, pembrolizumab demonstrates similar PFS to the pivotal clinical trial.

© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

PD-L1 tumor proportion score; Real world; first-line monotherapy; non-small cell lung cancer; pembrolizumab
PMID: 32022459 DOI: 10.1002/cam4.2806
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Select item 320207589.
Cancer Med. 2020 Feb 4. doi: 10.1002/cam4.2819. [Epub ahead of print]
Impact of self-perception of aging on mortality of older patients in oncology.
Schroyen S1, Letenneur L2, Missotten P1, Jérusalem G3,4, Adam S1.

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Abstract

OBJECTIVE:

Several studies show that self-perception of aging (SPA) is a significant predictor of mental and physical health. In this study, we analyze the effect of SPA on mortality in the specific context of geriatric oncology.
METHODS:

The sample constituted of 140 individuals aged 65 years and older suffering from a recent nonmetastatic cancer (breast, lung, gynecological, or hematological), followed up to 6 years. We used Cox proportional hazards model to assess the effect of SPA at baseline on mortality. It was adjusted for age, gender, educational and cognitive level, oncological information (the site and kind of cancer), number of comorbidities, and physical and mental health at baseline.
RESULTS:

Patients were aged 73 years at diagnosis and were more often women (85.7%). Individuals with more negative SPA were 3.62 times more likely to die than those with a more positive SPA, with control of gender, age, education and cognitive level, mental and physical health, the category (breast, lung, gynecological, or hematological), and kind (initial or recurrence) of cancer.
CONCLUSIONS:

These findings suggest that SPA influence the mortality of older people in the particular context of oncology. Therefore, the need to change our attitudes toward aging and older people implied indirectly by these results is discussed.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

cancer risk factors; medical oncology; psychosocial studies
PMID: 32020758 DOI: 10.1002/cam4.2819
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Select item 3201747210.
Cancer Med. 2020 Feb 3. doi: 10.1002/cam4.2906. [Epub ahead of print]
Identification of the plasma total cfDNA level before and after chemotherapy as an indicator of the neoadjuvant chemotherapy response in locally advanced breast cancer.
Ma G1,2, Wang J1,2, Huang H3, Han X1, Xu J4, Veeramootoo JS1, Xia T1,2, Wang S1,2.

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Abstract


This study aimed to retrospectively evaluate the circulating free DNA (cfDNA) level in patients with locally advanced breast cancer (LABC) having different neoadjuvant chemotherapy (NCT) responses and to investigate whether dynamic changes in cfDNA level could predict the effectiveness of NCT in patients with LABC. Data on 61 patients with LABC were included. NCT responses were evaluated using the response evaluation criteria. Blood samples were collected for cfDNA detection before treatment and after the first and eighth courses of chemotherapy. The Alu 111-bp and 260-bp fragment levels were evaluated by polymerase chain reaction, and the predictive value of the cfDNA level in the NCT response was determined. In vitro, the MCF-7 and MCF-7/ADR cell lines were applied to simulate the phenomenon of drug resistance and explain the underlying mechanism. The Alu 111-bp level increased after the first NCT course (P = .014) and then remained high after NCT in the high-R group (P = .047), but it remained steady in the low-R group during NCT. A similar tendency in the Alu 260-bp level was revealed in different groups. The ∆∆Ct value of Alu 260-bp had good diagnostic efficiency in assessing predictive ability. The area under the curve for the ∆∆Ct1 and ∆∆Ct2 of Alu 260-bp was 0.697 and 0.647, respectively. The cfDNA level was closely related to epirubicin-induced apoptosis and changes in the Ki-67 index in vitro. The elevation of cfDNA after one chemotherapy cycle was mediated by the apoptosis of tumor cells and related to the improved chemotherapy response.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

apoptosis; biomarkers; breast cancer; neoadjuvant chemotherapy
PMID: 32017472 DOI: 10.1002/cam4.2906
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Select item 3201747011.
Cancer Med. 2020 Feb 4. doi: 10.1002/cam4.2903. [Epub ahead of print]
Integrative analysis of highly mutated genes in hepatitis B virus-related hepatic carcinoma.
Kong F1, Kong D1, Yang X1, Yuan D1, Zhang N1, Hua X1, You H1, Zheng K1,2, Tang R1,2.

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Abstract


Gene mutation is responsible for the development of hepatocellular carcinoma (HCC) with hepatitis B virus (HBV) infection; however, the characteristics and associated biological functions of highly mutated genes, in which the mutation frequencies are at least 5% in HCC patients with HBV infection, are not clearly evaluated. In the study, we analyzed the information regarding somatic mutation obtained by whole-exome sequencing in 280 HBV-related HCC tissues from public databases and published studies. Via integrative analysis, 78 genes, including TP53, TTN, MUC16, CTNNB1, and PCLO were summarized as highly mutated genes, and some of these mutated genes were further identified as cancer driver genes. Besides, we discovered that the highly mutated genes were enriched with various biological functions and pathways. The expression of many of highly mutated genes was found to be significantly altered in HBV-related HCC, and several highly mutated genes were related to a variety of clinical factors and associated with the poor survival of the disease. Taken together, these results could enrich our understanding of highly mutated genes and their relationships with HBV-related HCC. Some of the identified highly mutated genes might be used as novel biomarkers of disease prognosis, or as molecular targets for the treatment of HCC with HBV infection.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

gene mutation; hepatitis B virus; hepatocellular carcinoma; integrative analysis
PMID: 32017470 DOI: 10.1002/cam4.2903
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Select item 3201746712.
Cancer Med. 2020 Feb 4. doi: 10.1002/cam4.2905. [Epub ahead of print]
Characterization of the immune microenvironment in brain metastases from different solid tumors.
Jiang J1, Wu L2, Yuan F3, Ji J4, Lin X2, Yang W2, Wu J1, Shi M1, Yang H1, Ma Y2, Song X2, Zhu Z1,4, Zhang H5, Zhang J1,4.

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Abstract

BACKGROUND:

Brain metastases are one of the most common intracranial neoplasms. Increasing evidence have indicated that systemic immunotherapy may provide long-term benefits for brain metastases. Herein, we presented the results of an immune oncology panel RNA sequencing platform for patients with brain metastases from different primary sites.
METHODS:

We investigated 25 samples of human brain metastases from lung cancer (n = 12), breast cancer (n = 6), and colorectal cancer (n = 7). Besides, 13 paired samples of adjacent noncancerous brain tissue (10 from patients with lung cancer and 3 from patients with breast cancer) were collected as controls. By comparing the brain metastases and paired samples of adjacent noncancerous brain tissue from 13 patients, we detected three upregulated and six downregulated genes, representing the malignant properties of cancer cells and increased immune infiltration in the microenvironment. Next, we profiled the immune-related genes in brain metastases from three primary cancer types.
RESULTS:

A group of genes were significantly overexpressed in the microenvironment of brain metastases from lung cancer, covering the checkpoint pathways, lymphocyte infiltration, and TCR-coexpression. Especially, immune checkpoint molecules, PD-L1, PD-L2, and IDO1 were expressed at higher levels in brain metastases from lung cancer than those from the other two cancer types.
CONCLUSIONS:

This study presents an immune landscape of brain metastases from different cancer types. With high RNA expression levels of PD-1/PD-L1 axis and immune infiltration in brain metastases, it would be worthwhile to explore the efficacy of immune checkpoint blockade for lung cancer patients with intracranial metastases.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

PD-L1; brain metastasis; immune checkpoint; immune system; lymphocyte
PMID: 32017467 DOI: 10.1002/cam4.2905
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Select item 3201745113.
Cancer Med. 2020 Feb 4. doi: 10.1002/cam4.2892. [Epub ahead of print]
Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1-mediated DNA methylation mechanism.
Zhao R1,2, Liu Z1, Xu W1, Song L1, Ren H1, Ou Y1, Liu Y1, Wang S1.

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Abstract


Krüppel-like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report that Helicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5-hmC levels were lower in GC cells with H pylori infection than in GC cells without H pylori infection. Thus, our study not only sheds new light on how H pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in the H pylori/CagA-TET1-KLF4 signaling pathway plays a critical role, suggesting that this pathway may be a prospective target for gastric carcinoma intervention and therapy.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

H pylori ; CagA; KLF4; TET1; gastric cancer
PMID: 32017451 DOI: 10.1002/cam4.2892
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Select item 3201744314.
Cancer Med. 2020 Feb 4. doi: 10.1002/cam4.2876. [Epub ahead of print]
Prospective study of the relevance of circulating tumor cell status and neoadjuvant chemotherapy effectiveness in early breast cancer.
Ni C1,2,3, Shen Y4, Fang Q3, Zhang M5, Yuan H3, Zhang J3, Zhong M3, Zheng Y3.

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Abstract


Although unequivocal evidence has shown the prognostic relevance of circulating tumor cells (CTCs) in patients with metastatic breast cancer (MBC), less evidence is available for its significance in neoadjuvant chemotherapy (NCT) in early breast cancer (BC). Here we conducted an analysis of individual data from 86 patients confirmed as invasive BC by core-needle biopsy in Zhejiang Provincial People's Hospital between June 2013 and January 2017. The CTCs were assessed at the time after diagnosis and before surgery with the CanPatrol technique. The median follow-up duration was 46.3 months. CTCs were detected in 37.2% of all patients (29/78) at baseline, and the presence of CTCs was associated with tumor size, tumor stage, and molecular classification. After NCT, the CTC-positive patients were dropped from 29 to 8, and the EC-T (epirubicin/cyclophosphamide followed by docetaxel) and TEC (docetaxel/epirubicin/cyclophosphamide) strategies reduce CTC-positive patients from 16 to 3 and 13 to 5, respectively. The CTC-negative conversion rates were similar in ER/PR+ HER2+ (5/7, 71.4%), ER/PR- HER2+ (8/11, 72.7%), and TNBC (7/10, 70%) during NCT. In addition, we explored the association between CTC-negative conversion and objective response rate (partial response and complete response, ORR) and pathological complete response rate (pCR), and our results indicate that ORR was higher in patients with positive CTCs and converted to negative after NCT (ORR, P = .013; pCR, P = .0608). Our study preliminarily highlights the relevance of CTC status and NCT effectiveness in early BC using the CanPatrol system.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

CTCs; CanPatrol system; early breast cancer; neoadjuvant chemotherapy
PMID: 32017443 DOI: 10.1002/cam4.2876
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Select item 3201740415.
Cancer Med. 2020 Feb 3. doi: 10.1002/cam4.2895. [Epub ahead of print]
Kras mutation correlating with circulating regulatory T cells predicts the prognosis of advanced pancreatic cancer patients.
Cheng H1,2,3, Luo G1,2,3, Jin K1,2,3, Fan Z1,2,3, Huang Q1,2,3, Gong Y1,2,3, Xu J1,2,3, Yu X1,2,3, Liu C1,2,3.

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Abstract

PURPOSE:

Kras mutation and abnormal immune status are associated with pancreatic cancer development and progression. In this study, we evaluated the Kras mutation status in circulating tumor DNA and circulating T cell subsets in a cohort of advanced pancreatic cancer patients.
METHODS:

Samples were retrospectively obtained from a series of 210 pathological advanced pancreatic cancer patients between 2012 and 2014. The Kras mutation status was detected in cell-free circulating tumor DNA (ctDNA) by ddPCR and circulating T cell subsets were analyzed by flow cytometry.
RESULTS:

Univariate analysis found that tumor node metastasis (TNM) stage, chemotherapy, circulating regulatory T cells, CA19-9 levels, CA125 levels, and KrasG12D and KrasG12V mutations were significantly related to overall survival in advanced pancreatic cancer patients. Multivariate analysis identified that TNM stage (P = .03, HR:1.422), Tregs (P = .004, HR:1.522), CA19-9 levels (P = .009, HR:1.488), KrasG12D mutation (P = .044, HR:1.353), and KrasG12V mutation (P = .001, HR:1.667) were independent prognostic markers. Furthermore, we found that KrasG12V mutation in ctDNA was correlated with high circulating proportion of Tregs, and patients with both KrasG12V mutation and high levels of Tregs were associated with extremely poor survival in advanced pancreatic cancer.
CONCLUSION:

KrasG12V mutation was associated with high circulating regulatory T cell levels, and both of them predicted worse prognosis in advanced pancreatic cancer patients.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

Kras mutation; Tregs; pancreatic cancer; prognosis
PMID: 32017404 DOI: 10.1002/cam4.2895
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Select item 3201738116.
Cancer Med. 2020 Feb 3. doi: 10.1002/cam4.2880. [Epub ahead of print]
Study on the targeted therapy of oral squamous cell carcinoma with a plasmid expressing PE38KDEL toxin under control of the SERPINB3 promoter.
Wu J1, Guo Q2, Zhang G1, Zhao L2, Lv Y3, Wang J1, Liu J1, Shi W2.

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Abstract


Oral squamous cell carcinoma (OSCC) has a poor prognosis and a high risk of recurrence. To improve the efficacy of OSCC therapy, it is of great significance to explore gene therapy for OSCC. The use of specific genes to regulate the targeted expression of suicide genes is a hot topic in gene therapy for cancer. The SERPINB3 gene is highly active in squamous cell carcinoma, but nearly undetectable or present at a low level in normal tissues. This specificity suggests that the SERPINB3 promoter can be used for targeted OSCC therapy. Pseudomonas aeruginosa secretes PE38KDEL, an exotoxin derivative, as a suicide gene used in gene therapy. A SERPINB3 promoter-mediated PE38KDEL expression vector was created. The SERPINB3 gene expression was tested in different cell lines by RT-qPCR and Western blotting, and the SERPINB3 promoter activity was detected by luciferase assay. The SERPINB3 promoter was more active in the TCA8113 cell line than in the other cell lines. The target therapeutic potential of the toxin vector pSERPINB3-PE38KDEL was tested in the SERPINB3-positive TCA8113 cell line, the SERPINB3-negative MG63 cell line, and normal L02 cell line. The SERPINB3 gene was expressed at a high level in TCA8113 cells but a low level in MG63 and L02 cells. Transfection of the pSERPINB3-PE38KDEL plasmid effectively inhibited the proliferation and invasion of TCA8113 cells and induced cell apoptosis, but no significant damage to MG63 and L02 cells was observed. The results of in vitro experiments indicated that the pSERPINB3-PE38KDEL plasmid could be a promising strategy for targeted OSCC gene therapy.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

PE38KDEL toxin; SERPINB3 promoter; oral squamous cell carcinoma; targeted therapy
PMID: 32017381 DOI: 10.1002/cam4.2880
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Select item 3201249717.
Cancer Med. 2020 Feb 3. doi: 10.1002/cam4.2885. [Epub ahead of print]
Computational analysis of morphological and molecular features in gastric cancer tissues.
Yasuda Y1,2, Tokunaga K1, Koga T1, Sakamoto C1, Goldberg IG3, Saitoh N4, Nakao M1.

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Abstract


Biological morphologies of cells and tissues represent their physiological and pathological conditions. The importance of quantitative assessment of morphological information has been highly recognized in clinical diagnosis and therapeutic strategies. In this study, we used a supervised machine learning algorithm wndchrm to classify hematoxylin and eosin (H&E)-stained images of human gastric cancer tissues. This analysis distinguished between noncancer and cancer tissues with different histological grades. We then classified the H&E-stained images by expression levels of cancer-associated nuclear ATF7IP/MCAF1 and membranous PD-L1 proteins using immunohistochemistry of serial sections. Interestingly, classes with low and high expressions of each protein exhibited significant morphological dissimilarity in H&E images. These results indicated that morphological features in cancer tissues are correlated with expression of specific cancer-associated proteins, suggesting the usefulness of biomolecular-based morphological classification.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

ATF7IP/MCAF1; PD-L1; gastric cancer; machine learning; tissue morphology
PMID: 32012497 DOI: 10.1002/cam4.2885
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Select item 3201110318.
Cancer Med. 2020 Feb 3. doi: 10.1002/cam4.2872. [Epub ahead of print]
A new prognostic score for disease progression and mortality in patients with newly diagnosed primary CNS lymphoma.
Liu CJ1,2, Lin SY3,4, Yang CF5, Yeh CM1,2, Kuan AS6, Wang HY1, Tsai CK1, Gau JP1,7, Hsiao LT1,7, Chen PM1,7, Liu YC1,7, Hong YC7,8, Ko PS1,7, Liu JH1,8,9, Lin CH1,3,7,10.

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Abstract

BACKGROUND:

Although various prognostic models for primary central nervous system lymphoma (PCNSL) have been developed, there is no consensus regarding the optimal prognostic index. We aimed to evaluate potential prognostic factors and construct a novel predictive model for PCNSL patients.
METHODS:

We enrolled newly diagnosed PCNSL patients between 2003 and 2015. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was overall survival (OS). The prognostic factors identified using multivariate Cox proportional hazards models were used to develop a predictive model. We subsequently validated the prognostic model in an independent cohort. We also evaluated the validity of the existing scores: the International Extranodal Lymphoma Study Group (IELSG), the Nottingham/Barcelona (NB), and the Memorial Sloan-Kettering Cancer Center models (MSKCC).
RESULTS:

We identified 101 patients with newly diagnosed PCNSL at our center. Multivariate analysis showed that age ≥80, deep brain lesions, and ECOG ≥2 were independent risk factors of PFS. Assigning one point for each factor, we constructed a novel prognostic model, the Taipei Score, with four distinct risk groups (0-3 points). The performances of the Taipei Score in discriminating both PFS and OS in the training cohort were significant, and the score was validated in the external validation cohort. The IELSG, NB and MSKCC models had insufficient discriminative ability for either PFS or OS in both cohorts.
CONCLUSION:

The Taipei Score is a simple model that discriminates PFS and OS for PCNSL patients. The score may offer disease risk stratification and facilitate clinical decision-making.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

epidemiology; external validation; primary CNS lymphoma; prognostic model
PMID: 32011103 DOI: 10.1002/cam4.2872
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Select item 3200930519.
Cancer Med. 2020 Feb 3. doi: 10.1002/cam4.2891. [Epub ahead of print]
Enrollment of adolescents and young adults onto SWOG cancer research network clinical trials: A comparative analysis by treatment site and era.
Roth ME1, Unger JM2, O'Mara AM3, Lewis MA4, Budd T3, Johnson RH5, Pollock BH6, Blanke C7, Freyer DR8.

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Abstract

BACKGROUND:

Few adolescents and young adults (AYAs, 15-39 years old) enroll onto cancer clinical trials, which hinders research otherwise having the potential to improve outcomes in this unique population. Prior studies have reported that AYAs are more likely to receive cancer care in community settings. The National Cancer Institute (NCI) has led efforts to increase trial enrollment through its network of NCI-designated cancer centers (NCICC) combined with community outreach through its Community Clinical Oncology Program (CCOP; replaced by the NCI Community Oncology Research Program in 2014).
METHODS:

Using AYA proportional enrollment (the proportion of total enrollments who were AYAs) as the primary outcome, we examined enrollment of AYAs onto SWOG therapeutic trials at NCICC, CCOP, and non-NCICC/non-CCOP sites from 2004 to 2013 by type of site, study period (2004-08 vs 2009-13), and patient demographics.
RESULTS:

Overall, AYA proportional enrollment was 10.1%. AYA proportional enrollment decreased between 2004-2008 and 2009-2013 (13.1% vs 8.5%, P < .001), and was higher at NCICCs than at CCOPs and non-NCICC/non-CCOPs (14.1% vs 8.3% and 9.2%, respectively; P < .001). AYA proportional enrollment declined significantly at all three site types. Proportional enrollment of AYAs who were Black or Hispanic was significantly higher at NCICCs compared with CCOPs or non-NCICC/non-CCOPs (11.5% vs 8.8, P = .048 and 11.5% vs 8.6%, P = .03, respectively).
CONCLUSION:

Not only did community sites enroll a lower proportion of AYAs onto cancer clinical trials, but AYA enrollment decreased in all study settings. Initiatives aimed at increasing AYA enrollment, particularly in the community setting with attention to minority status, are needed.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

CCOP; NCI; NCORP; SWOG; adolescent and young adult; cancer; clinical trials; enrollment
PMID: 32009305 DOI: 10.1002/cam4.2891
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