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  • Comprehensive profiling of circular RNA expressions reveals potential diagnostic and prognostic biomarkers in multiple myeloma
    BMC Cancer (IF 3.288) Pub Date : 2020-01-16
    Fan Zhou; Dongjiao Wang; Wei Wei; Haimin Chen; Haotian Shi; Nian Zhou; Lixia Wu; Rong Peng

    This study aimed to explore the heterogeneity of circRNA expression pattern via microarray, and further evaluate the potential of 10 specific circRNAs as diagnostic and prognostic biomarkers in multiple myeloma (MM). In exploration stage (stage I), circRNA expression profiles were detected by the microarray in bone marrow plasma cells from 4 MM patients and 4 healthy controls (HCs), and bioinformatic analyses were performed. In validation stage (stage II), top 10 upregulated and top 10 downregulated circRNAs identified in stage I were detected in 60 MM patients and 30 HCs for further validation; the diagnostic and prognostic values of these circRNAs in MM patients were analyzed. In stage I, 122 upregulated and 260 downregulated circRNAs were identified in MM patients compared with HCs. GO, KEGG and pathway enrichment analyses revealed that these circRNAs were implicated in neoplastic pathways such as MAPK and VEGF signaling pathways. In stage II, circ-PTK2, circ-RNF217, circ-RERE, circ-NAGPA and circ-KCNQ5 were validated to be upregulated and circ-AFF2, circ-WWC3, circ-DNAJC5, circ-KLHL2, circ-IQGAP1 and circ-AL137655 were validated to be downregulated in MM compared with controls. Circ-PTK2 and circ-RNF217 were correlated with poor treatment response and survival, while circ-AFF2 predicted good treatment response and survival in MM patients. This study provides valuable reference for profound understanding about circRNA expression patterns in MM, and validates that circ-PTK2, circ-RNF217 and circ-AFF2 might serve as potential prognostic biomarkers in MM.

    更新日期:2020-01-17
  • GC-PROM: validation of a patient-reported outcomes measure for Chinese patients with gastric cancer
    BMC Cancer (IF 3.288) Pub Date : 2020-01-16
    Xiaojuan Hu; Fen Zhao; Hongmei Yu; Yanhong Luo; Jinchun Liu; Yanbo Zhang

    There is increasing recognition that PROs are important in the estimation of the burden of long-term survival among patients with gastric cancer. The study aimed to develop a disease-specific instrument to assess patient-reported outcomes for Chinese patients with gastric cancer. Following the FDA’s draft guidance for patient-reported outcome, conceptual framework and item pool were defined based on relevant existing work. A draft scale was formed after revising some items based on feedback from experts and Chinese patients with gastric cancer. The pre-survey and formal survey were conducted in eight different hospitals in Shanxi Province, and two item-selection process based on classical test theory and item response theory. Finally, the patient-reported outcomes measure for Chinese patients with gastric cancer (GC-PROM) was validated in terms of reliability, validity, and feasibility. The minimal clinically important difference was determined by distribution-based method. The final GC-PROM consisted of 38 items, 13 subdomains, and 4 domains. Reliability was verified by Cronbach’s alpha coefficient for four domains and 13 subdomains respectively. The validity results showed that the multidimensional scale fulfilled expectations. In the formal survey, the completion rate was 96.16%, and the average filling time was less than half an hour. The values of the minimal clinically important difference were 4.14, 3.41, 3.37, and 3.28 in the four domains. The GC-PROM had good reliability, validity, and feasibility and thus can be considered an effective clinical evaluation instrument for Chinese patients with gastric cancer.

    更新日期:2020-01-17
  • Correction to: Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects
    BMC Cancer (IF 3.288) Pub Date : 2020-01-17
    Hongwei Tian; Gang Shi; Guoyou Yang; Junfeng Zhang; Yiming Li; Tao Du; Jianzhou Wang; Fen Xu; Lin Cheng; Xiaomei Zhang; Lei Dai; Xiaolei Chen; Shuang Zhang; Yang Yang; Dechao Yu; Yuquan Wei; Hongxin Deng

    Following publication of the original article [1], the authors reported an error in Fig 5 of this article, graphs presenting FCM and immunofluorescent for CD4T, CD8T and NK cell of the Control Groups (LL2, LL2-irradation, MCS-irradiation) were inadvertently duplicated from another parallel experiment.

    更新日期:2020-01-17
  • Bacteriocin production by mucosal bacteria in current and previous colorectal neoplasia
    BMC Cancer (IF 3.288) Pub Date : 2020-01-16
    Darina Kohoutova; Miroslava Forstlova; Paula Moravkova; Jiri Cyrany; Juraj Bosak; David Smajs; Stanislav Rejchrt; Jan Bures

    Optimal therapy for colorectal carcinoma (CRC), a frequently diagnosed malignancy, does not exist. Some of colicins and microcins, ribosomally synthesized peptides by gramnegative bacteria, have shown significant biological activity specifically against different cancer cells in vitro and in vivo conditions. The aim of this prospective study was to evaluate natural colicin and microcin production by large intestinal mucosal bacteria in each stage of colorectal neoplasia and in those with a history of colorectal neoplasia. A total of 21 patients with non-advanced adenoma (non-a-A; 16/21 with current and 5/21 with history of non-a-A), 20 patients with advanced colorectal adenoma (a-A; 11/20 with current and 9/20 with history of a-A), 22 individuals with CRC (9/22 with current and 13/22 with history of CRC) and 20 controls were enrolled. Mucosal biopsies from the caecum, transverse colon and the rectum were taken during colonoscopy in each individual. Microbiological culture followed. Production of colicins and microcins was evaluated by PCR methods. A total of 239 mucosal biopsies were taken. Production of colicins and microcins was significantly more frequent in individuals with non-a-A, a-A and CRC compared to controls. No significant difference in colicin and microcin production was found between patients with current and previous non-a-A, a-A and CRC. Significantly more frequent production of colicins was observed in men compared to women at the stage of colorectal carcinoma. A later onset of increased production of microcins during the adenoma-carcinoma sequence has been observed in males compared to females. Strains isolated from large intestinal mucosa in patients with colorectal neoplasia produce colicins and microcins more frequently compared to controls. Bacteriocin production does not differ between patients with current and previous colorectal neoplasia. Fundamental differences in bacteriocin production have been confirmed between males and females.

    更新日期:2020-01-16
  • Prognostic factors of patients with Gliomas – an analysis on 335 patients with Glioblastoma and other forms of Gliomas
    BMC Cancer (IF 3.288) Pub Date : 2020-01-15
    Jianfeng Liang; Xiaomin Lv; Changyu Lu; Xun Ye; Xiaolin Chen; Jia Fu; Chenghua Luo; Yuanli Zhao

    The prognosis of glioma is poor, despite recent advances in diagnosis and treatment of the disease. It is important to investigate the clinical characteristics and prognostic factors of glioma so as to provide basis for treatment and management of patients. A total of 335 patients with glioma were included in this study. These patients were admitted to the medical center between November 2015 and December 2018. The clinical data, including demographic data, tumor characteristics, treatment strategy, expression pattern of tumor markers, and survival data, were retrospectively reviewed. Survival data were analyzed using Kaplan-Meier curves with log-rank test, while multivariate analysis Cox regression model was used to investigate risk factors for mortality. In this patient cohort, glioblastoma (40%), diffuse glioma (14.6%) and oligodendroglioma (9.6%) were the most common pathological types. The expression of Ki-67 was associated with several clinicopathological parameters (e.g. tumor type, grade, and number of lesions). In addition, Ki-67 correlated with the mortality within the first year of the post-treatment follow-up (P < 0.001). Kaplan-Maier analysis revealed that older patients (≥ 45 years) displayed worse prognosis than those aged under 45 years (P = 0.038). Dismal prognosis was also associated with clinical parameters, including high tumor grade, multiple lesions, and Karnofsky performance score (KPS). Multivariate analysis showed that low KPS (< 85) increased the risk of mortality by 2.3 folds with a 95% CI of 1.141 to 4.776 (P = 0.020). Low tumor grade (grade 1–2) oppositely reduced the mortality risk by 0.22 folds (95% CI, 0.065 to 0.763, P = 0.0168). KPS and tumor grade were independent prognostic factors in patients with gliomas.

    更新日期:2020-01-15
  • Does chemoradiotherapy benefit elderly patients with esophageal squamous cell cancer? A propensity-score matched analysis on multicenter data (3JECROG R-03A)
    BMC Cancer (IF 3.288) Pub Date : 2020-01-15
    Mingqiu Chen; Xiaohong Liu; Chun Han; Xin Wang; Yidian Zhao; Qingsong Pang; Xinchen Sun; Gaofeng Li; Kaixian Zhang; Ling Li; Xueying Qiao; Yu Lin; Junqiang Chen; Zefen Xiao

    The aim of the present study was to assess the efficacy of concurrent chemoradiotherapy (CRT) or radiotherapy alone (RT-alone) in elderly patients with esophageal squamous cell carcinoma (ESCC). The clinical data of patients with ESCC treated with RT-alone or CRT were collected and retrospectively reviewed. The 1-, 3- and 5-year overall survival (OS) rates and the clinical characteristics correlated with survival were analyzed statistically. Propensity score matching (PSM) analyses were used to compensate for differences in baseline characteristics between the CRT and RT-alone groups to confirm the survival difference. A total of 729 patients fulfilling the inclusion criteria were reviewed. Diabetes, primary tumor volume (pTV), primary tumor location (pTLo), clinical T stage,(cT) clinical N stage (cN), clinical M stage (cM) and short-term response to RT were independent factors influencing OS (P = 0.002–0.044). The 5-year OS rate was 26.6, 26.0 and 30.1% in the whole cohort, RT-alone and CRT groups, respectively. The survival difference between RT alone and CRT was not significant before or following PSM. Compared with the corresponding subgroups treated with RT alone, CRT significantly benefited patients with diabetes (P = 0.003), cT4 (P = 0.030) and cN0 (P = 0.049), whereas no benefit was identified between CRT and RT alone in the other subgroups, including cT1–3, cN1, cM, pTLo, pTV, age and gender. CRT with the current chemotherapy regimens may not improve the survival of elderly ESCC patients compared to RT-alone, except in patients with cT4 stage, cN0 stage or diabetes. However, due to the limitation of the retrospective nature of the current study, further clinical trials are required for confirmation.

    更新日期:2020-01-15
  • Establishment and validation of a nomogram with intratumoral heterogeneity derived from 18F-FDG PET/CT for predicting individual conditional risk of 5-year recurrence before initial treatment of nasopharyngeal carcinoma
    BMC Cancer (IF 3.288) Pub Date : 2020-01-15
    Bingxin Gu; Jianping Zhang; Guang Ma; Shaoli Song; Liqun Shi; Yingjian Zhang; Zhongyi Yang

    Intratumoral heterogeneity has an enormous effect on patient treatment and outcome. The purpose of the current study was to establish and validate a nomogram with intratumoral heterogeneity derived from 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for prognosis of 5-Year progression-free survival (PFS) of patients with nasopharyngeal carcinoma (NPC). A total of 171 NPC patients who underwent pretreatment 18F-FDG PET/CT were retrospectively enrolled. Data was randomly divided into training cohort (n = 101) and validation cohort (n = 70). The clinicopathologic parameters and the following PET parameters were analyzed: maximum and mean standardized uptake value (SUVmax, SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and heterogeneity index (HI, SUVmax/SUVmean) for primary tumor and maximal neck lymph node. Cox analyses were performed on PFS in the training cohort. A prognostic nomogram based on this model was developed and validated. For the primary tumor, MTV-2.5, TLG-2.5, MTV-70%, and TLG-70% were significantly correlated with PFS. For the maximal neck lymph node, short diameter and HI were significantly correlated with PFS. Among the clinicopathologic parameters, M stage was a significant prognostic factor for recurrence. In multivariate analysis, M stage (P = 0.006), TLG-T-70% (P = 0.002), and HI-N (P = 0.018) were independent predictors. Based on this prognostic model, a nomogram was generated. The C-index of this model was 0.74 (95% CI: 0.63–0.85). For the cross validation, the C-index for the model was 0.73 (95% CI: 0.62–0.83) with the validation cohort. Patients with a risk score of ≥111 had poorer survival outcomes than those with a risk score of 0–76 and 77–110. Intratumoral heterogeneity derived from 18F-FDG PET/CT could predict long-term outcome in patients with primary NPC. A combination of PET parameters and the TNM stage enables better stratification of patients into subgroups with different PFS rates.

    更新日期:2020-01-15
  • Early relapse on adjuvant gemcitabine associated with an exceptional response to 2nd line capecitabine chemotherapy in a patient with pancreatic adenosquamous carcinoma with strong intra-tumoural expression of cytidine deaminase: a case report
    BMC Cancer (IF 3.288) Pub Date : 2020-01-15
    Claire M. Connell; Rebecca Brais; Hayley Whitaker; Sara Upponi; Ian Beh; Jane Risdall; Pippa Corrie; Tobias Janowitz; Duncan I. Jodrell

    Pancreatic adenosquamous carcinoma has a poor prognosis, with limited prospective trial data to guide optimal treatment. The potential impact of drug metabolism on the treatment response of patients with pancreatic adenosquamous carcinoma is largely unknown. We describe the case of a 51 year old woman with pancreatic adenosquamous carcinoma who, following surgical resection, experienced early disease relapse during adjuvant gemcitabine therapy. Paradoxically, this was followed by an exceptional response to capecitabine therapy lasting 34.6 months. Strong expression of cytidine deaminase was detected within the tumour. This case study demonstrates that early relapse during adjuvant chemotherapy for pancreatic adenosquamous carcinoma may be compatible with a subsequent exceptional response to second line chemotherapy, an important observation given the poor overall prognosis of patients with adenosquamous carcinoma. Cytidine deaminase is predicted to inactivate gemcitabine and, conversely, catalyze capecitabine activation. We discuss strong intra-tumoural expression of cytidine deaminase as a potential mechanism to explain this patient’s disparate responses to gemcitabine and capecitabine therapy, and highlight the benefit that may be gained from considering similar determinants of response to chemotherapy in clinical practice.

    更新日期:2020-01-15
  • Young-onset gastric cancer and Epstein–Barr Virus (EBV) – a major player in the pathogenesis?
    BMC Cancer (IF 3.288) Pub Date : 2020-01-14
    Assaf Moore; Elad Hikri; Tal Goshen-Lago; Tamar Barkan; Sara Morgenstern; Elena Brook; Annett Maderer; Wilfried Roth; Noa Gordon; Hanoch Kashtan; Baruch Brenner; Markus Moehler; Irit Ben Aharon

    Gastric cancer (GC) is a leading cause of cancer death, occurs predominantly in older age, with increasing incidence in young patients. The Cancer Genome Atlas indicates four subtypes for GC among which Epstein-Barr virus (EBV) subtype is estimated at 8.7%. We aim to determine the prevalence of EBV subtype in young GC patients (≤45 years) compared with an average-onset cohort (≥55 years) and characterize the clinicopathologic pattern of young-onset GC. Gastric cancer samples of patients of both cohorts were screened for EBV by qPCR. Additional staining was done for Human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status and Programmed death-ligand 1 (PD-L1). Demographics and clinical data were retrieved from the medical records. Thirty-nine young-onset and 35 average-onset GC patients were reviewed. There was no apparent difference in tumor location, family history, histology and HER2 status between the cohorts. More young-onset patients were diagnosed with metastatic disease (27% vs 9%, p = 0.0498). EBV was significantly more prevalent in the young-onset cohort (33% vs 11%, p = 0.025). 15/17 EBV positive patients were under the median age of diagnosis for GC in the US (68 years). MSI-H was found only in the average-onset cohort [0% vs 27%, p = 0.001). PD-L1 positivity was higher in the young-onset cohort (31% vs 3%, p = 0.002). Our study indicates that EBV subtype is more prevalent in young-onset GC and may play a key role in the pathogenesis. Higher rate of PD-L1 positivity in young-onset GC could change treatment strategies. We are currently evaluating these findings in a prospective trial.

    更新日期:2020-01-15
  • Elevated matrix metalloproteinase 7 expression promotes the proliferation, motility and metastasis of tongue squamous cell carcinoma
    BMC Cancer (IF 3.288) Pub Date : 2020-01-14
    Shuo Yuan; Li-song Lin; Rui-Huan Gan; Li Huang; Xiao-ting Wu; Yong Zhao; Bo-hua Su; Dali Zheng; You-Guang Lu

    Matrix metalloproteinase 7 (MMP7), as the smallest member of the matrix metalloproteinase family, has been verified to be implicated in cancer progression, especially metastasis. However, its expression pattern and function in tongue cancer is not clear. The expression of MMP7 in human tongue squamous cell carcinoma (TSCC) specimens compared with their respective paired nontumour tissues by real-time PCR and immunohistochemical staining. The effect of MMP7 on the proliferation, apoptosis, migration, invasion of tongue cancer cells was tested in appropriate ways after MMP7 siRNA knockdown or overexpression. The effect of MMP7 on lymph node metastasis in vivo was analyzed using a high-metastasis orthotopic nude mouse tongue transplanted tumour model. We found markedly elevated expression of MMP7 in human TSCC specimens compared with their respective paired nontumour tissues, and this high expression was correlated with the patients’ lymph node metastasis. Furthermore, the results of molecular functional assays confirmed that MMP7 promotes cell proliferation, migration and invasion of TSCC cells. Knockdown of MMP7 inhibited lymph nodes metastasis in vivo. MMP7 plays an oncogenic role in carcinogenesis and metastasis of tongue cancer, and may serve as a potential therapeutic target for tongue cancer.

    更新日期:2020-01-14
  • Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma
    BMC Cancer (IF 3.288) Pub Date : 2020-01-13
    Xia Liao; Ge Song; Zihan Xu; Yang Bu; Fan Chang; Fengan Jia; Xuelian Xiao; Xuejiao Ren; Mei Zhang; Qingan Jia

    Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ATP-binding cassette transporter G1 (ABCG1) and Wnt signaling in oxaliplatin resistance were confirmed. Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.

    更新日期:2020-01-13
  • Hypoxic induction of vasculogenic mimicry in hepatocellular carcinoma: role of HIF-1 α, RhoA/ROCK and Rac1/PAK signaling
    BMC Cancer (IF 3.288) Pub Date : 2020-01-13
    Ji-Gang Zhang; He-Ming Zhou; Xue Zhang; Wan Mu; Juan-Ni Hu; Gao-Lin Liu; Qin Li

    Vasculogenic mimicry (VM), defined as a capability of aggressive tumor Cells to mimic embryonic vasculogenic networks, caused poor prognosis in hepatocellular carcinoma (HCC). Rho kinases (ROCK), p21-activated kinase (PAK), hypoxia or epithelial-mesenchymal transition (EMT) contributed to the VM potential. However, the details underlying these biological behaviors have not been completely elucidated. Kaplan-Meier analysis was conducted to predict relationship with hypoxia Inducible factor (HIF-1α), EMT related markers: Vimentin and patient prognosis. CD34/periodic acid-Schiff (PAS) double staining was examined to differentiate VM-positive (VM+) and VM-negative (VM-) samples. Cells were cultured under controlled hypoxic environments (1% O2) or normoxic conditions. The effect of hypoxia on RhoA/ROCK, Rac1/PAK and EMT were evaluated by real time-qPCR and western blot. HIF-1α small interfering RNA (siRNA), overexpressed or short hairpin RNA (shRNA) of ROCK and kinase inhibitors were used to explore the effect of HIF-1α, RhoA/ROCK, Rac1/PAK and Vimentin on VM. HIF-1α or Vimentin was upregulated in VM+ HCC tissues, compared to non-cancerous tissues (P < 0.01), and patients with high expression of HIF-1α or Vimentin had worse prognosis (P < 0.001). We showed hypoxia induced RhoA/ROCK and Rac1/PAK signaling transduction, and EMT could be repressed by HIF-1α siRNA. Notably, RhoA/ROCK or Rac1/PAK stabilized HIF-1α in hypoxia, whereas HIF-1α did not significantly altered RhoA/ROCK or Rac1/PAK signaling in hypoxia. Moreover, we found distinct roles of ROCK1, ROCK2 and PAK in regulating Vimentin phosphorylation. RhoA/ROCK and Rac/PAK signaling played crucial roles in hypoxia-induced VM via Ser72 and Ser56 Vimentin phosphorylation in HCC.

    更新日期:2020-01-13
  • P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms
    BMC Cancer (IF 3.288) Pub Date : 2020-01-10
    Kirstine Nielsen; Tina Binderup; Seppo W. Langer; Andreas Kjaer; Pauline Knigge; Veronica Grøndahl; Linea Melchior; Birgitte Federspiel; Ulrich Knigge

    High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier’s method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5–30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1–30%), and abnormal when negative (0%) or strongly positive (> 30%). In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression. Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.

    更新日期:2020-01-11
  • Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway
    BMC Cancer (IF 3.288) Pub Date : 2020-01-10
    Ye Yang; Ping Yin Liu; Wei Bao; Song Jun Chen; Fang Su Wu; Ping Ya Zhu

    Pyroptosis belongs to a novel inflammatory programmed cell death pathway, with the possible prognosis of endometrial cancer related to the terminal protein GSDMD. Hydrogen exerts a biphasic effect on cancer by promoting tumor cell death and protecting normal cells, which might initiate GSDMD pathway-mediated pyroptosis. We performed immunohistochemical staining and western immunoblotting analysis to observe expression of NLRP3, caspase-1, and GSDMD in human and xenograft mice endometrial cancer tissue and cell lines. We investigated treatment with hydrogen could boost ROS accumulation in endometrial cancer cells by intracellular and mitochondrial sources. GSDMD shRNA lentivirus was used to transfect endometrial cancer cells to investigate the function of GSDMD protein in pyroptosis. Propidium iodide (PI) staining, TUNEL assay, measurement of lactate dehydrogenase (LDH) release and IL-1β ELISA were used to analysis pyroptosis between hydrogen-supplemented or normal culture medium. We conducted in vivo human endometrial tumor xenograft mice model to observe anti-tumor effect in hydrogen supplementation. We observed overexpression of NLRP3, caspase-1, and GSDMD in human endometrial cancer and cell lines by IHC and western immunoblotting. Hydrogen pretreatment upregulated ROS and the expression of pyroptosis-related proteins, and increased the number of PI- and TUNEL-positive cells, as well as the release of LDH and IL-1β, however, GSDMD depletion reduced their release. We further demonstrated that hydrogen supplementation in mice was sufficient for the anti-tumor effect to inhibit xenograft volume and weight of endometrial tumors, as mice subjected to hydrogen-rich water displayed decreased radiance. Tumor tissue sections in the HRW groups presented moderate-to-strong positive expression of NLRP3, caspase-1 and GSDMD. Hydrogen attenuated tumor volume and weight in a xenograft mouse model though the pyroptotic pathway. This study extended our original analysis of the ability of hydrogen to stimulate NLRP3 inflammasome/GSDMD activation in pyroptosis and revealed possible mechanism (s) for improvement of anti-tumor effects in the clinical management of endometrial cancer.

    更新日期:2020-01-11
  • A systematic review reporting quality of radiomics research in neuro-oncology: toward clinical utility and quality improvement using high-dimensional imaging features
    BMC Cancer (IF 3.288) Pub Date : 2020-01-10
    Ji Eun Park; Ho Sung Kim; Donghyun Kim; Seo Young Park; Jung Youn Kim; Se Jin Cho; Jeong Hoon Kim

    To evaluate radiomics analysis in neuro-oncologic studies according to a radiomics quality score (RQS) system to find room for improvement in clinical use. Pubmed and Embase were searched up the terms radiomics or radiogenomics and gliomas or glioblastomas until February 2019. From 189 articles, 51 original research articles reporting the diagnostic, prognostic, or predictive utility were selected. The quality of the methodology was evaluated according to the RQS. The adherence rates for the six key domains were evaluated: image protocol and reproducibility, feature reduction and validation, biologic/clinical utility, performance index, a high level of evidence, and open science. Subgroup analyses for journal type (imaging vs. clinical) and biomarker (diagnostic vs. prognostic/predictive) were performed. The median RQS was 11 out of 36 and adherence rate was 37.1%. Only 29.4% performed external validation. The adherence rate was high for reporting imaging protocol (100%), feature reduction (94.1%), and discrimination statistics (96.1%), but low for conducting test-retest analysis (2%), prospective study (3.9%), demonstrating potential clinical utility (2%), and open science (5.9%). None of the studies conducted a phantom study or cost-effectiveness analysis. Prognostic/predictive studies received higher score than diagnostic studies in comparison to gold standard (P < .001), use of calibration (P = .02), and cut-off analysis (P = .001). The quality of reporting of radiomics studies in neuro-oncology is currently insufficient. Validation is necessary using external dataset, and improvements need to be made to feature reproducibility, demonstrating clinical utility, pursuits of a higher level of evidence, and open science.

    更新日期:2020-01-11
  • Childhood cancer incidence and survival trends in Estonia (1970–2016): a nationwide population-based study
    BMC Cancer (IF 3.288) Pub Date : 2020-01-10
    Keiu Paapsi; Aleksei Baburin; Sirje Mikkel; Margit Mägi; Kadri Saks; Kaire Innos

    Childhood cancers represent a small proportion of all cancers but are still a major public health problem. The study analysed long-term trends in childhood cancer incidence and survival in Estonia in relation to societal and health care transition. Data on all malignant tumours, diagnosed in children aged 0–14 during 1970–2016, were derived from the Estonian Cancer Registry. Age-standardised (World standard) incidence rates were calculated by ICCC-3 site groups and joinpoint regression was used to estimate annual percentage change (APC) for incidence trends. Cohort and period approach were used to estimate 5-year survival. Internal age standardisation was applied. A total of 1628 incident cancer cases were diagnosed during the study period and overall incidence increased significantly at a rate of 0.5% per year. Significant increases were seen for neuroblastoma and germ cell tumours, for lymphoid leukemias and some CNS sub-sites. At the same time, decline in incidence was seen in almost all subgroups of unspecified neoplasms. The overall 5-year survival improved from 24% in 1970–1979 to 73% in 2010–2016, with the largest changes occurring in the 1990s and 2000s. For many sites, survival increase thereafter has been marginal. In this first comprehensive population-based study of childhood cancer incidence and survival in Estonia, long-term trends are shown in the context of societal and health care changes. Even though the increasing incidence of some sites may, at least partially, be explained by improved diagnostics reflected in the decreased incidence of unspecified neoplasms, the overall cancer incidence in children seems to be rising. Rapid progress in diagnosis and care have improved childhood cancer survival immensely, but deficit in Estonia persists compared to other European countries. Results of the study accentuate the need for a more in-depth analysis of clinical data, but also for the prioritization of childhood cancer in Estonia, to ensure access to standard care and innovative treatments.

    更新日期:2020-01-11
  • Combining therapy with recombinant human endostatin and cytotoxic agents for recurrent disseminated glioblastoma: a retrospective study
    BMC Cancer (IF 3.288) Pub Date : 2020-01-08
    Jing-jing Ge; Cheng Li; Shao-pei Qi; Feng-jun Xue; Zhi-meng Gao; Chun-jiang Yu; Jun-ping Zhang

    The optimal chemotherapeutics of recurrent disseminated glioblastoma has yet to be determined. We analyzed the efficacy and safety of recombinant human endostatin (rh-ES) combined with temozolomide and irinotecan in patients with recurrent disseminated glioblastoma. We retrospectively reviewed 30 adult patients with recurrent disseminated glioblastoma treated with this combination chemotherapy at Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University of China from November 2009 to August 2018. Temozolomide was given orally at 200 mg/m2 daily for 5 days and rh-ES was administrated 15 mg/d daily for 14 days of each 28-day treatment cycle. Irinotecan was given intravenously every 2 weeks on a 28-day cycle at 340 mg/m2 or 125 mg/m2 depending on antiepileptic drugs. Primary endpoint was progression-free survival (PFS) at 6 months (6 m-PFS). The 6 m-PFS was 23.3%. The median PFS was 3.2 months. The overall survival rate (OS) at 12 months was 28.6%. The median OS was 6.9 months. Six out of 30 (20%) patients demonstrated partial radiographic response and 11 (36.7%) remained stable. The PFS of the 6 patients who got partial response was 5.8, 6.3, 6.9, 13.6, 15.8 and 16.6 months, respectively, and the median time interval of first response was 4 (range, 2.0–6.6) months. The most common adverse events were hematologic toxicities and gastrointestinal effects. The Grade ≥ 3 adverse event was hematologic toxicities. The adverse events were manageable. Rh-ES, in combination with cytotoxic drugs, was an alternative effective regimen with manageable toxicities in treatment of recurrent disseminated glioblastoma.

    更新日期:2020-01-08
  • Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells
    BMC Cancer (IF 3.288) Pub Date : 2020-01-08
    Kazushige Yoshida; Masanori Okamoto; Jun Sasaki; Chika Kuroda; Haruka Ishida; Katsuya Ueda; Hirokazu Ideta; Takayuki Kamanaka; Atsushi Sobajima; Takashi Takizawa; Manabu Tanaka; Kaoru Aoki; Takeshi Uemura; Hiroyuki Kato; Hisao Haniu; Naoto Saito

    There are many types of therapies for cancer. In these days, immunotherapies, especially immune checkpoint inhibitors, are focused on. Though many types of immune checkpoint inhibitors are there, the difference of effect and its mechanism are unclear. Some reports suggest the response rate of anti-PD-1 antibody is superior to that of anti-PD-L1 antibody and could potentially produce different mechanisms of action. On the other hand, Treg also express PD-1; however, their relationship remains unclear. In this study, we used osteosarcoma cell lines in vitro and osteosarcoma mouse model in vivo. In vitro, we analyzed the effect of IFNγ for expression of PD-L1 on the surface of cell lines by flowcytometry. In vivo, murine osteosarcoma cell line LM8 was subcutaneously transplanted into the dorsum of mice. Mouse anti-PD-1 antibody was intraperitoneally administered. we analysed the effect for survival of anti-PD-1 antibody and proportion of T cells in the tumour by flowcytometry. We discovered that IFNγ increased PD-L1 expression on the surface of osteosarcoma cell lines. In assessing the relationship between anti-PD-1 antibody and Treg, we discovered the administration of anti-PD-1 antibody suppresses increases in tumour volume and prolongs overall survival time. In the tumour microenvironment, we found that the administration of anti-PD-1 antibody decreased Treg within the tumour and increased tumour-infiltrating lymphocytes. Here we clarify for the first time an additional mechanism of anti-tumour effect—as exerted by anti-PD-1 antibody decreasing Treg— we anticipate that our findings will lead to the development of new methods for cancer treatment.

    更新日期:2020-01-08
  • An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer
    BMC Cancer (IF 3.288) Pub Date : 2020-01-08
    Qing Wang; Zhijun Wang; Yan Wu; David J. Klinke

    Combining anti-cancer therapies with orthogonal modes of action, such as direct cytotoxicity and immunostimulatory, hold promise for expanding clinical benefit to patients with metastatic disease. For instance, a chemotherapy agent Oxaliplatin (OXP) in combination with Interleukin-12 (IL-12) can eliminate pre-existing liver metastatic colorectal cancer and protect from relapse in a murine model. However, the underlying dynamics associated with the targeted biology and the combinatorial space consisting of possible dosage and timing of each therapy present challenges for optimizing treatment regimens. To address some of these challenges, we developed a predictive simulation platform for optimizing dose and timing of the combination therapy involving Mifepristone-induced IL-12 and chemotherapy agent OXP. A multi-scale mathematical model comprised of impulsive ordinary differential equations was developed to describe the interaction between the immune system and tumor cells in response to the combined IL-12 and OXP therapy. An ensemble of model parameters were calibrated to published experimental data using a genetic algorithm and used to represent three different phenotypes: responders, partial-responders, and non-responders. The multi-scale model captures tumor growth patterns of the three phenotypic responses observed in mice in response to the combination therapy against a tumor re-challenge and was used to explore the impacts of changing the dose and timing of the mixed immune-chemotherapy on tumor growth subjected to a tumor re-challenge in mice. An increased ratio of CD8 + T effectors to regulatory T cells during and after treatment was key to improve tumor control in the responder cohort. Sensitivity analysis indicates that combined OXP and IL-12 therapy worked more efficiently in responders by increased priming of T cells, enhanced CD8 + T cell-mediated killing, and functional inhibition of regulatory T cells. In a virtual cohort that mimics non-responders and partial-responders, simulations show that an increased dose of OXP alone would improve the response. In addition, enhanced IL-12 expression alone or an increased number of treatment cycles of the mixed immune-chemotherapy can barely improve tumor control for non-responders and partial responders. Overall, this study illustrates how mechanistic models can be used for in silico screening of the optimal therapeutic dose and timing in combined cancer treatment strategies.

    更新日期:2020-01-08
  • Simultaneous occurrence of invasive pulmonary aspergillosis and diffuse large B-cell lymphoma: case report and literature review
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Lianyou Shao; Longxiang Jiang; Siyao Wu; Lihua Yu; Liangxing Wang; Xiaoying Huang

    Patients with lymphoma are at risk for developing pulmonary opportunistic infections due to immunocompromise. However, clinical reports of concurrent lymphoma and opportunistic infection at presentation are rare and often confined to single cases. A delayed diagnosis of either opportunistic infection or lymphoma usually occurs in this complex situation. Here, we report such a case and analyse 18 similar cases searched in the PubMed database to deepen clinicians’ understanding. A 48-year-old man presented with a 3-month history of fever, cough and emaciation. High-resolution computed tomography revealed bilateral cavitating lesions of different sizes. Aspergillus fumigatus complex was identified from a bronchoalveolar lavage fluid culture. However, antifungal treatment combined with multiple rounds of antibacterial therapy was unsuccessful, and the patient’s lung lesions continued to deteriorate. Multiple puncture biopsies finally confirmed the coexistence of diffuse large B-cell lymphoma. Despite the initiation of combination chemotherapy, the patient died of progressive respiratory failure. Synchronous pulmonary lymphoma and simultaneous opportunistic infection is rare and usually lacks specific clinical and imaging manifestations. Lymphoma should be considered as part of the differential diagnosis of patients with an opportunistic infection when treatment fails or other symptoms are present that could be considered “atypical” for the condition. Tissue biopsy is the gold standard, and multiple biopsies are essential for making the final diagnosis and should be performed upon early suspicion.

    更新日期:2020-01-07
  • Comprehensive assessments and related interventions to enhance the long-term outcomes of child, adolescent and young adult cancer survivors – presentation of the CARE for CAYA-Program study protocol and associated literature review
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    J. Salchow; J. Mann; B. Koch; J. von Grundherr; W. Jensen; S. Elmers; L. A. Straub; E. Vettorazzi; G. Escherich; S. Rutkowski; S. Dwinger; C. Bergelt; M. Sokalska-Duhme; S. Bielack; G. Calaminus; K. Baust; C. F. Classen; C. Rössig; J. Faber; H. Faller; I. Hilgendorf; J. Gebauer; T. Langer; M. Metzler; S. Schuster; C. Niemeyer; A. Puzik; D. Reinhardt; U. Dirksen; A. Sander; M. Köhler; J. K. Habermann; C. Bokemeyer; A. Stein

    Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15–39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).

    更新日期:2020-01-07
  • AJCC 8th edition prognostic staging provides no better discriminatory ability in prognosis than anatomical staging in triple negative breast cancer
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Jiehua He; Julia Y. Tsang; Xiaodan Xu; Jibin Li; Mei Li; Xue Chao; Yuanyuan Xu; Rongzhen Luo; Gary M. Tse; Peng Sun

    We retrospectively compared the prognostic value between the AJCC 8th edition anatomic (AS) and prognostic staging (PS) system for triple negative breast cancer (TNBC) in a cohort from two involved institutions and a large population database. Clinicopathological data of TNBCs were identified in two involved institutions (SYSUCC-PWH cohort). Data from SEER database during 2010–2015 was also accessed. We restaged all cases into AS and PS group according to the AJCC 8th staging system. A total of 611 and 31,941 TNBCs were identified in two cohorts, with a median follow-up of 53.5 and 27 months respectively. PS upstaged 46.1% of patients in SYSUCC-PWH cohort, and 62.4% in SEER cohort. No significant difference was observed in C index between AS and PS models for disease-specific survival (DSS), progression-free survival (PFS) or overall survival (OS) in either cohort. χ2 statistic and Hazard Ratio for PFS, DSS and OS showed better discrimination between IA and IB, IIB and IIIA, IIIA and IIIB in AS model than PS model. Besides, patients with IIIC unchanged stage showed worse PFS compared to those with AS IIIA or IIIB upstaged to PS IIIC in both cohorts(p = 0.049, p < 0.001). Our findings demonstrated that prognostic staging system did not provide better discriminatory ability in predicting TNBCs prognosis than anatomic staging system.

    更新日期:2020-01-07
  • Effect of adjuvant chemotherapy on survival benefit in stage III colon cancer patients stratified by age: a Japanese real-world cohort study
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Hidetaka Kawamura; Toshitaka Morishima; Akira Sato; Michitaka Honda; Isao Miyashiro

    Adjuvant chemotherapy is relatively underused in older patients with colon cancer in Japan, and its age-specific effects on clinical outcomes remain unclear. This study aimed to assess the effect of adjuvant chemotherapy on survival benefit in stage III colon cancer patients stratified by age in a Japanese real-world setting. In this multi-center retrospective cohort study, we analyzed patient-level information through a record linkage of population-based cancer registry data and administrative claims data. The study population comprised patients aged ≥18 years who received a pathological diagnosis of stage III colon cancer and underwent curative resection between 2010 and 2014 at 36 cancer care hospitals in Osaka Prefecture, Japan. Patients were divided into two groups based on age at diagnosis (< 75 and ≥ 75 years). The effect of adjuvant chemotherapy was analyzed using Cox proportional hazards regression models for all-cause mortality with inverse probability weighting of propensity scores. Adjusted hazard ratios were estimated for both age groups. A total of 783 patients were analyzed; 476 (60.8%) were aged < 75 years and 307 (39.2%) were aged ≥75 years. The proportion of older patients who received adjuvant chemotherapy (36.8%) was substantially lower than that of younger patients (73.3%). In addition, the effect of adjuvant chemotherapy was different between the age groups: the adjusted hazard ratio was 0.56 (95% confidence interval: 0.33–0.94, P = 0.027) in younger patients and 1.07 (0.66–1.74, P = 0.78) in older patients. The clinical effectiveness of adjuvant chemotherapy in older patients with stage III colon cancer appears limited under current utilization practices.

    更新日期:2020-01-07
  • Long-term outcomes of surgical resection for T1b gallbladder cancer: an institutional evaluation
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Kizuki Yuza; Jun Sakata; Pankaj Prasoon; Yuki Hirose; Taku Ohashi; Koji Toge; Kohei Miura; Masayuki Nagahashi; Takashi Kobayashi; Toshifumi Wakai

    There is no comprehensive agreement concerning the overall performance of radical resection for T1b gallbladder cancer (GBC). This research focused on addressing whether T1b GBC may spread loco-regionally and whether radical resection is necessary. A retrospective analysis was conducted of 1032 patients with GBC who underwent surgical resection at our centre and its affiliated institutions between January 1982 and December 2018. A total of 47 patients with T1b GBC, 29 (62%) of whom underwent simple cholecystectomy and 18 (38%) of whom underwent radical resection with regional lymph node dissection, were enrolled in the study. GBC was diagnosed pre-operatively in 16 patients (34%), whereas 31 patients (66%) had incidental GBC. There was no blood venous or perineural invasion in any patient on histology evaluation, except for lymphatic vessel invasion in a single patient. There were no metastases in any analysed lymph nodes. The open surgical approach was more prevalent among the 18 patients who underwent radical resection (open in all 18 patients) than among the 29 patients who underwent simple cholecystectomy (open in 21; laparoscopic in 8) (P = 0.017). The cumulative 10- and 20-year overall survival rates were 65 and 25%, respectively. The outcome following simple cholecystectomy (10-year overall survival rate of 66%) was akin to that following radical resection (64%, P = 0.618). The cumulative 10- and 20-year disease-specific survival rates were 93 and 93%, respectively. The outcome following simple cholecystectomy (10-year disease-specific survival rate of 100%) was equivalent to that following radical resection (that of 86%, P = 0.151). While age (> 70 years, hazard ratio 5.285, P = 0.003) and gender (female, hazard ratio 0.272, P = 0.007) had a strong effect on patient overall survival, surgical procedure (simple cholecystectomy vs. radical resection) and surgical approach (open vs. laparoscopic) did not. Most T1b GBCs represent local disease. As pre-operative diagnosis, including tumour penetration of T1b GBC, is difficult, the decision of radical resection is justified. Additional radical resection is not required following simple cholecystectomy provided that the penetration depth is restricted towards the muscular layer and that surgical margins are uninvolved.

    更新日期:2020-01-07
  • Adaptive radiotherapy in locally advanced esophageal cancer with atelectasis: a case report
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Katsuyuki Sakanaka; Kota Fujii; Takashi Mizowaki

    To the best of our knowledge, no study has reported mediastinal shift accompanied with obstructive atelectasis due to bulky primary esophageal tumor components treated with adaptive radiotherapy and concurrent chemotherapy. Here we report the case of a 65-year-old male patient diagnosed with locally advanced thoracic esophageal squamous cell cancer, clinical T4bN1M0, stage IVA. Bronchoscopy and computed tomography (CT) revealed an almost complete obstruction of the lumen of the left bronchus due to compression by bulky primary esophageal tumor components. On admission, the patient presented with dyspnea and decreased arterial oxygen saturation. Chest radiography and CT on admission revealed mediastinal shift with left atelectasis, as opposed to findings from the chest radiography performed 26 days before admission. Because of the patient’s overall good condition, we recommended definitive chemoradiotherapy instead of palliative bronchial stent placement. After obtaining the patient’s consent, chemoradiotherapy was initiated on the following day and it comprised three-dimensional conformal radiotherapy with 60 Gy in 30 fractions with concurrent administration of cisplatin and 5-fluorouracil. During chemoradiotherapy, tumor location was monitored with cone-beam CT and chest radiography. Chemoradiotherapy on day 8 revealed no evidence of the mediastinal shift. CT simulation was reperformed to adjust the radiotherapy fields to account for geometrical changes induced by the absence of the mediastinal shift. Subsequently, the mediastinal shift and bronchial obstruction did not recur during the course of chemoradiotherapy. The patient completed the planned radiotherapy with concurrent and adjuvant chemotherapy, and no non-hematological grade ≥ 3 adverse events were observed. Complete response was confirmed 7 months after initiating chemoradiotherapy. Currently, no disease recurrence, dysphagia, or respiratory symptoms have been reported at 13 months after initiating chemoradiotherapy. In this study, a bulky primary esophageal tumor caused mediastinal shift due to ipsilateral bronchial obstruction. The close follow-up for monitoring resolution of the mediastinal shift during the course of chemoradiotherapy enabled adequate dose delivery to targets, thus reflecting the geometrical changes induced by the absence of the mediastinal shift. Adaptive radiotherapy technique was crucial for favorable patient outcomes in this challenging clinical situation.

    更新日期:2020-01-07
  • Major differences in follow-up practice of patients with colorectal cancer; results of a national survey in the Netherlands
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    S. M. Qaderi; N. A. T. Wijffels; A. J. A. Bremers; J. H. W. de Wilt

    The precise content and frequency of follow-up of patients with colorectal cancer (CRC) is variable and guideline adherence is low. The aim of this study was to assess the view of colorectal surgeons on their local follow-up schedule and to clarify their opinions about risk-stratification and organ preserving therapies. Equally important, adherence to the Dutch national guidelines was determined. Colorectal surgeons were invited to complete a web-based survey about the importance and interval of clinical follow-up, CEA monitoring and the use of imaging modalities. Furthermore, the opinions regarding physical examination, risk-stratification, organ preserving strategies, and follow-up setting were assessed. Data were analyzed using quantitative and qualitative analysis methods. A total of 106 colorectal surgeons from 52 general and 5 university hospitals filled in the survey, yielding a hospital response rate of 74% and a surgeon response rate of 42%. The follow-up of patients with CRC was mainly done by surgeons (71%). The majority of the respondents (68%) did not routinely perform physical examination during follow-up of rectal patients. Abdominal ultrasound was the predominant modality used for detection of liver metastases (77%). Chest X-ray was the main modality for detecting lung metastases (69%). During the first year of follow-up, adherence to the minimal guideline recommendations was high (99–100%). The results demonstrate that, within the framework of the guidelines, some respondents applied a more intensive follow-up and others a less intensive schedule. The majority of the respondents (77%) applied one single follow-up imaging schedule for all patients that underwent treatment with curative intent. Dutch colorectal surgeons’ adherence to minimal guideline recommendations was high, but within the guideline framework, opinions differed about the required intensity and content of clinical visits, the interval of CEA monitoring, and the importance and frequency of imaging techniques. This national survey demonstrates current follow-up practice throughout the Netherlands and highlights the follow-up differences of curatively treated patients with CRC.

    更新日期:2020-01-07
  • Expression of the NEK family in normal and cancer tissue: an immunohistochemical study
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Talita Diniz Melo-Hanchuk; Mariana Bonjiorno Martins; Lucas Leite Cunha; Fernando Augusto Soares; Laura Sterian Ward; José Vassallo; Jörg Kobarg

    The NEK serine/threonine protein kinases are involved in cell cycle checkpoints, DNA damage repair, and apoptosis. Alterations in these pathways are frequently associated with cell malignant cellular transformations. Thyroid cancer is the most common malignant tumour in the endocrine system. Despite good treatment methods, the number of cases has increased significantly in recent years. Here, we studied the expression of NEK1, NEK2, NEK3, and NEK5 in different types of normal and malignant tissues, using tissue microarray analysis, and identified NEKs as potential markers in thyroid malignancy. The studied cases comprised multiple cancer tissue microarrays, including breast, colon, esophagus, kidney, lung, pancreas, prostate, stomach, thyroid and uterine cervix, as well as 281 patients who underwent thyroid resection for thyroid cancer or thyroid nodules. The expression of NEK1, NEK2, NEK3, and NEK5 was analyzed by immunohistochemistry. The expression pattern was evaluated in terms of intensity by two methods, semiquantitative and quantitative, and was compared between normal and cancer tissue. We analysed the expression of each member of the NEK family in a tissue-dependent manner. Compared to normal tissue, most of the evaluated proteins showed lower expression in lung tumour. However, in the thyroid, the expression was higher in malignant tissue, especially for NEK 1, NEK3 and NEK5. Concerning characteristics of the thyroid tumour, such as aggressiveness, NEK1 expression was higher in tumours with multifocality and in patients with lymph node metastasis. NEK3 expression was stronger in patients with stage II, that involved metastasis. NEK5, on the other hand, showed high expression in patients with invasion and metastasis and in patients with tumour size > 4 cm. Furthermore, this work, demonstrated for the first time a high specificity and sensitivity of over-expression of NEK1 in classical and follicular variants of papillary thyroid cancer and NEK3 in tall-cell papillary thyroid cancer. Taken together, the NEK protein kinases emerge as important proteins in thyroid cancer development and may help to identify malignancy and aggressiveness features during diagnosis. This study was retrospectively registered. www.accamargo.org.br/cientistas-pesquisadores/comite-de-etica-em-pequisa-cep.

    更新日期:2020-01-07
  • A cross sectional study to determine the prevalence of cough and its impact in patients with lung cancer: a patient unmet need
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Amélie Harle; Alex Molassiotis; Oliver Buffin; Jack Burnham; Jaclyn Smith; Janelle Yorke; Fiona H. Blackhall

    There is absence of literature related to cough prevalence and its characteristics in lung cancer patients, with information deriving only from broader symptoms occurrence studies. The aims of this study were to provide a snapshot of the prevalence of all-cause-cough in lung cancer patients and to characterise cough in terms of its impact and severity. A cross-sectional study recruiting consecutive lung cancer patients over a pre-defined period of time and using cough-specific validated tools in a tertiary referral centre in the UK, including a cough severity VAS and the Manchester Cough in Lung Cancer scale (MCLCS). Data was collected from 202 patients. All-cause cough prevalence was 57% (through VAS) both in the screened (N = 223) and research (N = 202) population or 67% (through the MCLCS), and cough severity was moderate at a mean of 32 mm (in a 100 mm VAS). Age, sex, smoking status, lung cancer histology, stage and comorbidities were not associated with cough prevalence. The only variable associated with lower cough reports was being ‘on anticancer treatment’; fewer patients on treatment reported a cough (40%) compared to those off treatment (54%) (p = 0.04). The impact of cough (as measured by MCLCS) was also significant (mean score = 22). About 18% of patients felt moderate/severe distress from their cough and about 15% often or always reported disturbed sleep due to coughing. Half the patients felt their cough warranted treatment. Cough is a common symptom in lung cancer with considerable impact on patients’ lives. Cough presence and severity should regularly be assessed in clinical practice. There is an urgent need to focus on developing more potent antitussive treatments and improve the management of this complex and distressing symptom.

    更新日期:2020-01-06
  • Nomogram for predicting the survival of gastric adenocarcinoma patients who receive surgery and chemotherapy
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Chao-Yang Wang; Jin Yang; Hao Zi; Zhong-Li Zheng; Bing-Hui Li; Yang Wang; Zheng Ge; Guang-Xu Jian; Jun Lyu; Xiao-Dong Li; Xue-Qun Ren

    Surgery is the only way to cure gastric adenocarcinoma (GAC), and chemotherapy is the basic adjuvant management for GAC. A significant prognostic nomogram for predicting the respective disease-specific survival (DSS) rates of GAC patients who receive surgery and chemotherapy has not been established. We were planning to establish a survival nomogram model for GAC patients who receive surgery and chemotherapy. We identified 5764 GAC patients who had received surgery and chemotherapy from the record of Surveillance, Epidemiology, and End Results (SEER) database. About 70% (n = 4034) of the chosen GAC patients were randomly assigned to the training set, and the rest of the included ones (n = 1729) were assigned to the external validation set. A prognostic nomogram was constructed by the training set and the predictive accuracy of it was validated by the validation set. Based on the outcome of a multivariate analysis of candidate factors, a nomogram was developed that encompassed age at diagnosis, number of regional lymph nodes examined after surgery, number of positive regional lymph nodes, sex, race, grade, derived AJCC stage, summary stage, and radiotherapy status. The C-index (Harrell’s concordance index) of the nomogram model was some larger than that of the traditional seventh AJCC staging system (0.707 vs 0.661). Calibration plots of the constructed nomogram displayed that the probability of DSS commendably accord with the survival rate. Integrated discrimination improvement (IDI) revealed obvious increase and categorical net reclassification improvement (NRI) showed visible enhancement. IDI for 3-, 5- and 10- year DSS were 0.058, 0.059 and 0.058, respectively (P > 0.05), and NRI for 3-, 5- and 10- year DSS were 0.380 (95% CI = 0.316–0.470), 0.407 (95% CI = 0.350–0.505), and 0.413 (95% CI = 0.336–0.519), respectively. Decision curve analysis (DCA) proved that the constructed nomogram was preferable to the AJCC staging system. The constructed nomogram supplies more credible DSS predictions for GAC patients who receive surgery and chemotherapy in the general population. According to validation, the new nomogram will be beneficial in facilitating individualized survival predictions and useful when performing clinical decision-making for GAC patients who receive surgery and chemotherapy.

    更新日期:2020-01-06
  • Complete blood count-based inflammatory score (CBCS) is a novel prognostic marker for gastric cancer patients after curative resection
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Jian-Xian Lin; Jun-Peng Lin; Jian-Wei Xie; Jia-bin Wang; Jun Lu; Qi-Yue Chen; Long-long Cao; Mi Lin; Ruhong Tu; Chao-Hui Zheng; Chang-Ming Huang; Ping Li

    We sought to investigate the prognostic value of complete blood count (CBC)-based biomarkers for patients with resectable gastric cancer (GC). Patients with GC who underwent primary surgical resection between December 2008 and December 2013 were included. The estimated area under the curve (AUC) and multivariate Cox regression models were used to identify the best CBC-based biomarker. Time-dependent receiver operating characteristic (t-ROC) curve analysis was used to predict overall survival and compare the prognostic impact. In the 1810 patients analyzed, the median follow-up period was 51.0 months (range 1–101 months). Based on multivariate analysis, the lymphocyte-monocyte ratio (LMR) and hemoglobin (Hb) level were independent prognostic factors (both P < 0.05). Based on the LMR and Hb level, we established the CBC-based inflammatory score (CBCS). A higher CBCS was associated with older age, female sex, higher American Society of Anesthesiologists (ASA) score, proximal tumor location, larger tumor size, later stage and vascular involvement (all P < 0.05). Univariate analyses showed that a higher CBCS was also associated with worse overall survival (OS), which was consistent in each stage (all P < 0.05). Multivariate analysis revealed that the CBCS was a significant independent biomarker (P < 0.05). The AUC for the CBCS (0.627) was significantly higher than the AUCs for the LMR (0.573) and Hb level (0.605) (both P < 0.05). Furthermore, the t-ROC curve of the CBCS was superior to that of the prognostic nutritional index (PNI), systemic immune-inflammation index (SII), modified Glasgow prognostic score (mGPS) and C-reactive protein/albumin ratio (CRP/Alb) throughout the observation period. The preoperative LMR and Hb level were optimal CBC-based biomarkers for predicting OS in GC patients after curative resection. Based on the LMR and Hb, we developed a novel and easily obtainable prognostic score called the CBCS, which may improve the prediction of clinical outcomes.

    更新日期:2020-01-06
  • Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Simon Schallenberg; Julian Bork; Ahlem Essakly; Hakan Alakus; Reinhard Buettner; Axel M. Hillmer; Christiane Bruns; Wolfgang Schroeder; Thomas Zander; Heike Loeser; Florian Gebauer; Alexander Quaas

    The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%. ARID1A is the most frequently mutated subunit gene. Almost nothing is known about the other familiar members of the SWI/SNF complexes, SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1), in oesophageal adenocarcinoma (EAC). We analysed a large cohort of 685 patients with EAC. We used four different antibodies to detect a loss-of-protein of ARID1A BRM, BRG1 and INI1 by immunohistochemistry and correlated these findings with molecular and clinical data. Loss of ARID1A, BRG1, BRM and INI1 was observed in 10.4, 3.4, 9.9 and 2% of EAC. We found a co-existing protein loss of ARID1A and BRM in 9.9% and of ARID1A and BRG1 in 2.2%. Patients with loss of ARID1A and TP53 wildtype EACs showed a shortened overall survival compared with AIRDA1A-positive tumours [median overall survival was 60.1 months (95%CI 1.2–139.9 months)] in patients with ARIDA-1A expression and 26.2 months (95%CI 3.7–19.1 months) in cases of ARIDA-1A loss (p = 0.044). Tumours with loss or expression of ARID1A and TP53 loss were not associated with a difference in survival. Only one tumour revealed high microsatellite instability (MSI-H) with concomitant ARID1A loss. All other ARID1A loss-EACs were microsatellite-stable (MSS). No predictive relevance was seen for SWI/SNF-complex alterations and simultaneous amplification of different genes (PIK3CA, KRAS, c-MYC, MET, GATA6, ERBB2). Our work describes, for the first time, loss of one of the SWI/SNF ATPase subunit proteins in a large number of adenocarcinomas of the oesophagus. Several papers discuss possible therapeutic interventions for tumours showing a loss of function of the SWI/SNF complex, such as PARP inhibitors or PI3K and AKT inhibitors. Future studies will be needed to show whether SWI/SNF complex-deficient EACs may benefit from personalized therapy.

    更新日期:2020-01-06
  • Fast growing angiosarcoma of the right atrium after radiofrequency catheter ablation: a missed diagnosis or misdiagnosis case report
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Yi Yu; Qunshan Wang; Jian Sun; Jing Zhao; Suyun Chen; Yigang Li

    Primary angiosarcomas of the right atrium are extremely rare, often resulted in missed diagnosis or misdiagnosis with routine examination tools. These malignant cardiac tumors are highly aggressive with generally poor prognosis. Surgical excision is the mainstay of treatment as it is essentially not responsive to current regimens of chemoradiotherapy. Herein, we describe a patient who initially presented with paroxysmal atrial fibrillation and was subsequently treated with radiofrequency catheter ablation (RFCA). Prior to RFCA, an initial transesophageal echocardiography revealed a local thickening of the intratrial septum. Three months later, she was hospitalized with progressive dyspnea and massive pericardial effusion. A large immobile, non-pedunculated mass, occupying almost half of the right atrium was detected by transthoracic and transesophageal echocardiogram. Multimodality cardiac imaging was useful in further characterizing this mass, which was ultimately diagnosed as an angiosarcoma based upon biopsy results. The growth rate was extremely rapid following RFCA, and patient underwent surgical excision. After discharge, the angiosarcoma recurred and patient survived for 7 months from the first episode of tamponade. Primary cardiac angiosarcoma of the right atrium can easily be mistaken for structural anomalies in its early stages, losing the opportunity for initiating earlier treatments to improve potential patient outcomes. The correct diagnosis of this rare case relied on the comprehensive utilization of multimodal imaging techniques including biopsy.

    更新日期:2020-01-06
  • Crizotinib-induced osteitis mimicking bone metastasis in a stage IV ALK-rearranged NSCLC patient: a case report
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    F. Guisier; N. Piton; M. Bellefleur; N. Delberghe; G. Avenel; E. Angot; O. Vittecoq; M. Ould-Slimane; H. Morisse-Pradier; M. Salaun; L. Thiberville

    Targeted therapies are a standard of care for first-line treatment of Anaplastic lymphoma kinase (ALK)-rearranged non small cell lung cancer (NSCLC). Giving the rapid pace of drug discovery and development in this area, reporting of adverse effects of ALK inhibitors is crucial. Here, we report a case of osteitis induced by an ALK inhibitor mimicking bone metastasis, a previously undescribed side effect of crizotinib. A 31-year-old woman with stage IV ALK-rearranged NSCLC presented with back pain after 3 months of crizotinib treatment. Diagnostic work-up showed osteitis on the 4th and 5th thoracic vertebrae, anterior soft tissue infiltration and epiduritis, without any sign of infection. Spinal cord decompression, histological removal and osteosynthesis were performed. Histologic examination showed necrosis with abundant peripheral neutrophils, no microorganism nor malignant cell. Symptoms and Computarized Tomography-abnormalities rapidly diseappeared after crizotinib withdrawal and did not recur after ceritinib onset. This is the first report of crizotinib-induced osteitis. Crizotinib differs from other ALK inhibitors as it targets other kinases as well, which may have been responsible for the osteitis. Crizotinib can induce rapidly extensive osteitis, which can mimic tumor progression.

    更新日期:2020-01-06
  • Increased levels of XPA might be the basis of cisplatin resistance in germ cell tumours
    BMC Cancer (IF 3.288) Pub Date : 2020-01-06
    Zuzana Cierna; Vera Miskovska; Jan Roska; Dana Jurkovicova; Lucia Borszekova Pulzova; Zuzana Sestakova; Lenka Hurbanova; Katarina Machalekova; Michal Chovanec; Katarina Rejlekova; Daniela Svetlovska; Katarina Kalavska; Karol Kajo; Pavel Babal; Jozef Mardiak; Thomas A. Ward; Michal Mego; Miroslav Chovanec

    Germ cell tumours (GCTs) represent a highly curable malignity as they respond well to cisplatin (CDDP)-based chemotherapy. Nevertheless, a small proportion of GCT patients relapse or do not respond to therapy. As this might be caused by an increased capacity to repair CDDP-induced DNA damage, identification of DNA repair biomarkers predicting inadequate or aberrant response to CDDP, and thus poor prognosis for GCT patients, poses a challenge. The objective of this study is to examine the expression levels of the key nucleotide excision repair (NER) factors, XPA, ERCC1 and XPF, in GCT patients and cell lines. Two hundred seven GCT patients’ specimens with sufficient follow-up clinical-pathological data and pairwise combinations of CDDP-resistant and -sensitive GCT cell lines were included. Immunohistochemistry was used to detect the ERCC1, XPF and XPA protein expression levels in GCT patients’ specimen and Western blot and qRT-PCR examined the protein and mRNA expression levels in GCT cell lines. GCT patients with low XPA expression had significantly better overall survival than patients with high expression (hazard ratio = 0.38, 95% confidence interval: 0.12–1.23, p = 0.0228). In addition, XPA expression was increased in the non-seminomatous histological subtype, IGCCCG poor prognosis group, increasing S stage, as well as the presence of lung, liver and non-pulmonary visceral metastases. Importantly, a correlation between inadequate or aberrant CDDP response and XPA expression found in GCT patients was also seen in GCT cell lines. XPA expression is an additional independent prognostic biomarker for stratifying GCT patients, allowing for improvements in decision-making on treatment for those at high risk of refractoriness or relapse. In addition, it could represent a novel therapeutic target in GCTs.

    更新日期:2020-01-06
  • Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas
    BMC Cancer (IF 3.288) Pub Date : 2020-01-03
    Julio Enríquez Pérez; Jan Kopecky; Edward Visse; Anna Darabi; Peter Siesjö

    Glioblastomas (GBM) are therapy-resistant tumors with a profoundly immunosuppressive tumor microenvironment. Chemotherapy has shown limited efficacy against GBM. Systemic delivery of chemotherapeutic drugs is hampered by the difficulty of achieving intratumoral levels as systemic toxicity is a dose-limiting factor. Although some of its effects might be mediated by immune reactivity, systemic chemotherapy can also inhibit induced or spontaneous antitumor immune reactivity. Convection-enhanced delivery of temozolomide (CED-TMZ) can tentatively increase intratumoral drug concentration while reducing systemic side effects. The objective of this study was to evaluate the therapeutic effect of intratumorally delivered temozolomide in combination with immunotherapy and whether such therapy can generate a cellular antitumor immune response. Single bolus intratumoral injection and 3-day mini-osmotic pumps (Alzet®) were used to deliver intratumoral TMZ in C57BL6 mice bearing orthotopic gliomas. Immunotherapy consisted of subcutaneous injections of irradiated GL261 or KR158 glioma cells. Tumor size and intratumoral immune cell populations were analyzed by immunohistochemistry. Combined CED-TMZ and immunotherapy had a synergistic antitumor effect in the GL261 model, compared to CED-TMZ or immunotherapy as monotherapies. In the KR158 model, immunization cured a small proportion of the mice whereas addition of CED-TMZ did not have a synergistic effect. However, CED-TMZ as monotherapy prolonged the median survival. Moreover, TMZ bolus injection in the GL261 model induced neurotoxicity and lower cure rate than its equivalent dose delivered by CED. In addition, we found that T-cells were the predominant cells responsible for the TMZ antitumor effect in the GL261 model. Finally, CED-TMZ combined with immunotherapy significantly reduced tumor volume and increased the intratumoral influx of T-cells in both models. We show that immunotherapy synergized with CED-TMZ in the GL261 model and cured animals in the KR158 model. Single bolus administration of TMZ was effective with a narrower therapeutic window than CED-TMZ. Combined CED-TMZ and immunotherapy led to an increase in the intratumoral influx of T-cells. These results form part of the basis for the translation of the therapy to patients with GBM but the dosing and timing of delivery will have to be explored in depth both experimentally and clinically.

    更新日期:2020-01-04
  • Radiation therapy before radical cystectomy combined with immunotherapy in locally advanced bladder cancer – study protocol of a prospective, single arm, multicenter phase II trial (RACE IT)
    BMC Cancer (IF 3.288) Pub Date : 2020-01-03
    Sebastian C. Schmid; Florestan J. Koll; Claus Rödel; Philipp Maisch; Andreas Sauter; Franziska Beckert; Anna Seitz; Hubert Kübler; Michael Flentje; Felix Chun; Stephanie E. Combs; Kilian Schiller; Jürgen E. Gschwend; Margitta Retz

    Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer. Study design: “RACE IT” (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb. Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11–15. Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15. Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up). Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy. Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy. Planned sample size: 33 patients, interim analysis after 11 patients. This trial aims to evaluate the safety and feasibility of the combined approach of preoperative PD-1 checkpoint-inhibitor therapy with concomitant radiation of bladder and pelvic region followed by radical cystectomy. The secondary objectives of therapy response and survival are thought to provide preliminary data for further clinical evaluation after successful completion of this trial. Recruitment has started in February 2019. Protocol Code RACE IT: AB 65/18; EudraCT: 2018–001823-38; Clinicaltrials.gov: NCT03529890; Date of registration: 27 June 2018.

    更新日期:2020-01-04
  • Loss of Stag2 cooperates with EWS-FLI1 to transform murine Mesenchymal stem cells
    BMC Cancer (IF 3.288) Pub Date : 2020-01-02
    Marc El Beaino; Jiayong Liu; Amanda R. Wasylishen; Rasoul Pourebrahim; Agata Migut; Bryan J. Bessellieu; Ke Huang; Patrick P. Lin

    Ewing sarcoma is a malignancy of primitive cells, possibly of mesenchymal origin. It is probable that genetic perturbations other than EWS-FLI1 cooperate with it to produce the tumor. Sequencing studies identified STAG2 mutations in approximately 15% of cases in humans. In the present study, we hypothesize that loss of Stag2 cooperates with EWS-FLI1 in generating sarcomas derived from murine mesenchymal stem cells (MSCs). Mice bearing an inducible EWS-FLI1 transgene were crossed to p53−/− mice in pure C57/Bl6 background. MSCs were derived from the bone marrow of the mice. EWS-FLI1 induction and Stag2 knockdown were achieved in vitro by adenovirus-Cre and shRNA-bearing pGIPZ lentiviral infection, respectively. The cells were then treated with ionizing radiation to 10 Gy. Anchorage independent growth in vitro was assessed by soft agar assays. Cellular migration and invasion were evaluated by transwell assays. Cells were injected with Matrigel intramuscularly into C57/Bl6 mice to test for tumor formation. Primary murine MSCs with the genotype EWS-FLI1 p53−/− were resistant to transformation and did not form tumors in syngeneic mice without irradiation. Stag2 inhibition increased the efficiency and speed of sarcoma formation significantly in irradiated EWS-FLI1 p53−/− MSCs. The efficiency of tumor formation was 91% for cells in mice injected with Stag2-repressed cells and 22% for mice receiving cells without Stag2 inhibition (p < .001). Stag2 knockdown reduced survival of mice in Kaplan-Meier analysis (p < .001). It also increased MSC migration and invasion in vitro but did not affect proliferation rate or aneuploidy. Loss of Stag2 has a synergistic effect with EWS-FLI1 in the production of sarcomas from murine MSCs, but the mechanism may not relate to increased proliferation or chromosomal instability. Primary murine MSCs are resistant to transformation, and the combination of p53 null mutation, EWS-FLI1, and Stag2 inhibition does not confer immediate conversion of MSCs to sarcomas. Irradiation is necessary in this model, suggesting that perturbations of other genes beside Stag2 and p53 are likely to be essential in the development of EWS-FLI1-driven sarcomas from MSCs.

    更新日期:2020-01-02
  • Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling
    BMC Cancer (IF 3.288) Pub Date : 2020-01-02
    Pradip Shahi Thakuri; Megha Gupta; Sunil Singh; Ramila Joshi; Eric Glasgow; Alexander Lekan; Seema Agarwal; Gary D. Luker; Hossein Tavana

    Cell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs. We used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis. Fisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells. We established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.

    更新日期:2020-01-02
  • TP53 and PTEN mutations were shared in concurrent germ cell tumor and acute megakaryoblastic leukemia
    BMC Cancer (IF 3.288) Pub Date : 2020-01-02
    Keiichi Akizuki; Masaaki Sekine; Yasunori Kogure; Takuro Kameda; Kotaro Shide; Junji Koya; Ayako Kamiunten; Yoko Kubuki; Yuki Tahira; Tomonori Hidaka; Takumi Kiwaki; Hiroyuki Tanaka; Yuichiro Sato; Hiroaki Kataoka; Keisuke Kataoka; Kazuya Shimoda

    The occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Due to its rarity, there have been only two reports of the concurrent cases undergoing detailed genetic analysis with whole-exome sequencing (WES), and the possible clonal relationship between the both tumors remained not fully elucidated. We performed whole-exome sequencing analysis of mediastinal GCT and acute myeloid leukemia (AML) samples obtained from one young Japanese male adult patient with concurrent both tumors, and investigated the possible clonal relationship between them. Sixteen somatic mutations were detected in the mediastinal GCT sample and 18 somatic mutations in the AML sample. Mutations in nine genes, including TP53 and PTEN both known as tumor suppressor genes, were shared in both tumors. All in our case and in the previous two cases with concurrent mediastinal GCT and AML undergoing with whole-exome sequencing analysis, TP53 and PTEN mutations were commonly shared in both tumors. These data not only suggest that these tumors share a common founding clone, but also indicate that associated mediastinal GCT and AML harboring TP53 and PTEN mutations represent a unique biological entity.

    更新日期:2020-01-02
  • Diagnostic value of plasma HSP90α levels for detection of hepatocellular carcinoma
    BMC Cancer (IF 3.288) Pub Date : 2020-01-02
    Wene Wei; Mengshu Liu; Shufang Ning; Jing Wei; Jianhong Zhong; Jilin Li; Zhengmin Cai; Litu Zhang

    Hepatocellular carcinoma (HCC) is a major health problem worldwide. However, the popular tumor marker, AFP, lacks sensitivity although its specificity is high. Tissue biopsy is an invasive operation and may increase the risk of needle-track metastases. Heat shock protein 90 (HSP90) is a potential biomarker for tumor diagnosis and prognosis. This study aims to determine whether levels of plasma HSP90α in HCC patients can be used as a cost-effective and simple test for the initial diagnosis of the disease. Plasma samples were collected from 659 HCC patients, 114 secondary hepatic carcinoma (SHC) patients, 28 hepatic hemangioma patients and 230 healthy donors. The levels of HSP90α were measured by ELISA. The levels of plasma HSP90α in HCC patients were significantly higher than in healthy donors and in patients with hepatic hemangioma or SHC (144.08 ± 4.98, 46.81 ± 1.11, 61.56 ± 8.20 and 111.96 ± 10.08 ng/mL, respectively; p < 0.05 in all cases). The levels were associated with age (p = 0.001), BCLC stage (p < 0.001), levels of AFP (p < 0.001), tumor size (p < 0.001), tumor number (p < 0.001), PVTT (p < 0.001), EHM (p < 0.001) and Child-Pugh stage in the HCC cohort. In addition, the levels of plasma HSP90α showed an upward trend along with the progression of the BCLC stage. ROC curve analysis showed that compared to AFP (AUC 0.922, 95%CI 0.902–0.938) or HSP90α (AUC 0.836, 95%CI 0.810–0.860), the combination of HSP90α and AFP (AUC0.943, 95%CI 0.925–0.957) significantly improved the diagnostic efficiency for HCC patients. The results suggest that plasma Hsp90 α levels can be used as an initial diagnosis for patients with HCC in both rural and cosmopolitan settings.

    更新日期:2020-01-02
  • A novel Bcl-2 inhibitor, BM-1197, induces apoptosis in malignant lymphoma cells through the endogenous apoptotic pathway
    BMC Cancer (IF 3.288) Pub Date : 2019-12-31
    Yue-Li Sun; Wen-Qi Jiang; Qiu-Yun Luo; Da-Jun Yang; Yu-Chen Cai; Hui-Qiang Huang; Jian Sun

    Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family proteins may be a new strategy for the treatment of malignant lymphoma. In this study, we investigate the antitumor effect and cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, in DCBCL and Burkitt lymphoma cells. The CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using a caspase-3/caspase-9 activity kit. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells that harbor high expression of Bcl-2 and Bcl-xL in vitro and has a synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interactions of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, and PUMA/Bcl-2 and induces conformational changes in the Bax protein, which result in the activation of Bax and release of cytochrome c, activate caspase − 9, − 3, and − 7 and finally induce cell apoptosis. Furthermore, our data demonstrate that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo and provides promising preclinical data for the further development of BM-1197 in malignant lymphoma.

    更新日期:2020-01-01
  • Administration of nimotuzumab combined with cisplatin plus 5-fluorouracil as induction therapy improves treatment response and tolerance in patients with locally advanced nasopharyngeal carcinoma receiving concurrent radiochemotherapy: a multicenter randomized controlled study
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Ying Lu; Dagui Chen; Jinhui Liang; Jianquan Gao; Zhanxiong Luo; Rensheng Wang; Wenqi Liu; Changjie Huang; Xuejian Ning; Meilian Liu; Haixin Huang

    Nimotuzumab (NTZ) is an anti-EGFR monoclonal antibody. However,the effect of targeted drugs combined with induction therapy in locally advanced nasopharyngeal carcinoma remains unclear. The aim of this study is to investigate the safety and efficacy of NTZ combined with cisplatin plus 5-fluorouracil (PF) as induction regimen in locally advanced nasopharyngeal carcinoma (NPC) patients receiving concurrent radiochemotherapy. This was a multicenter randomized controlled study performed in eight Guangxi hospitals in 2015–2017. Eligible patients with NPC were randomized into nimotuzumab/PF (NPF group) and docetaxel/PF (DPF group) regimens, respectively, as induction therapy. After 2 cycles of induction therapy, all patients received cisplatin and concurrent intensity modulated radiation therapy (IMRT). Then, the two groups were compared for safety and efficacy. A total of 118 patients with stage III-IVa NPC were assessed, with 58 and 60 in the NPF and DPF groups, respectively. Compared with DPF treatment, NPF induction therapy showed a more pronounced effect on cervical lymph nodes (P = 0.036), with higher response rate (RR) (81% vs 60%). Compared with the DPF group, the NPF group showed significantly reduced leukopenia, neutropenia and gastrointestinal reactions (all P < 0.05); rash only appeared in the NPF group, but all cases were grade 1. During concurrent treatment with radiotherapy and chemotherapy, the NPF group showed better tolerance to radiotherapy and chemotherapy; neutropenia, anemia, gastrointestinal reactions, oral mucositis and radiation dermatitis in the NPF group were significantly reduced (P < 0.05). The expression rate of EGFR was 94.9% (112/118). Compared with the DPF group, patients with EGFR expression in the NPF group showed better response (77.8% vs 63.0%, P = 0.033). For locally advanced NPC patients receiving follow-up cisplatin and IMRT, nimotuzumab/PF for induction therapy has better lymph node response rate and milder adverse reactions than the DPF regimen. In addition, the patients have better tolerance in subsequent concurrent radiotherapy and chemotherapy; however, long-term efficacy needs further follow-up evaluation. The registration number of the clinical trial is ChiCTR-OIC-16008201 and retrospectively registered on March 31, 2016.

    更新日期:2019-12-31
  • Risk of ischemic stroke in patients with prostate cancer receiving androgen deprivation therapy in Taiwan
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Kuang-Ming Liao; Yaw-Bin Huang; Chung-Yu Chen; Chen-Chun Kuo

    Androgen deprivation therapy (ADT) in the treatment of prostate cancer may be associated with an increased risk of thromboembolic disease. The aim of our study was to investigate the association of ADT in the treatment of prostate cancer with ischemic stroke risk. We identified individuals older than 20 years of age who were newly diagnosed with prostate cancer between January 1, 2005, and December 31, 2012. Patients who experienced ischemic stroke or transient ischemic stroke before the index date were excluded. Patients who received at least one prescription for ADT within 6 months were defined as the ADT user group. Patients who did not receive at least one prescription for ADT within 6 months were defined as the ADT nonuser group. The patients were followed until the first occurrence of one of the primary outcome measures (ischemic stroke or death) or until December 31, 2013. The primary composite outcome was the time to any cause of death or ischemic stroke. There was no significant difference in the primary composite outcomes in the prostate cancer patients between the ADT user and nonuser groups. Prostate cancer patients who received ADT had a higher mortality rate than those who were not treated with ADT, and the adjusted hazard ratio was 1.907 (95% confidence interval: 1.278–2.844; P = 0.0016) after adjusting for age, comorbidities and comedication use. ADT in the treatment of prostate cancer may not be associated with an increased risk of ischemic stroke. The differences in thromboembolic effects in cardiovascular disease and ischemic stroke secondary to ADT should be further discussed and evaluated prospectively.

    更新日期:2019-12-31
  • TOPK promotes metastasis of esophageal squamous cell carcinoma by activating the Src/GSK3β/STAT3 signaling pathway via γ-catenin
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Yanan Jiang; Jing Zhang; Jimin Zhao; Zhenzhen Li; Hanyong Chen; Yan Qiao; Xinhuan Chen; Kangdong Liu; Ziming Dong

    Esophageal squamous cell carcinoma (ESCC) is a fatal disease with poor prognosis. The predominant reason for ESCC-related death is distal metastasis. A comprehensive understanding of the molecular mechanism underlying metastasis is needed for improving patient prognosis. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase, which plays a vital role in various physiological and pathophysiological processes. However, the role of TOPK in ESCC metastasis is unclear. Tissue array was used to evaluate the correlation between TOPK expression and ESCC lymph node metastasis. Wound healing assay, transwell assay, and lung metastasis mice model were used to examine the role of TOPK in the migration of ESCC cells in vitro and in vivo. Protein kinase array, mass spectrometry (MS), and molecular modeling were used to examine the pathways and direct target proteins of TOPK that are involved in ESCC metastasis. Additionally, immunofluorescence and western blotting analyses were performed to verify these findings. The enhanced expression of TOPK was correlated with lymph node metastasis in the ESCC tissues. TOPK knockdown or treatment with the TOPK inhibitor (HI-TOPK-032) decreased the invasion and migration of ESCC cells in vitro. HI-TOPK-032 also inhibited the lung metastasis in ESCC cell xenograft in vivo model. Moreover, TOPK promoted the invasion of ESCC cells by activating the Src/GSK3β/STAT3 and ERK signaling pathways via γ-catenin. The findings of this study reveal that TOPK is involved in ESCC metastasis and promoted the ESCC cell mobility by activating the Src/GSK3β/STAT3 and ERK signaling pathways. This indicated that TOPK may be a potential molecular therapeutic target for ESCC metastasis.

    更新日期:2019-12-31
  • Occurrence of paratesticular ganglioneuroma 18 years after concurrent adrenal ganglioneuroma and papillary thyroid carcinoma – a case report
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Chu-Wen Fang; Jyh-Seng Wang; Tony T. Wu; Jen-Tai Lin

    Ganglioneuromas (GNs) are composed of mature ganglion cells and Schwann cells with a fibrous stroma; GNs are most often observed in children and young adults. The majority of non-cranial GNs are located in the retroperitoneum and posterior mediastinum. Other reported rare sites include the adrenal gland, small intestine, colon and urinary bladder. However, para-testicular GNs are even more rare. Herein, we report the case of a patient with concurrent adrenal GN and thyroid papillary carcinoma who developed paratesticular GN eighteen years later. We conclude that there is an association among papillary thyroid carcinoma, GN and MEN2 syndromes. This case report may provide important information for the proposed association. However, further studies are required.

    更新日期:2019-12-31
  • Gene signature characteristic of elevated stromal infiltration and activation is associated with increased risk of hematogenous and lymphatic metastasis in serous ovarian cancer
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Huiran Yue; Jieyu Wang; Ruifang Chen; Xiaoman Hou; Jun Li; Xin Lu

    The clinical significance of hematogenous and lymphatic metastasis in ovarian cancer has been increasingly addressed, as it plays an imperative role in the formation of both intraperitoneal and distant metastases. Our objective is to identify the key molecules and biological processes potentially related to this relatively novel metastatic route in serous ovarian cancer. Since lymphovascular space invasion (LVSI) is considered as the first step of hematogenous and lymphatic dissemination, we developed a gene signature mainly based on the transcriptome profiles with available information on LVSI status in the Cancer Genome Atlas (TCGA) dataset. We then explored the underlying biological rationale and prognostic value of the identified gene signature using multiple public databases. We observe that primary tumors with increased risk of hematogenous and lymphatic metastasis highly express a panel of genes, namely POSTN, LUM, THBS2, COL3A1, COL5A1, COL5A2, FAP1 and FBN1. The identified geneset is characterized by enhanced deposition of extracellular matrix and extensive stromal activation. Mechanistically, both the recruitment and the activation of stromal cells, especially fibroblasts, are closely associated with lymphovascular metastasis. Survival analysis further reveals that the elevated expression of the identified genes correlates to cancer progression and poor prognosis in patients with serous ovarian cancer. Our findings indicate that tumor stroma supports the hematogenous and lymphatic spread of ovarian cancer, increasing tumor invasiveness and ultimately resulting in worse survival. Thus stroma-targeted therapies may improve the clinical outcomes in combination with cytoreductive surgery and chemotherapy.

    更新日期:2019-12-31
  • Androgen receptor and FOXA1 coexpression define a “luminal-AR” subtype of feline mammary carcinomas, spontaneous models of breast cancer
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Elie Dagher; Violette Royer; Paul Buchet; Jérôme Abadie; Delphine Loussouarn; Mario Campone; Frédérique Nguyen

    Invasive mammary carcinomas that spontaneously develop in female cats are associated with high mortality, and resemble the most aggressive human breast cancers, especially triple-negative breast cancer (TNBC). Transcriptome studies showed that TNBCs are a heterogeneous group that includes a potentially hormone-dependent subtype named luminal-AR. Some authors proposed an immunohistochemical definition of the luminal-AR subtype, which is not only positive for Androgen Receptor (AR), but also either positive for the transcription factor Forkhead box A1 (FOXA1), or negative for basal markers. The objectives of this study were to describe AR and FOXA1 expressions in feline mammary carcinomas (FMCs), their prognostic value, and if their coexpression could define a “luminal-AR” subtype of triple-negative mammary carcinomas in cats. In a previously described retrospective cohort of 180 female cats with FMCs, with a 2-year follow-up post-mastectomy, we assessed AR, FOXA1, ER, PR, Ki-67, HER2, and CK14 expressions by automated immunohistochemistry. Of the 180 FMCs, 57 (32%) were luminal; i.e., ER and/or PR positive, and 123 (68%) were triple-negative (ER–, PR– and HER2–) FMCs. AR overexpression (found in 33 cases/180, 18%) and FOXA1 index ≥1% (64/180, 36%) were associated with a longer disease-free interval, overall survival, and cancer-specific survival in cats with FMC. Analysis of AR, FOXA1 and CK14 coexpression in triple-negative FMCs showed that AR+ triple-negative FMCs were heterogeneous: there existed an AR+ FOXA1+ CK14– subgroup (n = 7) associated with a better cancer-specific survival by multivariate survival analysis (HR = 0.26, 95% CI: 0.07–0.89, p = 0.03) compared to AR+ FOXA1–CK14+ triple-negative FMCs (n = 46) (HR = 1.00), independently of the pathologic tumor size and pathologic nodal stage. The non-basal-like subtype of triple-negative FMCs that coexpresses AR and FOXA1 (the AR+ FOXA1+ CK14– subgroup) could represent the equivalent of the luminal-AR subgroup of human triple-negative breast cancer. We identified an AR+ FOXA1+ CK14– subgroup of triple-negative FMCs that might correspond to the luminal-AR subgroup of human triple-negative breast cancers. Cats with FMC may be interesting spontaneous animal models to investigate new strategies targeting the androgen receptor, especially in the aggressive subtype of AR+ basal-like triple-negative mammary carcinomas with loss of FOXA1 expression (the AR+ FOXA1–CK14+ subgroup).

    更新日期:2019-12-31
  • Impact of dexamethasone-sparing regimens on delayed nausea caused by moderately or highly emetogenic chemotherapy: a meta-analysis of randomised evidence
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Luigi Celio; Erminio Bonizzoni; Emma Zattarin; Paolo Codega; Filippo de Braud; Matti Aapro

    Nausea can be particularly prominent during the delayed period. Therefore, we performed a meta-analysis of the available randomised evidence to assess the average effect of palonosetron plus one-day dexamethasone (DEX; also called the DEX-sparing strategy) compared with palonosetron plus 3-day DEX for control of chemotherapy-induced nausea and vomiting (CINV), focusing on delayed nausea. Eligible studies were identified through MEDLINE, Embase, and CENTRAL. Data on acute and delayed CINV were collected. Efficacy end points were complete response (CR; no vomiting, and no use of rescue medication), complete protection (CP; CR plus no clinically significant nausea), and total control (TC; CR plus no nausea) during the delayed period (days 2–5 after chemotherapy initiation). All randomised studies comparing palonosetron plus single-dose DEX (with or without another active agent) on day 1 followed by either no further DEX or additional DEX doses (both alone or in combination with another active agent) qualified. Of 864 citations screened, 8 studies with 1970 patients were included in the meta-analysis. During the delayed period, the combined odds ratio (OR) for all comparisons was 0.92 (95% confidence interval [CI], 0.76–1.12) for CR, 0.85 (95% CI, 0.71–1.03) for CP, and 0.92 (95% CI, 0.77–1.11) for TC in patients undergoing moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide-containing chemotherapy (AC). The absolute risk difference (RD) computations for all end points in the delayed period did not exceed the threshold of − 4% (range, − 1% to − 4%). The effect was similar in subgroups defined by various study design parameters. The absolute RD computations in the acute period did not exceed the threshold of 1% (range, 0 to 1%). For one-day vs. 3-day DEX, numbers needed to be treated in order for one additional patient to not experience CR, CP and TC over the delayed period were 100, 25 and 50, respectively. This meta-analysis demonstrates that DEX-sparing regimens do not cause any significant loss in protection against not only vomiting but also nausea induced by single-day MEC or AC during the delayed period. These data should lead clinicians to optimise use of prophylactic DEX in clinical practice.

    更新日期:2019-12-31
  • Elucidating the expression and function of Numbl during cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma (MM)
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Yuejiao Huang; Xianting Huang; Chun Cheng; Xiaohong Xu; Hong Liu; Xiaojing Yang; Li Yao; Zongmei Ding; Jie Tang; Song He; Yuchan Wang

    Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin β1 and its sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development. Development of an adhesion model of established MM cell lines and detection of Numbl and Integrinβ1 expression by Western Blot analysis. The interaction between Numbl and Integrinβ1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis. Our preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin β1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin β1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin β1 promotes the formation of CAM-DR in MM cells. Our findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.

    更新日期:2019-12-31
  • Reliable cell and tissue morphology-based diagnosis of endemic Burkitt lymphoma in resource-constrained settings in Ghana
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Cecilia Smith-Togobo; Mette Ø. Pedersen; Steffen G. Jensen; Babatunde Duduyemi; Richard K. Gyasi; Michael F. Ofori; Vivian Paintsil; Lorna Renner; Peter Nørgaard; Lars Hviid

    Endemic Burkitt lymphoma (eBL) is an aggressive B-cell lymphoma, which is a common childhood cancer in areas with intense transmission of Plasmodium falciparum parasites. Early and accurate diagnosis is a prerequisite for successful therapy, but it optimally involves advanced laboratory investigations. These are technologically demanding, expensive, and often difficult to implement in settings where eBL is prevalent. Diagnosis is thus generally based on clinical assessment and morphological examination of tumour biopsies or fine-needle aspirates (FNAs). The purpose of the present study was to assess the accuracy of eBL diagnosis at two tertiary hospitals in Ghana. To that end, we studied FNAs from 29 eBL patients and 21 non-eBL lymphoma patients originally diagnosed in 2018. In addition, we examined 111 archival formalin-fixed and paraffin-embedded (FFPE) biopsies from Ghanaian patients originally diagnosed as eBL (N = 55) or non-eBL (N = 56) between 2010 and 2017. Availability-based subsets of samples were subjected to haematoxylin-eosin or Giemsa staining, C-MYC immunohistochemistry, and fluorescence in situ hybridisation (FISH) analysis of c-myc rearrangements. We found a good correlation between original diagnosis and subsequent retrospective assessment, particularly for FNA samples. However, evidence of intact c-myc genes and normal C-MYC expression in samples from some patients originally diagnosed as eBL indicates that morphological assessment alone can lead to eBL over-diagnosis in our study area. In addition, several FFPE samples could not be assessed retrospectively, due to poor sample quality. Therefore, the simpler FNA method of obtaining tumour material is preferable, particularly when careful processing of biopsy specimens cannot be guaranteed. We conclude that the accuracy of eBL diagnostic tools available in Ghana is generally adequate, but could be improved by implementation of additional pathology laboratory investigations. Improved attention to adequate preservation of archival samples is recommended.

    更新日期:2019-12-31
  • Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Rebecca L. Glaser; Anne E. York; Constantine Dimitrakakis

    Testosterone implants have been used for over eighty years to treat symptoms of hormone deficiency in pre and postmenopausal women. Evidence supports that androgens are breast protective. However, there is a lack of data on the long-term effect of testosterone therapy on the incidence of invasive breast cancer (IBC). This study was specifically designed to investigate the incidence of IBC in pre and postmenopausal women (presenting with symptoms of androgen deficiency) treated with subcutaneous testosterone implants or testosterone implants combined with anastrozole. The 10-year prospective cohort study was approved in March 2008 at which time recruitment was initiated. Recruitment was closed March 2013. Pre and postmenopausal women receiving at least two pellet insertions were eligible for analysis (N = 1267). Breast cancer incidence rates were reported as an unadjusted, un-weighted value of newly diagnosed cases divided by the sum of ‘person-time of observation’ for the at-risk population. Incidence rates on testosterone therapy were compared to age-specific Surveillance Epidemiology and End Results (SEER) incidence rates and historical controls. Bootstrap sampling distributions were constructed to verify comparisons and tests of significance that existed between our results and SEER data. As of March 2018, a total of 11 (versus 18 expected) cases of IBC were diagnosed in patients within 240-days following their last testosterone insertion equating to an incidence rate of 165/100000 p-y, which is significantly less than the age-matched SEER expected incidence rate of 271/100000 p-y (p < 0.001) and historical controls. Long term therapy with subcutaneous testosterone, or testosterone combined with anastrozole, did not increase the incidence of IBC. Testosterone should be further investigated for hormone therapy and breast cancer prevention.

    更新日期:2019-12-31
  • Mammographic density is a potential predictive marker of pathological response after neoadjuvant chemotherapy in breast cancer
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Ida Skarping; Daniel Förnvik; Hanna Sartor; Uffe Heide-Jørgensen; Sophia Zackrisson; Signe Borgquist

    Our aim is to study if mammographic density (MD) prior to neoadjuvant chemotherapy is a predictive factor in accomplishing a pathological complete response (pCR) in neoadjuvant-treated breast cancer patients. Data on all neoadjuvant treated breast cancer patients in Southern Sweden (2005–2016) were retrospectively identified, with patient and tumor characteristics retrieved from their medical charts. Diagnostic mammograms were used to evaluate and score MD as categorized by breast composition with the Breast Imaging-Reporting and Data System (BI-RADS) 5th edition. Logistic regression was used in complete cases to assess the odds ratios (OR) for pCR compared to BI-RADS categories (a vs b-d), adjusting for patient and pre-treatment tumor characteristics. A total of 302 patients were included in the study population, of which 57 (18.9%) patients accomplished pCR following neoadjuvant chemotherapy. The number of patients in the BI-RADS category a, b, c, and d were separately 16, 120, 140, and 26, respectively. In comparison to patients with BI-RADS breast composition a, patients with denser breasts had a lower OR of accomplishing pCR: BI-RADS b 0.32 (95%CI 0.07–0.1.5), BI-RADS c 0.30 (95%CI 0.06–1.45), and BI-RADS d 0.06 (95%CI 0.01–0.56). These associations were measured with lower point estimates, but wider confidence interval, in premenopausal patients; OR of accomplishing pCR for BI-RADS d in comparison to BI-RADS a: 0.03 (95%CI 0.00–0.76). The likelihood of accomplishing pCR is indicated to be lower in breast cancer patients with higher MD, which need to be analysed in future studies for improved clinical decision-making regarding neoadjuvant treatment.

    更新日期:2019-12-31
  • In vitro activity of a G-quadruplex-stabilizing small molecule that synergizes with Navitoclax to induce cytotoxicity in acute myeloid leukemia cells
    BMC Cancer (IF 3.288) Pub Date : 2019-12-27
    Justin J. Montoya; Megan A. Turnidge; Daniel H. Wai; Apurvi R. Patel; David W. Lee; Vijay Gokhale; Laurence H. Hurley; Robert J. Arceci; Cynthia Wetmore; David O. Azorsa

    Acute Myeloid Leukemia (AML) is a malignancy of myeloid precursor cells that arise from genomic alterations in the expression of key growth regulatory genes causing cells to assume an undifferentiated state and continue to proliferate. Recent efforts have focused on developing therapies that target specific protein products of aberrantly expressed genes. However, many of the identified proteins are difficult to target and thought to be “undrugable” because of structural challenges, protein overexpression, or mutations that confer resistance to therapy. A novel technology that circumvents some of these issues is the use of small molecules that stabilize secondary DNA structures present in the promoters of many potential oncogenes and modulate their transcription. This study characterizes the in vitro activity of the G-quadruplex-stabilizing small molecule GQC-05 in AML cells. The effect of GQC-05 on three AML cell lines was analyzed using viability and apoptosis assays. GQC-05 has been shown to down-regulate MYC through G-quadruplex stabilization in Burkitt’s lymphoma cell lines. MYC expression was evaluated through qPCR and immunoblotting in the three AML cell lines following the treatment of GQC-05. In order to identify other therapeutic agents that potentiate the activity of GQC-05, combination drug screening was performed. The drug combinations were validated using in vitro cytotoxicity assays and compared to other commonly used chemotherapeutic agents. GQC-05 treatment of KG-1a, CMK and TF-1 cells decreased cell viability and resulted in increased DNA damage and apoptosis. Additionally, treatment of KG-1a, CMK and TF-1 with GQC-05 resulted in decreased expression of MYC mRNA and protein, with a more pronounced effect in KG-1a cells. Combination drug screening identified the Bcl-2/Bcl-XL inhibitor Navitoclax as a compound that potentiated GQC-05 activity. Co-treatment with GQC-05 and Navitoclax showed a synergistic decrease in cell viability of AML cells as determined by Chou-Talalay analysis, and induced more DNA damage, apoptosis, and rapid cytotoxicity. The cytotoxicity induced by GQC-05 and Navitoclax was more potent than that of Navitoclax combined with either cytarabine or doxorubicin. These results suggest that the G-quadruplex stabilizing small molecule GQC-05 induces down regulated MYC expression and DNA damage in AML cells. Treatment with both GQC-05 with a Bcl-2/Bcl-XL inhibitor Navitoclax results in increased cytotoxic activity, which is more pronounced than Navitoclax or GQC-05 alone, and more significant than Navitoclax in combination with cytarabine and doxorubicin that are currently being used clinically.

    更新日期:2019-12-30
  • Elevated expression of AGGF1 predicts poor prognosis and promotes the metastasis of colorectal cancer
    BMC Cancer (IF 3.288) Pub Date : 2019-12-27
    Xin Zhang; Huimin Sun; Wanyuan Chen; Xianglei He

    Angiogenic factor with G-patch and FHA domains 1 (AGGF1) can promote angiogenesis and increasing evidence has highlighted the important roles of AGGF1 in tumorigenesis. However, the differential expression as well as the biological functions of AGGF1 in colorectal cancer (CRC) remain to be established. The purpose of the present study is therefore to identify the effect of AGGF1 on prognosis and metastasis in CRC patients. The expression level of AGGF1 in CRC was examined by qPCR, western blot and immunohistochemistry in a tissue microarray containing 236 CRC specimens and paired normal mucosae. And the effect of AGGF1 on CRC cell malignance was investigated in our established stable AGGF1 upregulated and knockdown CRC cell lines. The expression level of AGGF1 in CRC tissue was not significantly different to that in adjacent normal mucosa at the mRNA level. However, at the protein level, AGGF1 expression in CRC tissues was significantly higher than in paired normal mucosa, which showed a clear association with TNM stage, AJCC stage, vascular invasion, and differentiation. Further, we revealed an apparent correlation between AGGF1 expression and poorer disease-free survival and overall survival of CRC patients. In addition, we discovered that AGGF1 significantly promoted CRC cell wound healing, migration, and invasion in vitro and distant metastasis in vivo. Our study demonstrates the aberrant overexpression of AGGF1 in CRC and provides a basis on which to explore the application of AGGF1 as a potential therapeutic target for CRC patients, especially for CRC patients with distant metastasis.

    更新日期:2019-12-30
  • Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer
    BMC Cancer (IF 3.288) Pub Date : 2019-12-27
    Daisuke Kotani; Yasutoshi Kuboki; Satoshi Horasawa; Asumi Kaneko; Yoshiaki Nakamura; Akihito Kawazoe; Hideaki Bando; Hiroya Taniguchi; Kohei Shitara; Takashi Kojima; Akihito Tsuji; Takayuki Yoshino

    A previous phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with heavily pretreated metastatic colorectal cancer (mCRC) showed promising activity with an acceptable toxicity profile. This retrospective study aimed to investigate the safety and efficacy of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC in clinical settings. Records of patients with mCRC refractory to standard therapies who initiated trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015 were retrospectively reviewed at our institution. Totally, 60 patients received trifluridine/tipiracil plus bevacizumab and 66 received trifluridine/tipiracil monotherapy. All patients had previously received standard chemotherapy. Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 2.3–5.1] in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI, 1.8–2.6) in the trifluridine/tipiracil monotherapy group [hazards ratio (HR) 0.69; 95% CI 0.48–0.99]. PFS rate at 16 weeks was 46.6% for the trifluridine/tipiracil plus bevacizumab group and 33.9% for the trifluridine/tipiracil monotherapy group. Although a relatively higher incidence of grade ≥ 3 neutropenia was observed in the trifluridine/tipiracil plus bevacizumab group than that in the other group (50.0% vs. 40.9%, p = 0.371), the incidence of febrile neutropenia was not high (3.3% vs. 7.8%, p = 0.444). In real-world settings, trifluridine/tipiracil plus bevacizumab prolonged PFS and helped achieve higher 16-week PFS rate compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC with manageable toxicities. Retrospectively registered.

    更新日期:2019-12-30
  • Bag-1 stimulates Bad phosphorylation through activation of Akt and Raf kinases to mediate cell survival in breast cancer
    BMC Cancer (IF 3.288) Pub Date : 2019-12-28
    Tugba Kizilboga; Emine Arzu Baskale; Jale Yildiz; Izzet Mehmet Akcay; Ebru Zemheri; Nisan Denizce Can; Can Ozden; Salih Demir; Fikret Ezberci; Gizem Dinler-Doganay

    Bag-1 (Bcl-2-associated athanogene) is a multifunctional anti-apoptotic protein frequently overexpressed in cancer. Bag-1 interacts with a variety of cellular targets including Hsp70/Hsc70 chaperones, Bcl-2, nuclear hormone receptors, Akt and Raf kinases. In this study, we investigated in detail the effects of Bag-1 on major cell survival pathways associated with breast cancer. Using immunoblot analysis, we examined Bag-1 expression profiles in tumor and normal tissues of breast cancer patients with different receptor status. We investigated the effects of Bag-1 on cell proliferation, apoptosis, Akt and Raf kinase pathways, and Bad phosphorylation by implementing ectopic expression or knockdown of Bag-1 in MCF-7, BT-474, MDA-MB-231 and MCF-10A breast cell lines. We also tested these in tumor and normal tissues from breast cancer patients. We investigated the interactions between Bag-1, Akt and Raf kinases in cell lines and tumor tissues by co-immunoprecipitation, and their subcellular localization by immunocytochemistry and immunohistochemistry. We observed that Bag-1 is overexpressed in breast tumors in all molecular subtypes, i.e., regardless of their ER, PR and Her2 expression profile. Ectopic expression of Bag-1 in breast cancer cell lines results in the activation of B-Raf, C-Raf and Akt kinases, which are also upregulated in breast tumors. Bag-1 forms complexes with B-Raf, C-Raf and Akt in breast cancer cells, enhancing their phosphorylation and activation, and ultimately leading to phosphorylation of the pro-apoptotic Bad protein at Ser112 and Ser136. This causes Bad’s re-localization to the nucleus, and inhibits apoptosis in favor of cell survival. Overall, Bad inhibition by Bag-1 through activation of Raf and Akt kinases is an effective survival and growth strategy exploited by breast cancer cells. Therefore, targeting the molecular interactions between Bag-1 and these kinases might prove an effective anticancer therapy.

    更新日期:2019-12-30
  • Correction to: Human papillomavirus type 18 oncoproteins exert their oncogenicity in esophageal and tongue squamous cell carcinoma cell lines distinctly
    BMC Cancer (IF 3.288) Pub Date : 2019-12-29
    Siaw Shi Boon; Zigui Chen; Jintao Li; Karen Y. C. Lee; Liuyang Cai; Rugang Zhong; Paul K. S. Chan

    Following publication of the original article [1], the authors reported that during the production process, Table 1 was omitted.

    更新日期:2019-12-30
  • Correction to: Prophylactic HIPEC with radical D2 gastrectomy improves survival and peritoneal recurrence rates for locally advanced gastric cancer: personal experience from a randomized case control study
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Maneesh Kumarsing Beeharry; Zheng-Lun Zhu; Wen-Tao Liu; Xue-Xin Yao; Min Yan; Zheng-Gang Zhu

    Following publication of the original article [1], the authors reported the following errors/updates.

    更新日期:2019-12-30
  • Association between ESR1, ESR2, HER2, UGT1A4, and UGT2B7 polymorphisms and breast Cancer in Jordan: a case-control study
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Laith N. AL-Eitan; Doaa M. Rababa’h; Mansour A. Alghamdi; Rame H. Khasawneh

    Breast cancer risk, development, and treatment are influenced by genetic variation in certain genes, namely those involved in cell proliferation, tumor suppression, and drug metabolism. In turn, the relevance of the aforementioned genetic variation to cancer depends on the ethnic group in question, highlighting the need for population-specific association studies. Therefore, the objective of the present study was to investigate the association between certain ESR1, ESR2, HER2, UGT1A4, and UGT2B7 single nucleotide polymorphisms and breast cancer. Blood samples were collected from 437 Jordanian-Arab breast cancer patients and healthy volunteers and subject to genotyping using the Sequenom MassARRAY® system (iPLEX GOLD). Our findings show a significant association between breast cancer and the allelic (P = 0.02486879) and genotypic (P = 0.04793066) frequencies of the ESR1 polymorphism rs3798577, a result which was confirmed in different genetic models. No other investigated polymorphism showed a significant association with breast cancer itself in Jordanian Arabs, but the Rare Hz (GG) vs Het (AG) genetic model revealed an association of the disease with the ESR1 polymorphism rs3798577. However, several associations were found between certain polymorphisms and breast cancer’s prognostic factors. This study suggests that certain polymorphisms may increase the risk of breast cancer in the Jordanian-Arab population. Future research and clinical translation could incorporate the current results in preventative breast cancer approaches tailored for Jordanian-Arab patients.

    更新日期:2019-12-30
  • Downregulated SPINK4 is associated with poor survival in colorectal cancer
    BMC Cancer (IF 3.288) Pub Date : 2019-12-30
    Xiaojie Wang; Qian Yu; Waleed M. Ghareeb; Yiyi Zhang; Xingrong Lu; Ying Huang; Shenghui Huang; Yanwu Sun; Jiayi Lin; Jin Liu; Pan Chi

    SPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown. We retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center. SPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort. We concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.

    更新日期:2019-12-30
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