Showing papers in "British Journal of Cancer in 2014"
TL;DR: Cancer-associated fibroblasts promoted aggressive phenotypes of breast cancer cells through EMT induced by paracrine TGF-β1, which might be a common mechanism for acquiring metastatic potential in Breast cancer cells with different biological characteristics.
Abstract: Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF- β signalling
482 citations
TL;DR: Recent advances in oncogenic KRAS signalling are reviewed and how these might benefit PDAC treatment in the future are discussed.
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.
450 citations
TL;DR: The DEB-TACE and the cTACE are equally effective and safe, with the only advantage of DEB -TACE being less post-procedural abdominal pain.
Abstract: Transcatheter arterial chemoembolisation (TACE) is the treatment of choice for intermediate stage hepatocellular carcinoma (HCC). Doxorubicin-loaded drug-eluting beads (DEB)-TACE is expected to improve the performance of conventional TACE (cTACE). The aim of this study was to compare DEB-TACE with cTACE in terms of time-to-tumour progression (TTP), adverse events (AEs), and 2-year survival. Patients were randomised one-to-one to undergo cTACE or DEB-TACE and followed-up for at least 2 years or until death. Transcatheter arterial chemoembolisation was repeated ‘on-demand’. We enrolled 177 patients: 89 underwent DEB-TACE and 88 cTACE. The median number of procedures was 2 in each arm, and the in-hospital stay was 3 and 4 days, respectively (P=0.323). No differences were found in local and overall tumour response. The median TTP was 9 months in both arms. The AE incidence and severity did not differ between the arms, except for post-procedural pain, more frequent and severe after cTACE (P<0.001). The 1- and 2-year survival rates were 86.2% and 56.8% after DEB-TACE and 83.5% and 55.4% after cTACE (P=0.949). Eastern Cooperative Oncology Group (ECOG), serum albumin, and tumour number independently predicted survival (P<0.05). The DEB-TACE and the cTACE are equally effective and safe, with the only advantage of DEB-TACE being less post-procedural abdominal pain.
405 citations
TL;DR: The key roles of imaging techniques and in particular the key role of MRI for an accurate investigation of tumour heterogeneity is reviewed with a particular emphasis on histogram approaches and derived methods.
Abstract: By definition, tumours are heterogeneous. They are defined by marked differences in cells, microenvironmental factors (oxygenation levels, pH, VEGF, VPF and TGF-α) metabolism, vasculature, structure and function that in turn translate into heterogeneous drug delivery and therapeutic outcome. Ways to estimate quantitatively tumour heterogeneity can improve drug discovery, treatment planning and therapeutic responses. It is therefore of paramount importance to have reliable and reproducible biomarkers of cancerous lesions' heterogeneity. During the past decade, the number of studies using histogram approaches increased drastically with various magnetic resonance imaging (MRI) techniques (DCE-MRI, DWI, SWI etc.) although information on tumour heterogeneity remains poorly exploited. This fact can be attributed to a poor knowledge of the available metrics and of their specific meaning as well as to the lack of literature references to standardised histogram methods with which surrogate markers of heterogeneity can be compared. This review highlights the current knowledge and critical advances needed to investigate and quantify tumour heterogeneity. The key role of imaging techniques and in particular the key role of MRI for an accurate investigation of tumour heterogeneity is reviewed with a particular emphasis on histogram approaches and derived methods.
386 citations
University of Cambridge1, Children's Medical Research Institute2, University of Hertfordshire3, London Research Institute4, University of Glasgow5, World Health Organization6, National Institute for Medical Research7, University College London8, National Institute for Biological Standards and Control9, Public Health England10
TL;DR: These Guidelines have been prepared to provide those new to the field and others engaged in teaching and instruction with the information necessary to increase their awareness of the problems and to enable them to deal with them effectively.
Abstract: Cell-line misidentification and contamination with microorganisms, such as mycoplasma, together with instability, both genetic and phenotypic, are among the problems that continue to affect cell culture. Many of these problems are avoidable with the necessary foresight, and these Guidelines have been prepared to provide those new to the field and others engaged in teaching and instruction with the information necessary to increase their awareness of the problems and to enable them to deal with them effectively. The Guidelines cover areas such as development, acquisition, authentication, cryopreservation, transfer of cell lines between laboratories, microbial contamination, characterisation, instability and misidentification. Advice is also given on complying with current legal and ethical requirements when deriving cell lines from human and animal tissues, the selection and maintenance of equipment and how to deal with problems that may arise.
350 citations
TL;DR: Randomised controlled trials and population-based observational research are partners in the evolution of medical evidence and provide a basis for future drug discovery.
Abstract: Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence
343 citations
TL;DR: First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC and plasma samples could be considered for mutation analysis if tumour tissue is unavailable.
Abstract: First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study
340 citations
TL;DR: Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure, observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies.
Abstract: The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have distinct biologic outcomes. Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed. Overall, 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33–83), 81.7% (n=58) had any family history of malignancy; 30% (n=21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10–23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6–15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P=0.039). Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.
323 citations
TL;DR: It is found that overexpression of MALAT1 could promote cell proliferation and migration in vitro, and promote tumour growth and metastasis in nude mice, implying that MALat1 might be a potential predictor for tumour metastasis and prognosis.
Abstract: Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex
315 citations
TL;DR: The data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV- positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC.
Abstract: Human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) is associated with improved survival compared with HPV-negative disease. However, a minority of HPV-positive patients have poor prognosis. Currently, there is no generally accepted strategy for identifying these patients. We retrospectively analysed 270 consecutively treated OPSCC patients from three centres for effects of clinical, pathological, immunological, and molecular features on disease mortality. We used Cox regression to examine associations between factors and OPSCC death, and developed a prognostic model for 3-year mortality using logistic regression analysis. Patients with HPV-positive tumours showed improved survival (hazard ratio (HR), 0.33 (0.21–0.53)). High levels of tumour-infiltrating lymphocytes (TILs) stratified HPV-positive patients into high-risk and low-risk groups (3-year survival; HPV-positive/TILhigh=96%, HPV-positive/TILlow=59%). Survival of HPV-positive/TILlow patients did not differ from HPV-negative patients (HR, 1.01; P=0.98). We developed a prognostic model for HPV-positive tumours using a ‘training’ cohort from one centre; the combination of TIL levels, heavy smoking, and T-stage were significant (AUROC=0·87). This model was validated on patients from the other centres (detection rate 67%; false-positive rate 5.6%; AUROC=0·82). Our data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV-positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC.
309 citations
TL;DR: It is demonstrated that stromal fibroblasts isolated from colon cancer produced significant amounts of IL-6 and that colon cancer cells enhanced IL- 6 production by stromals, thereby inducing angiogenesis and offering new approaches to cancer therapy.
Abstract: Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour–stroma interaction
TL;DR: Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe and can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.
Abstract: Patients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) produces localised tissue necrosis but previous studies using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This study assessed a shorter acting photosensitiser, verteporfin. Fifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg−1 verteporfin. After 60–90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently. In all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm3 at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple’s pancreaticoduodenectomy. Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.
TL;DR: There is now a need to intervene to moderate systemic inflammatory responses, where present, and the rationale for therapeutic intervention using nonselective anti-inflammatory agents is clear and compelling and likely to become a part of routine clinical practice in the near future.
Abstract: Determinants of cancer progression and survival are multifactorial and host responses are increasingly appreciated to have a major role. Indeed, the development and maintenance of a systemic inflammatory response has been consistently observed to confer poorer outcome, in both early and advanced stage disease. For patients, cancer-associated symptoms are of particular importance resulting in a marked impact on day-to-day quality of life and are also associated with poorer outcome. These symptoms are now recognised to cluster with one another with anorexia, weight loss and physical function forming a recognised cluster whereas fatigue, pain and depression forming another. Importantly, it has become apparent that these symptom clusters are associated with presence of a systemic inflammatory response in the patient with cancer. Given the understanding of the above, there is now a need to intervene to moderate systemic inflammatory responses, where present. In this context the rationale for therapeutic intervention using nonselective anti-inflammatory agents is clear and compelling and likely to become a part of routine clinical practice in the near future. The published literature on therapeutic intervention using anti-inflammatory agents for cancer-associated symptoms was reviewed. There are important parallels with the development of useful treatments for the systemic inflammatory response in patients with rheumatological disease and cardiovascular disease.
TL;DR: Eribulin exerted significant effects on EMT/MET-related pathway components in human breast cancer cells in vitro and in vivo, consistent with a phenotypic switch from mesenchymal to epithelial states, and corresponding to observed decreases in migration and invasiveness in vitro as well as experimental metastasis in vivo.
Abstract: Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) states
TL;DR: PVT-1, which maps to 8q24, generates antiapoptotic activity in CRC, and abnormal expression of PVT-1 was a prognostic indicator for CRC patients, according to univariate and multivariate analysis.
Abstract: Amplification of PVT-1 is involved in poor prognosis via apoptosis inhibition in colorectal cancers
TL;DR: The LMR might be an independent prognostic marker for TTR in stage III colon cancer patients and the results suggest that high-risk patients based on the LMR do not benefit from adjuvant chemotherapy.
Abstract: The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer
TL;DR: The combination of CD4+ and CD8+ TILs is a predictor of clinical outcome in glioblastoma patients, and a high level ofCD4+ Tils combined with low CD8-TILs was associated with unfavourable prognosis.
Abstract: Tumour-infiltrating CD4 + and CD8 + lymphocytes as predictors of clinical outcome in glioma
TL;DR: The positive correlation between a high number of infiltrating CD3+ and CD8+ cells and clinical outcome indicates that TILs may have a beneficial role in HNSCC patients and may serve as a biomarker to identify patients likely to benefit from definitive CRT.
Abstract: Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer
TL;DR: Overall, high generalised tumour inflammatory infiltrate could be a good prognostic marker for CRC, however, significant heterogeneity and an insufficient number of studies underscore the need for further prospective studies on subsets of T lymphocytes to increase the robustness of the analyses.
Abstract: The role of tumour-infiltrating inflammation in the prognosis of patients with colorectal cancer (CRC) has not been fully evaluated. The primary objective of our meta-analysis was to determine the impact of tumour-infiltrating inflammation on survival outcomes. Ovid MEDLINE and EMBASE were searched to identify studies reporting the prognostic significance of tumour-infiltrating inflammation for patients with CRC. The primary outcome measures were overall survival (OS), cancer-specific survival (CS) and disease-free survival (DFS). A total of 30 studies involving 2988 patients were identified. Studies were subdivided into those considering the associations between CRC survival and generalised tumour inflammatory infiltrate (n=12) and T lymphocyte subsets (n=18). Pooled analyses revealed that high generalised tumour inflammatory infiltrate was associated with good OS (HR, 0.59; 95% CI, 0.48–0.72), CS (HR, 0.40; 95% CI, 0.27–0.61) and DFS (HR, 0.72; 95% CI, 0.57–0.91). Stratification by location and T lymphocyte subset indicated that in the tumour centre, CD3+, CD8+ and FoxP3+ infiltrates were not statistically significant prognostic markers for OS or CS. In the tumour stroma, high CD8+, but not CD3+ or FoxP3+ cell infiltrates indicated increased OS. Furthermore, high CD3+ cell infiltrate was detected at the invasive tumour margin in patients with good OS and DFS; and high CCR7+ infiltrate was also indicated increased OS. Overall, high generalised tumour inflammatory infiltrate could be a good prognostic marker for CRC. However, significant heterogeneity and an insufficient number of studies underscore the need for further prospective studies on subsets of T lymphocytes to increase the robustness of the analyses.
TL;DR: This study identified the preoperative PLR as an independent prognostic marker for survival in breast cancer patients and revealed significant associations of the elevated PLR on the primary end point CSS for all breast cancer subtypes.
Abstract: The elevation of the platelet-to-lymphocyte ratio (PLR), an easily applicable blood test based on platelet and lymphocyte counts has been associated with poor prognosis in patients with different types of cancer. The present study was aimed to investigate the prognostic significance of the preoperative PLR in a large cohort of breast cancer patients. Data from 793 consecutive non-metastatic breast cancer patients, treated between 1999 and 2004, were evaluated retrospectively. The optimal cutoff values for the PLR were calculated using receiver operating curve analysis. Cancer-specific survival (CSS), overall survival (OS) as well as distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of PLR, multivariable Cox regression models were applied for all three different end points. Univariable analysis revealed a significant association between the elevated preoperative PLR and CSS (hazard ratio (HR): 2.75, 95% confidence interval (CI): 1.57–4.83, P<0.001) that remained statistically significant in multivariable analysis (HR: 2.03, 95% CI: 1.03–4.02, P=0.042). An increased PLR was also significantly associated with decreased OS in univariable (HR: 2.45, 95% CI: 1.43–4.20, P=0.001) and in multivariable analysis (HR: 1.92, 95% CI: 1.01–3.67, P=0.047). Furthermore, univariable analysis showed a significant impact of increased PLR on DMFS (HR: 2.02, 95% CI: 1.18–3.44, P=0.010). Subgroup analysis revealed significant associations of the elevated PLR on the primary end point CSS for all breast cancer subtypes. This association retained its significance in multivariable analysis in patients with luminal B tumours (HR: 2.538, 95% CI: 1.043–6.177, P=0.040). In this study, we identified the preoperative PLR as an independent prognostic marker for survival in breast cancer patients. Independent validation of our findings is needed.
TL;DR: Endometriosis is strongly associated with the increased risk of ovarian cancer, and EAOC shows favourable characteristics including early-stage disease, low-grade disease and a specific histology such as endometrioid or clear cell carcinoma.
Abstract: The risk and prognosis of ovarian cancer have not been well established in women with endometriosis. Thus, we investigated the impact of endometriosis on the risk and prognosis for ovarian cancer, and evaluated clinicopathologic characteristics of endometriosis-associated ovarian cancer (EAOC) in comparison with non-EAOC. After we searched an electronic search to identify relevant studies published online between January 1990 and December 2012, we found 20 case–control and 15 cohort studies including 444 255 patients from 1 625 potentially relevant studies. In the meta-analysis, ovarian cancer risk by endometriosis and clinicopathologic characteristics were evaluated using risk ratio (RR) or standard incidence ratio (SIR), and prognosis was investigated using hazard ratio (HR) with 95% confidence interval (CI). Heterogeneity was evaluated using Higgins I2 to select fixed-effect (I2 ⩽50%) or random effects models (I2>50%), and found no publication bias using funnel plots with Egger’s test (P>0.05). Furthermore, we performed subgroup analyses based on study design, assessment of endometriosis, histology, disease status, quality of study and adjustment for potential confounding factors to minimise bias. Endometriosis increased ovarian cancer risk in case–control or two-arm cohort studies (RR, 1.265; 95% CI, 1.214–1.318) and single-arm cohort studies (SIR, 1.797; 95% CI, 1.276–2.531), which were similar in subgroup analyses. Although progression-free survival was not different between EAOC and non-EAOC (HR, 1.023; 95% CI, 0.712–1.470), EAOC was associated with better overall survival than non-EAOC in crude analyses (HR, 0.778; 95% CI, 0.655–0.925). However, progression-free survival and overall survival were not different between the two groups in subgroup analyses. Stage I–II disease, grade 1 disease and nulliparity were more common in EAOC (RRs, 1.959, 1.319 and 1.327; 95% CIs, 1.367–2.807, 1.149–1.514 and 1.245–1.415), whereas probability of optimal debulking surgery was not different between the two groups (RR, 1.403; 95% CI, 0.915–2.152). Furthermore, endometrioid and clear cell carcinomas were more common in EAOC (RRs, 1.759 and 2.606; 95% CIs, 1.551–1.995 and 2.225–3.053), whereas serous carcinoma was less frequent in EAOC than in non-EAOC (RR, 0.733; 95% CI, 0.617–0.871), and there was no difference in the risk of mucinous carcinoma between the two groups (RR, 0.805; 95% CI, 0.584–1.109). These clinicopathologic characteristics were also similar in subgroup analyses. Endometriosis is strongly associated with the increased risk of ovarian cancer, and EAOC shows favourable characteristics including early-stage disease, low-grade disease and a specific histology such as endometrioid or clear cell carcinoma. However, endometriosis may not affect disease progression after the onset of ovarian cancer.
TL;DR: The five-miRNA panel in plasma may serve as a potential non-invasive biomarker in detecting the early-stage GC in patients diagnosed with gastric cancer.
Abstract: Circulating microRNAs (miRNAs) have been implicated as novel biomarkers for gastric cancer (GC) diagnosis. However, the mixture of GC subtypes may have led to the inconsistent circulating miRNA profiles, and the clinical performance of circulating miRNAs has not yet been evaluated independently on early detection of GC. A four-phase study was designed with a total of 160 cancer-free controls, 124 patients with gastric non-cardia adenocarcinoma (GNCA) and 36 patients diagnosed gastric cardia adenocarcinoma (GCA). In the discovery phase, we screened the miRNA expression profile in plasma of 40 GNCA patients (stage I) and 40 matched controls by TaqMan low density array (TLDA) chips with pooled samples. Differentially expressed miRNAs were further validated in individual sample using quantitative reverse-transcriptase PCR (qRT–PCR) in the training phase. Subsequently, in an independent validation phase, the identified miRNAs were evaluated in 48 GNCA patients (stage I) and 102 matched controls. Finally, the identified miRNAs were further assessed in an external validation phase including advanced GNCA and GCA patients. Additionally, the expression levels of identified miRNAs were measured in the media of BGC823 and MGC803 cell lines. Five miRNAs (miR-16, miR-25, miR-92a, miR-451 and miR-486-5p) showed consistently elevated levels in plasma of the GC patients as compared with controls, and were identified to be potential markers for GNCA with area under the receiver operating characteristic (ROC) curves (AUCs) ranging from 0.850 to 0.925 and 0.694 to 0.790 in the training and validation phases, respectively. The five-miRNA panel presented a high diagnostic accuracy for the early-stage GNCA (AUCs=0.989 and 0.812 for the training and validation phases, respectively). Three miRNAs (miR-16, miR-25 and miR-92a) were excreted into the culture media of GC cell lines. The five-miRNA panel in plasma may serve as a potential non-invasive biomarker in detecting the early-stage GC.
TL;DR: Changes to the BOADICEA model are described that extend its capabilities, make it easier to use in a clinical setting and yield more accurate predictions, and have a significant impact on risk predictions.
Abstract: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction model that is used to compute probabilities of carrying mutations in the high-risk breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, and to estimate the future risks of developing breast or ovarian cancer. In this paper, we describe updates to the BOADICEA model that extend its capabilities, make it easier to use in a clinical setting and yield more accurate predictions. We describe: (1) updates to the statistical model to include cancer incidences from multiple populations; (2) updates to the distributions of tumour pathology characteristics using new data on BRCA1 and BRCA2 mutation carriers and women with breast cancer from the general population; (3) improvements to the computational efficiency of the algorithm so that risk calculations now run substantially faster; and (4) updates to the model’s web interface to accommodate these new features and to make it easier to use in a clinical setting. We present results derived using the updated model, and demonstrate that the changes have a significant impact on risk predictions. All updates have been implemented in a new version of the BOADICEA web interface that is now available for general use: http://ccge.medschl.cam.ac.uk/boadicea/
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TL;DR: EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers.
Abstract: Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study. Five thousand one hundred and twenty-five NSCLC patients’ pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations were detected by multiplex testing. The mutation status of EGFR, KRAS, BRAF and PIK3CA and their association with gender, age, smoking history and histological type were evaluated by appropriate statistical analysis. EGFR, KRAS, BRAF and PIK3CA mutation rates revealed 36.2%, 8.4%, 0.5% and 3.3%, respectively, across the 5125 pathology samples. For the first time, evidence of KRAS mutations were detected in two female, non-smoking patients, age 5 and 14, with NSCLC. Furthermore, we identified 153 double and coexisting mutations and 7 triple mutations. Interestingly, the second drug-resistant mutations, T790M or E545K, were found in 44 samples from patients who had never received TKI treatments. EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers. Activating and resistant mutations to EGFR-TKI drugs can coexist and ‘second drug-resistant mutations’, T790M or E545K, may be primary mutations in some patients. These results will help oncologists to decide candidates for mutation testing and EGFR-TKI treatment.
TL;DR: Gastric cancer tissue-derived mesenchymal stem cells favour gastric cancer progression by transferring exosomal miRNAs to Gastric cancer cells, thus providing a novel mechanism for the role of GC-MSCs and new biomarkers for gastric cancers.
Abstract: MicroRNAs (miRNAs) are involved in gastric cancer development and progression. However, the expression and role of miRNAs in gastric cancer stromal cells are still unclear. The miRNAs differentially expressed in gastric cancer tissue-derived mesenchymal stem cells (GC-MSCs) relative to adjacent non-cancerous tissue-derived MSCs (GCN-MSCs) and in cancer tissues relative to adjacent non-cancerous tissues were screened using miRNA microarray and validated by quantitative RT–PCR. The impact of GC-MSCs on HGC-27 cells was observed in vitro using colony formation and transwell assays, and these cells were subcutaneously co-injected into mice to assess tumour growth in vivo. Exogenous downregulation of miR-221 expression in cells was achieved using an miRNA inhibitor. miR-214, miR-221 and miR-222 were found to be commonly upregulated in GC-MSCs and cancer tissues. Their levels were tightly associated with lymph node metastasis, venous invasion and the TNM stage. Gastric cancer tissue-derived mesenchymal stem cells significantly promoted HGC-27 growth and migration and increased the expression of miR-221 via paracrine secretion, and the targeted inhibition of miR-221 in GC-MSCs could block its tumour-supporting role. GC-MSC-derived exosomes were found to deliver miR-221 to HGC-27 cells and promoted their proliferation and migration. Gastric cancer tissue-derived mesenchymal stem cells favour gastric cancer progression by transferring exosomal miRNAs to gastric cancer cells, thus providing a novel mechanism for the role of GC-MSCs and new biomarkers for gastric cancer.
TL;DR: Emerging evidence shows very few measurable benefits of SCPs, and survivor satisfaction with, and self-reported understanding of, their SCP were very high.
Abstract: Eight years after the Institute of Medicine recommended survivorship care plans (SCPs) for all cancer survivors, this study systematically reviewed the evidence for their use. Studies evaluating outcomes after implementation of SCPs for cancer survivors were identified by searching databases (MEDLINE, EMBASE and Cochrane). Data were extracted and summarised. Ten prospective studies (2286 survivors) met inclusion criteria (5 randomised controlled trials (RCTs)). Study populations included survivors of breast, gynaecological, colorectal and childhood cancer. Several models of SCP were evaluated (paper based/on-line, oncologist/nurse/primary-care physician-delivered and different templates). No significant effect of SCPs was found on survivor distress, satisfaction with care, cancer-care coordination or oncological outcomes in RCTs. Breast cancer survivors with SCPs were better able to correctly identify the clinician responsible for their follow-up care. One study suggested a positive impact on reducing unmet needs. Levels of survivor satisfaction with, and self-reported understanding of, their SCP were very high. Feasibility was raised by health professionals as a significant barrier, as SCPs took 1–4 h of their time to develop. Emerging evidence shows very few measurable benefits of SCPs. Survivors reported high levels of satisfaction with SCPs. Resource issues were identified as a significant barrier to implementation.
TL;DR: The findings suggest that modulation of HIF-1α activity by anaesthetics may affect cancer recurrence following surgery, and isoflurane but not propofol should be avoided for use in cancer surgery.
Abstract: Prostate cancer cell malignancy via modulation of HIF-1 α pathway with isoflurane and propofol alone and in combination
TL;DR: There are substantial differences in how studies diagnose HPV and define p16 overexpression, and p16 staining is better to predict the presence of HPV when the cutoff is set at ⩾70% of cytoplasmatic and nuclear staining.
Abstract: A significant proportion of squamous cell carcinomas of the oropharynx (OP-SCC) are related to human papillomavirus (HPV) infection and p16 overexpression. This subgroup proves better prognosis and survival but no evidence exists on the correlation between HPV and p16 overexpression based on diagnostic measures and definition of p16 overexpression. We evaluated means of p16 and HPV diagnostics, and quantified overexpression of p16 in HPV-positive and -negative OP-SCCs by mode of immunohistochemical staining of carcinoma cells. PubMed, Embase, and the Cochrane Library were searched from 1980 until October 2012. We applied the following inclusion criteria: a minimum of 20 cases of site-specific OP-SCCs, and HPV and p16 results present. Studies were categorised into three groups based on their definition of p16 overexpression: verbal definition, nuclear and cytoplasmatic staining between 5 and 69%, and ⩾70% staining. We identified 39 studies with available outcome data (n=3926): 22 studies (n=1980) used PCR, 6 studies (n=688) used ISH, and 11 studies (n=1258) used both PCR and ISH for HPV diagnostics. The methods showed similar HPV-positive results. Overall, 52.5% of the cases (n=2062) were HPV positive. As to p16 overexpression, 17 studies (n=1684) used a minimum of 5–69% staining, and 7 studies (n=764) used ⩾70% staining. Fifteen studies (n=1478) referred to a verbal definition. Studies showed high heterogeneity in diagnostics of HPV and definition of p16. The correlation between HPV positivity and p16 overexpression proved best numerically in the group applying ⩾70% staining for p16 overexpression. The group with verbal definitions had a significantly lower false-positive rate, but along with the group applying 5–69% staining showed a worse sensitivity compared with ⩾70% staining. There are substantial differences in how studies diagnose HPV and define p16 overexpression. Numerically, p16 staining is better to predict the presence of HPV (i.e. larger sensitivity), when the cutoff is set at ⩾70% of cytoplasmatic and nuclear staining.
TL;DR: According to extrapolations from cohort effects, cervical cancer incidence rates in the Nordic countries would have been otherwise comparable to the highest incidence rates currently detected in low-income countries.
Abstract: Nordic countries’ data offer a unique possibility to evaluate the long-term benefit of cervical cancer screening in a context of increasing risk of human papillomavirus infection. Ad hoc-refined age-period-cohort models were applied to the last 50-year incidence data from Denmark, Finland, Norway and Sweden to project expected cervical cancer cases in a no-screening scenario. In the absence of screening, projected incidence rates for 2006–2010 in Nordic countries would have been between 3 and 5 times higher than observed rates. Over 60 000 cases or between 41 and 49% of the expected cases of cervical cancer may have been prevented by the introduction of screening in the late 1960 s and early 1970 s. Our study suggests that screening programmes might have prevented a HPV-driven epidemic of cervical cancer in Nordic countries. According to extrapolations from cohort effects, cervical cancer incidence rates in the Nordic countries would have been otherwise comparable to the highest incidence rates currently detected in low-income countries.
TL;DR: It is suggested that the implementation of the 2005 NICE Guidelines may have contributed to this reduction in diagnostic intervals between 2001–2002 and 2007–2008 and remains considerable scope to achieve more timely cancer diagnosis, with the ultimate aim of improving cancer outcomes.
Abstract: The primary aim was to use routine data to compare cancer diagnostic intervals before and after implementation of the 2005 NICE Referral Guidelines for Suspected Cancer. The secondary aim was to compare change in diagnostic intervals across different categories of presenting symptoms. Using data from the General Practice Research Database, we analysed patients with one of 15 cancers diagnosed in either 2001–2002 or 2007–2008. Putative symptom lists for each cancer were classified into whether or not they qualified for urgent referral under NICE guidelines. Diagnostic interval (duration from first presented symptom to date of diagnosis in primary care records) was compared between the two cohorts. In total, 37 588 patients had a new diagnosis of cancer and of these 20 535 (54.6%) had a recorded symptom in the year prior to diagnosis and were included in the analysis. The overall mean diagnostic interval fell by 5.4 days (95% CI: 2.4–8.5; P<0.001) between 2001–2002 and 2007–2008. There was evidence of significant reductions for the following cancers: (mean, 95% confidence interval) kidney (20.4 days, −0.5 to 41.5; P=0.05), head and neck (21.2 days, 0.2–41.6; P=0.04), bladder (16.4 days, 6.6–26.5; P⩽0.001), colorectal (9.0 days, 3.2–14.8; P=0.002), oesophageal (13.1 days, 3.0–24.1; P=0.006) and pancreatic (12.6 days, 0.2–24.6; P=0.04). Patients who presented with NICE-qualifying symptoms had shorter diagnostic intervals than those who did not (all cancers in both cohorts). For the 2007–2008 cohort, the cancers with the shortest median diagnostic intervals were breast (26 days) and testicular (44 days); the highest were myeloma (156 days) and lung (112 days). The values for the 90th centiles of the distributions remain very high for some cancers. Tests of interaction provided little evidence of differences in change in mean diagnostic intervals between those who did and did not present with symptoms specifically cited in the NICE Guideline as requiring urgent referral. We suggest that the implementation of the 2005 NICE Guidelines may have contributed to this reduction in diagnostic intervals between 2001–2002 and 2007–2008. There remains considerable scope to achieve more timely cancer diagnosis, with the ultimate aim of improving cancer outcomes.