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1.  Sex differences in cancer survival in Estonia: a population-based study 
BMC Cancer  2015;15:72.
Background
In Estonia, women have much longer life expectancy than men. The aim of this study was to examine sex differences in cancer survival in Estonia and to explore the role of age at diagnosis, stage at diagnosis and tumour subsite.
Methods
Using data from the population-based Estonian Cancer Registry, we examined the relative survival of adult patients diagnosed with nine common cancers in Estonia in 1995–2006 and followed up through 2011. Excess hazard ratios (EHR) of death associated with female gender adjusted for age, stage at diagnosis and tumour subsite were estimated.
Results
A total of 20 828 male and 13 166 female cases were analysed. The main data quality indicators were similar between men and women. Women had more cases with unknown extent of disease at diagnosis. Overall, the age-adjusted 5-year relative survival ratio was higher among women than men for all studied sites, but the difference was significant for cancers of mouth and pharynx (22% units), lung (5% units), skin melanoma (17% units) and kidney (8% units). The increase in survival over time was larger for women than men for cancers of mouth and pharynx, colon, rectum, kidney and skin melanoma. In multivariate analysis, women had a significantly lower EHR of death within five years after diagnosis for five of the nine cancers studied (cancers of mouth and pharynx, stomach, lung, skin melanoma and kidney). Adjustment for stage and subsite explained some, but not all of the women’s advantage.
Conclusions
We found a significant female survival advantage in Estonia for cancers of mouth and pharynx, stomach, lung, kidney and skin melanoma. The differences in favour of women tended to increase over time as from the 1990s to the 2000s, survival improved more among women than among men. A large part of the women’s advantage is likely attributable to biological factors, but other factors, such as co-morbidities, treatment compliance or health behaviour, are also probable contributors to gender survival disparities in Estonia and merit further investigation. Our findings have implications for public health, early detection and cancer care in Estonia.
doi:10.1186/s12885-015-1080-9
PMCID: PMC4336752
Relative survival; Cancer registry; Population-based; Gender differences; Data quality
2.  Circadian variation in plasma 5-fluorouracil concentrations during a 24 hour constant-rate infusion 
BMC Cancer  2015;15:69.
Background
Varying the rate of continuous intravenous infusions of 5-fluorouracil (5FU) chemotherapy over a 24-hour period has been reported to improve patient outcomes. It has been hypothesized that circadian variation in drug disposition is a contributing factor. We analyzed 5-FU concentrations during a 24-hour continuous 5-FU infusion.
Methods
Sixty-four subjects with advanced malignancies including pancreatic, hepatocellular, colorectal as well as other epithelial malignancies and either abnormal hepatic or renal function were treated on a phase I and pharmacokinetic study of weekly 24-hour intravenous infusions of 5-FU and leucovorin. No other concomitant anticancer therapy was administered. Blood samples were collected every three hours from 61 subjects for measurement of plasma 5-FU during the first two weekly infusions.
Results
After adjusting for differences in dose, elapsed time from start of infusion and infusion number (2 versus 1), mean 5-FU concentration was highest at 6 am and lowest at 3 pm, with an overall change in the mean from 3 pm to 6 am of +20 percent (95% CI = 12–28%). However, this variation in mean concentration associated with time of day was comparable in magnitude to the between-patient differences, within-patient differences between infusions, and the residual variation within infusion (coefficient of variation = 21%).
Conclusions
Our data show systematic variation by time of day in plasma concentrations of 5-FU administered at a constant rate over 24 hours, but it is small compared to the total variation in plasma concentration contributed by other sources. Circadian variation in men was more pronounced than in women.
doi:10.1186/s12885-015-1075-6
PMCID: PMC4336691
Circadian; 5-fluorouracil; Cancer
3.  Multiple myeloma cells alter the senescence phenotype of bone marrow mesenchymal stromal cells under participation of the DLK1-DIO3 genomic region 
BMC Cancer  2015;15:68.
Background
Alterations and senescence in bone marrow mesenchymal stromal cells of multiple myeloma patients (MM-BMMSCs) have become an important research focus. However the role of senescence in the pathophysiology of MM is not clear.
Methods
Correlation between senescence, cell cycle and microRNA expression of MM-BMMSCs (n = 89) was analyzed. Gene expression analysis, copy number analysis and methylation specific PCR were performed by Real-Time PCR. Furthermore, cyclin E1, cyclin D1, p16 and p21 genes were analyzed at the protein level using ELISA. Cell cycle and senescence were analyzed by FACS. MiRNA transfection was performed with miR-485-5p inhibitor and mimic followed by downstream analysis of senescence and cell cycle characteristics of MM-BMMSCs. Results were analyzed by Mann–Whitney U test, Wilcoxon signed-rank test and paired t-test depending on the experimental set up.
Results
MM-BMMSCs displayed increased senescence associated β-galactosidase activity (SA-βGalA), cell cycle arrest in S phase and overexpression of microRNAs. The overexpressed microRNAs miR-485-5p and miR-519d are located on DLK1-DIO3 and C19MC, respectively. Analyses revealed copy number accumulation and hypomethylation of both clusters. KMS12-PE myeloma cells decreased SA-βGalA and influenced cell cycle characteristics of MM-BMMSCs. MiR-485-5p was significantly decreased in co-cultured MM-BMMSCs in connection with an increased methylation of DLK1-DIO3. Modification of miR-485-5p levels using microRNA mimic or inhibitor altered senescence and cell cycle characteristics of MM-BMMSCs.
Conclusions
Here, we show for the first time that MM-BMMSCs have aberrant methylation and copy number of the DLK1-DIO3 and C19MC genomic region. Furthermore, this is the first study pointing that multiple myeloma cells in vitro reduce both the senescence phenotype of MM-BMMSCs and the expression of miR-223 and miR-485-5p. Thus, it is questionable whether senescence of MM-BMMSCs plays a pathological role in active multiple myeloma or is more important when cell interaction with myeloma cells is inhibited. Furthermore, we found that MiR-485-5p, which is located on the DLK1-DIO3 cluster, seems to participate in the regulation of senescence status and cell cycle characteristics of MM-BMMSCs. Thus, further exploration of the microRNAs of DLK1-DIO3 could provide further insights into the origin of the senescence state and its reversal in MM-BMMSCs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1078-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1078-3
PMCID: PMC4336751
Multiple myeloma; Bone marrow stromal cells; Senescence; Cell cycle; DLK1-DIO3; miR-485-5p
4.  Breast and prostate cancer patients differ significantly in their serum Thymidine kinase 1 (TK1) specific activities compared with those hematological malignancies and blood donors: implications of using serum TK1 as a biomarker 
BMC Cancer  2015;15:66.
Background
Thymidine kinase 1 (TK1) is a cellular enzyme involved in DNA precursor synthesis, and its activity has been used as a proliferation marker for monitoring malignant diseases. Here, for the first time, we evaluated both TK1 activity and protein levels in sera from patients with different malignancies.
Methods
Serum samples from patients with myelodysplastic syndrome (MDS, n = 22), breast cancer (n = 42), prostate cancer (n = 47) and blood donors (n = 30) were analyzed for TK1 protein and activity levels, using a serum TK1 (STK1) protein assay based on antibodies and an activity assay that measured [3H]-deoxythymidine (dThd) phosphorylation. The molecular forms of TK1 in sera from some of these patients were analyzed using size-exclusion chromatography.
Results
Mean STK1 activities in sera from MDS, breast and prostate cancer were 11 ± 17.5, 6.7 ± 19 and 1.8 ± 1.4 pmol/min/mL, differing significantly from blood donors (mean ± standard deviation (SD) = 1.1 ± 0.9 pmol/min/mL). Serum TK1 protein (25 kDa polypeptide) levels were also significantly higher in MDS, breast, prostate cancer compared to blood donors (mean ± SD = 19 ± 9, 22 ± 11, 20 ± 12, and 5 ± 3.5 ng/mL, respectively). The STK1 specific activities of sera from patients with MDS and blood donors were significantly higher when compared with activities in sera from breast and prostate cancer patients. Size-exclusion analysis of sera from breast and prostate cancer showed that the detected active TK1 was primarily a high molecular weight complex, similar to the forms found in sera from MDS patients and blood donors. However, Western blotting demonstrated high TK1 25 kDa protein levels in fractions lacking TK1 activity in sera from cases with breast and prostate cancer.
Conclusions
These results demonstrate that there are differences in the specific activities and the subunit compositions of STK1 in hematological malignancies compared with breast and prostate cancer. This fact has several important implications for the use of STK1 as a tumor biomarker. One is that STK1 protein assays may differentiate early-stage tumor development in breast and prostate cancer more effectively than STK1 activity assays.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1073-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1073-8
PMCID: PMC4336758
Serum thymidine kinase 1; STK1 protein assays; Size exclusion chromatography; Anti-human TK1 antibodies; TK1 specific activity
5.  The differential anti-tumour effects of zoledronic acid in breast cancer – evidence for a role of the activin signaling pathway 
BMC Cancer  2015;15:55.
Background
Neo-adjuvant breast cancer clinical trials of zoledronic acid (ZOL) have shown that patients with oestrogen negative (ER-ve) tumours have improved disease outcomes. We investigated the molecular mechanism behind this differential anti-tumour effect according to ER status, hypothesising it may in part be mediated via the activin signaling pathway.
Methods
The effects of activin A, its inhibitor follistatin and zoledronic acid on proliferation of breast cancer cells was evaluated using either an MTS proliferation assay or trypan blue. Secretion of activin A and follistatin in conditioned medium (CM) from MDA-MB-231, MDA-MB-436, MCF7 and T47D cell lines were measured using specific ELISAs. The effects of ZOL on phosphorylation domains of Smad2 (pSmad2c + pSmad2L) were evaluated using immunofluorescence. Changes seen in vitro were confirmed in a ZOL treated subcutaneous ER-ve MDA-MB-436 xenograft model.
Results
Activin A inhibits proliferation of both ER-ve and oestrogen positive (ER + ve) breast cancer cells, an effect impaired by follistatin. ZOL significantly inhibits proliferation and the secretion of follistatin from ER-ve cells only, which increases the biological activity of the canonical activin A pathway by significantly increasing intracellular pSmad2c and decreasing nuclear accumulation of pSmad2L. In vivo, ZOL significantly decreases follistatin and pSmad2L expression in ER-ve subcutaneous xenografts compared to saline treated control animals.
Conclusions
This is the first report showing a differential effect of ZOL, according to ER status, on the activin pathway and its inhibitors in vitro and in vivo. These data suggest a potential molecular mechanism contributing to the differential anti-tumour effects reported from clinical trials and requires further evaluation in clinical samples.
doi:10.1186/s12885-015-1066-7
PMCID: PMC4329195
Breast cancer; Zoledronic acid; Activin; Follistatin; Phosphorylated Smad2
6.  Gamma knife radiosurgery for elderly patients with brain metastases: evaluation of scoring systems that predict survival 
BMC Cancer  2015;15:54.
Background
Gamma knife radiosurgery (GKRS) has been increasingly employed for the treatment of elderly patients with brain metastases, mainly due to its demonstrated effectiveness and low complication rate. However, only a few studies have investigated the prognostic factors that influence the survival of elderly patients after GKRS. The purpose of this study was to identify a scoring system that is able to predict the survival of elderly patients undergoing GKRS using data obtained at the time of diagnosis for brain metastases.
Methods
Between 2004 and 2011, death was confirmed in 147 patients aged 70 years and older who had been treated with GKRS for brain metastases. Median age at the time of GKRS was 75.7 years (range, 70–86 years). The median tumor volume was 5.1 cm3 (range, 0.05–59.9 cm3). The median marginal prescription dose was 21.4 Gy (range, 14–25 Gy).
Results
The median survival was 167 days. Overall survival rates at 6 months and 1 year were 60.4% and 29.4%, respectively. Among the patient characteristics pertaining to systemic cancer and brain metastasis for which data were obtained preoperatively, a multivariate analysis showed that low Karnofsky performance status (KPS ≤ 80, P = 0.047) and the presence of extracranial metastases (P = 0.014) detected at the time of brain metastasis diagnosis were independent prognostic factors for short survival. A high score index for radiosurgery (SIR score ≥ 4, P = 0.024) and a high graded prognostic assessment (GPA score ≥ 2, P = 0.004) were associated with longer survival. A multivariate analysis of the important characteristics of systemic cancer, and the scoring system evaluating survival duration showed that a low GPA score was the most powerful independent factor for predicting short survival (hazard ratio 1.756, 95% confidence interval 1.252–2.456, P = 0.001).
Conclusions
GKRS is a safe approach to treat brain metastases in patients age 70 years and older. In this group, our study identified GPA score at the time of GKRS as a powerful prognostic factor for survival.
doi:10.1186/s12885-015-1070-y
PMCID: PMC4333254
Brain metastasis; Elderly; Gamma knife radiosurgery; Prognosis; Survival
7.  Plasma clusterin as a candidate pre-diagnosis marker of colorectal cancer risk in the Florence cohort of the European Prospective Investigation into Cancer and Nutrition: a pilot study 
BMC Cancer  2015;15:56.
Background
Colorectal cancer is one of the major causes of cancer mortality world-wide. Prevention would improve if at-risk subjects could be identified. The aim of this study was to characterise plasma protein biomarkers associated with the risk of colorectal cancer in samples collected prospectively, before the disease diagnosis.
Methods
After an exploratory study on the comprehensive plasma proteome analysis by liquid chromatography-tandem mass spectrometry from ten colorectal cancer cases enrolled at diagnosis, and ten matched controls (Phase 1), a similar preliminary study was performed on prospective plasma samples from ten colorectal cancer cases, enrolled years before disease development, and ten matched controls identified in a nested case–control study within the Florence cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) study (Phase 2); in Phase 3 the validation of the candidate biomarkers by targeted proteomics on 48 colorectal cancer cases and 48 matched controls from the Florence-EPIC cohort, and the evaluation of the disease risk were performed.
Results
Systems biology tools indicated that both in the Phase 1 and Phase 2 studies circulating protein levels differing in cases more than 1.5 times from controls, were involved in inflammation and/or immune response. Eight proteins including apolipoprotein C-II, complement C4-B, complement component C9, clusterin, alpha-2-HS-glycoprotein, mannan-binding lectin serine-protease, mannose-binding protein C, and N-acetylmuramoyl-L-alanine amidase were selected as promising candidate biomarkers. Targeted proteomics of the selected proteins in the EPIC samples showed significantly higher clusterin levels in cases than controls, but only in men (mean ± SD, 1.98 ± 0.46 and 1.61 ± 0.43 nmol/mL respectively, Mann–Whitney U, two-tailed P = 0.0173). The remaining proteins were unchanged. Using multivariate logistic models a significant positive association emerged for clusterin, with an 80% increase in the colorectal cancer risk with protein’s unit increase, but only in men.
Conclusions
The results show that plasma proteins can be altered years before colorectal cancer detection. The high circulating clusterin in pre-diagnostic samples suggests this biomarker can improve the identification of people at risk of colorectal cancer and might help in designing preventive interventions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1058-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1058-7
PMCID: PMC4334607
Early plasma biomarkers; Colorectal cancer; Prospective study; Proteomics; Mass spectrometry
8.  Single arm NCRI phase II study of CHOP in combination with Ofatumumab in induction and maintenance for patients with newly diagnosed Richter’s syndrome 
BMC Cancer  2015;15:52.
Background
Transformation of B-cell chronic lymphocytic leukaemia (B-CLL) to diffuse large B cell lymphoma (DLBCL) (Richter’s syndrome (RS)) is a rare (2-15% of patients) but catastrophic complication of B-CLL. Dose-intense chemotherapy regimens investigated in small single institution trials, but with the exception of bone marrow transplantation for a minority of patients, little has improved the median overall survival of patients with RS beyond eight months. Patients are often elderly, immunosuppressed, possess co-morbidities and have a deteriorating performance status. TP53 disruption is a common molecular abnormality noted in RS and contributes to the tumour’s chemotherapy resistance. Ofatumumab is a fully human anti-CD20 monoclonal IgG1κ antibody that targets a unique epitope on B lymphocytes. It has displayed increased binding affinity and a longer dissociation time when compared to rituximab resulting in improved complement dependent cellular cytotoxicity (CDCC); a mechanism with the potential to overcome apoptosis-resistance in TP53 disruption. Given the prevalence of TP53 disruption in RS, Ofatumumab was considered a relatively non-toxic agent with a sound rationale to test in a prospective multicentre trial as an adjunct to CHOP induction and subsequent ofatumumab maintenance therapy in responding patients.
Methods/Design
The CHOP-OR study is a prospective phase II study to evaluate the safety, feasibility and activity of a CHOP chemotherapy in combination with ofatumumab in induction and subsequent maintenance for patients with newly diagnosed RS. The primary objective will be the overall response rate (ORR) in patients with RS after six cycles of CHOP-O. The secondary objectives include feasibility of recruitment, progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by exploratory analysis of the genomic landscape of RS in newly diagnosed patients.
Discussion
The CHOP-OR trial evaluates the safety, feasibility and activity of CHOP plus Ofatumumab induction and Ofatumumab maintenance in new RS patients. The study is currently recruiting and has met the interim analysis criteria, with more than 7 of the first 25 participants achieving a CR or PR after six cycles of CHOP-O. The study has the potential to identify predictive biomarkers for this treatment modality.
Trial registration
NCT01171378.
doi:10.1186/s12885-015-1048-9
PMCID: PMC4329650
Ofatumumab; CHOP; TP53; Richter’s syndrome; Chronic lymphocytic leukaemia; Diffuse large B cell lymphoma; Phase II; Rare cancers
9.  Impact of diabetes type II and chronic inflammation on pancreatic cancer 
BMC Cancer  2015;15:51.
Background
We explored if known risk factors for pancreatic cancer such as type II diabetes and chronic inflammation, influence the pathophysiology of an established primary tumor in the pancreas and if administration of metformin has an impact on tumor growth.
Methods
Pancreatic carcinomas were assessed in a syngeneic orthotopic pancreas adenocarcinoma model after injection of 6606PDA cells in the pancreas head of either B6.V-Lepob/ob mice exhibiting a type II diabetes-like syndrome or normoglycemic mice. Chronic pancreatitis was then induced by repetitive administration of cerulein. Cell proliferation, cell death, inflammation and the expression of cancer stem cell markers within the carcinomas was evaluated by immunohistochemistry. In addition, the impact of the antidiabetic drug, metformin, on the pathophysiology of the tumor was assessed.
Results
Diabetic mice developed pancreatic ductal adenocarcinomas with significantly increased tumor weight when compared to normoglycemic littermates. Diabetes caused increased proliferation of cancer cells, but did not inhibit cancer cell necrosis or apoptosis. Diabetes also reduced the number of Aldh1 expressing cancer cells and moderately decreased the number of tumor infiltrating chloracetate esterase positive granulocytes. The administration of metformin reduced tumor weight as well as cancer cell proliferation. Chronic pancreatitis significantly diminished the pancreas weight and increased lipase activity in the blood, but only moderately increased tumor weight.
Conclusion
We conclude that diabetes type II has a fundamental influence on pancreatic ductal adenocarcinoma by stimulating cancer cell proliferation, while metformin inhibits cancer cell proliferation. Chronic inflammation had only a minor effect on the pathophysiology of an established adenocarcinoma.
doi:10.1186/s12885-015-1047-x
PMCID: PMC4336675
Cancer stem cells; Cancer heterogeneity; Cancer cell plasticity; Aldh1; CD133
10.  GRECCAR 8: impact on survival of the primary tumor resection in rectal cancer with unresectable synchronous metastasis: a randomized multicentre study 
BMC Cancer  2015;15:47.
Background
A majority of patients with rectal cancer and metastasis are not eligible to curative treatment because of an extensive and unresectable metastatic disease. Primary tumor resection is still debated in this situation. Rectal surgery treats or prevents the symptoms and avoids the risk of acute complications related to the primary tumor. Several studies on colorectal cancers seem to show interesting results in terms of survival in favor to the resection of the primary tumor. To date, no randomized trial or even a prospective study has assessed the impact of primary tumor resection on overall survival in patients with colorectal cancer with unresectable metastasis. All published studies were retrospective and included colon and rectal cancers. Rectal cancer is associated with specific problems related to the rectal surgery. Surgery is more complex, and may be source of more morbidity and postoperative functional dysfunctions (stoma, digestive, sexual, urinary) than colic surgery. On the other hand, symptoms related to the progression of rectal tumor are often very disabling: pain, rectal syndrome.
Methods/Design
GRECCAR 8 is a multicentre randomized open-label controlled trial aimed to evaluate the impact on survival of the primary tumor resection in rectal cancer with unresectable synchronous metastasis. Patients must undergo upfront systemic chemotherapy for at least 4 courses before inclusion. Patients with progressive metastatic disease during upfront chemotherapy will be excluded from the study. Patients will be randomly assigned in a 1:1 ratio to Arm A: primary tumor resection followed by systemic chemotherapy versus Arm B: systemic chemotherapy alone. Primary endpoint will be overall survival measured from the date of randomization to the date of death or to the end of follow-up (2 years). Secondary endpoints will include progression-free survival, quality of life, toxicity of chemotherapy, response of the primary tumor and metastatic disease to chemotherapy, postoperative morbidity and mortality, rate of patient not eligible for postoperative chemotherapy (arm A), primary tumor related complications and rate of emergency surgery (arm B). The number of patients needed is 290.
Trial registration
ClinicalTrial.gov: NCT02314182
doi:10.1186/s12885-015-1060-0
PMCID: PMC4327953
Rectal cancer; Primary tumor resection; Unresectable metastasis; Palliative treatment; Survival; Quality of life
11.  NEOSCOPE: a randomised Phase II study of induction chemotherapy followed by either oxaliplatin/capecitabine or paclitaxel/carboplatin based chemoradiation as pre-operative regimen for resectable oesophageal adenocarcinoma 
BMC Cancer  2015;15:48.
Background
Both oxaliplatin/capecitabine-based chemoradiation (OXCAP-RT) and carboplatin-paclitaxel based radiation (CarPac-RT) are active regimens in oesophageal adenocarcinoma, but no randomised study has compared their efficacy and toxicity. This randomised phase II “pick a winner” trial will identify the optimum regimen to take forward to a future phase III trial against neo-adjuvant chemotherapy, the current standard in the UK.
Methods/Design
Patients with resectable adenocarcinoma of the oesophagus or Siewert Type 1–2 gastro-oesophageal junction (GOJ), ≥T3 and/or ≥ N1 are eligible for the study. Following two cycles of induction OXCAP chemotherapy (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m2 D1-21, q 3 wk), patients are randomised 1:1 to OXCAP-RT (oxaliplatin 85 mg/m2 Day 1,15,29; capecitabine 625 mg/m2 twice daily on days of RT; RT-45 Gy/25 fractions/5 weeks) or CarPac-RT (Carboplatin AUC2 and paclitaxel 50 mg/m2 Day 1,8,15,22,29; RT-45 Gy/25 fractions/5 weeks). Restaging CT/PET-CT is performed 4–6 weeks after CRT, and a two-phase oesophagectomy with two-field lymphadenectomy is performed six to eight weeks after CRT. The primary end-point is pathological complete response rate (pCR) at resection and will include central review. Secondary endpoints include: recruitment rate, toxicity, 30-day surgical morbidity/mortality, resection margin positivity rate and overall survival (median, 3- and 5-yr OS. 76 patients (38/arm) gives 90% power and one-sided type 1 error of 10% if patients on one novel treatment have a response rate of 35% while the second treatment has a response rate of 15%. A detailed RT Quality Assurance (RTQA) programme includes a detailed RT protocol and guidance document, pre-accrual RT workshop, outlining exercise, and central evaluation of contouring and planning. This trial has been funded by Cancer Research UK (C44694/A14614), sponsored by Velindre NHS Trust and conducted through the Wales Cancer Trials Unit at Cardiff University on behalf of the NCRI Upper GI CSG.
Discussion
Following encouraging results from previous trials, there is an interest in neo-adjuvant chemotherapy and CRT containing regimens for treatment of oesophageal adenocarcinoma. NEOSCOPE will first establish the efficacy, safety and feasibility of two different neo-adjuvant CRT regimens prior to a potential phase III trial.
Trial registration
Eudract No: 2012-000640-10. ClinicalTrials.gov: NCT01843829.
doi:10.1186/s12885-015-1062-y
PMCID: PMC4329217
Oesophageal; Phase II; Neo-adjuvant; Chemotherapy; Chemoradiotherapy; Radiotherapy; Carboplatin; Paclitaxel; Oxaliplatin; Capecitabine
12.  Clinical outcome of patients with pancreatic metastases from renal cell cancer 
BMC Cancer  2015;15:46.
Background
Renal cell cancer (RCC) is one of the most frequent primary sites for metastatic pancreatic tumors although metastatic tumors are rare among pancreatic malignant tumors. The purpose of this study is to disclose the characterization and treatment outcomes of pancreatic metastases from RCC.
Methods
Of 262 patients with metastatic RCC treated at our hospital between 1999 and 2013, the data of 20 (7.6%) who simultaneously developed or subsequently acquired pancreatic metastases were retrospectively reviewed and statistically analyzed.
Results
The median follow-up period from RCC diagnosis and pancreatic metastases was 13.4 years (inter-quartile range: IQR, 7.8–15.5 years) and 3.8 years (IQR, 2.1–5.5 years), respectively. Median duration from diagnosis of RCC to pancreatic metastasis was 7.8 years (IQR, 4.2–12.7 years). During this observation period, the estimated median overall survival (OS) time from the diagnosis of RCC to death or from pancreatic metastasis to death was not reached. The probability of patients surviving after pancreatic metastasis at 1, 3, and 5 years was 100, 87.7, and 78.9%, respectively. The estimated OS period from the diagnosis of metastases to death of the patients with pancreatic metastasis was significantly longer than that of the patients with non-pancreatic metastasis (median OS 2.7 years) (P < 0.0001). Surgical management for pancreatic metastasis was performed in 15 patients (75%). When the median follow-up period for these surgeries was 3.5 years (IQR, 1.9–5.2 years), the estimated median recurrence-free survival was 1.8 years. For the patients with multiple metastatic sites, molecularly targeted therapies were given to six (30%) patients. When the median follow-up period was 4.1 years (IQR, 3.0–4.4 years), no disease progression was observed.
Conclusions
The pancreas is frequently the only metastatic site and metastasis typically occurs a long time after nephrectomy. The OS period of these patients is long and both surgical and medical treatment resulted in good outcomes.
doi:10.1186/s12885-015-1050-2
PMCID: PMC4332740
Renal cell cancer; Outcome; Pancreas metastasis; Prognostic factor; Pseudocapsule
13.  S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance 
BMC Cancer  2015;15:44.
Background
The tumor microenvironment plays a determinative role in stimulating tumor progression and metastasis. Notably, tumor-stroma signals affect the pattern of infiltrated immune cells and the profile of tumor-released cytokines. Among the known molecules that are engaged in stimulating the metastatic spread of tumor cells is the S100A4 protein. S100A4 is known as an inducer of inflammatory processes and has been shown to attract T-cells to the primary tumor and to the pre-metastatic niche. The present study aims to examine the immunomodulatory role of S100A4 in vivo and in vitro and assess the mode of action of 6B12, a S100A4 neutralizing antibody.
Methods
The therapeutic effect of the 6B12 antibody was evaluated in two different mouse models. First, in a model of spontaneous breast cancer we assessed the dynamics of tumor growth and metastasis. Second, in a model of metastatic niche formation we determined the expression of metastatic niche markers. The levels of cytokine expression were assessed using antibody as well as PCR arrays and the results confirmed by qRT-PCR and ELISA. T-cell phenotyping and in vitro differentiation analyses were performed by flow cytometry.
Results
We show that the S100A4 protein alters the expression of transcription factor and signal transduction pathway genes involved in the T-cell lineage differentiation. T-cells challenged with S100A4 demonstrated reduced proportion of Th1-polarized cells shifting the Th1/Th2 balance towards the Th2 pro-tumorigenic phenotype. The 6B12 antibody restored the Th1/Th2 balance. Furthermore, we provide evidence that the 6B12 antibody deploys its anti-metastatic effect, by suppressing the attraction of T-cells to the site of primary tumor and pre-metastatic niche. This was associated with delayed primary tumor growth, decreased vessel density and inhibition of metastases.
Conclusion
The S100A4 blocking antibody (6B12) reduces tumor growth and metastasis in a model of spontaneous breast cancer. The 6B12 antibody treatment inhibits T cell accumulation at the primary and pre-metastatic tumor sites. The 6B12 antibody acts as an immunomodulatory agent and thus supports the view that the 6B12 antibody is a promising therapeutic candidate to fight cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1034-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1034-2
PMCID: PMC4335362
14.  Clonal distribution of BCR-ABL1 mutations and splice isoforms by single-molecule long-read RNA sequencing 
BMC Cancer  2015;15:45.
Background
The evolution of mutations in the BCR-ABL1 fusion gene transcript renders CML patients resistant to tyrosine kinase inhibitor (TKI) based therapy. Thus screening for BCR-ABL1 mutations is recommended particularly in patients experiencing poor response to treatment. Herein we describe a novel approach for the detection and surveillance of BCR-ABL1 mutations in CML patients.
Methods
To detect mutations in the BCR-ABL1 transcript we developed an assay based on the Pacific Biosciences (PacBio) sequencing technology, which allows for single-molecule long-read sequencing of BCR-ABL1 fusion transcript molecules. Samples from six patients with poor response to therapy were analyzed both at diagnosis and follow-up. cDNA was generated from total RNA and a 1,6 kb fragment encompassing the BCR-ABL1 transcript was amplified using long range PCR. To estimate the sensitivity of the assay, a serial dilution experiment was performed.
Results
Over 10,000 full-length BCR-ABL1 sequences were obtained for all samples studied. Through the serial dilution analysis, mutations in CML patient samples could be detected down to a level of at least 1%. Notably, the assay was determined to be sufficiently sensitive even in patients harboring a low abundance of BCR-ABL1 levels. The PacBio sequencing successfully identified all mutations seen by standard methods. Importantly, we identified several mutations that escaped detection by the clinical routine analysis. Resistance mutations were found in all but one of the patients. Due to the long reads afforded by PacBio sequencing, compound mutations present in the same molecule were readily distinguished from independent alterations arising in different molecules. Moreover, several transcript isoforms of the BCR-ABL1 transcript were identified in two of the CML patients. Finally, our assay allowed for a quick turn around time allowing samples to be reported upon within 2 days.
Conclusions
In summary the PacBio sequencing assay can be applied to detect BCR-ABL1 resistance mutations in both diagnostic and follow-up CML patient samples using a simple protocol applicable to routine diagnosis. The method besides its sensitivity, gives a complete view of the clonal distribution of mutations, which is of importance when making therapy decisions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1046-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1046-y
PMCID: PMC4335374
15.  Number of negative lymph nodes is associated with disease-free survival in patients with breast cancer 
BMC Cancer  2015;15:43.
Background
The aim of this study was to evaluate the prognostic value of the number of negative lymph nodes (NLNs) in breast cancer patients after mastectomy.
Methods
2,455 breast cancer patients who received a mastectomy between January 1998 and December 2007 were retrospectively reviewed. The prognostic impact of the number of NLNs with respect to disease-free survival (DFS) was analyzed.
Results
The median follow-up time was 62.0 months, and the 5-year and 10-year DFS was 87.1% and 74.3%, respectively. The DFS of patients with >10 NLNs was significantly higher than that of patents with ≤10 NLNs, and the 5-year DFS rates were 87.5% and 69.5%, respectively (P < 0.001). Univariate Cox analysis showed that the NLN count (continuous variable) was a prognostic factor of DFS (hazard ratio [HR] = 0.913, 95% confidence interval [CI]: 0.896-0.930, P < 0.001). In multivariate Cox analysis, patients with a higher number of NLNs had a better DFS (HR = 0.977, 95% CI: 0.958-0.997, P = 0.022). Subgroup analysis showed that the NLN count had a prognostic value in patients at different pT stages and pN positive patients (log-rank P < 0.001). However, it had no prognostic value in pN0 patients (log-rank P = 0.684).
Conclusions
The number of NLNs is an independent prognostic factor of DFS in breast cancer patients after mastectomy, and patients with a higher number of NLNs have a better DFS.
doi:10.1186/s12885-015-1061-z
PMCID: PMC4324425
Breast cancer; Mastectomy; Negative lymph nodes; Prognosis; Disease-free survival
16.  Melatonin attenuates the TLR4-mediated inflammatory response through MyD88- and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer 
BMC Cancer  2015;15:34.
Background
Toll-like receptors (TLRs) are effector molecules expressed on the surface of ovarian cancer (OC) cells, but the functions of the TLR2/TLR4 signaling pathways in these cells remain unclear. Melatonin (mel) acts as an anti-inflammatory factor and has been reported to modulate TLRs in some aggressive tumor cell types. Therefore, we investigated OC and the effect of long-term mel therapy on the signaling pathways mediated by TLR2 and TLR4 via myeloid differentiation factor 88 (MyD88) and toll-like receptor-associated activator of interferon (TRIF) in an ethanol-preferring rat model.
Methods
To induce OC, the left ovary of animals either consuming 10% (v/v) ethanol or not was injected directly under the bursa with a single dose of 100 μg of 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 μL of sesame oil. The right ovaries were used as sham-surgery controls. After developing OC, half of the animals received i.p. injections of mel (200 μg/100 g b.w./day) for 60 days.
Results
Although mel therapy was unable to reduce TLR2 levels, it was able to suppress the OC-associated increase in the levels of the following proteins: TLR4, MyD88, nuclear factor kappa B (NFkB p65), inhibitor of NFkB alpha (IkBα), IkB kinase alpha (IKK-α), TNF receptor-associated factor 6 (TRAF6), TRIF, interferon regulatory factor 3 (IRF3), interferon β (IFN-β), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6. In addition, mel significantly attenuated the expression of IkBα, NFkB p65, TRIF and IRF-3, which are involved in TLR4-mediated signaling in OC during ethanol intake.
Conclusion
Collectively, our results suggest that mel attenuates the TLR4-induced MyD88- and TRIF-dependent signaling pathways in ethanol-preferring rats with OC.
doi:10.1186/s12885-015-1032-4
PMCID: PMC4322437  PMID: 25655081
Ovarian cancer; Melatonin; Inflammation; TLR4; MyD88; TRIF
17.  Retrospective review using targeted deep sequencing reveals mutational differences between gastroesophageal junction and gastric carcinomas 
BMC Cancer  2015;15:32.
Background
Adenocarcinomas of both the gastroesophageal junction and stomach are molecularly complex, but differ with respect to epidemiology, etiology and survival. There are few data directly comparing the frequencies of single nucleotide mutations in cancer-related genes between the two sites. Sequencing of targeted gene panels may be useful in uncovering multiple genomic aberrations using a single test.
Methods
DNA from 92 gastroesophageal junction and 75 gastric adenocarcinoma resection specimens was extracted from formalin-fixed paraffin-embedded tissue. Targeted deep sequencing of 46 cancer-related genes was performed through emulsion PCR followed by semiconductor-based sequencing. Gastroesophageal junction and gastric carcinomas were contrasted with respect to mutational profiles, immunohistochemistry and in situ hybridization, as well as corresponding clinicopathologic data.
Results
Gastroesophageal junction carcinomas were associated with younger age, more frequent intestinal-type histology, more frequent p53 overexpression, and worse disease-free survival on multivariable analysis. Among all cases, 145 mutations were detected in 31 genes. TP53 mutations were the most common abnormality detected, and were more common in gastroesophageal junction carcinomas (42% vs. 27%, p = 0.036). Mutations in the Wnt pathway components APC and CTNNB1 were more common among gastric carcinomas (16% vs. 3%, p = 0.006), and gastric carcinomas were more likely to have ≥3 driver mutations detected (11% vs. 2%, p = 0.044). Twenty percent of cases had potentially actionable mutations identified. R132H and R132C missense mutations in the IDH1 gene were observed, and are the first reported mutations of their kind in gastric carcinoma.
Conclusions
Panel sequencing of routine pathology material can yield mutational information on several driver genes, including some for which targeted therapies are available. Differing rates of mutations and clinicopathologic differences support a distinction between adenocarcinomas that arise in the gastroesophageal junction and those that arise in the stomach proper.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1021-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1021-7
PMCID: PMC4322811  PMID: 25656989
Gastric cancer; Gastroesophageal junction cancer; Gastric cancer genomics; Gastric cancer sequencing
18.  Concurrent paclitaxel-based chemo-radiotherapy for post-surgical microscopic residual tumor at the bronchial margin (R1 resection) in non-small-cell lung cancer 
BMC Cancer  2015;15:36.
Background
The microscopic residual tumor at the bronchial margin after radical surgery (R1 resection) affects prognosis negatively in non-small-cell lung cancer (NSCLC) patients. For patients with good performance status, a potential cure still exists. Here, we report the outcomes of concurrent paclitaxel-based chemo-radiotherapy (CRT) for NSCLC patients with microscopically positive bronchial margins or peribronchial infiltration.
Methods
A retrospective search in the clinical database was conducted in three hospitals. Patients were identified and evaluated if treated with radiotherapy combined with paclitaxel-based chemotherapy. The objects analyzed were local control time, progression-free survival (PFS), overall survival (OS), and treatment-related toxicity.
Results
Sixty-one patients with microscopic residual tumor at the bronchial stump following pulmonary lobectomy were identified. Forty-six patients who had received concurrent paclitaxel-based CRT were analyzed. The median follow-up was 40 months (range: 15.0–77.5 months). The 1-, 2- and 3-year survival rates were 97.8%, 60.9% and 36.9%, respectively. The local recurrences were recorded in 19.6% (9/46) patients. Median PFS and OS for the evaluated cohort were 23.0 [95% confidence interval (CI): 21.3–24.7] and 32.0 (95% CI: 23.7–40.3) months, respectively. The most common side effects were hematological toxicity (neutropenia, 93.5%; anemia, 89.1%; and thrombocytopenia, 89.1%) and no treatment-related deaths. Grade ≥2 acute radiation-induced pneumonitis and esophagitis were recorded in 43.5% (20/46) and 26.1% (12/46) patients, respectively. By univariate analysis, non-squamous cell lung cancer was associated with a significantly longer survival time (45.1 vs 26.4 months, p = 0.013).
Conclusions
For NSCLC patients with post-surgical microscopic residual tumor at the bronchial stump, concurrent paclitaxel-based chemo-radiotherapy achieved promising outcomes with accepted treatment-related toxicity.
doi:10.1186/s12885-015-1036-0
PMCID: PMC4324030  PMID: 25655307
19.  Cholangiocarcinoma: spectrum of appearances on Gd-EOB-DTPA-enhanced MR imaging and the effect of biliary function on signal intensity 
BMC Cancer  2015;15:38.
Background
To describe the Gd-EOB-DTPA-enhanced MRI appearances of cholangiocarcinoma, and evaluate the relative signal intensities (RSIs) changes of major abdominal organs, and investigate the effect of total bilirubin (TB) levels on the RSI.
Methods
25 patients with pathologically-proven cholangiocarcinoma underwent Gd-EOB-DTPA-enhanced MRI. The visualization of the biliary system during biliary phase (BP) was observed. RSIs of the abdominal aorta (A), portal vein (V), liver (L), and spleen (S) were measured.
Results
On hepatocellular phase (HP), exophytic tumors (n =10) and infiltrative tumors (n =10) were hypointense, polypoid tumors (n = 2) were hypointense, and combined type tumors (n = 3) had mixed appearances. While patients with normal TB levels (≤22 μmol/L, n = 12) had clear visualization of the biliary tree during BP, those with elevated TB levels (>22 μmol/L, n = 13) had obscured or no visualization. In addition, patients with normal TB levels had higher RSIA, RSIV and RSIS than those with elevated TB levels on all dynamic phases (P <0.001), and lower RSIA, RSIV and RSIS on HP and BP (P <0.001). Patients with normal TB levels had higher RSIL than those with elevated TB levels on all phases (P <0.001).
Conclusions
RSIs of major abdominal organs reflected underlying biliary function. Cholangiocarcinoma patients with elevated TB levels had delayed excretion of Gd-EOB-DTPA compared with patients with normal TB levels.
doi:10.1186/s12885-015-1039-x
PMCID: PMC4324426  PMID: 25655565
Cholangiocarcinoma; Gd-EOB-DTPA; Magnetic resonance imaging; Biliary function
20.  High levels of dietary soy decrease mammary tumor latency and increase incidence in MTB-IGFIR transgenic mice 
BMC Cancer  2015;15:37.
Background
Epidemiologic data indicates that Asian diets, which are high in soy protein, reduce a women’s risk of developing breast cancer. However, it has been difficult to dissociate the benefits of soy from other variables including environmental and lifestyle factors. Since prospective studies in humans would take decades to complete, rodent models provide a valuable research alternative.
Methods
In this study, MTB-IGFIR transgenic mice, which develop mammary tumors resulting from overexpression of the type I insulin-like growth factor receptor (IGF-IR), were utilized. MTB-IGFIR mice were fed a soy-based or casein-based diet throughout all stages of development to reflect soy exposure in Asian cultures. Mammary tumors were initiated at 2 different developmental stages by commencing IGF-IR transgene expression either during puberty or in adult mice.
Results
MTB-IGFIR mice fed a soy-based diet displayed increased tumor incidence and accelerated tumor onset compared to MTB-IGFIR mice fed a casein diet. Two markers of estrogen receptor signaling, Pgr and Areg, were elevated in mammary tissue from mice fed the soy diet compared to mice fed the casein diet suggesting that high levels of soy may promote mammary tumor development through acting as an estrogen receptor agonist. Mammary tumors from mice fed a soy diet more frequently expressed metaplastic markers such as cytokeratins 5 and 14 as well as p63 and displayed reduced lung metastases compared to mammary tumors from mice fed a casein diet.
Conclusions
Diets consisting of very high levels of soy protein promote mammary tumor development and decrease tumor latency possibly through activating estrogen receptor signaling. Additional studies are required to determine whether a more moderate amount of dietary soy can inhibit oncogene-induced mammary tumorigenesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1037-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1037-z
PMCID: PMC4324669  PMID: 25655427
Breast cancer; Soy; IGF-IR; Tumor initiation; Tumor progression; Metastasis; Metaplastic breast cancer; Amphiregulin
21.  Rosiglitazone may reduce non-melanoma skin cancer risk in Taiwanese 
BMC Cancer  2015;15:41.
Background
Whether rosiglitazone may affect the risk of non-melanoma skin cancer (NMSC) has not been investigated.
Methods
The reimbursement databases of all Taiwanese diabetic patients from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2006 and a total of 886418 patients with type 2 diabetes were followed up for NMSC incidence until the end of 2009. Incidences for ever-users, never-users and subgroups of rosiglitazone exposure (using tertile cutoffs of duration of therapy and cumulative dose) were calculated and hazard ratios estimated by Cox regression. Additional models were created as sensitivity analyses.
Results
There were 103097 ever-users and 783321 never-users, respective numbers of incident NMSC 250 (0.24%) and 2084 (0.27%), and respective incidence 68.90 and 76.77 per 100000 person-years. Although the overall hazard ratio was not significant in the unadjusted, age-sex-adjusted or fully adjusted model, the risk was significantly lower in the third tertile of duration of therapy and cumulative dose, with significant P for trends. The fully adjusted hazard ratio (95% confidence interval) for a duration of therapy >13.77 months and a cumulative dose of >1752 mg was 0.723 (0.566, 0.923) and 0.783 (0.618, 0.993), respectively. The findings were supported by various sensitivity analyses.
Conclusions
Rosiglitazone may reduce the risk of NMSC, but further confirmation is required.
doi:10.1186/s12885-015-1057-8
PMCID: PMC4325941  PMID: 25655946
Diabetes mellitus; Non-melanoma skin cancer; Rosiglitazone; Taiwan
22.  Fluoroquinolone resistance in bacteremic and low risk febrile neutropenic patients with cancer 
BMC Cancer  2015;15:42.
Background
The low risk febrile neutropenic patients with Multinational Association for Supportive Care in Cancer (MASCC) score of more than 20 are recommended to be treated with fluoroquinolone-based oral treatment by the National Comprehensive Cancer Network (NCCN) guideline. This recommendation relies, at least partially, on the high sensitivity of the blood culture isolates to fluoroquinolone in clinical trials conducted in Western countries. Whether this also applies in middle or low income countries like China where antibiotic resistance is becoming prevalent recently has not been evaluated.
Methods
All the positive blood culture results from January 2010 to December 2013 in the 2 large Chinese cancer centers were reviewed. The patients were included into the study with the following criteria: febrile neutropenia, solid tumor or lymphoma, MASCC score >20, positive blood cultures within two days of the onset of fever, and detailed treatment history.
Results
A total of 38 patients were included in this analysis. Two patients had polymicrobial bacteremia (Enterococcus faecalis and Flavimonas oryzihabitans). Other isolates included coagulase-negative staphylococcus, micrococcal species, viridans streptococci, Klebsiella pneumoniae, and Escherichia coli. The majority of the monomicrobial isolates from these 36 patients was Escherichia coli (28 patients, 74%). Notably, in contrast to the high sensitivity to fluoroquinolone from blood culture of the low risk patients in previous reports in Westen countries, a very high drug resistance was observed: 13 out of 28 Escherichia coli isolates (46%) or 14 out of all 38 positive cultures (37%).
Conclusion
The results warrant further validations in prospective clinical trials in countries where antibiotic resistance is prevalent to ensure appropriate antibiotic administration.
doi:10.1186/s12885-015-1063-x
PMCID: PMC4326398
23.  High-density SNP arrays improve detection of HER2 amplification and polyploidy in breast tumors 
BMC Cancer  2015;15:35.
Background
Human epidermal growth factor receptor-2 (HER2) overexpression and gene amplification are currently established by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. This study investigates whether high-density single nucleotide polymorphism (SNP) arrays can provide additional diagnostic power to assess HER2 gene status.
Methods
DNA from 65 breast tumor samples previously diagnosed by HER2 IHC and FISH analysis were blinded and examined for HER2 copy number variation employing SNP array analysis.
Results
SNP array analysis identified 24 (37%) samples with selective amplification or imbalance of the HER2 region in the q-arm of chromosome 17. In contrast, only 15 (23%) tumors were found to have HER2 amplification by IHC and FISH analysis. In total, there was a discrepancy in 19 (29%) samples between SNP array and IHC/FISH analysis. In 12 of these cases, the discrepancy towards FISH could be attributed to concomitant amplification or deletion of the centromeric region, which harbors the FISH reference probe sequence. In 3 tumors, repeated IHC/FISH analysis revealed that the original IHC/FISH analysis had failed to indicate the correct HER2 expression level. Finally, the SNP array analysis revealed that more than two thirds of the samples exhibited polyploidy that was unrecognized by conventional FISH.
Conclusions
Collectively, the data show that determination of HER2 copy number variations by SNP array-based genomic segmentation analysis is an effective supplement to IHC/FISH HER2 analysis that, by providing additional diagnostic sensitivity and accuracy, may elect more women for targeted treatment with HER2 inhibitors.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1035-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1035-1
PMCID: PMC4326399  PMID: 25655188
Breast cancer; HER2 amplification; Polyploidy; SNP array
24.  Supervised physical exercise to improve the quality of life of cancer patients: the EFICANCER randomised controlled trial 
BMC Cancer  2015;15:40.
Background
The optimal form of exercise for individuals with cancer has yet to be identified, but there is evidence that exercise improves their quality of life. The aim of this study is to assess the efficacy and efficiency of an innovative physical exercise programme, for individuals undergoing chemotherapy for breast, gastrointestinal or non-small cell lung tumours, for improving quality of life, reducing level of fatigue, and enhancing functional capacity over time.
Design/Methods
We will conduct a clinical trial in 66 patients with stage IV breast, gastrointestinal or non-small cell lung cancer, recruited by the Department of Oncology of the referral hospital from 4 primary care health centres of the Basque Health Service (Osakidetza). These patients will be randomised to one of two groups. The treatment common to both groups will be the usual care for cancer: optimized usual drug therapies and strengthening of self-care; in addition, patients in the intervention group will participate in a 2-month exercise programme, including both aerobic and strength exercises, supervised by nurses in their health centre. The principal outcome variable is health-related quality of life, measured blindly with the 30-item European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire and Short Form-36 four times: at baseline, and 2, 6 and 12 months later. The secondary outcome variables are fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire), functional capacity (6-Minute Walk Test and cardiorespiratory test), muscle strength (hand-held dynamometry and sit-to-stand test), radiological response to treatment (Response Evaluation Criteria In Solid Tumors) and progression-free and overall survival. Age, sex, diagnosis, chemotherapy regimen, Eastern Cooperative Oncology Group performance status and smoking status will be considered as predictive variables. Data will be analysed on an intention-to-treat basis, comparing changes at each time point between groups, adjusting for baseline values by analysis of covariance.
Discussion
As well as achieving the objectives set, this study will provide us with information on patient perception of the care received and an opportunity to develop a project based on collaborative action between the primary care and oncology professionals.
Trial registration
ClinicalTrials.gov Identifier: NCT01786122 Registration date: 02/05/2013.
doi:10.1186/s12885-015-1055-x
PMCID: PMC4327975  PMID: 25655792
Breast cancer; Colorectal cancer; Lung cancer; Metastasis; Physical exercise; Quality of life
25.  Trogocytosis-mediated expression of HER2 on immune cells may be associated with a pathological complete response to trastuzumab-based primary systemic therapy in HER2-overexpressing breast cancer patients 
BMC Cancer  2015;15:39.
Background
Trogocytosis is defined as the transfer of cell-surface membrane proteins and membrane patches from one cell to another through contact. It is reported that human epidermal growth factor receptor 2 (HER2) could be transferred from cancer cells to monocytes via trogocytosis; however, the clinical significance of this is unknown. The aim of this study is to demonstrate the presence and evaluate the clinical significance of HER2+ tumor-infiltrated immune cells (arising through HER2 trogocytosis) in HER2-overexpressing (HER2+) breast cancer patients receiving trastuzumab-based primary systemic therapy (PST).
Methods
To assess the trogocytosis of HER2 from cancer cells to immune cells, and to evaluate the up- and down-regulation of HER2 on immune and cancer cells, peripheral blood mononuclear cells from healthy volunteers and breast cancer patients were co-cultured with HER2+ and HER2-negative breast cancer cell lines with and without trastuzumab, respectively. The correlation between HER2 expression on tumor-infiltrated immune cells and a pathological complete response (pCR) in HER2+ breast cancer patients treated with trastuzumab-based PST was analyzed.
Results
HER2 was transferred from HER2+ breast cancer cells to monocytes and natural killer cells by trogocytosis. Trastuzumab-mediated trogocytosed-HER2+ effector cells exhibited greater CD107a expression than non-HER2-trogocytosed effector cells. In breast cancer patients, HER2 expression on tumor-infiltrated immune cells in treatment naïve HER2+ tumors was associated with a pCR to trastuzumab-based PST.
Conclusions
HER2-trogocytosis is visible evidence of tumor microenvironment interaction between cancer cells and immune cells. Given that effective contact between these cells is critical for immune destruction of target cancer cells, this interaction is of great significance. It is possible that HER2 trogocytosis could be used as a predictive biomarker for trastuzumab-based PST efficacy in HER2+ breast cancer patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1041-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1041-3
PMCID: PMC4329225  PMID: 25655677
Breast cancer; HER2; Trogocytosis; Trastuzumab

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