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Background: Randomized clinical trials compare participants receiving an experimental intervention to participants receiving standard of care (SOC). If one could predict the outcome for participants receiving SOC, a trial could be designed where all participants received the experimental intervention, with the observed outcome of the experimental group compared to the prediction for those individuals. Methods: We used the CancerMath calculator to predict outcomes for participants in two large clinical trials of adjuvant chemotherapy for breast cancer: NSABPB15 and CALGB9344. NSABPB15 was the training set, and we used the modified algorithm to predict outcomes for two groups from CALGB9344: one which received standard of care (SOC) chemotherapy and one which received paclitaxel in addition. We made a prediction for each individual CALGB9344 participant, assuming each received only SOC. Results: The predicted outcome for the group which received only SOC matched what was observed in the CALGB9344 trial. In contrast, the predicted outcome for the group also receiving paclitaxel was significantly worse than what was observed for this group. This matches the conclusion of CALGB9344 that adding paclitaxel to SOC improves survival. Conclusion: This project proves that a statistical model can predict the outcome of clinical trial participants treated with SOC. In some circumstances, a predictive model could be used instead of a control arm, allowing all participants to receive experimental treatment. Predictive models for cancer and other diseases could be constructed using the vast amount of outcomes data available to the federal government, and made available for public use. [ABSTRACT FROM AUTHOR]

Human protein biomarker discovery relies heavily on pre-clinical models, in particular established cell lines and patient-derived xenografts, but confirmation studies in primary tissue are essential to demonstrate clinical relevance. We describe in this study the process that was followed to clinically translate a 5-protein response signature predictive for the activity of an anti-HER3 monoclonal antibody (lumretuzumab) originally measured in fresh frozen xenograft tissue. We detail the development, qualification, and validation of the multiplexed targeted mass spectrometry assay used to assess the signature performance in formalin-fixed, paraffin-embedded human clinical samples collected in a phase Ib trial designed to evaluate lumretuzumab in patients with metastatic breast cancer. We believe that the strategy delineated here provides a path forward to avoid the time- and cost-consuming step of having to develop immunological reagents against unproven targets. We expect that mass spectrometry-based platforms may become part of a rational process to rapidly test and qualify large number of candidate biomarkers to identify the few that stand a chance for further development and validation. [ABSTRACT FROM AUTHOR]

Informed consent is an essential part of an ethical clinical trial; to this end, researchers have developed several interventions to promote participants’ full understanding of trials and thereby improve the consent process. However, few empirical studies have examined how patients make the decision of whether to give consent. The objective of this study, therefore, is to analyze patients’ decision-making process when participating in clinical trials. We conduct an internet survey (n = 2,045) and interview data analysis (n = 40) with patients and categorize respondents into three types of participants: active, passive, and non-participation. Our results show that patients often make informal and quick decisions before medical staff provide them with relevant information during the informed consent process. For example, 55.9% of patients received initial information on clinical trials from an online article or web advertising, and 54.5% consulted no one about whether to participate in the clinical trial before making a decision. Only 20.7% of respondents subjectively spent time making the decision whether to participate; 43.0% of patients who said that they “spent time” coming to a decision took four or more days to reach a decision, while 8.3% of people who “did not spend time” making a decision took this among of time. Based on these results, we were able to break patients’ decision-making process into four steps: first contact, informal decision making, relevant information, and formal decision making. Our results show that patients are most likely to make a decision based on the first information they receive on the clinical trial, whatever the source. To this end, having a list of questions for potential participants to ask researchers would be useful in helping better collecting information of clinical trials. In addition, research teams should give patients more than four days to decide between providing them with relevant information and obtaining written consent, even if the patient seems to make a quick decision. [ABSTRACT FROM AUTHOR]

Background: Synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy. Materials and methods: We established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer. Results: Twelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies. Conclusion: A set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to assess the estimated “per patient” total cost for a single Oncologic Italian Cancer Center participating in a multicenter clinical trial with new anticancer biological agents using the activity-based costing (ABC) methodology. Methodology: Nine randomized phase 3 clinical trials employing biological agents at the National Cancer Institute of Napoli, Italy, were analyzed to indentify “per patient” costs of each trial, according to the ABC methodology. The average consumption of resources for a patient completing the entire planned treatment was estimated for each trial. Through interviews of the personnel (doctors, nurses and technicians) and by analyses of the clinical trials protocols, the main activities of the 9 clinical trials were identified and, for each trial, the complete health care pathway of the patients and the treatment programmes were minutely reconstructed. Drug costs were not included because provided by Sponsors. Principal findings: The average costs of the pre-study, treatment, monitoring, follow-up, audit, and administrative activities accounted for 2.357, 4.783, 700, 372, 1.263, and 9 Euro, respectively. The average total cost estimated for all “per patient” activities, including overhead costs, was 11.379 Euro. Staff costs accounted for € 5.988, while costs of diagnostic test accounted for 3.494 Euro. Clinical trials with immunotherapeutic drugs accounted for higher costs (+601 Euro as oncological staff costs, +1.318 Euro as intermediate services cost and +384 Euro as overheads). Conclusions: The average total cost estimated for all “per patient” activities of a clinical trial with new anticancer biological agents was 11.379 Euro using the ABC methodology. [ABSTRACT FROM AUTHOR]

Background: Preclinical evidence suggests statins may have anti-tumor properties. Large observational studies are also consistent with improved survival and cancer-specific outcomes among cancer patients on statins. We sought to evaluate the randomized controlled trials of statins in addition to usual anti-cancer therapy. Methods: A systematic search of MEDLINE, Embase, CINAHL, Cochrane Library, Web of Science, Papers First and Clinicaltrials.gov was performed from inception through to July 4, 2017 to identify randomized clinical trials that investigated statin therapy in cancer patients. Our primary outcome was overall survival and our secondary outcome was progression-free survival. We calculated summary hazard ratio’s (HR) and 95% confidence intervals (CI) based on random-effects models using aggregate data. PROSPERO (CRD42017065503). Results: Ten studies with 1,881 individuals were included with 1,572 deaths and a median follow-up of 23 months. All trials included patients with advanced (stage 3 or higher) disease. There was minimal between-study statistical heterogeneity (I2 = 1.8%, for OS; I2 = 0%, for PFS). The pooled HR for overall survival in patients randomized to statins plus standard anti-cancer therapy versus standard therapy alone was 0.94 (95% CI, 0.85 to 1.04). In the 9 studies that reported progression-free survival (1,798 participants), the pooled HR for statin plus standard therapy versus standard therapy alone was 0.97 (95% CI, 0.87 to 1.07). Conclusions: In patients with advanced cancer and a prognosis <2 years, the addition of statins to standard anti-cancer therapy does not appear to improve overall survival or progression-free survival. Future research should assess if cancer patients with better prognosis benefit from longer-term statin therapy. [ABSTRACT FROM AUTHOR]

PIKfyve, an evolutionarily conserved kinase synthesizing PtdIns5P and PtdIns(3,5)P2, is crucial for mammalian cell proliferation and viability. Accordingly, PIKfyve inhibitors are now in clinical trials as anti-cancer drugs. Among those, apilimod is the most promising, yet its potency to inhibit PIKfyve and affect endomembrane homeostasis is only partially characterized. We demonstrate here for the first time that apilimod powerfully inhibited in vitro synthesis of PtdIns5P along with that of PtdIns(3,5)P2. HPLC-based resolution of intracellular phosphoinositides (PIs) revealed that apilimod triggered a marked reduction of both lipids in the context of intact cells. Notably, there was also a profound rise in PtdIns3P resulting from arrested PtdIns3P consumption for PtdIns(3,5)P2 synthesis. As typical for PIKfyve inhibition and the concomitant PtdIns(3,5)P2 reduction, apilimod induced the appearance of dilated endomembrane structures in the form of large translucent cytoplasmic vacuoles. Remarkably, bafilomycin A1 (BafA1) fully reversed the aberrant cell phenotype back to normal and completely precluded the appearance of cytoplasmic vacuoles when added prior to apilimod. Inspection of the PI profiles ruled out restoration of the reduced PtdIns(3,5)P2 pool as a molecular mechanism underlying BafA1 rescue. Rather, we found that BafA1 markedly attenuated the PtdIns3P elevation under PIKfyve inhibition. This was accompanied by profoundly decreased endosomal recruitment of fusogenic EEA1. Together, our data demonstrate that apilimod inhibits not only PtdIns(3,5)P2 but also PtdIns5P synthesis and that the cytoplasmic vacuolization triggered by the inhibitor is precluded or reversed by BafA1 through a mechanism associated, in part, with reduction in both PtdIns3P levels and EEA1 membrane recruitment. [ABSTRACT FROM AUTHOR]

Introduction: Despite the importance of chemotherapy in the treatment of early stage triple negative breast cancer (TNBC), no one optimal regimen has been identified. We conducted a pilot trial comparing outcomes for the three most commonly used chemotherapy regimens to assess the feasibility of conducting a larger definitive trial. Methods: Using integrated consent, newly diagnosed TNBC patients were randomised to one of three standard regimens: dose-dense doxorubicin-cyclophosphamide then paclitaxel, doxorubicin-cyclophosphamide then weekly paclitaxel or 5-FU-epirubicin-cyclophosphamide then docetaxel. Feasibility endpoints included; physician engagement, accrual rates, physician compliance and patient satisfaction with the integrated consent model. Our anticipated pilot trial sample size was 35 randomised patients in one year. Results: Between August 30th, 2016 and January 31st 2017, 2 patients met eligibility and were randomised. A survey of 10 participating oncologists was performed to identify potential strategies to enhance accrual. Most investigators (9/10) believed that the best regimen for TNBC was unknown, and 4/10 felt this was a pressing clinical question. Physicians’ responses suggested that poor accrual was due to: a lack of interest in some study arms as oncologists already had a preferred regimen (4/10) and concerns about trial demands in busy clinics (3/10). The pilot feasibility endpoints were not met and the study was closed. Conclusions: Despite initial interest in the trial question and multiple investigators agreeing to approach patients, this trial failed to meet feasibility endpoints. The reasons for poor accrual were multiple and require further evaluation if this important patient-centred question is to be answered. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

Purpose: Clinical Trials have emerged as the main force in driving the development of medicine. However, little is known about the current status of clinical trials regarding nasopharyngeal carcinoma (NPC). This study aimed at providing a comprehensive landscape of NPC-related trials on the basis of ClinicalTrials.gov database. Patients and methods: We used the keyword “nasopharyngeal carcinoma” to search the ClinicalTrials.gov database and assessed the characteristics of these trials. Results: Up to December 30, 2016, 462 eligible trials in total were identified, of which 222 (48.0%) recruited only NPC (NPC trials) and the other 240 (52.0%) recruited both NPC and other cancers (multiple cancer trials). Moreover, 47 (10.2%) were Epstein-Barr virus (EBV)-related trials and 267 (57.8%) focused on metastatic/recurrent disease. Compared with NPC trials, the multiple cancer trials had a higher percentage of phase 1 (26.7% vs. 6.7%, P < 0.001) studies and more patients with metastatic/recurrent disease (72.5% vs. 41.9%, P < 0.001). Notably, non-EBV trials had more phase 2 or 3 (78.4% vs. 48.8%, P < 0.001) and interventional studies (89.5% vs. 70.7%, P = 0.002) than EBV trials. Obviously, more phase 2/3 or 3 trials were conducted in patients with non-metastatic/recurrent disease (29.4% vs. 4.9%, P < 0.001); however, metastatic/recurrent trials were more likely to be anticancer (94.6% vs. 63.6%, P < 0.001). Conclusions: The role of plasma EBV DNA in clinical trials is underestimated, and high-level randomized clinical trials should be performed for patients with metastatic/recurrent disease. [ABSTRACT FROM AUTHOR]

Aim: Chemotherapy side effects are often reported in clinical trials; however, there is little evidence about their incidence in routine clinical care. The objective of this study was to describe the frequency and severity of patient-reported chemotherapy side effects in routine care across treatment centres in Australia. Methods: We conducted a prospective cohort study of individuals with breast, lung or colorectal cancer undergoing chemotherapy. Side effects were identified by patient self-report. The frequency, prevalence and incidence rates of side effects were calculated by cancer type and grade, and cumulative incidence curves for each side effect computed. Frequencies of side effects were compared between demographic subgroups using chi-squared statistics. Results: Side effect data were available for 449 eligible individuals, who had a median follow-up of 5.64 months. 86% of participants reported at least one side effect during the study period and 27% reported a grade IV side effect, most commonly fatigue or dyspnoea. Fatigue was the most common side effect overall (85%), followed by diarrhoea (74%) and constipation (74%). Prevalence and incidence rates were similar across side effects and cancer types. Age was the only demographic factor associated with the incidence of side effects, with older people less likely to report side effects. Conclusion: This research has produced the first Australian estimates of self-reported incidence of chemotherapy side effects in routine clinical care. Chemotherapy side effects in routine care are common, continue throughout chemotherapy and can be serious. This work confirms the importance of observational data in providing clinical practice-relevant information to decision-makers. [ABSTRACT FROM AUTHOR]

Background: Very little is known about the proportion of oncology trials that get published, the time it takes to publish them, or the reasons why oncology trials do not get published. Methods: We analyzed all clinical trials that closed to accrual at our cancer center between 2009–2013. Trials were categorized by study purpose (therapeutic vs. diagnostic), phase (pilot, phase I, II, or III), and sponsor (industrial, cooperative group, institutional, or peer-reviewed). Final publications were identified in MEDLINE and EMBASE by NCT numbers, or by querying the principal investigator. For trials not published, we surveyed the principal investigators to identify the reason for non-publication. Findings: 469 of 809 protocols (58%) had been published by November 2016. The calculated probability of publication 7 years after completing accrual was 70.4%; the calculated median time to publication was 47 months. Only 18.8% of protocols overall were estimated to be published within 2 years from completing accrual. The calculated probability of publication was higher for therapeutic trials than non-therapeutic trials, but there was no difference based on phase or sponsor. Among protocols not published, 45.3% had completed accrual, and among these, a majority had a manuscript in preparation or review, or the trial was still collecting data. Failure to publish due to a pharmaceutical sponsor was rare. 30.6% of unpublished trials had closed for various reasons before completing accrual, usually due to poor accrual or pharmaceutical sponsor issues. Interpretation: Almost 30% of trials were calculated to be unpublished by 7 years after closing to accrual at our institution. Failure to reach accrual goals was an important factor in non-publication. We have devised new institutional policies that identify trials likely not to meet accrual goals and require early closure. We should be able to shorten the time from accrual completion to publication, especially for pilot and phase I trials for which long follow up is not needed. [ABSTRACT FROM AUTHOR]

Satish Gopal discusses the challenges of deliverable cancer care and cancer trials in sub-Saharan Africa as well as a potential framework for overcoming these challenges. [ABSTRACT FROM AUTHOR]

Paul Pinsky of the US National Cancer Institute and colleagues describe the implementation and outcomes of web-based data sharing from the PLCO and NLST cancer screening trials. [ABSTRACT FROM AUTHOR]

Background: Informed consent forms (ICFs) for oncology clinical trials have grown increasingly longer and more complex. We evaluated objective understanding of critical components of informed consent among patients enrolling in contemporary trials of conventional or novel biologic/targeted therapies. Methods: We evaluated ICFs for cancer clinical trials for length and readability, and patients registered on those studies were asked to complete a validated 14-question survey assessing their understanding of key characteristics of the trial. Mean scores were compared in groups defined by trial and patient characteristics. Results: Fifty patients, of whom half participated in trials of immunotherapy or biologic/targeted agents and half in trials of conventional therapy, completed the survey. On average, ICFs for industry-originated trials (N = 9 trials) were significantly longer (P < .0001) and had lower Flesch ease-of-reading scores (P = .003) than investigator-initiated trials (N = 11). At least 80% of patients incorrectly responded to three key questions which addressed the experimental nature of their trial therapy, its purported efficacy and potential risks relative to alternative treatments. The mean objective understanding score was 76.9±8.8, but it was statistically significantly lower for patients who had not completed high school (P = .011). The scores did not differ significantly by type of cancer therapy (P = .12) or trial sponsor (P = .38). Conclusions: Many participants enrolled on cancer trials had poor understanding of essential elements of their trial. In order to ensure true informed consent, innovative approaches, such as expanded in-person counseling adapted to the patient’s education level or cultural characteristics should be evaluated across socio-demographic groups. Trial registration: Clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Background: Single gene tests to predict whether cancers respond to specific targeted therapies are performed increasingly often. Advances in sequencing technology, collectively referred to as next generation sequencing (NGS), mean the entire cancer genome or parts of it can now be sequenced at speed with increased depth and sensitivity. However, translation of NGS into routine cancer care has been slow. Healthcare stakeholders are unclear about the clinical utility of NGS and are concerned it could be an expensive addition to cancer diagnostics, rather than an affordable alternative to single gene testing.Methods and Findings: We validated a 46-gene hotspot cancer panel assay allowing multiple gene testing from small diagnostic biopsies. From 1 January 2013 to 31 December 2013, solid tumour samples (including non-small-cell lung carcinoma [NSCLC], colorectal carcinoma, and melanoma) were sequenced in the context of the UK National Health Service from 351 consecutively submitted prospective cases for which treating clinicians thought the patient had potential to benefit from more extensive genetic analysis. Following histological assessment, tumour-rich regions of formalin-fixed paraffin-embedded (FFPE) sections underwent macrodissection, DNA extraction, NGS, and analysis using a pipeline centred on Torrent Suite software. With a median turnaround time of seven working days, an integrated clinical report was produced indicating the variants detected, including those with potential diagnostic, prognostic, therapeutic, or clinical trial entry implications. Accompanying phenotypic data were collected, and a detailed cost analysis of the panel compared with single gene testing was undertaken to assess affordability for routine patient care. Panel sequencing was successful for 97% (342/351) of tumour samples in the prospective cohort and showed 100% concordance with known mutations (detected using cobas assays). At least one mutation was identified in 87% (296/342) of tumours. A locally actionable mutation (i.e., available targeted treatment or clinical trial) was identified in 122/351 patients (35%). Forty patients received targeted treatment, in 22/40 (55%) cases solely due to use of the panel. Examination of published data on the potential efficacy of targeted therapies showed theoretically actionable mutations (i.e., mutations for which targeted treatment was potentially appropriate) in 66% (71/107) and 39% (41/105) of melanoma and NSCLC patients, respectively. At a cost of £339 (US$449) per patient, the panel was less expensive locally than performing more than two or three single gene tests. Study limitations include the use of FFPE samples, which do not always provide high-quality DNA, and the use of "real world" data: submission of cases for sequencing did not always follow clinical guidelines, meaning that when mutations were detected, patients were not always eligible for targeted treatments on clinical grounds.Conclusions: This study demonstrates that more extensive tumour sequencing can identify mutations that could improve clinical decision-making in routine cancer care, potentially improving patient outcomes, at an affordable level for healthcare providers. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is the most intractable type of breast cancer, and there is a lack of effective targeted therapy. Insulin-like growth factor-1 receptor (IGF-1R) is reportedly a potential target for TNBC treatment. However, satisfying treatment outcomes in breast cancer patients have yet to be achieved with IGF-1R-targeted agents. Methods: To confirm whether inhibiting IGF-1R could induce autophagy, we detected autophagy-related proteins by western blotting and immunofluorescence staining of LC3-II. The IGF-1R inhibitor NVP-AEW541, autophagy inhibitor 3-methyladenine (3-MA) and Atg7 small interfering RNA (siRNA) were used to further investigate the effects of autophagy induced by IGF-1R inhibition in TNBC cells. The CCK8 assay, EdU assay, apoptosis and cell cycle analyses were applied to test cell function after treatment. Results: NVP-AEW541 markedly induced autophagy in TNBC cells by increasing the levels of the autophagy-related protein Beclin-1 and the LC3-II/LC-I ratio and reducing the selective autophagy substrate p62. Joint application of 3-MA or Atg7 siRNA enhanced the cell growth inhibition and apoptosis effects of NVP-AEW541 by arresting cells at G1/G0 phase and increasing Bax expression and decreasing that of Bcl-2. Conclusion: Targeting IGF-1R in TNBC induces cell-protective autophagy, thereby weakening the therapeutic effect of agents directed toward IGF-1R. Our findings reveal that combined use autophagy-disrupting agents can enhance the therapeutic efficacy of IGF-1R inhibitors in TNBC cells and may provide a valuable treatment strategy for IGF-1R inhibitor-based therapies for TNBC and other IGF-1 signaling-associated tumors. [ABSTRACT FROM AUTHOR]

Clinical trials have provided conflicting results regarding whether epidermal growth factor receptor (EGFR) overexpression predicts poor survival in cervical cancer patients. In this study, we perform a meta-analysis of the association between EGFR expression and survival in cervical cancer patients. We searched clinical studies in the Medline, PubMed, Embase, and Web of Science databases. A total of 22 studies with 2,505 patients were included, and pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for each study. Heterogeneity was assessed using Higgins I2 to select a Mantel-Haenszel fixed effects model (I2 ≤50%) or a DerSimonian-Laird random effects model (I2 ≥50%). High EGFR levels predicted poor overall survival (OS) (HR: 1.40, 95% CI: 1.10–1.78) and disease-free survival (DFS) (HR: 1.84, 95% CI: 1.51–2.24). Stratified analyses showed that EGFR overexpression was significantly related to poor DFS in patients treated with chemoradiation or surgery. Moreover, the pooled odds ratios (ORs) revealed associations between EGFR expression and clinicopathological features, such as lymph node metastasis (OR: 1.72, 95% CI: 1.23–2.40) and tumor size ≥4 cm (OR: 1.64, 95% CI: 1.20–2.23). This meta-analysis demonstrates that EGFR overexpression is closely associated with reduced survival in patients with cervical cancer. These results may facilitate the individualized management of clinical decisions for anti-EGFR therapies in cervical cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Enrolling cancer patients in phase I clinical trials (P1s) requires that they fulfill specific criteria. Between the time they sign the consent form and the 1st administration of the experimental drug, some patients may be excluded and considered as screen failures (SFs). Our objective was to assess SF patients profiles and the reasons and risk factors for SFs. Materials and Methods: All patients included in P1s at Gustave Roussy from 2008 to 2013 were reviewed retrospectively. SFs were matched with control P1 patients who were successfully enrolled. Patient and tumor characteristics, P1 types and the reasons for SF were analyzed. Results: Among 1,293 patients, 192 (15%) were SF cases; 182 SF cases were matched with 182 controls: median age was 57 (48–64) and 55 (47–63), median home-cancer center distance was 69 vs 55 km, 45% vs 34% had more than 2 metastatic sites, median screening period was 14 vs 11 days, median progression-free survival during the previous line was 12 vs 14 weeks, 37% vs 29% of LDH values were above the upper limit of normal, 42% vs 36% of albumin values were < 35 g/L, respectively. Reasons for SFs were cancer progression (44%), sponsor decision unrelated to a clinical reason (25%), patient retrieval (13.5%), relevant comorbidity (13.5%). Multivariate analysis revealed that a high Royal Marsden Hospital (RMH) prognostic score was potentially associated with higher risk of SFs (OR = 2.3; 95% CI [1.0–5.7], p = 0.06). Conclusion: Cancer progression led to half of the SFs in P1s. Physicians should pay attention to the RMH score at the time of patient inclusion to avoid further SFs. [ABSTRACT FROM AUTHOR]

Background: Our objective is to compare the cost-utility of icotinib and gefitinib for the second-line treatment of advanced non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Methods: Model technology was applied to assess the data of randomized clinical trials and the direct medical costs from the perspective of the Chinese healthcare system. Five-year quality-adjusted life years (QALYs) and incremental cost-utility ratios (ICURs) were calculated. One-way and probabilistic sensitivity analyses (PSA) were performed. Results: Our model suggested that the median progression-free survival (PFS) was 4.2 months in the icotinib group and 3.5 months in the gefitinib group while they were 4.6 months and 3.4 months, respectively, in the trials. The 5-year QALYs was 0.279 in the icotinib group and 0.269 in the gefitinib group, and the according medical costs were $10662.82 and $13127.57. The ICUR/QALY of icotinib versus gefitinib presented negative in this study. The most sensitive parameter to the ICUR was utility of PFS, ranging from $-1,259,991.25 to $-182,296.61; accordingly the icotinib treatment consistently represented a dominant cost-utility strategy. Conclusions: The icotinib strategy, as a second-line therapy for advanced NSCLC patients in China, is the preferred strategy relative to gefitinib because of the dominant cost-utility. In addition, icotinib shows a good curative effect and safety, resulting in a strong demand for the Chinese market. [ABSTRACT FROM AUTHOR]

Background: Metastatic breast cancer (MBC) remains a devastating and incurable disease. Over the past decade, the implementation of clinical trials both with and without molecular targeted therapeutics has impacted the daily clinical treatment of patients with MBC. In this study, we determine whether including MBC patients in clinical trials affects clinical outcomes. Methods: We retrospectively reviewed data for a total of 863 patients diagnosed with initial or recurrent (after receiving adjuvant systemic treatments following surgery) metastatic disease between January 2000 and December 2013. Data were obtained from the breast cancer database of Samsung Medical Center. Results: Among the 806 patients selected for inclusion, 188 (23%) had participated in clinical trials. A total of 185 clinical trials were conducted from 2000 to 2014. When compared with earlier periods (n = 10 for 2000–2004), clinical trial enrollment significantly increased over time (n = 103 for 2005–2009, P = 0.024; n = 110 for 2010–2014, P = 0.046). Multivariate analyses revealed that biologic subtype, distant recurrence free interval (DRFI), and clinical trial enrollment were independent predictors of overall survival. Patients who participated in clinical trials showed improved survival, with a hazard ratio of 0.75 (95% CI, 0.59–0.95), which was associated with a 25% reduction in the risk of death. However, subgroup analysis showed that this improved survival benefit was not maintained in patients with triple negative breast cancer (TNBC). Conclusions: Although not conclusive, we could speculate that there were differences in the use of newer agents or regimens over time, and these differences appear to be associated with improved survival. [ABSTRACT FROM AUTHOR]

Mid-study design modifications are becoming increasingly accepted in confirmatory clinical trials, so long as appropriate methods are applied such that error rates are controlled. It is therefore unfortunate that the important case of time-to-event endpoints is not easily handled by the standard theory. We analyze current methods that allow design modifications to be based on the full interim data, i.e., not only the observed event times but also secondary endpoint and safety data from patients who are yet to have an event. We show that the final test statistic may ignore a substantial subset of the observed event times. An alternative test incorporating all event times is found, where a conservative assumption must be made in order to guarantee type I error control. We examine the power of this approach using the example of a clinical trial comparing two cancer therapies. [ABSTRACT FROM AUTHOR]

Purpose: The increased practice of traditional Chinese medicine worldwide has raised concerns regarding herb-drug interactions. We analyzed the usage of Chinese herbal products containing dang-qui and investigated whether dang-qui therapy increases endometrial cancer risk among tamoxifen-treated breast cancer survivors in Taiwan. Methods: All patients newly diagnosed with invasive breast cancer who received tamoxifen treatment from January 1, 1998, to December 31, 2008 were selected from the National Health Insurance Research Database. The usage, frequency of service and type of Chinese herbal products containing dang-qui prescribed across the 31,970 survivors were evaluated. Logistic regression method was employed to estimate the odds ratios for utilization of Chinese herbal products containing dang-qui. Cox proportional hazard regression was performed to calculate the hazard ratio of endometrial cancer associated with dang-qui use within the cohort. Results: Almost one in two study subjects had used dang-qui. Among 31,938 tamoxifen-treated breast cancer survivors, 157 cases of subsequent endometrial cancer were identified. The hazard ratio for development of endometrial cancer among breast cancer survivors aged 20–79 years who had taken dang-qui after tamoxifen treatment was decreased compared to survivors who had never used dang-qui (HR: 0.61, 95%CI: 0.44–0.84). To minimise potential confounding factors, women with breast cancer in the reproductive age were excluded from further analysis, and the negative relationship between dang-qui consumption and subsequent endometrial cancer among breast cancer survivors aged 55–79 years was still observed, although not significantly (HR: 0.74, 95%CI: 0.46–1.17). Conclusions: Dang-qui consumption is common among breast cancer survivors aged 20–79 years and seems decrease the risk of subsequent endometrial cancer after less than a cumulative dose of 7,500 mg of tamoxifen treatment. [ABSTRACT FROM AUTHOR]

Background: The efficacy of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of sorafenib for treating patients with advanced HCC. Methods: The PubMed, Embase, and Web of Science databases were searched. Eligible studies were randomized controlled trials (RCTs) that assessed sorafenib therapy in patients with advanced HCC. The outcomes included overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicities. Hazard ratio (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals (CIs). Results: Seven RCTs, with a total of 3807 patients, were included in this meta-analysis. All patients received sorafenib alone, or with other chemotherapeutic regimens. Pooled estimates showed that sorafenib improved the OS (HR = 0.74, 95% CI: 0.61, 0.90; P = 0.002), or TTP outcomes (HR = 0.69, 95% CI: 0.55, 0.86; P = 0.001). Subgroup analysis revealed that sorafenib was more effective in the patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1–2 (HR = 0.77, 95% CI: 0.60, 1.0; P = 0.05), or macroscopic vascular invasion (MVI), and/or extrahepatic spread (EHS) (HR = 0.65, 95% CI: 0.46, 0.93; P = 0.02), in terms of OS. Patients who received sorafenib did not have a higher ORR (RR = 0.85, 95% CI: 0.65, 1.11; P = 0.10). In addition, there was a slight increase in toxicity in the sorafenib group. Conclusion: Treatment with sorafenib significantly improved OS and TTP in patients with advanced HCC. Additional large-scale, well-designed RCTs are needed to evaluate the efficacy of sorafenib-based therapy in the treatment of advanced HCC. [ABSTRACT FROM AUTHOR]

Background: The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX). Materials and Methods: The anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models. Results: The in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status. Conclusions: The combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models. [ABSTRACT FROM AUTHOR]

The anti-cancer activities of berberine (BBR) have been reported extensively in various cancer cell lines. However, the minimal inhibitory concentrations of BBR varied greatly among different cell lines and very few studies have been devoted to elucidate this aspect. In this study, we employed three cancer cell lines, HepG2, HeLa and SY5Y, to compare the transportation and distribution of BBR. HPLC results demonstrated that BBR was capable of penetrating all the cell lines whereas the cumulative concentrations were significantly different. HepG2 cells accumulated higher level of BBR for longer duration than the other two cell lines. Molecular docking studies revealed the BBR binding site on P-glycoprotein 1 (P-gp). In addition, we elucidated that BBR regulated P-gp at both mRNA and protein levels. BBR induced the transcription and translation of P-gp in HeLa and SY5Y cells, whereas BBR inhibited P-gp expression in HepG2 cells. Further study showed that BBR regulates P-gp expression depending on different mechanisms (or affected by different factors) in different cell lines. To summarize, our study has revealed several mechanistic aspects of BBR regulation on P-gp in different cancer cell lines and might shed some useful insights into the use of BBR in the anti-cancer drug development. [ABSTRACT FROM AUTHOR]

Statins may inhibit the expression of the mutant KRAS phenotype by preventing the prenylation and thus the activation of the KRAS protein. This study was aimed at retrospectively evaluating the effect of statin use on outcome in KRAS mutant metastatic colorectal cancer patients (mCRC) treated with cetuximab. Treatment data were obtained from patients who were treated with capecitabine, oxaliplatin bevacizumab ± cetuximab in the phase III CAIRO2 study. A total of 529 patients were included in this study, of whom 78 patients were on statin therapy. In patients with a KRAS wild type tumor (n = 321) the median PFS was 10.3 vs. 11.4 months for non-users compared to statin users and in patients with a KRAS mutant tumor (n = 208) this was 7.6 vs. 6.2 months, respectively. The hazard ratio (HR) for PFS for statin users was 1.12 (95% confidence interval 0.78–1.61) and was not influenced by treatment arm, KRAS mutation status or the KRAS*statin interaction. Statin use adjusted for covariates was not associated with increased PFS (HR = 1.01, 95% confidence interval 0.71–1.54). In patients with a KRAS wild type tumor the median OS for non-users compared to statin users was 22.4 vs. 19.8 months and in the KRAS mutant tumor group the OS was 18.1 vs. 14.5 months. OS was significantly shorter in statin users versus non-users (HR = 1.54; 95% confidence interval 1.06–2.22). However, statin use, adjusted for covariates was not associated with increased OS (HR = 1.41, 95% confidence interval 0.95–2.10). In conclusion, the use of statins at time of diagnosis was not associated with an improved PFS in KRAS mutant mCRC patients treated with chemotherapy and bevacizumab plus cetuximab. [ABSTRACT FROM AUTHOR]

Introduction: 131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of 131I-CLR1404. Methods: Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of 131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15–35 minutes, 4–6, 18–24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on 127I-CLR1404 mass measurements. To evaluate renal clearance of 131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software. Results: Single administrations of 370 MBq of 131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma 127I-CLR1404 concentrations declined in a bi-exponential manner with a mean t½ value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ng•hr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow. Conclusions: Preliminary data suggest that 131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

In a Perspective, Francisco Beca and Andrew Beck discuss Charles Swanton and colleagues' accompanying Research Article on somatic mutations in patients with inflammatory breast cancer treated in a Phase II clinical trial. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present meta-analysis is to evaluate the response rate, median survival time (MST) and toxicity in patients with brain metastases (BM) originating from non-small cell lung cancer (NSCLC) and who were treated using either whole brain radiotherapy (WBRT) plus concurrent chemotherapy or WBRT alone. Methods: PubMed, EMBASE, Web of Science, The Cochrane Library, clinical trials and current controlled trials were searched to identify any relevant publications. After screening the literature and undertaking quality assessment and data extraction, the meta-analysis was performed using Stata11.0 software. Results: In total, six randomized controlled trials (RCT) involving 910 participants were included in the meta-analysis. The results of the analysis indicate that WBRT plus concurrent chemotherapy was more effective at improving response rate (RR = 2.06, 95% CI [1.13, 3.77]; P = 0.019) than WBRT alone. However, WBRT plus concurrent chemotherapy did not improve median survival time (MST) (HR = 1.09, 95%CI [0.94, 1.26]; P = 0.233) or time of neurological progression (CNS-TTP) (HR = 0.93, 95%CI [0.75, 1.16]; P = 0.543), and increased adverse events (Grade≥3) (RR = 2.59, 95% CI [1.88, 3.58]; P = 0.000). There were no significant differences in Grade 3–5 neurological or hematological toxicity between two patient groups (RR = 1.08, 95%CI [0.23, 5.1]; P = 0.92). Conclusion: The combination of chemotherapy plus WBRT in patients with BM originating from NSCLC may increase treatment response rates of brain metastases with limited toxicity. Although the therapy schedule did not prolong MST or CNS-TTP, further assessment is warranted. [ABSTRACT FROM AUTHOR]

Purpose: Lung inflammation leading to pulmonary toxicity after radiotherapy (RT) can occur in patients with non-small cell lung cancer (NSCLC). We investigated the kinetics of RT induced plasma inflammatory cytokines in these patients in order to identify clinical predictors of toxicity. Experimental Design: In 12 NSCLC patients, RT to 60 Gy (30 fractions over 6 weeks) was delivered; 6 received concurrent chemoradiation (chemoRT) and 6 received RT alone. Blood samples were taken before therapy, at 1 and 24 hours after delivery of the 1st fraction, 4 weeks into RT, and 12 weeks after completion of treatment, for analysis of a panel of 22 plasma cytokines. The severity of respiratory toxicities were recorded using common terminology criteria for adverse events (CTCAE) v4.0. Results: Twelve cytokines were detected in response to RT, of which ten demonstrated significant temporal changes in plasma concentration. For Eotaxin, IL-33, IL-6, MDC, MIP-1α and VEGF, plasma concentrations were dependent upon treatment group (chemoRT vs RT alone, all p-values <0.05), whilst concentrations of MCP-1, IP-10, MCP-3, MIP-1β, TIMP-1 and TNF-α were not. Mean lung radiation dose correlated with a reduction at 1 hour in plasma levels of IP-10 (r2 = 0.858, p<0.01), MCP-1 (r2 = 0.653, p<0.01), MCP-3 (r2 = 0.721, p<0.01), and IL-6 (r2 = 0.531, p = 0.02). Patients who sustained pulmonary toxicity demonstrated significantly different levels of IP-10 and MCP-1 at 1 hour, and Eotaxin, IL-6 and TIMP-1 concentration at 24 hours (all p-values <0.05) when compared to patients without respiratory toxicity. Conclusions: Inflammatory cytokines were induced in NSCLC patients during and after RT. Early changes in levels of IP-10, MCP-1, Eotaxin, IL-6 and TIMP-1 were associated with higher grade toxicity. Measurement of cytokine concentrations during RT could help predict lung toxicity and lead to new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear. Methods: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ASCO meeting abstracts up to May 2013 to identify randomized controlled trials that included advanced pancreatic cancer comparing the following regimens: G, G+5-fluorouracil, G+ capecitabine, G+S1, G+ cisplatin, G+ oxaliplatin, G+ erlotinib, G+ nab-paclitaxel, and FOLFIRINOX. Overall survival and progression-free survival with 95% credible regions were extracted using the Parmar method. A Bayesian multiple treatment comparisons was performed to compare all regimens simultaneously. Results: Twenty-two studies were identified and 16 were included in the meta-analysis. Median overall survival, progression free survival, and response rates for G arms from all trials were similar, suggesting no significant clinical heterogeneity. For overall survival, the mixed treatment comparisons found that the probability that FOLFIRINOX was the best regimen was 83%, while it was 11% for G+ nab-paclitaxel and 3% for G+ S1 and G+ erlotinib, respectively. The overall survival hazard ratio for FOLFIRINOX versus G+ nab-paclitaxel was 0.79 [0.50–1.24], with no obvious difference in toxicities. The hazard ratios from direct pairwise comparisons were consistent with the mixed treatment comparisons results. Conclusions: FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in survival when compared with other regimens by indirect comparisons. [ABSTRACT FROM AUTHOR]

Purpose: We sought to develop placental growth factor as a predictive pharmacodynamic biomarker for motesanib efficacy as first-line therapy in patients with advanced nonsquamous non–small-cell lung cancer. Experimental Design: Placental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models. Results: In the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with ≥2.2-fold change from baseline in placental growth factor (n = 18) had significantly longer overall survival than those with <2.2-fold change (n = 19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12–0.74; P = 0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log-transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79–1.22; P = 0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with ≥2.0-fold change in placental growth factor (n = 229) compared with <2.0-fold change (n = 127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67–1.15, P = 0.340). Conclusions: Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

To identify molecular alterations in prostate cancers associating with relapse following neoadjuvant chemotherapy and radical prostatectomy patients with high-risk localized prostate cancer were enrolled into a phase I-II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pre-treatment prostate tissue was acquired by needle biopsy and post-treatment tissue was acquired by prostatectomy. Prostate cancer gene expression measurements were determined in 31 patients who completed 4 cycles of neoadjuvant chemotherapy. We identified 141 genes with significant transcript level alterations following chemotherapy that associated with subsequent biochemical relapse. This group included the transcript encoding monoamine oxidase A (MAOA). In vitro, cytotoxic chemotherapy induced the expression of MAOA and elevated MAOA levels enhanced cell survival following docetaxel exposure. MAOA activity increased the levels of reactive oxygen species and increased the expression and nuclear translocation of HIF1α. The suppression of MAOA activity using the irreversible inhibitor clorgyline augmented the apoptotic responses induced by docetaxel. In summary, we determined that the expression of MAOA is induced by exposure to cytotoxic chemotherapy, increases HIF1α, and contributes to docetaxel resistance. As MAOA inhibitors have been approved for human use, regimens combining MAOA inhibitors with docetaxel may improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Introduction: We report exploratory gene-expression profiling data from a single-arm Phase-II-study in patients with non-squamous (ns)NSCLC treated with pemetrexed and cisplatin. Previously disclosed results indicated a significant association of low thymidylate-synthase (TS)-expression with longer progression-free and overall survival (PFS/OS). Methods: Treatment-naïve nsNSCLC patients (IIIB/IV) received 4 cycles of pemetrexed/cisplatin; non-progressing patients continued on pemetrexed-maintenance. Diagnostic tissue-samples were used to assess TS-expression by immunohistochemistry (IHC) and mRNA-expression array-profiling (1,030 lung cancer-specific genes). Cox proportional-hazard models were applied to explore the association between each gene and PFS/OS. Genes significantly correlated with PFS/OS were further correlated with TS-protein expression (Spearman-rank). Unsupervised clustering was applied to all evaluable samples (n = 51) for all 1,030 genes and an overlapping 870-gene subset associated with adenocarcinoma (ADC, n = 47). Results: 51/70 tissue-samples (72.9%) were evaluable; 9 of 1,030 genes were significantly associated with PFS/OS (unadjusted p<0.01, genes: Chromosome 16 open reading frame 89, napsin A, surfactant protein B, aquaporin 4, TRAF2- and Nck-interacting kinase, Lysophosphatidylcholine acyltransferase 1, Interleukin 1 receptor type II, NK2 homeobox 1, ABO glycosyl-transferase); expression for all except IL1R2 correlated negatively with nuclear TS-expression (statistically significant for 5/8 genes, unadjusted p<0.01). Cluster-analysis based on 1,030 genes revealed no clear trend regarding PFS/OS; the ADC-based cluster analysis identified 3 groups (n = 21/11/15) with median (95%CI) PFS of 8.1(6.9,NE)/2.4(1.2,NE)/4.4(1.2,NE) months and OS of 20.3(17.5,NE)/4.3(1.4,NE)/8.3(3.9,NE) months, respectively. Conclusions: These exploratory gene-expression profiling results describe genes potentially linked to low TS-expression. Nine genes were significantly associated with PFS/OS but could not be differentiated as prognostic or predictive as this was a single-arm study. Although these hypotheses-generating results are interesting, they provide no evidence to change the current histology-based treatment approach with pemetrexed. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is associated with high pathological complete remission (pCR) rate in neoadjuvant treatment (NAT). TNBC patients who achieve pCR have superior outcome than those without pCR. A meta-analysis was done to evaluate whether integrating novel approaches into NAT can improve the pCR rate in TNBC. Medical subject heading terms (Breast Neoplasm) and key words (triple negative OR estrogen receptor (ER) negative OR HER2 negative) AND (primary systemic OR neoadjuvant OR preoperative) were used to select eligible studies. Experimental arm in each study was considered as the testing regimen, and control arm was defined as the standard regimen in this meta-analysis. A total of 11 studies with 14 paired regimens were included in the final analysis. Aggregate pCR rate was 37.3% and 44.6% in the standard and testing group, respectively. Novel approaches in the testing regimen significantly improved the pCR rate in NAT of TNBC patients compared with the standard regimen, with an odds ratio (OR) of 1.34 (95% confidence interval (CI) 1.11–1.62, P = 0.002). Considering specific regimens, we demonstrated the pCR rate to be much higher in the carboplatin-containing (OR = 1.80, 95% CI 1.39–2.32, P<0.001) or bevacizumab-containing regimens (OR = 1.36, 95% CI 1.11–1.66, P = 0.003) than in the control regimens. The addition of carboplatin in NAT had a pCR rate as high as 51.2% in TNBC patients, with an absolute pCR difference of 13.8% as compared with control regimens. No significant heterogeneity was identified among studies evaluating the addition of carboplatin or bevacizumab efficacy in NAT. This meta-analysis indicates that these novel NAT regimens have achieved a significant pCR improvement in TNBC patients, especially among patients treated with carboplatin-containing or bevacizumab-containing regimen. This can help us design appropriate trials in the adjuvant setting and guide clinical practice. [ABSTRACT FROM AUTHOR]

Background: Lung cancer, particularly non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality. Chemotherapy combined dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) immunotherapy has been applied in advanced NSCLC patients' treatment, but couldn't provide consistent beneficial results. Therefore, it is necessary to evaluate the efficiency and safety of combination therapy to promote the application. Methods: A literature search for randomized controlled trials of NSCLC was conducted in PubMed database. Before meta-analysis was performed, studies were evaluated heterogeneity. Pooled risk ratios (RRs) were estimated and 95% confidence intervals (CIs) were calculated using a fixed-effect model. Sensitivity analysis was also performed. Results: Six eligible trials were enrolled. Efficiency and safety of chemotherapy followed by DC-CIK immunotherapy (experimental group) and chemotherapy alone (control group) were compared. 1-year overall survival (OS) (P = 0.02) and progression free survival (PFS) (P = 0.005) in the experimental group were significantly increased compared with the control. Disease control rate (DCR) (P = 0.006) rose significantly in experimental group. However, no significant differences between the two groups were observed in 2-year OS (P = 0.21), 2-year PFS (P = 0.10), overall response rate (ORR) (P = 0.76) and partial response (PR) (P = 0.22). Temporary fever, anemia, leukopenia and nausea were the four major adverse events (AEs) treated by chemotherapy. The incidence of anemia, leukopenia and nausea in the experimental group was obviously lower than the control group. Temporary fever rate was higher in experimental group than that in the control, but could be alleviated by taking sufficient rest. Conclusions: Chemotherapy combined with DC-CIK immunotherapy showed superiority in DCR, 1-year OS and PFS, and no more AEs appeared, however, there was no significant improvement in ORR, PR, 2-year OS and PFS. As a whole, the combination therapy is safer but modest in efficacy for advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: Orbital marginal zone B-cell lymphoma (OAML) constitutes for the most frequent diagnosis in orbital lymphoma. Relatively little data, however, have been reported in larger cohorts of patients staged in a uniform way and no therapy standard exists to date. Material and Methods: We have retrospectively analyzed 60 patients diagnosed and treated at our institution 1999–2012. Median age at diagnosis was 64 years (IQR 51–75) and follow-up time 43 months (IQR 16–92). All patients had undergone uniform extensive staging and histological diagnosis was made by a reference pathologist according to the WHO classification. Results: The majority of patients presented with stage IE (n = 40/60, 67%), three had IIE/IIIE and the remaining 17 stage IVE. Seven patients with IVE had bilateral orbital disease whereas the others showed involvement of further organs. Treatment data were available in 58 patients. Local treatment with radiotherapy (14/58, 24%) or surgery (3/58, 5%) resulted in response in 82% of patients. A total of 26 patients (45%) received systemic treatment with a response rate of 85%. Nine patients received antibiotics as initial therapy; response rate was 38%. Watchful-waiting was the initial approach in 6/58 patients. In total 28/58 patients (48%) progressed and were given further therapy. Median time-to-progression in this cohort was 20 months (IQR 9–39). There was no difference in time-to-progression after first-line therapy between the different therapy arms (p = 0.14). Elevated beta-2-microglobulin, plasmacytic differentiation, autoimmune disorder and site of lymphoma were not associated with a higher risk for progress. Conclusion: Our data underscore the excellent prognosis of OAML irrespective of initial therapy, as there was no significant difference in time-to-progression and response between local or systemic therapy. In the absence of randomized trials, the least toxic individual approach should be chosen for OAML. [ABSTRACT FROM AUTHOR]

Objectives: To compare surgical efficacy and postoperative recovery of ultrasonic scalpel (USS) with conventional techniques for the resection of gastric carcinoma. Methods: A systematic search of major medical databases (PubMed, Embase, CCRT and CNKI) was conducted. Both randomized and non-randomized controlled trials (RCTs and nRCTs) were considered eligible. Operation time (OT), intraoperative blood loss (BL) and postoperative complications (POC) rates as well as postoperative hospitalization days, number of dissected lymph nodes, abdominal drainage volume and time for recovery of gastrointestinal functions were synthesized and compared. Results: Nineteen studies were included (7 RCTs and 12 nRCTs), in which 1930 patients were enrolled totally (946 in the USS group and 984 in the conventional group). Monopolar electrocautery and ligation were used as the conventional methods. Comparative meta-analysis showed perioperative outcomes were significantly improved using USS compared with conventional surgical instrumentation. OT was reduced from a weighted mean of 185.3 min in the conventional group to 151.0 min in the USS group (MD = −33.30, 95% CI [−41.75, −24.86], p<0.001) and intraoperative BL was decreased from a weighted mean of 217.9 ml in the conventional group to 111.6 ml in the USS group (MD = −113.42, 95% CI [−142.05, −84.79], p<0.001). Results from RCTs subgroup were consistent with those from nRCTs subgroup. The weighted cumulative risk of POC accounted for 8.9% (0%–25%) and 12.9% (5.5%–45%) in the USS and conventional groups, respectively. Pooled estimated results from nRCTs (OR = 0.54, 95% CI [0.27, 1.06], p = 0.07) and RCTs (RR = 0.75, 95% CI [0.44, 1.26], p = 0.27) showed no significant difference between the USS and control groups. Analysis of secondary outcomes showed the improvements of the USS group over control group regarding the number of dissected lymph nodes, postoperative hospitalization days, abdominal drainage volume and time for recovery of gastrointestinal functions. Conclusion: Compared with conventional electrosurgery, the USS is a safe and effective technique with more short-term advantages in open surgery for gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Overexpression of Met tyrosine kinase receptor is associated with poor prognosis. Overexpression, and particularly MET amplification, are predictive of response to Met-specific therapy in preclinical models. Immunohistochemistry (IHC) of formalin-fixed paraffin-embedded (FFPE) tissues is currently used to select for ‘high Met’ expressing tumors for Met inhibitor trials. IHC suffers from antibody non-specificity, lack of quantitative resolution, and, when quantifying multiple proteins, inefficient use of scarce tissue. Methods: After describing the development of the Liquid-Tissue-Selected Reaction Monitoring-mass spectrometry (LT-SRM-MS) Met assay, we evaluated the expression level of Met in 130 FFPE gastroesophageal cancer (GEC) tissues. We assessed the correlation of SRM Met expression to IHC and mean MET gene copy number (GCN)/nucleus or MET/CEP7 ratio by fluorescence in situ hybridization (FISH). Results: Proteomic mapping of recombinant Met identified 418TEFTTALQR426 as the optimal SRM peptide. Limits of detection (LOD) and quantitation (LOQ) for this peptide were 150 and 200 amol/µg tumor protein, respectively. The assay demonstrated excellent precision and temporal stability of measurements in serial sections analyzed one year apart. Expression levels of 130 GEC tissues ranged (<150 amol/µg to 4669.5 amol/µg. High correlation was observed between SRM Met expression and both MET GCN and MET/CEP7 ratio as determined by FISH (n = 30; R2 = 0.898). IHC did not correlate well with SRM (n = 44; R2 = 0.537) nor FISH GCN (n = 31; R2 = 0.509). A Met SRM level of ≥1500 amol/µg was 100% sensitive (95% CI 0.69–1) and 100% specific (95% CI 0.92–1) for MET amplification. Conclusions: The Met SRM assay measured the absolute Met levels in clinical tissues with high precision. Compared to IHC, SRM provided a quantitative and linear measurement of Met expression, reliably distinguishing between non-amplified and amplified MET tumors. These results demonstrate a novel clinical tool for efficient tumor expression profiling, potentially leading to better informed therapeutic decisions for patients with GEC. [ABSTRACT FROM AUTHOR]

Background: Cervical cancers are ranked the second-most hazardous ailments among women worldwide. In the past two decades, microarray technologies have been applied to study genes involved in malignancy progress. However, in most of the published microarray studies, only a few genes were reported leaving rather a large amount of data unused. Also, RNA-Seq data has become more standard for transcriptome analysis and is widely applied in cancer studies. There is a growing demand for a tool to help the experimental researchers who are keen to explore cervical cancer gene therapy, but lack computer expertise to access and analyze the high throughput gene expression data. Description: The dbCerEx database is designed to retrieve and process gene expression data from cervical cancer samples. It includes the genome wide expression profiles of cervical cancer samples, as well as a web utility to cluster genes with similar expression patterns. This feature will help researchers conduct further research to uncover novel gene functions. Conclusion: The dbCerEx database is freely available for non-commercial use at http://128.135.207.10/dbCerEx/, and will be updated and integrated with more features as needed. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of the copy number (GCN) and protein expression of the mesenchymal-epithelial transition (MET) gene for survival of patients with non-small cell lung cancer (NSCLC) remains controversial. This study aims to comprehensively and quantitatively asses the suitability of MET GCN and protein expression to predict patients' survival. Methods: PubMed, Embase, Web of Science and Google Scholar were searched for articles comparing overall survival in patients with high MET GCN or protein expression with those with low level. Pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also performed. Results: Eighteen eligible studies enrolling 5,516 patients were identified. Pooled analyses revealed that high MET GCN or protein expression was associated with poor overall survival (OS) (GCN: HR = 1.90, 95% CI 1.35–2.68, p<0.001; protein expression: HR = 1.52, 95% CI 1.08–2.15, p = 0.017). In Asian populations (GCN: HR = 2.22, 95% CI 1.46–3.38, p<0.001; protein expression: HR = 1.89, 95% CI 1.34–2.68, p<0.001), but not in the non-Asian subset. For adenocarcinoma, high MET GCN or protein expression indicated decreased OS (GCN: HR = 1.49, 95% CI 1.05–2.10, p = 0.025; protein expression: HR = 1.69, 95% CI 1.31–2.19, p<0.001). Results were similar for multivariate analysis (GCN: HR = 1.61, 95% CI 1.15–2.25, p = 0.005; protein expression: HR = 2.18, 95% CI 1.60–2.97, p<0.001). The results of the sensitivity analysis were not materially altered and did not draw different conclusions. Conclusions: Increased MET GCN or protein expression was significantly associated with poorer survival in patients with surgically resected NSCLC; this information could potentially further stratify patients in clinical treatment. [ABSTRACT FROM AUTHOR]

Background: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previously shown deregulation of mammalian target of rapamycin (mTOR). Topical use of the mTOR inhibitor rapamycin is an effective treatment for the skin tumours (angiofibromas) in tuberous sclerosis complex, which is also characterised by mTOR deregulation. In this study we aimed to determine if topical rapamycin is also an effective treatment for fibrofolliculomas in BHD. Methods: We performed a double blinded, randomised, facial left-right controlled trial of topical rapamycin 0.1% versus placebo in 19 BHD patients. Trial duration was 6 months. The primary outcome was cosmetic improvement as measured by doctors and patients. Changes in fibrofolliculoma number and size were also measured, as was occurrence of side effects. Results: No change in cosmetic status of fibrofolliculomas was reported in the majority of cases for the rapamycin treated (79% by doctors, 53% by patients) as well as the placebo treated facial sides (both 74%). No significant differences between rapamycin and placebo treated facial halves were observed (p = 1.000 for doctors opinion, p = 0.344 for patients opinion). No significant difference in fibrofolliculoma number or change in size of the fibrofolliculomas was seen after 6 months. Side effects occurred more often after rapamycin treatment (68% of patients) than after placebo (58% of patients; p = 0.625). A burning sensation, erythema, itching and dryness were most frequently reported. Conclusions: This study provides no evidence that treatment of fibrofolliculomas with topical rapamycin in BHD results in cosmetic improvement. Trial Registration: ClinicalTrials.gov +NCT00928798 [ABSTRACT FROM AUTHOR]

Aims: The purpose of the present study was to compare the efficacies of transarterial chemoembolization (TACE) combined with sorafenib versus TACE monotherapy for treating patients with advanced hepatocellular carcinoma (HCC). Methods: We enrolled 321 patients and selected 280 with advanced HCC (Barcelona Clinic Liver Cancer stage C) who underwent TACE therapy between February 2009 and February 2013. TACE alone (monotherapy group) was administered to 198 patients (70.7%), and the remaining 82 (29.3%) underwent repeat combined TACE and sorafenib therapy (combined group). To minimize selection bias, these latter 82 patients were matched using propensity-score matching at a 1∶2 ratio with 164 patients who received TACE monotherapy. The primary endpoints were overall survival (OS) and related subgroup analysis. The secondary endpoints were time to progression (TTP) and treatment-related adverse events. Results: Of the respective patients in the combined and monotherapy groups, 64.6% and 49.2% had vascular invasion, 87.8% and 91.1% had extrahepatic metastasis, and 54.3% and 47.1% had both. In the propensity-score–matched cohort, the OS survival of the combined group was significantly higher compared with the monotherapy group (7.0 months vs. 4.9 months, respectively, P = 0.003). The TTP was significantly longer in the combined group (2.6 months vs. 1.9 months, respectively, P = 0.001). Subgroup analysis showed that the outcomes of patients with advanced HCC without main portal vein invasion who were treated with combined therapy were significantly better compared with those who received monotherapy (P<0.05). Univariate and subsequent multivariate analyses revealed that the addition of sorafenib was an independent predictor of favorable OS and TTP (adjusted hazard ratios, 0.63 and 0.62, respectively; P<0.05 for both). Conclusion: Sorafenib plus TACE was more effective than TACE monotherapy for treating patients with advanced HCC without main portal vein invasion. Future trials with larger samples are required to validate these preliminary findings. [ABSTRACT FROM AUTHOR]

Background: The US FDA and the EMA have approved seven agents for the treatment of renal cell carcinoma, primarily based on differences in progression-free survival (PFS). Because PFS is an arbitrary endpoint we hypothesized that an analysis would demonstrate the growth rate of tumors remained constant at the time of RECIST-defined disease progression. Methods: We previously estimated the growth (g) and regression (d) rates and the stability of g using data from the Phase III trial comparing sunitinib and interferon. Results: Sufficient data were available and rate constants statistically valid in 321 of 374 patients randomized to sunitinib. Median d was 0•0052 days−1; in 53 patients no tumor growth was recorded. Median g was 0•00082 days-1 and was stable for a median of 275 days on therapy, remaining stable beyond 300, 600 and 900 days in 122, 65 and 27 patients, respectively. A possible increase in g while receiving sunitinib could be discerned in only 18 of 321 patients. Given a median g of 0•00082 days−1 the estimated median time to a second progression were sunitinib continued past RECIST-defined progression was 7.3 months. At 100, 200, and 300 days after starting therapy, an estimated 47%, 27%, and 13% of tumor remains sunitinib sensitive and could explain a RECIST-defined response to a new TKI. Conclusion: Prolonged stability of g with sunitinib suggests continued sunitinib beyond RECIST-defined progression may provide a beneficial outcome. Randomized trials in patients whose disease has “progressed” on sunitinib are needed to test this hypothesis. [ABSTRACT FROM AUTHOR]

Background: Rectal washout can prevent local recurrence after anterior resection of rectal cancer. Few studies have focused particularly on the association between irrigation fluids volume or agents and the risk of local recurrence after anterior resection of rectal cancer. Objective: To estimate the association between irrigation fluids types, volumes of rectal washout and risk of local recurrence after anterior resection for cancer. Data Sources: Relevant studies were identified by a search of Medline, Embase, Wiley Online Library, China National Knowledge Infrastructure, Cochrane Oral Health Group Specialized Register, Wanfang databases and Google Website from their inception until October 18,2013. Study Selection: Studies reporting the association between rectal washout types and volumes and risk of local recurrence after anterior resection for cancer were included. Interventions: Eligible studies used rectal washout. Control groups were defined as no washout. Study Appraisal and Synthesis Methods: Random-effects model were used to obtain summary estimates of RR and 95% CI, with Stata version 11 and RevMan 5.2.5 softwares used. The quality of report was appraised in reference to the MINORS item. Results: Of the 919 rectal cancer patients in 8 included studies, a total of 61(6.64%) cases of local recurrence were reported, with a pooled RR 0.51 (95%CI = 0.28–0.92, P = 0.03). The RRs 0.37 and 0.39 in normal saline and washout volume (≥1500 ml normal saline) subgroup, respectively, indicated that rectal washout with normal saline, or ≥1500 ml in volume could significantly reduce local recurrence (LR) rate (95% CI = 0.17–0.79, P = 0.01; 95% CI = 0.18–0.87, P = 0.02) after anterior resection for cancer. Limitation: The included studies were non-randomized observational studies, with diversity of study designs. Conclusion: Rectal washout with normal saline alone can reduce the risk of local recurrence in patients with resectable rectal cancer, and 1.5 liters rectal washout in volume is recommended. [ABSTRACT FROM AUTHOR]