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Objectives: To investigate the impact of provider payment reforms and associated care delivery models on cost and quality in cancer care. Methods: Data sources/study setting: Review of English-language literature published in PubMed, Embase and Cochrane library (2007–2019). Study design: We performed a systematic literature review (SLR) to identify the impact of cancer care reforms. Primary endpoints were resource use, cost, quality of care, and clinical outcomes. Data collection/extraction methods: For each study, we extracted and categorized comparative data on the impact of policy reforms. Given the heterogeneity in patients, interventions and outcome measures, we did a qualitative synthesis rather than a meta-analysis. Results: Of the 26 included studies, seven evaluations were in fact qualified as quasi experimental designs in retrospect. Alternative payment models were significantly associated with reduction in resource use and cost in cancer care. Across the seventeen studies reporting data on the implicit payment reforms through care coordination, the adoption of clinical pathways was found effective in reduction of unnecessary use of low value services and associated costs. The estimates of all measures in ACO models varied considerably across participating providers, and our review found a rather mixed impact on cancer care outcomes. Conclusion: The findings suggest promising improvement in resource utilization and cost control after transition to prospective payment models, but, further primary research is needed to apply robust measures of performance and quality to better ensure that providers are delivering high-value care to their patients, while reducing the cost of care. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy (NAC) is used in patients with breast cancer to reduce tumor focus, metastatic risk, and patient mortality. Monitoring NAC effects is necessary to capture resistant patients and stop or change treatment. The existing methods for evaluating NAC results have some limitations. The aim of this study was to assess the tumor response at an early stage, after the first doses of the NAC, based on the variability of the backscattered ultrasound energy, and backscatter statistics. The backscatter statistics has not previously been used to monitor NAC effects. Methods: The B-mode ultrasound images and raw radio frequency data from breast tumors were obtained using an ultrasound scanner before chemotherapy and 1 week after each NAC cycle. The study included twenty-four malignant breast cancers diagnosed in sixteen patients and qualified for neoadjuvant treatment before surgery. The shape parameter of the homodyned K distribution and integrated backscatter, along with the tumor size in the longest dimension, were determined based on ultrasound data and used as markers for NAC response. Cancer tumors were assigned to responding and non-responding groups, according to histopathological evaluation, which was a reference in assessing the utility of markers. Statistical analysis was performed to rate the ability of markers to predict the final NAC response based on data obtained after subsequent therapeutic doses. Results: Statistically significant differences (p<0.05) between groups were obtained after 2, 3, 4, and 5 doses of NAC for quantitative ultrasound markers and after 5 doses for the assessment based on maximum tumor dimension. Statistical analysis showed that, after the second and third NAC courses the classification based on integrated backscatter marker was characterized by an AUC of 0.69 and 0.82, respectively. The introduction of the second quantitative marker describing the statistical properties of scattering increased the corresponding AUC values to 0.82 and 0.91. Conclusions: Quantitative ultrasound information can characterize the tumor's pathological response better and at an earlier stage of therapy than the assessment of the reduction of its dimensions. The introduction of statistical parameters of ultrasonic backscatter to monitor the effects of chemotherapy can increase the effectiveness of monitoring and contribute to a better personalization of NAC therapy. [ABSTRACT FROM AUTHOR]

Objective: A Clinical Decision Support System (CDSS) that can amass Electronic Health Record (EHR) and other patient data holds promise to provide accurate classification and guide treatment choices. Our objective is to develop the ecision Support System for Making ersonalized ssessments and Recommendations Concerning Breast ancer Patients (DPAC), which is a CDSS learned from data that recommends the optimal treatment decisions based on a patient’s features. Method: We developed a Bayesian network architecture called Causal Modeling with Internal Layers (CAMIL), and an algorithm called Treatment Feature Interactions (TFI), which learns from data the interactions needed in a CAMIL model. Using the TFI algorithm, we learned interactions for six treatments from the LSDS-5YDM dataset. We created a CAMIL model using these interactions, resulting in a DPAC which recommends treatments towards preventing 5-year breast cancer metastasis. Results: In a 5-fold cross-validation analysis, we compared the probability of being metastasis free in 5 years for patients who made decisions recommended by DPAC to those who did not. These probabilities are (the probability for those making the decisions appears first): chemotherapy (.938, .872); breast/chest wall radiation (.939, .902); nodal field radiation (.940, .784); antihormone (.941, .906); HER2 inhibitors (.934, .880); neadjuvant therapy (.931, .837). In an application of DPAC to the independent METABRIC dataset, the probabilities for chemotherapy were (.845, .788). Discussion: Patients who took the advice of DPAC had, as a group, notably better outcomes than those who did not. We conclude that DPAC is effective at amassing and analyzing data towards treatment recommendations. Some of the findings in DPAC are controversial. For example, DPAC says that chemotherapy increases the chances of metastasis for many node negative patients. This controversy shows the importance of developing a conclusive version of DPAC to ensure we provide patients with the best patient-specific treatment recommendations. [ABSTRACT FROM AUTHOR]

Background: Association between obesity and cardiovascular diseases is well known, however increased susceptibility of obese patients to develop several cancer types is not so commonly known. Current data suggest that poorer overall survival in cancer patients might be associated to non-cancer-related causes such as higher risk of cardiotoxicity in obese patients treated with chemotherapeutic agents. Omentin, a novel adipokine decreased in obesity, is actually in the spotlight due to its favourable effects on inflammation, glucose homeostasis and cardiovascular diseases. Also, recent data showed that in vitro anthracycline-induced cardiomyocyte apoptosis is counteracted by omentin suggesting its cardioprotective role. Objective: Our aim was to evaluate omentin effects against docetaxel toxicity. Results: Our data indicate that omentin inhibits docetaxel-induced viability loss and that increased viability is associated to decreased caspase-3 expression and cell death. Although omentin reduces NOX4 expression, it failed to reduce docetaxel-induced reactive oxygen species production. Our results indicate that omentin decreases docetaxel-induced endoplasmic reticulum stress, suggesting that cardioprotective role might be associated to ERS inhibition. Conclusion: These data suggest that omentin treatment may contribute to decrease susceptibility to DTX-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Background: Pure squamous cell carcinoma (SCC) of the urinary tract is rare in the UK and has a poor prognosis compared with transitional cell carcinoma (TCC). Cisplatin based chemotherapy has been shown to be effective in TCC. Methods: Patients with T3-T4, pelvic relapsed, nodal or metastatic SCC of the urinary tract were recruited into an open-label, single-arm, non-randomised, phase 2 trial evaluating the activity and safety of cisplatin, methotrexate and vinblastine (CMV) chemotherapy. CMV was given as three 21-day cycles of methotrexate 30mg/m2 (day 1 & 8), vinblastine 4mg/m2 (day 1 & 8) and cisplatin 100mg/m2 (day 2). Results: 38 patients were recruited. Overall response was 39% (95% CI 24%, 55%)–13% CR and 26% PR. Median OS was 7.8 months (95% CI 3.4, 12.6) with 39% 1-year survival. Toxicity was acceptable. Conclusion: CMV is well tolerated and active in patients with pure SCC of the urinary tract. [ABSTRACT FROM AUTHOR]

Objective: The standard treatment for patients with advanced/metastatic soft tissue sarcomas (ASTS) is systemic chemotherapy with doxorubicin. A previous meta-analysis of 8 randomized controlled trials (RCTs) demonstrated the superiority of single-agent doxorubicin over doxorubicin-based combination chemotherapy for ASTS. However, meta-analyses of all RCTs that compare doxorubicin to other single-agent or combination regimens as first-line treatments for ASTS are lacking. We conducted a systematic review and meta-analysis to evaluate the efficacy and toxicity of current primary treatments for ASTS. Methods: Eligible studies were RCTs of first-line chemotherapies for ASTS comparing doxorubicin alone to other single agents or to combination therapies (experimental arm). Data from studies reporting hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS) were pooled. Other time-to-event endpoints were extracted from the studies based on Kaplan-Meier estimates, and pooled odds ratios (OR) and 95% CI were calculated. Results: Twenty-seven eligible RCTs comprising 6156 patients were identified. Overall, the 1-year OS (OR 0.88, 95% CI 0.79–0.99, P = 0.03) was significantly improved in the experimental arm over the doxorubicin-only arm; however, there was no significant difference in 2-year OS (OR 0.87, 95% CI 0.73–1.03, P = 0.11) or OS (HR 0.97, 95% CI 0.91–1.03, P = 0.28) between the two groups. PFS and other time-to-event endpoints were not significantly different between the two treatment arms. While incidences of overall severe adverse events were not significantly different (OR 1.20, 95% CI 0.88–1.65, P = 0.26), severe nausea/vomiting was significantly more frequent in the experimental arm (OR 1.90, 95% CI 1.27–2.83, P = 0.002). Conclusion: The efficacies of doxorubicin-only and experimental arm regimens were similar, although toxicities were more frequent in the experimental arms. Hence, doxorubicin monotherapy remains suitable as a standard first-line regimen for ASTS. [ABSTRACT FROM AUTHOR]

Background/Purpose: Limited evidence has been obtained on varicella-zoster virus (VZV) infection in patients with breast cancer as a complication related to adjuvant radiotherapy. We conducted a cohort study aimed to assess the risk of VZV infection in this patient setting. Materials and methods: We used the National Health Insurance Research Database to identify 65,981 patients with breast cancer in Taiwan who underwent breast surgery between 2000 and 2011. After a 1:1 propensity score match was obtained between patients with and without radiotherapy, a competing risk regression model was constructed to estimate the hazard ratios and the incidence rate difference (IRD) of VZV infection in the patients with breast cancer receiving radiotherapy and those not receiving radiotherapy. Results: After adjusting for covariates, the radiotherapy cohort showed a 1.51-fold higher risk (95% confidence interval = 1.06–5.16, p = 0.02, IRD = 4.98/10000 person-years) of subsequent VZV infection than the nonradiotherapy cohort. Furthermore, VZV infection risk was 3.85-fold higher among patients aged >65 years who received radiotherapy than among those of the same age who did not receive radiotherapy (95% confidence interval = 1.1–13.4, p < 0.05, IRD = 11.09/10000 person-years). The risk increased with adjusted hazard ratio of 6.6 (95% confidence interval I = 1.51–28.8, p < 0.05, IRD = 32.01/10,000 person-years) and 7.08 (95% confidence interval = 1.64–30.5, p < 0.01, IRD = 35.72/10,000 person-years) in follow-up period less than 3 months and 3–5 months respectively. Conclusion: Radiotherapy was associated with an increased risk of VZV infection among patients with breast cancer. The risk was significantly higher in older patient (>65 years old) and/or those who received chemotherapy. Regular clinical follow-up and additional serological testing in the first 5 months after radiotherapy are recommended. [ABSTRACT FROM AUTHOR]

Purpose: Many breast cancer patients suffer from chemotherapy-induced hair loss. Accurate information about temporal changes in chemotherapy-induced hair loss is important for supporting patients scheduled to receive chemotherapy, because it helps them to prepare. However, accurate information, on issues such as the frequency of hair loss after chemotherapy, when regrowth starts, the condition of regrown hair, and the frequency of incomplete hair regrowth, is lacking. This study aimed to clarify the long-term temporal changes in chemotherapy-induced hair loss using patient-reported outcomes for chemotherapy-induced hair loss. Methods: We conducted a multicenter, cross-sectional questionnaire survey. Disease-free patients who had completed adjuvant chemotherapy consisting of anthracycline and/or taxanes for breast cancer within the prior 5 years were enrolled from 47 hospitals and clinics in Japan. Descriptive statistics were obtained in this study. The study is reported according to the STROBE criteria. Results: The response rate was 81.5% (1511/1853), yielding 1478 questionnaires. Hair loss occurred in 99.9% of patients. The mean time from chemotherapy until hair loss was 18.0 days. Regrowth of scalp hair occurred in 98% of patients. The mean time from the completion of chemotherapy to the beginning of regrowth was 3.3 months. Two years after chemotherapy completion, the scalp-hair recovery rate was <30% in approximately 4% of patients, and this rate showed no improvement 5 years after chemotherapy. Eighty-four percent of the patients initially used wigs, decreasing to 47% by 1 year after chemotherapy and 15.2% after 2 years. The mean period of wig use was 12.5 months. However, a few patients were still using wigs 5 years after completing chemotherapy. Conclusions: Our survey focused on chemotherapy-induced hair loss in breast cancer patients. We believe these results to be useful for patients scheduled to receive chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Prolonged angiogenesis inhibition may improve treatment outcome in metastatic colorectal cancer (mCRC) patients. However, due to the complexity of the angiogenic pathways there is a lack of valid predictive biomarkers for anti-angiogenic agents. Here, we describe and optimize a procedure for simultaneous dynamic profiling of multiple angiogenesis related proteins in patient serum to explore associations with the response and acquired resistance to anti-angiogenic therapy. Materials and methods: Patients (n=22) were selected from a clinical trial investigating maintenance treatment with bevacizumab alone after response to induction chemotherapy + bevacizumab in mCRC. Serum samples were analysed for 55 unique angiogenesis related proteins using a commercial proteome profiler array and a publicly available image analysis program for quantification. Samples were collected at baseline before induction treatment start, at start of maintenance treatment, and at end of treatment after tumour progression. Main results and conclusion: For eight proteins, the antibody array signals were below detection range in all patient samples. None of the proteins showed levels at baseline or at start of maintenance with strong evidence for correlation to time to progression (lowest nominal p-value 0.03). The dynamic ranges of protein levels measured during the induction treatment period and during the maintenance period were analysed separately for time trends. Evidence for changing trends (up/down) in the levels of MMP-8, TIMP-4 and EGF was observed both during response to induction treatment and at progressive disease, respectively. For three of the proteins (IL-8, Activin A and IGFBP-2), weak evidence for correlation between increasing protein levels during induction with chemotherapy and bevacizumab and time to progression was observed. In conclusion, semi-quantitative profiling of angiogenesis related proteins in patient serum may be a versatile tool to screen for protein patterns aiming at identifying resistance mechanisms of anti-angiogenic treatment in patients with mCRC. [ABSTRACT FROM AUTHOR]

Cutaneous mast cell tumours are one of the most common canine cancers. Approximately 25% of the tumours metastasise. Activating c-kit mutations are present in about 20% of tumours, but metastases occur in the absence of mutations. Tumour metastasis is associated with significantly diminished survival in spite of adjuvant chemotherapy. Available prognostic tests do not reliably predict whether a tumour will metastasise. In this study we compared the global expression profiles of 20 primary cutaneous mast cell tumours that metastasised with those of 20 primary tumours that did not metastasise. The objective was to identify genes associated with mast cell tumour metastatic progression that may represent targets for therapeutic intervention and biomarkers for prediction of tumour metastasis. Canine Gene 1.1 ST Arrays were employed for genome-wide expression analysis of formalin-fixed, paraffin-embedded biopsies of mast cell tumours borne by dogs that either died due to confirmed mast cell tumour metastasis, or were still alive more than 1000 days post-surgery. Decreased gene expression in the metastasising tumours appears to be associated with a loss of cell polarity, reduced cell-cell and cell-ECM adhesion, and increased cell deformability and motility. Dysregulated gene expression may also promote extracellular matrix and base membrane degradation, suppression of cell cycle arrest and apoptosis, and angiogenesis. Down-regulation of gene expression in the metastasising tumours may be achieved at least in part by small nucleolar RNA-derived RNA and microRNA-effected gene silencing. Employing cross-validation, a linear discriminant analysis-based classifier featuring 19 genes that displayed two-fold differences in expression between metastasising and non-metastasising tumours was estimated to classify metastasising and non-metastasising tumours with accuracies of 90–100% and 70–100%, respectively. The differential expression of 9 of the discriminator genes was confirmed by quantitative reverse transcription-PCR. [ABSTRACT FROM AUTHOR]

Background: Anastomotic leakage can be classified by free and contained leakage according to clinical manifestations. The risk factors and their comparison between these leakage subtypes are uncertain. This study aims to evaluate anastomotic leakage patterns and to compare clinical features between free and contained leakages after low anterior resection for rectal cancer. Materials and methods: Between January 2005 and December 2012, a total of 2035 consecutive patients who underwent low anterior resection for primary rectal cancer were evaluated retrospectively at two-tertiary referral centers. The primary end points of this study were to assess detailed clinical features among leakage subtypes. The secondary end point was to compare risk factors between free and contained leakages. Results: Patients were subdivided into a no leakage group (n = 1890), free leakage group (n = 73), and contained leakage group (n = 72). Free leakage occurred more frequently in laparoscopic and robotic surgeries than open surgery (p = 0.015). On the other hand, contained leakage was developed in a higher rate of patients who received preoperative chemoradiotherapy (p<0.001). The mean development time was 4.6 days in the free leakage group, and 23.6 days in the contained leakage group. Patients with free leakage had a lower rate of a defunctioning stoma than contained leakage (5.5% vs. 29.2%, p<0.001). Risk factors for free leakage were smoking, tumor location, and laparoscopic surgery. However, tumor location and preoperative chemoradiotherapy increased the risk for contained leakage. Conclusions: Contained leakage in rectal cancer surgery showed different clinical manifestations and risk factors compared to free leakage. It is necessary to pay more attention to patients with particular risk factors for anastomotic leakage subtypes. [ABSTRACT FROM AUTHOR]

Background: Cancer related cognitive impairments have been subjectively reported and objectively detected in breast cancer patients treated with chemotherapy and are known to have a profound negative impact on productivity, psychosocial well-being and overall quality of life. Moderate levels of walking are known to be of benefit to the psychosocial well-being of those affected by breast cancer and for managing cognitive impairment in healthy adults, children, and the elderly. The purpose of this study is to investigate the effects of a home-based, self-managed, moderate intensity walking intervention on subjective and objective cognitive functioning in breast cancer patients undergoing chemotherapy. Methods: A home-based, self-managed intervention that consisted of moderate levels of walking was compared to usual care among breast cancer patients treated with chemotherapy in a randomised controlled trial. Outcome measures included changes in subjective (CFQ) and objectively detected cognitive functioning (Stroop, SART and two subscales from the WAIS- Digit Span and Block Design). Fifty participants were randomised to either the intervention group (n = 25), who completed 12 weeks of moderate intensity walking, or to the control group (n = 25) mid-way through chemotherapy. Results: Compared with the control group, the self-managed walking intervention had positive effects on perceived cognitive function but not on sustained attention, executive function, memory or visual spatial skills when assessed objectively using neuropsychological measures. Conclusion: This home-based, self-managed intervention is beneficial for protecting against perceived cognitive decline in breast cancer patients treated with chemotherapy. There is a need for further research to objectively assess cognitive decline within this population with larger sample sizes of patients. Trial registration: Current Controlled Trials [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is the leading cause of death by gynecologic cancers in the Western world. The aim of the study was to identify microRNAs (miRNAs) associated with prognosis and/or resistance to chemotherapy among patients with epithelial ovarian cancer. Methods: Using information from the Pelvic Mass Study we identified a cohort of women with epithelial ovarian cancer. Tumor tissues were then collected and analyzed by global miRNA microarrays. MiRNA profiling was then linked to survival and time to progression using Cox proportional-hazards regression models. Logistic regression models were used for the analysis of resistance to chemotherapy. Our results were validated using external datasets retrieved from the NCBI Gene Expression Omnibus database. Results: A total of 197 patients with epithelial ovarian cancer were included for miRNA microarray analysis. In multivariate analyses we identified a number of miRNAs significantly correlated with overall survival (miR-1183 (HR: 1.42, 95% CI:1.17–1.74, p = 0.0005), miR-126-3p (HR: 1.38, 95% CI:1.11–1.71, p = 0.0036), time to progression (miR-139-3p (HR: 1.48, 95% CI: 1.13–1.94, p = 0.0047), miR-802 (HR: 0.48, 95% CI: 0.29–0.78, p = 0.0035)), progression free survival (miR-23a-5p (HR:1.32, 95% CI:1.09–1.61, p = 0.004), miR-23a-3p (HR:1.70, 95% CI:1.15–2.51, p = 0.0074), miR-802 (HR: 0.48, 95% CI: 0.29–0.80, p = 0.0048)), and resistance to chemotherapy (miR-1234 (HR: 0.26, 95% CI: 0.11–0.64, p = 0.003)). A few miRNAs identified in our training cohort, were validated in external cohorts with similar results. Conclusion: Eight miRNAs were identified as significant predictors of overall survival, progression free survival, time to progression, and chemotherapy resistance. A number of these miRNAs were significantly validated using external datasets. Inter-platform and inter-laboratory variations may have influence on the ability to compare and reproduce miRNA results. The use of miRNAs as potential markers of relapse and survival in ovarian cancer warrants further investigation. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch-wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC. [ABSTRACT FROM AUTHOR]

A systematic understanding of the evolution and growth dynamics of invasive solid tumors in response to different chemotherapy strategies is crucial for the development of individually optimized oncotherapy. Here, we develop a hybrid three-dimensional (3D) computational model that integrates pharmacokinetic model, continuum diffusion-reaction model and discrete cell automaton model to investigate 3D invasive solid tumor growth in heterogeneous microenvironment under chemotherapy. Specifically, we consider the effects of heterogeneous environment on drug diffusion, tumor growth, invasion and the drug-tumor interaction on individual cell level. We employ the hybrid model to investigate the evolution and growth dynamics of avascular invasive solid tumors under different chemotherapy strategies. Our simulations indicate that constant dosing is generally more effective in suppressing primary tumor growth than periodic dosing, due to the resulting continuous high drug concentration. In highly heterogeneous microenvironment, the malignancy of the tumor is significantly enhanced, leading to inefficiency of chemotherapies. The effects of geometrically-confined microenvironment and non-uniform drug dosing are also investigated. Our computational model, when supplemented with sufficient clinical data, could eventually lead to the development of efficient in silico tools for prognosis and treatment strategy optimization. [ABSTRACT FROM AUTHOR]

In patients with triple-negative breast cancer (TNBC), tumor-infiltrating lymphocytes (TILs) are associated with improved survival. Lehmann et al. identified 4 molecular subtypes of TNBC [basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor (LAR)], and an immunomodulatory (IM) gene expression signature indicates the presence of TILs and modifies these subtypes. The association between TNBC subtype and TILs is not known. Also, the association between inflammatory breast cancer (IBC) and the presence of TILs is not known. Therefore, we studied the IM subtype distribution among different TNBC subtypes. We retrospectively analyzed patients with TNBC from the World IBC Consortium dataset. The molecular subtype and the IM signature [positive (IM+) or negative (IM-)] were analyzed. Fisher’s exact test was used to analyze the distribution of positivity for the IM signature according to the TNBC molecular subtype and IBC status. There were 88 patients with TNBC in the dataset, and among them 39 patients (44%) had IBC and 49 (56%) had non-IBC. The frequency of IM+ cases differed by TNBC subtype (p = 0.001). The frequency of IM+ cases by subtype was as follows: BL1, 48% (14/29); BL2, 30% (3/10); LAR, 18% (3/17); and M, 0% (0/21) (in 11 patients, the subtype could not be determined). The frequency of IM+ cases did not differ between patients with IBC and non-IBC (23% and 33%, respectively; p = 0.35). In conclusion, the IM signature representing the underlying molecular correlate of TILs in the tumor may differ by TNBC subtype but not by IBC status. [ABSTRACT FROM AUTHOR]

Covariate selection is a fundamental step when building sparse prediction models in order to avoid overfitting and to gain a better interpretation of the classifier without losing its predictive accuracy. In practice the LASSO regression of Tibshirani, which penalizes the likelihood of the model by the L1 norm of the regression coefficients, has become the gold-standard to reach these objectives. Recently Lee and Oh developed a novel random-effect covariate selection method called the modified unbounded penalty (MUB) regression, whose penalization function can equal minus infinity at 0 in order to produce very sparse models. We sought to compare the predictive accuracy and the number of covariates selected by these two methods in several high-dimensional datasets, consisting in genes expressions measured to predict response to chemotherapy in breast cancer patients. These comparisons were performed by building the Receiver Operating Characteristics (ROC) curves of the classifiers obtained with the selected genes and by comparing their area under the ROC curve (AUC) corrected for optimism using several variants of bootstrap internal validation and cross-validation. We found consistently in all datasets that the MUB penalization selected a remarkably smaller number of covariates than the LASSO while offering a similar—and encouraging—predictive accuracy. The models selected by the MUB were actually nested in the ones obtained with the LASSO. Similar findings were observed when comparing these results to those obtained in their first publication by other authors or when using the area under the Precision-Recall curve (AUCPR) as another measure of predictive performance. In conclusion, the MUB penalization seems therefore to be one of the best options when sparsity is required in high-dimension. Further investigation in other datasets is however required to validate these findings. [ABSTRACT FROM AUTHOR]

Background: Stage IV non-small cell lung cancer (NSCLC) is associated with a five-year survival rate of around 1%. Treatment with Viscum album L. (VA) extracts has been shown to reduce chemotherapy (CTx)-related adverse events, decrease CTx dose reductions and improve quality of life in a number of cancers. Recent data suggest a beneficial effect of add-on treatment with Viscum album L. (VA, European mistletoe) on survival in cancer patients. The objective of this study was to evaluate the effect of VA in addition to chemotherapy on survival in stage IV NSCLC patients. Methods: The observational study was conducted using data from the Network Oncology clinical registry which is an accredited conjoint clinical registry of German oncological hospitals, practitioners and out-patient centers.Patients were included if they had stage IV NSCLC at diagnosis, lived at least for four weeks post-diagnosis and received chemotherapeutic treatment. Patients with EGFR mutations as well as patients receiving tyrosine kinase inhibitors or immune checkpoint inhibitors were not included. Overall survival and impact on hazard in patients with chemotherapy (CTx) to patients receiving CTx plus VA were compared. To identify factors associated with survival and to address potential sources of bias a multivariate analyses using Cox proportional hazard model was performed. Results: The median age of the population was 64.1 years with 55.7% male patients. The highest proportion of patients had adenocarcinoma (72.2%) and most of the patients were current or past smokers (70.9%). Of 158 stage IV NSCLC patients, 108 received CTx only and 50 additional VA. Median survival was 17.0 months in the CTx plus VA group (95%CI: 11.0–40.0) and was 8.0 months (95%CI: 7.0–11.0) in the CTx only group (χ2 = 7.2, p = .007). Overall survival was significantly prolonged in the VA group (HR 0.44, 95%CI: 0.26–0.74, p = .002). One-year and three-year overall survival rates were greater with CTx plus VA compared to CTX alone (1y: 60.2% vs. 35.5%; 3y: 25.7% vs. 14.2%). Conclusion: Our findings suggest that concomitant VA is positively associated with survival in stage IV NSCLC patients treated with standard CTx. These findings complement pre-existing knowldedge of add-on VA’s clinical impact, however, results should be interpreted with caution in light of the study’s observational character. [ABSTRACT FROM AUTHOR]

As reported by the Taiwan Cancer Registry in 2013 squamous cell carcinoma of head and neck cancer (HNSCC) was the sixth most frequently diagnosed cancer and the 5th most common cause of cancer related death and its incidence and mortality rate is still rising. The co-occurrence of HNSCC and secondary primary cancer (SPC) and the chemopreventive effect of aspirin on certain malignancies had been reported. Therefore we conducted this national study to investigate the use of aspirin associated with risk reduction of secondary primary cancer for patients with head and neck cancer in Taiwan. We searched the Registry for Catastrophic Illness in the National Health Insurance Research Database (NHIRD) for 18,234 patients (3,576 aspirin users and 14,667 non-aspirin users) diagnosed with HNSCC during 2000–2005. The SPC incidence density during follow-up in 2000–2011 was compared between the groups. For HNSCC patients, aspirin use after diagnosis was significantly associated with SPC risk reduction by 25% (adjusted HR, 0.75; 95% CI, 0.63–0.89; p = 0.001) after multivariate analysis. In the subgroup analysis, we found that esophageal cancer and stomach cancer incidence were significantly reduced after aspirin use (adjusted HR, 0.60; 95% CI, 0.41–0.90; p = 0.01 for esophageal cancer; adjusted HR, 0.27; 95% CI, 0.08–0.87; p = 0.03 for stomach cancer). Aspirin use for 1–3 years was associated with SPC risk reduction by 35% (adjusted HR, 0.65; 95% CI, 0.49–0.87; p = 0.003). SPC risk reduction extended continuously for more than 3 years of follow up (adjusted HR, 0.72; 95% CI, 0.53–0.98; p = 0.030). Our data shows aspirin use was associated with reduced SPC incidence for HNSCC patients, attributed mainly to reduced risk of esophageal and stomach cancer. [ABSTRACT FROM AUTHOR]

It is unknown whether urban versus rural residency affects pancreatic cancer survival in a universal tax-financed healthcare system. We conducted a nationwide, population-based cohort study of all patients diagnosed with pancreatic cancer in Denmark from 2004–2015. We used nationwide registries to collect information on characteristics, comorbidity, cancer-directed treatment, and vital status. We followed the patients from pancreatic cancer diagnosis until death, emigration, or 1 October 2017, whichever occurred first. We truncated at five years of follow up. We stratified patients into calendar periods according to year of diagnosis (2004–2007, 2008–2011, and 2012–2015). We used Cox proportional hazards model to compute hazard ratios (HRs) with associated 95% confidence intervals (CIs) of death, comparing patients in urban and rural areas. HRs were adjusted for age, sex, comorbidity, tumor stage, and localization. In a sub-analysis, we also adjusted for cancer-directed treatment. We included 10,594 patients diagnosed with pancreatic cancer. Median age was 71 years (inter-quartile range: 63–78 years), and half were men. The majority (61.7%) lived in an urban area at the time of diagnosis. When adjusting for potential confounders, we observed a better survival rate among pancreatic cancer patients residing in urban areas compared with rural areas (adjusted HR: 0.92; 95% CI: 0.87–0.98). When taking treatment into account, the association was unclear (adjusted HR: 0.96; 95% CI: 0.88–1.04). Pancreatic cancer patients residing in urban areas had a slightly better survival rate compared with patients in rural areas. [ABSTRACT FROM AUTHOR]

To cope with intrinsic and environmental stress, cancer cells rely on adaptive pathways more than non-transformed counterparts. Such non-oncogene addiction offers new therapeutic targets and strategies to overcome chemoresistance. In an attempt to study the role of adaptive pathways in acquired drug resistance in carcinoma cells, we devised a model of in vitro conditioning to three standard chemotherapeutic agents, cisplatin, 5-fluorouracil, and docetaxel, from the epithelial cancer cell line, HEp-2, and investigated the mechanisms underlying reduced drug sensitivity. We found that triple-resistant cells suffered from higher levels of oxidative stress, and showed heightened anti-stress responses, including the antioxidant Nrf2 pathway and autophagy, a conserved pleiotropic homeostatic strategy, mediating the clearance of aggregates marked by the adapter p62/SQSTM1. As a result, re-administration of chemotherapeutic agents failed to induce further accumulation of reactive oxygen species and p62. Moreover, autophagy proved responsible for chemoresistance through the avoidance of p62 accumulation into toxic protein aggregates. Indeed, p62 ablation was sufficient to confer resistance in parental cells, and genetic and pharmacological autophagic inhibition restored drug sensitivity in resistant cells in a p62-dependent manner. Finally, exogenous expression of mutant p62 lacking the ubiquitin- and LC3-binding domains, required for autophagic engulfment, increased chemosensitivity in TDR HEp-2 cells. Altogether, these findings offer a cellular system to investigate the bases of acquired chemoresistance of epithelial cancers and encourage challenging the prognostic and antineoplastic therapeutic potential of p62 toxicity. [ABSTRACT FROM AUTHOR]

A metastatic cancer diagnosis is associated with high levels of distress in patients and caregivers. Mindfulness interventions can reduce distress and improve quality of life in cancer patients. However, standard mindfulness training relies on in-person instruction, which is often not practical for either patients receiving chemotherapy or their caregivers. In the Being Present single arm pilot study, we designed and tested an 8-week audio-based mindfulness meditation program for patients with metastatic colorectal cancer receiving chemotherapy with or without a participating caregiver. The study accrued 33 of 74 (45%) eligible patients consenting together with 20 family caregivers (53 participants total) within nine months. Forty-one participants were evaluable (77%); 10 of 12 cases of attrition were attributable to hospitalization or death. Median participant age was 51 (range 21–78 years); 38% were men. Baseline levels of distress were similar in patients and caregivers. The top reasons for participation cited in pre-intervention interviews were to increase relaxation/calm, improve mood/emotions, and reduce stress/anxiety. In measures of adherence, 59% of responses to weekly texts asking: “Have you practiced today?” were “Yes” and 59% of interviewees reported practicing >50% of the time. Compared to baseline, post-intervention surveys demonstrated significantly reduced distress (p = 0.01) and anxiety (p = 0.03); as well as increased non-reactivity (p<0.01), and feeling at peace (p<0.01). Post-intervention qualitative interviews, where 71% of participants reported benefit, were consistent with quantitative findings. In the interviews, participants spontaneously described reduced stress/anxiety and increased relaxation/calm. Benefits appeared to be accentuated in patient-caregiver pairs as compared to unpaired patients. Seventy-nine percent of participants reported plans for continued practice after study completion. We conclude that the Being Present audio-based mindfulness meditation program is of interest to, feasible, and acceptable for patients with metastatic colorectal cancer and caregivers, with initial evidence of efficacy. These results will guide plans for a follow-up study. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background and purpose: The role of preoperative short-course radiotherapy (SCRT) in rectal cancer treatment, when compared to long-course radiochemotherapy (LCRT), is still controversial. Thus the meta-analysis with trial sequential analysis (TSA) was performed to evaluate the long-term survival of SCRT and LCRT as therapeutic regimens for locally advanced rectal cancer. Material and methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to August 2017 for eligible studies. Hazard ratios (HRs) or odds ratios (ORs) of overall survival (OS), disease free survival (DFS) and local recurrence (LR) with the corresponding 95% confidence intervals (CIs) were calculated and TSA was applied. Results: 11 studies with 1984 patients were included. There was no significant difference in OS (HR = 0.92, 95% CI: 0.75–1.13, p = 0.44), DFS (HR = 0.94, 95% CI: 0.79–1.12, p = 0.50) and LR (OR = 0.73, 95% CI: 0.49–1.08, p = 0.11) between SCRT and LCRT groups. TSA suggested firm evidence for lacking on average a -10% relative risk reduction (RRR) in 4-year OS but no statistical significance in 4-year DFS. Conclusions: Preoperative SCRT is as effective as LCRT for locally advanced colorectal cancer in long-term survival. SCRT could be preferential while facing long waiting lists or lacking medical resource. [ABSTRACT FROM AUTHOR]

Background: There is no single standard chemotherapy regimen for elderly patients with advanced gastric cancer (AGC). A phase III trial has confirmed that both capecitabine monotherapy and capecitabine plus oxaliplatin are well tolerated for elderly patients with AGC, but their economic influence in China is unknown. Objective: The purpose of this cost-effectiveness analysis was to estimate the effects of capecitabine monotherapy and capecitabine plus oxaliplatin in elderly patients with AGC on health and economic outcomes in China. Methods: We created a Markov model based on data from a Korean clinical phase III trial to analyze the cost-effectiveness of the treatment of elderly patients in the capecitabine monotherapy (X) group and capecitabine plus oxaliplatin (XELOX) group. The costs were obtained from published reports and the local health system. The utilities were assumed on the basis of the published literature. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were estimated. One-way and probabilistic sensitivity analyses (Monte Carlo simulations) were performed. Results: In the cost-effectiveness analysis, X had a lower total cost ($45,731.68) and cost-effectiveness ratio ($65,918.93/QALY). The one-way sensitivity analysis suggested that the most influential parameter was the risk of requiring second-line chemotherapy in XELOX group. The probabilistic sensitivity analysis predicted that the X regimen was cost-effective 100% of the time, given a willingness-to-pay threshold of $26,598. Conclusions: Our findings show that the XELOX regimen is less cost-effective compared to the X regimen for elderly patients with AGC in China from a Chinese healthcare perspective. [ABSTRACT FROM AUTHOR]

Background and objectives: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal peroperative chemotherapy (HIPEC), indicated for patients with peritoneal metastases from digestive or gynecological malignancies alike, demonstrates a considerable impact on hemostatic metabolism, both on platelet and on coagulation level. The potential hemostatic interference in CRS and HIPEC is phase dependent. The hypothesis of this prospective cohort study is that the procedure exposed an increased thrombotic risk, resulting in a faster and increased thrombin generation and hyper platelet function. Methods: This study explores the combined use of ROTEM (rotational thromboelastometry), PACT (platelet activation test) and CAT (thrombin generation test) assays during CRS and HIPEC with a follow-up of 7 days postoperative in 27 patients with confirmed histological diagnosis of peritoneal disease. Results: Platelet reactivity (relative to before incision values) to CRP (collagen-related peptide) (p value 0.02) and TRAP (thrombin receptor activator peptide) (p value 0.048) seems to be slightly reduced during CRS and HIPEC with regard to αIIbβ3 activation, while P-selectin expression is not affected. During surgery, CAT demonstrates that, the LT (lagtime) (p value 0.0003) and TTP (time-to-thrombin peak) values (p value 0.002) decrease while and the TP (thrombin peak) (p value 0.004) and ETP (endogenous thrombin potential) (p value 0.02) increase. Subsequently, after surgery, the LT and TTP increase and ETP and TP decrease in time. ROTEM EXTEM (extrinsic) MCF (maximum clot firmness) (p value 0.005), INTEM (intrinsic) MCF (p value 0.003) and FIBTEM (fibrinogen) MCF (p value <0.001) decreased during CRS. At day 7 INTEM and FIBTEM MCF values (p values of 0.004 and <0.001) were significantly higher than before surgery. No considerable changes in platelet count and hemoglobin concentration and absence of leukopenia are noticed. Conclusion: This approach detects changes in coagulation much earlier than noticed by standard coagulation tests. [ABSTRACT FROM AUTHOR]

Objective: Mucositis is a side effect of chemotherapy seen in the digestive tract, with symptoms including pain, diarrhoea, inflammation and ulcerations. Our aim was to investigate whether endogenous glucagon-like peptide -1 and -2 (GLP-1 and GLP-2) are implicated in intestinal healing after chemotherapy-induced mucositis. Design: We used a transgenic mouse model Tg(GCG.DTR)(Tg) expressing the human diphtheria toxin receptor in the proglucagon-producing cells. Injections with diphtheria toxin ablated the GLP-1 and GLP-2 producing L-cells in Tg mice with no effect in wild-type (WT) mice. Mice were injected with 5-fluorouracil or saline and received vehicle, exendin-4, teduglutide (gly2-GLP-2), or exendin-4/teduglutide in combination. The endpoints were body weight change, small intestinal weight, morphology, histological scoring of mucositis and myeloperoxidase levels. Results: Ablation of L-cells led to impaired GLP-2 secretion; increased loss of body weight; lower small intestinal weight; lower crypt depth, villus height and mucosal area; and increased the mucositis severity score in mice given 5-fluorouracil. WT mice showed compensatory hyperproliferation as a sign of regeneration in the recovery phase. Co-treatment with exendin-4 and teduglutide rescued the body weight of the Tg mice and led to a hyperproliferation in the small intestine, whereas single treatment was less effective. Conclusion: The ablation of L-cells leads to severe mucositis and insufficient intestinal healing, shown by severe body weight loss and lack of compensatory hyperproliferation in the recovery phase. Co-treatment with exendin-4 and teduglutide could prevent this. Because both peptides were needed, we can conclude that both GLP-1 and GLP-2 are essential for intestinal healing in mice. [ABSTRACT FROM AUTHOR]

DNA-protein cross-links (DPCs) are important DNA lesions induced by endogenous crosslinking agents such as formaldehyde or acetaldehyde, as well as ionizing radiation, cancer chemotherapeutic drugs, and abortive action of some enzymes. Due to their very bulky nature, they are expected to interfere with DNA and RNA synthesis and DNA repair. DPCs are highly genotoxic and the ability of cells to deal with them is relevant for many chemotherapeutic interventions. However, interactions of DNA polymerases with DPCs have been poorly studied due to the lack of a convenient experimental model. We have used NaBH4-induced trapping of E. coli formamidopyrimidine-DNA glycosylase with DNA to construct model DNA polymerase substrates containing a DPC in single-stranded template, or in the template strand of double-stranded DNA, or in the non-template (displaced) strand of double-stranded DNA. Nine DNA polymerases belonging to families A, B, X, and Y were studied with respect to their behavior upon encountering a DPC: Klenow fragment of E. coli DNA polymerase I, Thermus aquaticus DNA polymerase I, Pyrococcus furiosus DNA polymerase, Sulfolobus solfataricus DNA polymerase IV, human DNA polymerases β, κ and λ, and DNA polymerases from bacteriophages T4 and RB69. Although none were able to fully bypass DPCs in any context, Family B DNA polymerases (T4, RB69) and Family Y DNA polymerase IV were able to elongate the primer up to the site of the cross-link if a DPC was located in single-stranded template or in the displaced strand. In other cases, DNA synthesis stopped 4–5 nucleotides before the site of the cross-link in single-stranded template or in double-stranded DNA if the polymerases could displace the downstream strand. We suggest that termination of DNA polymerases on a DPC is mostly due to the unrelieved conformational strain experienced by the enzyme when pressing against the cross-linked protein molecule. [ABSTRACT FROM AUTHOR]

Purpose: To report associations between disease- and treatment-related variables and rates of recurrence-free survival and ocular survival in eyes treated with ophthalmic artery chemosurgery (OAC) for retinoblastoma. Design: Pre-post study. Subjects: All eyes treated with OAC for retinoblastoma at Memorial Sloan Kettering Cancer Center between May 2006 and February 2017. Methods: This retrospective review included 452 retinoblastoma eyes treated with OAC. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS), progression-free survival (PFS) and ocular survival (OcS), and Cox regression was used to estimate hazard ratios. Eyes treated in the pre-intravitreous chemotherapy era were analyzed separately from eyes treated in the intravitreal era. Main outcome measures: Recurrence-free survival, ocular survival, associations with risk of recurrence Results: Disease and treatment characteristics were recorded over a median 23.6 month follow-up. One-year OcS, PFS and RFS were 96% (95% CI 93–99%), 88% (95% CI 88–94%) and 74% (95% CI 67–81%) in the pre-intravitreal era and 96% (95% CI 94–99%), 93% (95% CI 89–96%) and 78% (95% CI 72–83%) in the intravitreal era, respectively. Presence of vitreous seeds was associated with increased risk of recurrence in the pre-intravitreal era but not in the intravitreal era. Longer time interval between OAC sessions was associated with increased risk of recurrence and majority OAC access via the ophthalmic artery was associated with decreased risk of recurrence in both eras. Conclusions: Approximately a quarter of eyes initially treated with ophthalmic artery chemosurgery develop recurrent disease, with the majority of recurrences within the first year following completion of OAC. Despite this, these eyes have a very good chance of salvage. In eyes with vitreous seeds at presentation, intravitreal injections are useful in minimizing future vitreous recurrence. Eyes that receive the majority of drug infusions via non-ophthalmic artery routes or greater interval between OAC are more likely to recur and might warrant closer monitoring. [ABSTRACT FROM AUTHOR]

Purine and pyrimidine analogues have important uses in chemotherapies against cancer, and a better understanding of the mechanisms that cause resistance to these drugs is therefore of importance in cancer treatment. In the yeast Saccharomyces cerevisiae, overexpression of the HAM1 gene encoding inosine triphosphate pyrophosphatase confers resistance to both the purine analogue 6-N-hydroxylaminopurine (HAP) and the pyrimidine analogue 5-fluorouracil (5-FU) (Carlsson et al., 2013, PLoS One 8, e52094). To find out more about the mechanisms of resistance to nucleotide analogues, and possible interdependencies between purine and pyrimidine analogue resistance mechanisms, we screened a plasmid library in yeast for genes that confer HAP resistance when overexpressed. We cloned four such genes: ADE4, DUT1, APT2, and ATR1. We further looked for genetic interactions between these genes and genes previously found to confer resistance to 5-FU. We found that HMS1, LOG1 (YJL055W), HAM1, and ATR1 confer resistance to both 5-FU and HAP, whereas ADE4, DUT1 and APT2 are specific for HAP resistance, and CPA1 and CPA2 specific for 5-FU resistance. Possible mechanisms for 5-FU and HAP detoxification are discussed based on the observed genetic interactions. Based on the effect of LOG1 against both 5-FU and HAP toxicity, we propose that the original function of the LOG (LONELY GUY) family of proteins likely was to degrade non-canonical nucleotides, and that their role in cytokinin production is a later development in some organisms. [ABSTRACT FROM AUTHOR]

Although studies from pediatric cancers (largely acute lymphoblastic leukemia) have shown that patients undergoing systemic chemotherapy may experience decreased growth velocity during the treatment phase, no such data exist for retinoblastoma patients treated with systemic chemotherapy or ophthalmic artery chemosurgery (OAC). The purpose of this study is to report growth patterns of our retinoblastoma (Rb) population who were treated with OAC in a retrospective, single center (Memorial Sloan Kettering Cancer Center) review of 341 patients treated between 2006 and 2016. Children who only received OAC were classified as naive; those who were treated initially with systemic chemotherapy and subsequently presented to our center for OAC were termed secondary; and a small group of patients who received single-agent systemic chemotherapy prior to OAC were labeled bridge. For all patients, height and weight were recorded at monthly intervals during OAC (short-term) and then annually during a follow-up period (long-term) up to 3 years after treatment. Excluded from this study were children who received external radiation therapy and those with genetic syndromes, which are independently associated with growth derangements. During OAC, there was no significant difference in growth velocity between the naïve and secondary groups. In either group, number of treatments also did not affect growth rate. Three years after the end of OAC, naïve patients were in the 68th percentile by height (95% CI 61.30, 74.63) compared to secondary patients in the 61st percentile (95% CI 51.1, 71.47). Both groups were in the same weight percentiles during the first two years of follow-up but at the three-year follow-up period, naïve patients were in the 63rd percentile (95% CI 57.4, 69.4) and secondary patients were in the 60th percentile (95% CI 50.4, 69.7). OAC for retinoblastoma does not appear to impact short-term growth velocity, weight gain during the treatment period or after three years. [ABSTRACT FROM AUTHOR]

Aim: Acute and subacute cardiotoxicity are characterized by prolongation of the corrected QT interval (QTc) and other measures derived from the QTc interval, such as QTc dispersion (QTdc) and transmural dispersion of repolarization (DTpTe). Although anthracyclines prolong the QTc interval, it is unclear whether breast cancer patients who undergo the ACT chemotherapy regimen of anthracycline (doxorubicin: A), cyclophosphamide (C) and taxane (T) may present with QTc, QTdc and DTpTe prolongation. Methods: Twenty-three consecutive patients with breast cancer were followed prospectively during ACT chemotherapy and were analyzed according to their QT measurements. QTc, QTdc and DTpTe measurements were determined by a 12-lead electrocardiogram (EKG) prior to chemotherapy (baseline), immediately after the first phase of anthracycline and cyclophosphamide (AC) treatment, and immediately after T treatment. Serum troponin and B-type natriuretic peptide (BNP) levels were also measured. Results: Compared to baseline values, the QTc interval was significantly prolonged after the AC phase (439.7 ± 33.2 ms vs. 472.5 ± 36.3 ms, p = 0.001) and after T treatment (439.7 ± 33.2 ms vs. 467.9 ± 42.6 ms, p < 0.001). Troponin levels were elevated after the AC phase (23.0 pg/mL [min-max: 6.0–85.0] vs. 6.0 pg/mL [min-max: 6.0–22.0], p < 0.001) and after T treatment (25.0 pg/mL [min-max: 6.0–80.0] vs. 6.0 pg/mL [min-max: 6.0–22.0], p < 0.001) compared to baseline values. Conclusion: In this prospective study of patients with non-metastatic breast cancer who underwent ACT chemotherapy, significant QTc prolongation and an elevation in serum troponin levels were observed. [ABSTRACT FROM AUTHOR]

Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers—either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized. We performed exome array analysis to identify genetic variants that contribute to adverse reactions. Our final dataset consisted of 504 European ancestry individuals undergoing fluoropyrimidine-based therapy for gastrointestinal cancer. A subset of 254 of these were treated with Capecitabine. All individuals were genotyped on the Illumina HumanExome Array. Firstly, we performed SNP and gene-level analyses of protein-altering variants on the array to identify novel associations the following ADRs, which were grouped into four phenotypes based on symptoms of diarrhea, mucositis, and neutropenia and hand-and-foot syndrome. Secondly, we performed detailed analyses of the HLA region on the same phenotypes after imputing the HLA alleles and amino acids. No protein-altering variants, or sets of protein-altering variants collapsed into genes, were associated with the main outcomes after Bonferroni correction. We found evidence that the HLA region was enriched for associations with Hand-and-Foot syndrome (p = 0.023), but no specific SNPs or HLA alleles were significant after Bonferroni correction. Larger studies will be required to characterize the genetic contribution to ADRs to 5FU. Future studies that focus on the HLA region are likely to be fruitful. [ABSTRACT FROM AUTHOR]

Cancer affects 39.6% of Americans at some point during their lifetime. Solid tumor microenvironments are characterized by a disorganized, leaky vasculature that promotes regions of low oxygenation (hypoxia). Tumor hypoxia is a key predictor of poor treatment outcome for all radiotherapy (RT), chemotherapy and surgery procedures, and is a hallmark of metastatic potential. In particular, the radiation therapy dose needed to achieve the same tumor control probability in hypoxic tissue as in normoxic tissue can be up to 3 times higher. Even very small tumors (<2–3 mm3) comprise 10–30% of hypoxic regions in the form of chronic and/or transient hypoxia fluctuating over the course of seconds to days. We investigate the potential of recently developed lipid-stabilized oxygen microbubbles (OMBs) to improve the therapeutic ratio of RT. OMBs, but not nitrogen microbubbles (NMBs), are shown to significantly increase dissolved oxygen content when added to water in vitro and increase tumor oxygen levels in vivo in a rat fibrosarcoma model. Tumor control is significantly improved with OMB but not NMB intra-tumoral injections immediately prior to RT treatment and effect size is shown to depend on initial tumor volume on RT treatment day, as expected. [ABSTRACT FROM AUTHOR]

Background: There have been few large-scale, real world studies in Spain to assess change in pain and quality of life (QOL) outcomes in cancer patients with moderate to severe pain. This study aimed to assess changes on both outcomes after 3 months of usual care and to investigate factors associated with change in QoL. Patients and methods: Large, multi-centre, observational study in patients with lung, head and neck, colorectal or breast cancer experiencing a first episode of moderate to severe pain while attending one of the participating centres. QoL was assessed using the EuroQol-5D questionnaire and pain using the Brief Pain Inventory (BPI). Instruments were administered at baseline and after 3 months of follow up. Multivariate analyses were used to assess the impact of treatment factors, demographic and clinical variables, pain and other symptoms on QoL scores. Results: 1711 patients were included for analysis. After 3 months of usual care, a significant improvement was observed in pain and QoL in all four cancer groups (p<0.001). Effect sizes were medium to large on the BPI and EQ-5D Index and Visual Analogue Scale (VAS). Improvements were seen on the majority of EQ-5D dimensions in all patient groups, though breast cancer patients showed the largest gains. Poorer baseline performance status (ECOG) and the presence of anxiety/depression were associated with significantly poorer QOL outcomes. Improvements in BPI pain scores were associated with improved QoL. Conclusion: In the four cancer types studied, pain and QoL outcomes improved considerably after 3 months of usual care. Improvements in pain made a substantial contribution to QoL gains whilst the presence of anxiety and depression and poor baseline performance status significantly constrained improvement. [ABSTRACT FROM AUTHOR]

Background: This study assessed the prognostic value of HE4 marker measurements at various stages of first-line chemotherapy for ovarian cancer. Methods: The study consisted of 90 ovarian cancer patients, including 48 women undergoing primary surgical treatment and 42 patients qualified for neoadjuvant chemotherapy. Each patient underwent HE4 and CA 125 level measurements at the time of diagnosis and subsequently as follows: after surgical treatment, after the third course of adjuvant chemotherapy, before interval cytoreductive surgery and after chemotherapy. The HE4 value was assessed based on the PSF, OS, DFS, surgical outcome, two-year survival and platinum sensitivity. Results: Preoperative HE4 levels were a predictor of platinum sensitivity (AUC– 0.644; p = 0.035) and DFS (AUC = 0.637; p = 0.0492). A univariate logistic regression analysis showed that serum HE4 significantly correlated with PFS (baseline results over median HR = 2.96, p = 0.0009; baseline over 75 percentile HR = 2.44, p = 0.0062; normalization after treatment HR = 0.46, p = 0.0125; 50% reduction before IDS HR = 0.64, p = 0.0017). In the multivariate analysis, normalization after treatment and 50% reduction before IDS significantly influenced the PFS (HR = 0.29, p = 0.00008; HR = 0.23, p = 0.0024). The HE4 levels also correlated with the OS as follows: values below the median (HR = 1.88, p = 0.0087), normalization after chemotherapy (HR = 0.08, p = 0.0003), and 50% reduction before IDS (HR = 0.39, p = 0.0496). Conclusions: The significant effect of the normalization of the HE4 marker after therapy and 50% reduction of HE4 levels before interval cytoreductive surgery on PFS and OS confirmed that HE4 might be an independent prognostic factor of treatment response. HE4 measurements performed during first-line treatment of ovarian cancer may have prognostic significance. [ABSTRACT FROM AUTHOR]

Objectives: To compare clinical outcomes of concurrent chemoradiotherapy (CCRT) with those of radiotherapy alone for stage II nasopharyngeal carcinoma in the intensity-modulated radiotherapy (IMRT) era. Materials and methods: We comprehensively searched PubMed, Embase, and the Cochrane Library to identify eligible studies. Overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), locoregional recurrence-free survival (LRRFS) with hazard ratios (HRs), and toxicities with odd ratios (ORs) were analyzed. Results: A total of seven studies met the criteria, with 1302 patients who were treated with IMRT alone or IMRT plus concurrent chemotherapy. No significant survival benefit was shown by CCRT regardless of OS (HR = 1.17, 95% CI 0.73–1.89, P = 0.508), PFS (HR = 0.76, 95% CI 0.38–1.50, P = 0.430), DMFS (HR = 0.89, 95% CI 0.33–2.41, P = 0.816), or LRRFS (HR = 1.03, 95% CI 0.95–1.12, P = 0.498). Additionally, CCRT notably increased the risk of acute grade 3–4 leukopenia (OR = 4.432, 95% CI 2.195–8.952, P < 0.001), compared to IMRT alone. Conclusion: Adding concurrent chemotherapy to IMRT led to no survival benefit and increased acute toxicity reactions for stage II nasopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Chemotherapy in childhood can result in long-term neurophysiological side-effects, which could extend to visual processing, specifically the degree to which a person relies on vision to determine vertical and horizontal (visual dependency). We investigated whether adults treated with chemotherapy in childhood experience elevated visual dependency compared to controls and whether any difference is associated with the age at which subjects were treated. Visual dependency was measured in 23 subjects (mean age 25.3 years) treated in childhood with chemotherapy (CTS) for malignant, solid, non-CNS tumors. We also stratified CTS into two groups: those treated before 12 years of age and those treated from 12 years of age and older. Results were compared to 25 healthy, age-matched controls. The subjective visual horizontal (SVH) and vertical (SVV) orientations was recorded by having subjects position an illuminated rod to their perceived horizontal and vertical with and without a surrounding frame tilted clockwise and counter-clockwise 20° from vertical. There was no significant difference in rod accuracy between any CTS groups and controls without a frame. However, when assessing visual dependency using a frame, CTS in general (p = 0.006) and especially CTS treated before 12 years of age (p = 0.001) tilted the rod significantly further in the direction of the frame compared to controls. Our findings suggest that chemotherapy treatment before 12 years of age is associated with elevated visual dependency compared to controls, implying a visual bias during spatial activities. Clinicians should be aware of symptoms such as visual vertigo in adults treated with chemotherapy in childhood. [ABSTRACT FROM AUTHOR]

As part of a major project to investigate protective and diagnostic immune markers against tuberculosis (TB), we measured antibody isotype responses to Mycobacterium tuberculosis (Mtb) antigens (LAM, Rv2031, and HBHA) in cohorts of 149 pulmonary tuberculosis patients (PTBP), 148 household contacts (HHCs), and 68 community controls (CCs) in an endemic setting. ELISA was used to measure levels of IgA, IgG, and IgM from sera of cohorts at baseline, and at 6 and 12 months from entry. The results show that there were significant differences in IgA, IgG, and IgM responses to the different antigens and in the three cohorts. At baseline, the level of IgM against RV2031 and LAM did not vary between cohorts, but the levels of IgA and IgG against Rv2031 were significantly higher in PTB patients than HHCs and CCs, followed by HHCs, and the lowest in CCs. In patients, there was a significant variation in antibody responses before and after chemotherapy. The levels of IgA and IgG against HBHA, and IgA against Rv2031 decreased significantly and remained low, while IgA and IgG against LAM increased significantly and remained high following chemotherapy. However, the levels of IgM against Rv2031 and LAM increased at 6 months but decreased again at 12 months. IgM against HBHA did not show any significant variation before and after chemotherapy. Similarly, there were also significant variations in antibody responses in HHCs over time. Our results show that there are significant variations in IgA, IgG and IgM responses to the different antigens and in the three cohorts, implying that not all antibody isotype responses are markers of clinical TB. In addition, the current and previous studies consistently show that IgA and IgG against Rv2031 discriminate between clinical disease, Mtb-infected and non-infected individuals. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy before radical gastrectomy is preferred for locally advanced gastric cancer. To avoid the problematic use of pTNM for patients after neoadjuvant chemotherapy, the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) gastric cancer TNM staging system (8th edition) added ypTNM for the first time. But patients achieving pathological complete response were not covered by the new ypTNM staging system. To investigate whether pathological complete response is associated with better outcome in gastric cancer, as was reported in rectal, breast and bladder cancer. Methods: We systematically searched the databases of PubMed, EMBASE, Web of Science and Cochrane Collaboration’s Central register of controlled trials from January 1988 to April 2015 for publications which reported outcomes of patients with and without pathological complete response (pCR) (pT0N0M0) to investigate whether pCR after neoadjuvant chemotherapy in gastric or gastroesophageal junction (GEJ) treated with radical surgery is associated with better survival. The primary outcome was overall survival (OS). The secondary outcome was disease-free survival (DFS). Both were measured with a relative risk (RR). A meta-analysis was performed using the fixed effects model. Forest plots and the Q test was used to evaluate overall heterogeneity for OS and DFS. Results: A total of seven trials, 1143 patients were included and analyzed after neoadjuvant chemotherapy and radical surgery with no other preoperative treatment. The average rate of pCR was 6.74% (range: 3%-15%). The RR of patients who achieved pCR in the primary tumor and lymph nodes is 0.5 (95% confidence interval [CI], 0.25–0.98; p = 0.04), 0.34 (95% CI, 0.21–0.55; p<0.0001) and 0.44 (95% CI, 0.30–0.63; p<0.0001) for one-year-OS, three-year-OS and five-year-OS, respectively. The summary RR for three-year-DFS was 0.43 (95% CI, 0.25–0.72; p = 0.002). Conclusion: Patients with resectable gastric or GEJ cancer who achieved pCR after neoadjuvant chemotherapy can gain a better outcome than patients without pCR. [ABSTRACT FROM AUTHOR]

Static magnetic field (SMF) has shown some possibilities for cancer therapies. In particular, the combinational effect between SMF and anti-cancer drugs has drawn scientists’ attentions in recent years. However, the underlying mechanism for the drug-specific synergistic effect is far from being understood. Besides, the drugs used are all conventional chemotherapy drugs, which may cause unpleasant side effects. In this study, our results demonstrate for the first time that SMF could enhance the anti-cancer effect of natural compound, capsaicin, on HepG2 cancer cells through the mitochondria-dependent apoptosis pathway. We found that the synergistic effect could be due to that SMF increased the binding efficiency of capsaicin for the TRPV1 channel. These findings may provide a support to develop an application of SMF for cancer therapy. The present study offers the first trial in combining SMF with natural compound on anti-cancer treatment, which provides additional insight into the interaction between SMF and anti-cancer drugs and opens the door for the development of new strategies in fighting cancer with minimum cytotoxicity and side effects. [ABSTRACT FROM AUTHOR]

Olfactory neuroblastoma (ONB) is a rare, locally aggressive, malignant neoplasm originating in the olfactory epithelium in the nasal vault. The recurrence rate of ONB remains high and there are no specific treatment guidelines for recurrent/metastatic ONBs. This study retrospectively evaluated 23 ONB samples profiled at Caris Life Sciences (Phoenix, Arizona) using DNA sequencing (Sanger/NGS [Illumina], n = 15) and gene fusions (Archer FusionPlex, n = 6), whole genome RNA microarray (HumanHT-12 v4 beadChip, Illumina, n = 4), gene copy number assays (chromogenic and fluorescent in situ hybridization), and immunohistochemistry. Mutations were detected in 63% ONBs including TP53, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, and SMAD4 genes. Twenty-one genes were over-expressed and 19 genes under-expressed by microarray assay. Some of the upregulated genes included CD24, SCG2, and IGFBP-2. None of the cases harbored copy number variations of EGFR, HER2 and cMET genes, and no gene fusions were identified. Multiple protein biomarkers of potential response or resistance to classic chemotherapy drugs were identified, such as low ERCC1 [cisplatin sensitivity in 10/12], high TOPO1 [irinotecan sensitivity in 12/19], high TUBB3 [vincristine resistance in 13/14], and high MRP1 [multidrug resistance in 6/6 cases]. None of the cases (0/10) were positive for PD-L1 in tumor cells. Overexpression of pNTRK was observed in 67% (4/6) of the cases without underlying genetic alterations. Molecular alterations detected in our study (e.g., Wnt and cKIT/PDGFRA pathways) are potentially treatable using novel therapeutic approaches. Identified protein biomarkers of response or resistance to classic chemotherapy could be useful in optimizing existing chemotherapy treatment(s) in ONBs. [ABSTRACT FROM AUTHOR]

The openEHR specifications are designed to support implementation of flexible and interoperable Electronic Health Record (EHR) systems. Despite the increasing number of solutions based on the openEHR specifications, it is difficult to find publicly available healthcare datasets in the openEHR format that can be used to test, compare and validate different data persistence mechanisms for openEHR. To foster research on openEHR servers, we present the openEHR Benchmark Dataset, ORBDA, a very large healthcare benchmark dataset encoded using the openEHR formalism. To construct ORBDA, we extracted and cleaned a de-identified dataset from the Brazilian National Healthcare System (SUS) containing hospitalisation and high complexity procedures information and formalised it using a set of openEHR archetypes and templates. Then, we implemented a tool to enrich the raw relational data and convert it into the openEHR model using the openEHR Java reference model library. The ORBDA dataset is available in composition, versioned composition and EHR openEHR representations in XML and JSON formats. In total, the dataset contains more than 150 million composition records. We describe the dataset and provide means to access it. Additionally, we demonstrate the usage of ORBDA for evaluating inserting throughput and query latency performances of some NoSQL database management systems. We believe that ORBDA is a valuable asset for assessing storage models for openEHR-based information systems during the software engineering process. It may also be a suitable component in future standardised benchmarking of available openEHR storage platforms. [ABSTRACT FROM AUTHOR]

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients’ intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients’ post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth. [ABSTRACT FROM AUTHOR]

Intervention: Few studies have documented the interruption of onchocerciasis and Lymphatic Filariasis (LF) by integrated chemotherapy in Uganda. The study describes the interruption of transmission of the two diseases co-endemic in Obongi focus, north western Uganda. Base line data for Onchocerciasis and LF were collected in 1994 and 2006, respectively. Annual mass drug administration for onchocerciasis (Ivermectin) and Lymphatic Filariasis (Ivermectin + albendazole) was conducted for 20 and 6 years, respectively. Thereafter, assessments by skin snip, larval searches in rivers and human landing catches were performed. Children <10 years were screened for IgG4 antibodies using Ov16 ELISA technique in 2013. LF Pre-TAS and TAS1 were conducted in sentinel sites. ITN coverage and utilization for the implementation unit was also reported. Intervention coverage: Onchocerciasis treatment coverage was <80% but improved with the introduction of CDTI in 1999. While for LF, effective coverage of >65% was achieved in the six treatment rounds. Household ownership of ITN’s and utilization was 96% and 72.4%., respectively. Impact: Parasitological examinations conducted for onchocerciasis among 807 adults and children, revealed a reduction in mf prevalence from 58% in 1994 to 0% in 2012. Entomological monitoring conducted at the two sites had no single Simulium damnosum fly caught. Serological analysis using Ov16 ELISA for onchocerciasis revealed that out of the 3,308 children <10 years old screened in 2013, only 3/3308 (0.091%) positive cases were detected. All Ov16 positive children were negative when tested for patent infection by skin snip PCR. A reduction in LF microfilaria prevalence from 2.5% (n = 13/522) in 2006 to 0.0% (n = 602) in 2014 was observed. LF TAS1 conducted in 2015 among 1,532 children 6–7 years, all were negative for antigens of W. bancrofti. Conclusion: The results concluded that interruption of onchocerciasis and LF has been achieved. [ABSTRACT FROM AUTHOR]

Conflicting reports regarding whether high tumor-associated neutrophils (TAN) are associated with outcomes in colorectal cancer (CRC) exist. Previous investigators have counted TAN using non-neutrophil-specific immunohistochemistry (IHC) stains. We examined whether TAN levels as determined by multi-field manual counting would predict prognosis. IRB approval was obtained and two pathologists, blinded to stage/outcome, counted TAN in 20 high power fields (HPF) per specimen. TAN score was defined as the mean of these counts. High TAN was defined as at or greater than the median score for that stage. Demographics, tumor characteristics, and overall survival (OS) were obtained from the records and examined for association with TAN score. IHC for arginase expression was performed in a subset of samples. 221 patients were included. Stage II patients with high TAN scores had an OS of 232 months as compared to those with low TAN (OS = 85 months, p = 0.03). The survival benefit persisted in multivariable analysis (HR 0.48, CI 0.25–0.91, p = 0.026) controlling for age and sex. Women had increased survival as compared to men, and there were no significant prognostic associations with TAN count in stage III/IV patients, although there were only 12 stage IV patients. Arginase staining did not provide additional information. Stage II colorectal cancer patients with high TAN live nearly 3 times longer than those with low TAN. Women with stage II disease and high TAN counts appear to be driving the survival benefit seen in the stage II patients and have increased overall survival in all stages. [ABSTRACT FROM AUTHOR]

Background: Tumor vasculature is critical for tumor growth, formation of distant metastases and efficiency of radio- and chemotherapy treatments. However, how the vasculature itself is affected during cancer treatment regarding to the metastatic behavior has not been thoroughly investigated. Therefore, the aim of this study was to analyze the influence of hypofractionated radiotherapy and cisplatin chemotherapy on vessel tree geometry and metastasis formation in a small cell lung cancer xenograft mouse tumor model to investigate the spread of malignant cells during different treatments modalities. Methods: The biological data gained during these experiments were fed into our previously developed computer model “Cancer and Treatment Simulation Tool” (CaTSiT) to model the growth of the primary tumor, its metastatic deposit and also the influence on different therapies. Furthermore, we performed quantitative histology analyses to verify our predictions in xenograft mouse tumor model. Results: According to the computer simulation the number of cells engrafting must vary considerably to explain the different weights of the primary tumor at the end of the experiment. Once a primary tumor is established, the fractal dimension of its vasculature correlates with the tumor size. Furthermore, the fractal dimension of the tumor vasculature changes during treatment, indicating that the therapy affects the blood vessels’ geometry. We corroborated these findings with a quantitative histological analysis showing that the blood vessel density is depleted during radiotherapy and cisplatin chemotherapy. The CaTSiT computer model reveals that chemotherapy influences the tumor’s therapeutic susceptibility and its metastatic spreading behavior. Conclusion: Using a system biological approach in combination with xenograft models and computer simulations revealed that the usage of chemotherapy and radiation therapy determines the spreading behavior by changing the blood vessel geometry of the primary tumor. [ABSTRACT FROM AUTHOR]

Small molecule screens are widely used to prioritize pharmaceutical development. However, determining the pathways targeted by these molecules is challenging, since the compounds are often promiscuous. We present a network strategy that takes into account the polypharmacology of small molecules in order to generate hypotheses for their broader mode of action. We report a screen for kinase inhibitors that increase the efficacy of gemcitabine, the first-line chemotherapy for pancreatic cancer. Eight kinase inhibitors emerge that are known to affect 201 kinases, of which only three kinases have been previously identified as modifiers of gemcitabine toxicity. In this work, we use the SAMNet algorithm to identify pathways linking these kinases and genetic modifiers of gemcitabine toxicity with transcriptional and epigenetic changes induced by gemcitabine that we measure using DNaseI-seq and RNA-seq. SAMNet uses a constrained optimization algorithm to connect genes from these complementary datasets through a small set of protein-protein and protein-DNA interactions. The resulting network recapitulates known pathways including DNA repair, cell proliferation and the epithelial-to-mesenchymal transition. We use the network to predict genes with important roles in the gemcitabine response, including six that have already been shown to modify gemcitabine efficacy in pancreatic cancer and ten novel candidates. Our work reveals the important role of polypharmacology in the activity of these chemosensitizing agents. [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]

Purpose: The objective of this retrospective work was to evaluate the prognostic value on histological response and survival of quantitative indices derived from FDG-PET performed before and after chemotherapy (CHT), in a homogeneous pediatric Ewing sarcoma (EWS) and Osteosarcoma (OST) population. Methods: Thirty-one patients with EWS and 31 with OST were included. All patients were treated with neoadjuvant CHT, and underwent surgery for local control. All patients had FDG-PET at diagnosis and after CHT, prior to surgery. Several parameters were evaluated: SUVmax, SUVpeak, SUVmean, metabolic tumor volume, total lesion glycolysis, 7 textural features and 3 shape features (SF). The segmentation was performed using an adaptive approach. Results were compared to histopathological regression of the resected tumor and to clinical follow-up for survival evaluation. Results: For EWS, univariate analysis did not highlight any prognostic value on histological response, or survival regardless of all the considered metrics. For OST, only one of the SF, namely elongation, was significantly associated with PFS and OS on both univariate and multivariate analysis (PFS: p = 0.019, HR = 5.583; OS: p = 0.0062, HR = 7.113). Conclusion: Only elongation determined on initial FDG-PET has a potential interest as a prognostic factor of PFS and OS in pediatric OST patients. Unlike recent studies of the literature realized in adult population, all the metrics reveal limited additional prognostic value in pediatric EWS patients. This seems to reinforce the question of whether children experience different subtypes of the same pathologies than older patients, with different outcomes. [ABSTRACT FROM AUTHOR]

Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinum-based chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy. Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan-Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progression-free survival (PFS). Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50–0.90 and HR 0.66, 95% CI 0.48–0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively). Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy. [ABSTRACT FROM AUTHOR]