Adenosine A2 receptor activation ameliorates mitochondrial oxidative stress upon reperfusion through the posttranslational modification of NDUFV2 subunit of complex I in the heart

Publication date: Available online 20 February 2017
Source:Free Radical Biology and Medicine
Author(s): Jingman Xu, Xiyun Bian, Yuan Liu, Lan Hong, Tianming Teng, Yuemin Sun, Zhelong Xu
While it is well known that adenosine receptor activation protects the heart from ischemia/reperfusion injury, the precise mitochondrial mechanism responsible for the action remains unknown. This study probed the mitochondrial events associated with the cardioprotective effect of 5'-(N-ethylcarboxamido) adenosine (NECA), an adenosine A2 receptor agonist. Isolated rat hearts were subjected to 30min ischemia followed by 10min of reperfusion, whereas H9c2 cells experienced 20min ischemia and 10min reperfusion. NECA prevented mitochondrial structural damage, decreases in respiratory control ratio (RCR), and collapse of mitochondrial membrane potential (ΔΨm). Both the adenosine A2A receptor antagonist SCH58261 and A2B receptor antagonist MRS1706 inhibited the action of NECA. NECA reduced mitochondrial proteins carbonylation, H2O2, and superoxide generation at reperfusion, but did not change superoxide dismutase (SOD) activity. In support, the protective effects of NECA and Peg-SOD on ΔΨm upon reperfusion were additive, implying that NECA's protection is attributable to the reduced superoxide generation but not to the enhancement of the superoxide-scavenging capacity. NECA increased the mitochondrial Src tyrosine kinase activity and suppressed complex I activity at reperfusion in a Src-dependent manner. NECA also reduced mitochondrial superoxide through Src tyrosine kinase. Studies with liquid chromatography-mass spectrometer (LC-MS) identified Tyr118 of the NDUFV2 subunit of complex 1 as a likely site of the tyrosine phosphorylation. Furthermore, the complex I activity of cells transfected with the Y118F mutant was increased, suggesting that this site might be a negative regulator of complex I activity. In support, NECA failed to suppress complex I activity at reperfusion in cells transfected with the Y118F mutant of NDUFV2. In conclusion, NECA prevents mitochondrial oxidative stress by decreasing mitochondrial superoxide generation through inhibition of complex I via the mitochondrial Src tyrosine kinase. Phosphorylation of Tyr¹¹⁸ residue in NDUFV2 subunit may account for the inhibitory effect of NECA on complex I.

Graphical abstract

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Conversion to purpurogallin, a key step in the mechanism of the potent xanthine oxidase inhibitory activity of pyrogallol

Publication date: Available online 20 February 2017
Source:Free Radical Biology and Medicine
Author(s): Sari Honda, Yuya Fukuyama, Hisashi Nishiwaki, Akiko Masuda, Toshiya Masuda
In this study, the mechanism of the xanthine oxidase (XO) inhibitory activity of pyrogallol, the main inhibitor found in roasted coffee, was investigated. Pyrogallol was unstable and readily converted to purpurogallin in a pH 7.4 solution, a physiological model of human body fluids. The XO inhibitory activity of the produced purpurogallin was higher than that of pyrogallol, as evidenced by comparing their IC50 values (0.2 µmol L⁻¹ for purpurogallin, 1.6 µmol L⁻¹ for pyrogallol). The XO activity of pyrogallol was enhanced by pre-incubation in pH 7.4 solution. Although the initial XO inhibitory activity of 4-methylpyrogallol was weak (IC50 33.3 µmol L⁻¹), its XO inhibitory activity was also enhanced by pre-incubation in the pH 7.4 solution. In contrast, 5-methylpyrogallol, which could not be transformed into corresponding purpurogallin derivatives, did not show XO inhibitory activity before or after incubation in pH 7.4 solution. Molecular docking simulations clarified that purpurogallins have stronger affinities for XO than corresponding pyrogallols. These results revealed that the potent XO inhibitory activity seemingly observed in pyrogallol is actually derived from its chemical conversion, under alkaline conditions, into purpurogallin.

Graphical abstract

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Muscle Response to Complete Peripheral Nerve Injury: Changes of Acetylcholine Receptor and Creatine Kinase Activity over Time

J reconstr Microsurg
DOI: 10.1055/s-0037-1598619

Background This study was designed to assess the changes of acetylcholine receptor (AChR) and creatine kinase (CK) levels, which are important biochemical markers for muscle viability in cases of long-term muscle denervation. Scientists and peripheral nerve surgeons may find these data important regarding maximal range of muscle viability applicable for timing of effective peripheral nerve reconstructive surgery. Methods The study was conducted on 48 rats (96 gastrocnemius muscles), whose right legs were denervated by removing a 10-mm segment of sciatic nerve, while their left legs remained intact. Under general anesthesia, the rats were euthanized at seven points in time, on days 7, 14, 21, 30, 60, 120, and 210. In both legs, AChR was quantified by 125I-α-bungarotoxin, whereas CK activity was measured using a spectrophotometric method. Results CK levels in the denervated limb reached a minimal level of 34% on day 30 in comparison to the intact limb and remained at this level up to 210 days after operation. AChR levels in the denervated limb reached a minimal level of 38% on day 120 in comparison to the intact limb and remained at this level up to 210 days after operation. Conclusion The present study shows that AChR and CK levels in rat denervated muscles remain constant at about third of its intact condition for a period of at least a third of rat's lifetime postinjury.
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Forehead flaps for nasal reconstruction: A single-center experience

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Management of Cancer in the Older Age Person: An Approach to Complex Medical Decisions

The management of cancer in older aged people is becoming a common problem due to the aging of the population. There are many variables determining the complex situation that are interconnected. Some of them can be assessed, such as risk of mortality and risk of treatment complications, but many others are still unknown, such as the course of disease, the host-related factors that influence cancer aggressiveness, and the phenotype heralding risk of permanent treatment-related damage.

This article presents a dynamic and personalized approach to older people with cancer based on our experience on aging, cancer, and their biological interactions. Also, novel treatments and management approaches to older individuals, based on their functional age and their social and emotional needs, are thoughtfully explored here. The Oncologist 2017;22:1–8

Implications for Practice: The goal of this article is to suggest a practical approach to complexity, a clinical situation becoming increasingly common with the aging of the population. Beginning with the analysis of two clinical cases, the authors offer an algorithm for approaching cancer in the older person that involves the assessment of life expectancy without cancer, the risk that cancer might compromise a patient's survival, function, or quality of life, and the potential benefits and risks of the treatments based on a clinical evaluation. The authors then review possible laboratory assessment of functional age and the importance of rapid-learning databases in the study of cancer and age.

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Early Palliative Care Reduces End-of-Life Intensive Care Unit (ICU) Use but Not ICU Course in Patients with Advanced Cancer

Background.

Early palliative care for advanced cancer patients improves quality of life and survival, but less is known about its effect on intensive care unit (ICU) use at the end of life. This analysis assessed the effect of a comprehensive early palliative care program on ICU use and other outcomes among patients with advanced cancer.

Patients and Methods.

A retrospective cohort of patients with advanced cancer enrolled in an early palliative care program (n = 275) was compared with a concurrent control group of patients receiving standard care (n = 195) during the same time period by using multivariable logistic regression analysis. The multidisciplinary outpatient palliative care program used early end-of-life care planning, weekly interdisciplinary meetings to discuss patient status, and patient-reported outcomes assessment integrated within the electronic health record.

Results.

Patients in the control group had statistically significantly higher likelihood of ICU admission at the end of life (odds ratios [ORs]: last 6 months, 3.07; last month, 3.59; terminal admission, 4.69), higher likelihood of death in the hospital (OR, 4.14) or ICU (OR, 5.57), and lower likelihood of hospice enrollment (OR, 0.13). Use of chemotherapy or radiation did not significantly differ between groups, nor did length of ICU stay, code status, ICU procedures (other than cardiopulmonary resuscitation), disposition location, and outcomes after ICU admission.

Conclusion.

Early palliative care significantly reduced ICU use at the end of life but did not change ICU events. This study supports early initiation of palliative care for advanced cancer patients before hospitalizations and intensive care. The Oncologist 2017;22:1–6

Implications for Practice: Palliative care has shown clear benefit in quality of life and survival in advanced cancer patients, but less is known about its effect on intensive care. This retrospective cohort study at a university hospital showed that in the last 6 months of life, palliative care significantly reduced intensive care unit (ICU) and hospital admissions, reduced deaths in the hospital, and increased hospice enrollment. It did not, however, change patients' experiences within the ICU, such as number of procedures, code status, length of stay, or disposition. The findings further support that palliative care exerts its benefit before, rather than during, the ICU setting.

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Population-Level Differences in Rectal Cancer Survival in Uninsured Patients Are Partially Explained by Differences in Treatment

Background.

Rectal cancer (RC) is a common malignancy with a substantial mortality but good survival for patients with optimally treated nonmetastatic disease. Lack of insurance may compromise access to care and therefore compromise survival. Here, we examine RC survival by insurance type.

Methods.

Data from the Surveillance, Epidemiology, and End Results database were used to determine 1- to 3-year survival for patients with RC by insurance type (Medicaid, uninsured, other insurance).

Results.

Patients with Medicaid or no insurance presented at later stages and were less likely to receive definitive surgery. Overall 3-year survival was higher for patients with other insurance compared with Medicaid-insured (+22.2% units) and uninsured (+18.8% units) patients. Major differences in survival were still observed after adjustment for stage. When patients with stage II and III RC were considered, 3-year survival was higher for patients with other insurance versus those with Medicaid (+16.2% units) and uninsured patients (+12.2% units). However, when the analysis was limited to patients with stage II and III disease who received radiation therapy followed by definitive surgery, the difference decreased to +11.8% units and +7.3% units, respectively, for Medicaid and no insurance.

Conclusion.

For patients with stage II and III RC, much of the difference in survival between uninsured patients and those with insurance other than Medicaid can be explained by differences in treatment. Further efforts to determine the cause of residual differences as well as efforts to improve access to standard-of-care treatment for uninsured patients may improve population-level survival for RC. The Oncologist 2017;22:1–8

Implications for Practice: Insurance status affects survival for patients with rectal cancer, but a substantial proportion of the difference in survival can be corrected if standard-of-care treatment is given. Every effort should be made to ensure that uninsured or publically insured patients receive standard-of-care treatment with as little delay as possible to improve patient outcomes.

Implications for Practice: Insurance status affects survival for patients with rectal cancer, but a substantial proportion of the difference in survival can be corrected if standard-of-care treatment is given. Every effort should be made to ensure that uninsured or publically insured patients receive standard-of-care treatment with as little delay as possible to improve patient outcomes.

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Molecular Subtypes Improve Prognostic Value of International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Model

Introduction.

Gene-expression signatures for prognosis have been reported in localized renal cell carcinoma (RCC). The aim of this study was to test the predictive power of two different signatures, ClearCode34, a 34-gene signature model [Eur Urol 2014;66:77–84], and an 8-gene signature model [Eur Urol 2015;67:17–20], in the setting of systemic therapy for metastatic disease.

Materials and Methods

Metastatic RCC (mRCC) patients from five institutions who were part of TCGA were identified and clinical data were retrieved. We trained and implemented each gene model as described by the original study. The latter was demonstrated by faithful regeneration of a figure and results from the original study. mRCC patients were dichotomized to good or poor prognostic risk groups using each gene model. Cox proportional hazard regression and concordance index (C-Index) analysis were used to investigate an association between each prognostic risk model and overall survival (OS) from first-line therapy.

Results.

Overall, 54 patients were included in the final analysis. The primary endpoint was OS. Applying the ClearCode34 model, median survival for the low-risk—ccA (n = 17)—and the high-risk—ccB (n = 37)—subtypes were 27.6 and 22.3 months (hazard ratio (HR): 2.33; p = .039), respectively. ClearCode34 ccA/ccB and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classifications appear to represent distinct risk criteria in mRCC, and we observed no significant overlap in classification (p > .05, chi-square test). On multivariable analyses and adjusting for IMDC groups, ccB remained independently associated with a worse OS (p = .044); the joint model of ccA/ccB and IMDC was significantly more accurate in predicting OS than a model with IMDC alone (p = .045, F-test). This was also observed in C-Index analysis; a model with both ccA and ccB subtypes had higher accuracy (C-Index 0.63, 95% confidence interval [CI] = 0.51–0.75) and 95% CIs of the C-Index that did not include the null value of 0.5 in contrast to a model with IMDC alone (0.60, CI = 0.47–0.72). The 8-gene signature molecular subtype model was a weak but insignificant predictor of survival in this cohort (p = .13). A model that included both the 8-gene signature and IMDC (C-Index 0.62, CI = 0.49–0.76) was more prognostic than IMDC alone but did not reach significance, as the 95% CI included the null value of 0.5. These two genomic signatures share no genes in common and are enriched in different biological pathways. The ClearCode34 included genes ARNT and EPAS1 (also known as HIF2a), which are involved in regulation of gene expression by hypoxia-inducible factor.

Conclusion.

The ClearCode34 but not the 8-gene molecular model improved the prognostic predictive power of the IMDC model in this cohort of 54 patients with metastatic clear cell RCC. The Oncologist 2017;22:1–7

Implications for Practice: The clinical and laboratory factors included in the International Metastatic Renal Cell Carcinoma Database Consortium model provide prognostic information in metastatic renal cell carcinoma (mRCC). The present study shows that genomic signatures, originally validated in localized RCC, may add further complementary prognostic information in the metastatic setting. This study may provide new insights into the molecular basis of certain mRCC subgroups. The integration of clinical and molecular data has the potential to redefine mRCC classification, enhance the understanding of mRCC biology, and potentially predict response to treatment in the future.

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Using Metaphors to Explain Molecular Testing to Cancer Patients

Background.

Molecular testing to identify targetable molecular alterations is routine practice for several types of cancer. Explaining the underlying molecular concepts can be difficult, and metaphors historically have been used in medicine to provide a common language between physicians and patients. Although previous studies have highlighted the use and effectiveness of metaphors to help explain germline genetic concepts to the general public, this study is the first to describe the use of metaphors to explain molecular testing to cancer patients in the clinical setting.

Methods.

Oncologist-patient conversations about molecular testing were recorded, transcribed verbatim, and coded. If a metaphor was used, patients were asked to explain it and assess its helpfulness.

Results.

Sixty-six patients participated. Nine oncologists used metaphors to describe molecular testing; 25 of 66 (38%) participants heard a metaphor, 13 of 25 (52%) were questioned, 11 of 13 (85%) demonstrated understanding and reported the metaphor as being useful. Seventeen metaphors (bus driver, boss, switch, battery, circuit, broken light switch, gas pedal, key turning off an engine, key opening a lock, food for growth, satellite and antenna, interstate, alternate circuit, traffic jam, blueprint, room names, Florida citrus) were used to explain eight molecular testing terms (driver mutations, targeted therapy, hormones, receptors, resistance, exon specificity, genes, and cancer signatures).

Conclusion.

Because metaphors have proven to be a useful communication tool in other settings, these 17 metaphors may be useful for oncologists to adapt to their own setting to explain molecular testing terms. The Oncologist 2017;22:1–5

Implications for Practice: This article provides a snapshot of 17 metaphors that proved useful in describing 8 complicated molecular testing terms at 3 sites. As complex tumor sequencing becomes standard of care in clinics and widely used in clinical research, the use of metaphors may prove a useful communication tool, as it has in other settings. Although this study had a small sample, almost all of the patients who were exposed to metaphors in explaining molecular testing reported it as being helpful to their understanding. These 17 metaphors are examples of potentially useful communication tools that oncologists can adapt to their own practice.

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The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review

Background.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research.

Methods.

Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016.

Results.

Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full-length publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)-NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET.

Conclusion.

Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. The Oncologist 2017;22:1–14

Implications for Practice: This review presents the current clinical evidence for the antiproliferative activity of lanreotide Autogel in patients with midgut or pancreatic neuroendocrine tumors (NETs) and shows its effectiveness, safety, and tolerability in these patient populations. By systematically presenting all the clinical evidence, the review adds to existing publications by discussing results in a broad range of settings. The review also indicates future directions for investigation of the use of lanreotide Autogel in NETs originating in other locations, in combination therapy, or as maintenance therapy in progressive disease.

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Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer

Background.

Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer.

Methods.

Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m² orally twice daily, days 1–14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM + CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR + CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics.

Results.

Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1–36.1) weeks on RAM + CAP, 7.3 (6.3–13.0) weeks on ICR + CAP, and 19.0 (12.1–24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM + CAP versus CAP; 1.480, p = .0851, ICR + CAP versus CAP). Median OS was 67.4 weeks on RAM + CAP, 62.1 weeks on ICR + CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM + CAP versus CAP; 1.468, p = .1550, ICR + CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM + CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR + CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea.

Conclusion.

Combining RAM or ICR with CAP did not improve PFS in the targeted study population. The Oncologist 2017;22:1–10

Implications for Practice

Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.

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Survival of patients with colorectal peritoneal metastases is affected by treatment disparities among hospitals of diagnosis: A nationwide population-based study

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Koen P. Rovers, Geert A. Simkens, Pauline A. Vissers, Valery E. Lemmens, Victor J. Verwaal, Andre J. Bremers, Marinus J. Wiezer, Jacobus W. Burger, Patrick H. Hemmer, Henk Boot, Wilhelmina M. van Grevenstein, Wilhelmus J. Meijerink, Arend G. Aalbers, Cornelis J. Punt, Pieter J. Tanis, Ignace H. de Hingh
BackgroundIn the Netherlands, surgery for peritoneal metastases of colorectal cancer (PMCRC) is centralised, whereas PMCRC is diagnosed in all hospitals. This study assessed whether hospital of diagnosis affects treatment selection and overall survival (OS).MethodsBetween 2005 and 2015, all patients with synchronous PMCRC without systemic metastases were selected from the Netherlands Cancer Registry. Treatment was classified as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), systemic therapy or other/no treatment. Hospitals of diagnosis were classified as: (1) non-teaching or academic/teaching hospital and (2) HIPEC centre or referring hospital. Referring hospitals were further classified based on the frequency of CRS/HIPEC as high-, medium- or low-frequency hospital. Multivariable regression analyses were used to assess the independent influence of hospital categories on the likelihood of CRS/HIPEC and OS.ResultsA total of 2661 patients, diagnosed in 89 hospitals, were included. At individual hospital level, CRS/HIPEC and systemic therapy ranged from 0% to 50% and 6% to 67%, respectively. Hospital of diagnosis influenced the likelihood of CRS/HIPEC: 33% versus 13% for HIPEC centres versus referring hospitals (odds ratio (OR) 3.66 [2.40−5.58]) and 11% versus 17% for non-teaching hospitals versus academic/teaching hospitals (OR 0.60 [0.47–0.77]). Hospital of diagnosis affected median OS: 14.1 versus 9.6 months for HIPEC centres versus referring hospitals (hazard ratio (HR) 0.82 [0.67–0.99]) and 8.7 versus 11.5 months for non-teaching hospitals versus academic/teaching hospitals (HR 1.15 [1.06–1.26]). Compared with diagnosis in medium-frequency referring hospitals, median OS was increased in high-frequency referring hospitals (12.6 months, HR 0.82 [0.73−0.91]) and reduced in low-frequency referring hospitals (8.1 months, HR 1.12 [1.01–1.24]).ConclusionTreatment disparities among hospitals of diagnosis and their impact on survival indicate suboptimal treatment selection for PMCRC.



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Phase-II trials in osteosarcoma recurrences: A systematic review of past experience

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Natacha Omer, Marie-Cécile Le Deley, Sophie Piperno-Neumann, Perrine Marec-Berard, Antoine Italiano, Nadège Corradini, Carine Bellera, Laurence Brugières, Nathalie Gaspar
BackgroundThe most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined.ObjectiveTo study consistency in phase-II clinical trials evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results.MethodsSystematic review of clinical trials registered on clinicaltrials.gov, clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II).ResultsAmong the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%.ConclusionNo robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point.



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Anthropometrics at birth and risk of a primary central nervous system tumour: A systematic review and meta-analysis

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Marios K. Georgakis, Eleni I. Kalogirou, Athanasios Liaskas, Maria A. Karalexi, Paraskevi Papathoma, Kyriaki Ladopoulou, Maria Kantzanou, Georgios Tsivgoulis, Eleni Th. Petridou
BackgroundThe aetiology of primary central nervous system (CNS) tumours remains largely unknown, but their childhood peak points to perinatal parameters as tentative risk factors. In this meta-analysis, we opted to quantitatively synthesise published evidence on the association between birth anthropometrics and risk of primary CNS tumour.MethodsEligible studies were identified via systematic literature review; random-effects meta-analyses were conducted for the effect of birth weight and size-for-gestational-age on childhood and adult primary CNS tumours; subgroup, sensitivity, meta-regression and dose–response by birth weight category analyses were also performed.ResultsForty-one articles, encompassing 53,167 CNS tumour cases, were eligible. Birth weight >4000 g was associated with increased risk of childhood CNS tumour (OR: 1.14, [1.08–1.20]; 22,330 cases). The risk was higher for astrocytoma (OR: 1.22, [1.13–1.31]; 7456 cases) and embryonal tumour (OR: 1.16, [1.04–1.29]; 3574 cases) and non-significant for ependymoma (OR: 1.12, [0.94–1.34]; 1374 cases). Increased odds for a CNS tumour were also noted among large-for-gestational-age children (OR: 1.12, [1.03–1.22]; 10,339 cases), whereas insufficient data for synthesis were identified for other birth anthropometrics. The findings remained robust across subgroup and sensitivity analyses controlling for several sources of bias, whereas no significant heterogeneity or publication bias were documented. The limited available evidence on adults (4 studies) did not reveal significant associations between increasing birth weight (500-g increment) and overall risk CNS tumour (OR: 0.99, [0.98–1.00]; 1091 cases) or glioma (OR: 1.03, [0.98–1.07]; 2052 cases).ConclusionsThis meta-analysis confirms a sizeable association of high birth weight, with childhood CNS tumour risk, particularly astrocytoma and embryonal tumour, which seems to be independent of gestational age. Further research is needed to explore underlying mechanisms, especially modifiable determinants of infant macrosomia, such as gestational diabetes.



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Advanced breast cancer rates in the epoch of service screening: The 400,000 women cohort study from Italy

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Donella Puliti, Lauro Bucchi, Silvia Mancini, Eugenio Paci, Susanna Baracco, Cinzia Campari, Debora Canuti, Claudia Cirilli, Natalina Collina, Giovanni Maria Conti, Enza Di Felice, Fabio Falcini, Maria Michiara, Rossella Negri, Alessandra Ravaioli, Priscilla Sassoli de' Bianchi, Monica Serafini, Manuel Zorzi, Adele Caldarella, Luigi Cataliotti, Marco Zappa
BackgroundThe objective of this study was to evaluate if mammography screening attendance is associated with a reduction in late-stage breast cancer incidence.MethodsThe cohort included over 400,000 Italian women who were first invited to participate in regional screening programmes during the 1990s and were followed for breast cancer incidence for 13 years. We obtained individual data on their exposure to screening and correlated this with total and stage-specific breast cancer incidence. Socio-economic status and pre-screening incidence data were used to assess the presence of self-selection bias.ResultsOverall, screening attendance was associated with a 10% excess risk of in situ and invasive breast cancer (IRR = 1.10; 95% confidence interval (CI): 1.06–1.14), which dropped to 5% for invasive cancers only (IRR = 1.05; 95% CI: 1.01–1.09). There were significant reductions among attenders for specific cancer stages; we observed a 39% reduction for T2 or larger (IRR = 0.61; 95% CI: 0.57–0.66), 19% for node positives (IRR = 0.81; 95% CI: 0.76–0.86) and 28% for stage II and higher (IRR = 0.72; 95% CI: 0.68–0.76). Our data suggest that the presence of self-selection bias is limited and, overall, invited women experienced a 17% reduction of advanced cancers compared with pre-screening rates.ConclusionsComparing attenders' and non-attenders' stage-specific breast cancer incidence, we have estimated that screening attendance is associated with a reduction of nearly 30% for stages II+.



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Rationale for stimulator of interferon genes–targeted cancer immunotherapy

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Thaiz Rivera Vargas, Isis Benoit-Lizon, Lionel Apetoh
The efficacy of checkpoint inhibitor therapy illustrates that cancer immunotherapy, which aims to foster the host immune response against cancer to achieve durable anticancer responses, can be successfully implemented in a routine clinical practice. However, a substantial proportion of patients does not benefit from this treatment, underscoring the need to identify alternative strategies to defeat cancer. Despite the demonstration in the 1990's that the detection of danger signals, including the nucleic acids DNA and RNA, by dendritic cells (DCs) in a cancer setting is essential for eliciting host defence, the molecular sensors responsible for recognising these danger signals and eliciting anticancer immune responses remain incompletely characterised, possibly explaining the disappointing results obtained so far upon the clinical implementation of DC-based cancer vaccines. In 2008, STING (stimulator of interferon genes), was identified as a protein that is indispensable for the recognition of cytosolic DNA. The central role of STING in controlling anticancer immune responses was exemplified by observations that spontaneous and radiation-induced adaptive anticancer immunity was reduced in the absence of STING, illustrating the potential of STING-targeting for cancer immunotherapy. Here, we will discuss the relevance of manipulating the STING signalling pathway for cancer treatment and integrating STING-targeting based strategies into combinatorial therapies to obtain long-lasting anticancer immune responses.



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Can chance cause cancer? A causal consideration

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Mats Julius Stensrud, Susanne Strohmaier, Morten Valberg, Odd Olai Aalen
The role of randomness, environment and genetics in cancer development is debated. We approach the discussion by using the potential outcomes framework for causal inference. By briefly considering the underlying assumptions, we suggest that the antagonising views arise due to estimation of substantially different causal effects. These effects may be hard to interpret, and the results cannot be immediately compared. Indeed, it is not clear whether it is possible to define a causal effect of chance at all.



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Comparative analysis of PD-L1 expression between primary and metastatic pulmonary adenocarcinomas

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Sehui Kim, Jaemoon Koh, Dohee Kwon, Bhumsuk Keam, Heounjeong Go, Young A Kim, Yoon Kyung Jeon, Doo Hyun Chung
Programmed death-ligand 1 (PD-L1) expression in pulmonary adenocarcinomas (pADCs) was implicated in predicting anti-PD-1/PD-L1 therapy efficacy. However, the differential expression of PD-L1 between primary and metastatic pADC remains unclear. Thus, we addressed this issue. In total, 161 paired primary and metastatic tumour tissues from 146 patients with pADC were collected. Most of the cases had regional nodal metastasis (134/161, 83.2%). PD-L1 expression was categorised based on the proportion of immunostained tumour cells using cutoff values of 1%, 5%, 10% and 50%. In primary tumours, PD-L1 positivity was observed in 28.1% (41/146), 27.4% (40/146), 22.6% (33/146) and 13.0% (19/146) of cases using cutoff values of 1%, 5%, 10% and 50%, respectively. The overall concordance rate for PD-L1 expression between primary and metastatic tumours was 75.2% (121/161). The concordance rate in primary tumours expressing PD-L1 in <1% or ≥50% of tumour cells was 87.2% (102/117) or 70% (14/20), respectively. In contrast, the concordance rate in tumours expressing PD-L1 in ≥1% to <50% of cells was only 20.8% (5/24). After dichotomising the cases using cutoff values of 1% and 50%, the concordance rate increased to 80.1% (129/161) and 90.7% (146/161) in all paired cases and to 70.4% (19/27) and 85.2% (23/27) in cases with distant metastases, respectively. This study demonstrates that the concordance of PD-L1 expression between primary and metastatic pADC is high when using cutoff values of 1% and 50%. Thus, evaluation of PD-L1 in either primary or metastatic tumours would be helpful for guiding anti–PD-1/PD-L1 immunotherapy in patients with advanced pADC.



http://ift.tt/2kGdHHL

In situ-synthesized cadmium sulfide nanowire photosensor with a parylene passivation layer for chemiluminescent immunoassays

Publication date: 15 June 2017
Source:Biosensors and Bioelectronics, Volume 92
Author(s): Ju-Hee Im, Hong-Rae Kim, Byoung-Gi An, Young Wook Chang, Min-Jung Kang, Tae-Geol Lee, Jin Gyeng Son, Jae-Gwan Park, Jae-Chul Pyun
The direct in situ synthesis of cadmium sulfide (CdS) nanowires (NWs) was presented by direct synthesis of CdS NWs on the gold surface of an interdigitated electrode (IDE). In this work, we investigated the effect of a strong oxidant on the surfaces of the CdS NWs using X-ray photoelectron spectroscopy, transmission electron microscopy, and time-of-flight secondary ion mass spectrometry. We also fabricated a parylene-C film as a surface passivation layer for in situ-synthesized CdS NW photosensors and investigated the influence of the parylene-C passivation layer on the photoresponse during the coating of parylene-C under vacuum using a quartz crystal microbalance and a photoanalyzer. Finally, we used the in situ-synthesized CdS NW photosensor with the parylene-C passivation layer to detect the chemiluminescence of horseradish peroxidase and luminol and applied it to medical detection of carcinoembryonic antigen.



http://ift.tt/2lFKw7d

A magnetite/PMAA nanospheres-targeting SERS aptasensor for tetracycline sensing using mercapto molecules embedded core/shell nanoparticles for signal amplification

Publication date: 15 June 2017
Source:Biosensors and Bioelectronics, Volume 92
Author(s): Huanhuan Li, Quansheng Chen, Md. Mehedi Hassan, Xiaoxing Chen, Qin Ouyang, Zhiming Guo, Jiewen Zhao
Surface-enhanced Raman scattering (SERS) biosensors have promising potential in the field of antibiotics detection because of their ultrahigh detection sensitivity. This paper reports a rapid and sensitive SERS-based magnetic nanospheres-targeting strategy for sensing tetracycline (TTC) using aptamer-conjugated magnetite colloid nanocrystal clusters (MCNCs)-polymethacrylic acid (PMAA) magnetic nanospheres (MNs) as the recognition and the Au/PATP/SiO2 (APS) as the labels. Initially, MNs were fabricated and conjugated with the aptamers through condensation reaction. MNs possessed high saturation magnetization (Ms) value of 71.5emu/g and excellent biocompatibility, which facilitated the rapid and easy magnetic separation. Then, complementary DNA (cDNA) were loaded on the APS nanocarrier to produce a large amplification factor of Raman signals. The MNs-targeting aptasensor was thus fabricated by immobilizing the APS to the MNs' surfaces via the hybrid reaction between cDNA and aptamers. Sequel, TTC bound successfully to the aptamer upon its addition with the subsequent release of some cDNA-APS into the bulk solution. Under magnet attraction, the nanospheres were deposited together. Consequently, a display of strong SERS signals by supernatants of the resulting mixtures with increasing TTC concentrations was observed. The proposed aptasensor showed excellent performances for TTC detection along with wide linear range of 0.001–100ng/mL, low detection limit 0.001ng/mL, high sensitivity, and good selectivity to the general coexisted interferences.



http://ift.tt/2kT70NN