Emerging clinical applications in oncology for non-invasive multi- and hyperspectral imaging of cell and tissue autofluorescence.

Hyperspectral and multispectral imaging of cell and tissue autofluorescence is an emerging technology in which fluorescence imaging is applied to biological materials across multiple spectral channels. This produces a stack of images where each matched pixel contains information about the sample's spectral properties at that location. This allows precise collection of molecularly specific data from a broad range of native fluorophores. Importantly, complex information, directly reflective of biological status, is collected without staining and tissues can be characterised in situ, without biopsy. For oncology, this can spare the collection of biopsies from sensitive regions and enable accurate tumour mapping. For in vivo tumour analysis, the greatest focus has been on oral cancer, whereas for ex vivo assessment head-and-neck cancers along with colon cancer have been the most studied, followed by oral and eye cancer. This review details the scope and progress of research undertaken towards clinical translation in oncology.

Clinical applications of non-invasive multi and hyperspectral imaging of cell and tissue autofluorescence beyond oncology.

Hyperspectral and multispectral imaging of cell and tissue autofluorescence employs fluorescence imaging, without exogenous fluorophores, across multiple excitation/emission combinations (spectral channels). This produces an image stack where each pixel (matched by location) contains unique information about the sample's spectral properties. Analysis of this data enables access to a rich, molecularly specific data set from a broad range of cell-native fluorophores (autofluorophores) directly reflective of biochemical status, without use of fixation or stains. This non-invasive, non-destructive technology has great potential to spare the collection of biopsies from sensitive regions. As both staining and biopsy may be impossible, or undesirable, depending on the context, this technology great diagnostic potential for clinical decision making. The main research focus has been on the identification of neoplastic tissues. However, advances have been made in diverse applications-including ophthalmology, cardiovascular health, neurology, infection, assisted reproduction technology and organ transplantation.

Non-invasive, label-free optical analysis to detect aneuploidy within the inner cell mass of the preimplantation embryo.

STUDY QUESTION: Can label-free, non-invasive optical imaging by hyperspectral autofluorescence microscopy discern between euploid and aneuploid cells within the inner cell mass (ICM) of the mouse preimplantation embryo? SUMMARY ANSWER: Hyperspectral autofluorescence microscopy enables discrimination between euploid and aneuploid ICM in mouse embryos. WHAT IS KNOWN ALREADY: Euploid/aneuploid mosaicism affects up to 17.3% of human blastocyst embryos with trophectoderm biopsy or spent media currently utilized to diagnose aneuploidy and mosaicism in clinical in vitro fertilization. Based on their design, these approaches will fail to diagnose the presence or proportion of aneuploid cells within the foetal lineage ICM of some blastocyst embryos. STUDY DESIGN, SIZE, DURATION: The impact of aneuploidy on cellular autofluorescence and metabolism of primary human fibroblast cells and mouse embryos was assessed using a fluorescence microscope adapted for imaging with multiple spectral channels (hyperspectral imaging). Primary human fibroblast cells with known ploidy were subjected to hyperspectral imaging to record native cell fluorescence (4-6 independent replicates, euploid n = 467; aneuploid n = 969). For mouse embryos, blastomeres from the eight-cell stage (five independent replicates: control n = 39; reversine n = 44) and chimeric blastocysts (eight independent replicates: control n = 34; reversine n = 34; 1:1 (control:reversine) n = 30 and 1:3 (control:reversine) n = 37) were utilized for hyperspectral imaging. The ICM from control and reversine-treated embryos were mechanically dissected and their karyotype confirmed by whole genome sequencing (n = 13 euploid and n = 9 aneuploid). PARTICIPANTS/MATERIALS, SETTING, METHODS: Two models were employed: (i) primary human fibroblasts with known karyotype and (ii) a mouse model of embryo aneuploidy where mouse embryos were treated with reversine, a reversible spindle assembly checkpoint inhibitor, during the four- to eight-cell division. Individual blastomeres were dissociated from control and reversine-treated eight-cell embryos and either imaged directly or used to generate chimeric blastocysts with differing ratios of control:reversine-treated cells. Individual blastomeres and embryos were interrogated by hyperspectral imaging. Changes in cellular metabolism were determined by quantification of metabolic co-factors (inferred from their autofluorescence signature): NAD(P)H and flavins with the subsequent calculation of the optical redox ratio (ORR: flavins/[NAD(P)H + flavins]). Autofluorescence signals obtained from hyperspectral imaging were examined mathematically to extract features from each cell/blastomere/ICM. This was used to discriminate between different cell populations. MAIN RESULTS AND THE ROLE OF CHANCE: An increase in the relative abundance of NAD(P)H and decrease in flavins led to a significant reduction in the ORR for aneuploid cells in primary human fibroblasts and reversine-treated mouse blastomeres (P < 0.05). Mathematical analysis of endogenous cell autofluorescence achieved separation between (i) euploid and aneuploid primary human fibroblast cells, (ii) control and reversine-treated mouse blastomeres cells, (iii) control and reversine-treated chimeric blastocysts, (iv) 1:1 and 1:3 chimeric blastocysts and (v) confirmed euploid and aneuploid ICM from mouse blastocysts. The accuracy of these separations was supported by receiver operating characteristic curves with areas under the curve of 0.97, 0.99, 0.87, 0.88 and 0.93, respectively. We believe that the role of chance is low as mathematical features separated euploid from aneuploid in both human fibroblasts and ICM of mouse blastocysts. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Although we were able to discriminate between euploid and aneuploid ICM in mouse blastocysts, confirmation of this approach in human embryos is required. While we show this approach is safe in mouse, further validation is required in large animal species prior to implementation in a clinical setting. WIDER IMPLICATIONS OF THE FINDINGS: We have developed an original, accurate and non-invasive optical approach to assess aneuploidy within the ICM of mouse embryos in the absence of fluorescent tags. Hyperspectral autofluorescence imaging was able to discriminate between euploid and aneuploid human fibroblast and mouse blastocysts (ICM). This approach may potentially lead to a new diagnostic for embryo analysis. STUDY FUNDING/COMPETING INTEREST(S): K.R.D. is supported by a Mid-Career Fellowship from the Hospital Research Foundation (C-MCF-58-2019). This study was funded by the Australian Research Council Centre of Excellence for Nanoscale Biophotonics (CE140100003) and the National Health and Medical Research Council (APP2003786). The authors declare that there is no conflict of interest.

Non-invasive assessment of exfoliated kidney cells extracted from urine using multispectral autofluorescence features.

Optimally preserved urinary exfoliated renal proximal tubule cells were assessed by multispectral imaging of cell autofluorescence. We demonstrated different multispectral autofluorescence signals in such cells extracted from the urine of patients with healthy or diseased kidneys. Using up to 10 features, we were able to differentiate cells from individuals with heathy kidneys and impaired renal function (indicated by estimated glomerular filtration rate (eGFR) values) with the receiver operating characteristic area under the curve (AUC) of 0.99. Using the same method, we were also able to discriminate such urine cells from patients with and without renal fibrosis on biopsy, where significant differences in multispectral autofluorescence signals (AUC = 0.90) were demonstrated between healthy and diseased patients (p < 0.05). These findings show that multispectral assessment of the cell autofluorescence in urine exfoliated proximal tubule kidney cells has the potential to be developed as a sensitive, non-invasive diagnostic method for CKD.

Ageing human bone marrow mesenchymal stem cells have depleted NAD(P)H and distinct multispectral autofluorescence.

Stem cell exhaustion plays a major role in the ageing of different tissues. Similarly, in vitro cell ageing during expansion prior to their use in regenerative medicine can severely compromise stem cell quality through progressive declines in differentiation and growth capacity. We utilized non-destructive multispectral assessment of native cell autofluorescence to investigate the metabolic mechanisms of in vitro mesenchymal stem cell (MSC) ageing in human bone marrow MSCs over serial passages (P2-P10). The spectral signals for NAD(P)H, flavins and protein-bound NAD(P)H were successfully isolated using Robust Dependent Component Analysis (RoDECA). NAD(P)H decreased over the course of hMSC ageing in absolute terms as well as relative to flavins (optical redox ratio). Relative changes in other fluorophore levels (flavins, protein-bound NAD(P)H) suggested that this reduction was due to nicotinamide adenine dinucleotide depletion rather than a metabolic shift from glycolysis to oxidative phosphorylation. Using multispectral features, which are determined without cell fixation or fluorescent labelling, we developed and externally validated a reliable, linear model which could accurately categorize the age of culture-expanded hMSCs. The largest shift in spectral characteristics occurs early in hMSC ageing. These findings demonstrate the feasibility of applying multispectral technology for the non-invasive monitoring of MSC health in vitro.

Mechanisms for Tuning Engineered Nanomaterials to Enhance Radiation Therapy of Cancer.

Engineered nanomaterials that produce reactive oxygen species on exposure to X- and gamma-rays used in radiation therapy offer promise of novel cancer treatment strategies. Similar to photodynamic therapy but suitable for large and deep tumors, this new approach where nanomaterials acting as sensitizing agents are combined with clinical radiation can be effective at well-tolerated low radiation doses. Suitably engineered nanomaterials can enhance cancer radiotherapy by increasing the tumor selectivity and decreasing side effects. Additionally, the nanomaterial platform offers therapeutically valuable functionalities, including molecular targeting, drug/gene delivery, and adaptive responses to trigger drug release. The potential of such nanomaterials to be combined with radiotherapy is widely recognized. In order for further breakthroughs to be made, and to facilitate clinical translation, the applicable principles and fundamentals should be articulated. This review focuses on mechanisms underpinning rational nanomaterial design to enhance radiation therapy, the understanding of which will enable novel ways to optimize its therapeutic efficacy. A roadmap for designing nanomaterials with optimized anticancer performance is also shown and the potential clinical significance and future translation are discussed.

Application of Mitochondrially Targeted Nanoconstructs to Neoadjuvant X-ray-Induced Photodynamic Therapy for Rectal Cancer.

In this work, we brought together two existing clinical techniques used in cancer treatment-X-ray radiation and photodynamic therapy (PDT), whose combination termed X-PDT uniquely allows PDT to be therapeutically effective in deep tissue. To this end, we developed mitochondrially targeted biodegradable polymer poly(lactic-co-glycolic acid) nanocarriers incorporating a photosensitizer verteporfin, ultrasmall (2-5 nm) gold nanoparticles as radiation enhancers, and triphenylphosphonium acting as the mitochondrial targeting moiety. The average size of the nanocarriers was about 160 nm. Upon X-ray radiation our nanocarriers generated cytotoxic amounts of singlet oxygen within the mitochondria, triggering the loss of membrane potential and mitochondria-related apoptosis of cancer cells. Our X-PDT strategy effectively controlled tumor growth with only a fraction of radiotherapy dose (4 Gy) and improved the survival rate of a mouse model bearing colorectal cancer cells. In vivo data indicate that our X-PDT treatment is cytoreductive, antiproliferative, and profibrotic. The nanocarriers induce radiosensitization effectively, which makes it possible to amplify the effects of radiation. A radiation dose of 4 Gy combined with our nanocarriers allows equivalent control of tumor growth as 12 Gy of radiation, but with greatly reduced radiation side effects (significant weight loss and resultant death).

Non-invasive real-time imaging of reactive oxygen species (ROS) using auto-fluorescence multispectral imaging technique: A novel tool for redox biology.

Detecting reactive oxygen species (ROS) that play a critical role as redox modulators and signalling molecules in biological systems currently requires invasive methods such as ROS -specific indicators for imaging and quantification. We developed a non-invasive, real-time, label-free imaging technique for assessing the level of ROS in live cells and thawed cryopreserved tissues that is compatible with in-vivo imaging. The technique is based on autofluorescence multispectral imaging (AFMI) carried out in an adapted fluorescence microscope with an expanded number of spectral channels spanning specific excitation (365 nm-495 nm) and emission (420 nm-700 nm) wavelength ranges. We established a strong quantitative correlation between the spectral information obtained from AFMI and the level of ROS obtained from CellROX staining. The results were obtained in several cell types (HeLa, PANC1 and mesenchymal stem cells) and in live kidney tissue. Additioanly,two spectral regimes were considered: with and without UV excitation (wavelengths > 400 nm); the latter being suitable for UV-sensitive systems such as the eye. Data were analyzed by linear regression combined with an optimization method of swarm intelligence. This allowed the calibration of AFMI signals to the level of ROS with excellent correlation (R = 0.84, p = 0.00) in the entire spectral range and very good correlation (R = 0.78, p = 0.00) in the limited, UV-free spectral range. We also developed a strong classifier which allowed us to distinguish moderate and high levels of ROS in these two regimes (AUC = 0.91 in the entire spectral range and AUC = 0.78 for UV-free imaging). These results indicate that ROS in cells and tissues can be imaged non-invasively, which opens the way to future clinical applications in conditions where reactive oxygen species are known to contribute to progressive disease such as in ophthalmology, diabetes, kidney disease, cancer and neurodegenerative diseases.

Prognostic Differences in ISUP Grade Group 4: a Systematic Review and Meta-Analysis.

The ISUP (Internal Society of Urologic Pathology) recently adopted a five-tiered prognostication system. There is evidence to suggest that the ISUP grade group 4 is a heterogeneous entity regarding prognosis. Our aim was to systematically examine the existing evidence to determine if outcome differences exist within the ISUP grade group 4. A systematic search of the literature for all studies examining the heterogeneity of the ISUP grade group 4 was conducted. Available studies were combined with meta-analysis to evaluate prognostic differences within the ISUP grade group 4 measured by all-cause mortality (ACM) and the prostate cancer-specific mortality (PCSM). Eight studies were identified and utilised a variety of outcome measures to answer the question of heterogeneity within the ISUP grade group 4. Four of these studies examined prognosis using both ACM and PCSM. These were combined into a meta-analysis. The combined group of 5 + 3/3 + 5 had statistically significant higher ACM (hazard ratio [HR] 1.23, 95% confidence internal [Cl] 1.08-1.41) when compared to the 4 + 4 group. There was no difference in the PCSM between the two groups (HR 1.34, 95% CI 0.89-2.01). However, heterogeneity was high for this analysis secondary to a range of methodological differences. Our meta-analysis showed that Gleason grade 3 + 5/5 + 3 had higher ACM than Gleason grade group 4 + 4. Measures of PCSM were statistically insignificant, although heterogeneity was high. Evidence suggests that heterogeneity is likely, although inconclusive. Further studies with consistent methodologies are required to answer this question.

Non-destructive, label free identification of cell cycle phase in cancer cells by multispectral microscopy of autofluorescence.

BACKGROUND: Cell cycle analysis is important for cancer research. However, available methodologies have drawbacks including limited categorisation and reliance on fixation, staining or transformation. Multispectral analysis of endogenous cell autofluorescence has been shown to be sensitive to changes in cell status and could be applied to the discrimination of cell cycle without these steps. METHODS: Cells from the MIA-PaCa-2, PANC-1, and HeLa cell lines were plated on gridded dishes and imaged using a multispectral fluorescence microscope. They were then stained for proliferating cell nuclear antigen (PCNA) and DNA intensity as a reference standard for their cell cycle position (G1, S, G2, M). The multispectral data was split into training and testing datasets and models were generated to discriminate between G1, S, and G2 + M phase cells. A standard decision tree classification approach was taken, and a two-step system was generated for each line. RESULTS: Across cancer cell lines accuracy ranged from 68.3% (MIA-PaCa-2) to 73.3% (HeLa) for distinguishing G1 from S and G2 + M, and 69.0% (MIA-PaCa-2) to 78.0% (PANC1) for distinguishing S from G2 + M. Unmixing the multispectral data showed that the autofluorophores NADH, FAD, and PPIX had significant differences between phases. Similarly, the redox ratio and the ratio of protein bound to free NADH were significantly affected. CONCLUSIONS: These results demonstrate that multispectral microscopy could be used for the non-destructive, label free discrimination of cell cycle phase in cancer cells. They provide novel information on the mechanisms of cell-cycle progression and control, and have practical implications for oncology research.

The prevalence of disability among people with cancer, cardiovascular disease, chronic respiratory disease and/or diabetes: a systematic review.

BACKGROUND: Cardiovascular disease (CVD), cancer, diabetes and chronic respiratory disease are noncommunicable diseases (NCDs) that cause extensive social and economic burden worldwide, particularly in low-income and middle-income countries. There is growing recognition of the importance of the disabilities that individuals experience as a consequence of these NCDs. OBJECTIVES: This systematic review examined the prevalence of disabilities associated with cancer, CVD, chronic respiratory disease and diabetes. METHODS: A comprehensive literature search was conducted in PubMed, CINAHL, Embase, Web of Science, PsycINFO, CIRRIE, WHO database, LILACS and AIM. Studies were included if their samples were representative of people with at least one of these four conditions and if prevalence estimates of disability were provided. As random sampling was not feasible in the majority of cases, studies were included where they offered evidence that their sample was representative of the general population being investigated. RESULTS: A total of 105 articles were included in the review. Most studies were conducted in high-income countries. The prevalence of difficulties with activities of daily living (i.e. eating, bathing, dressing) was reported to be 10.4-34.5% amongst cancer survivors, 21.1-64.1% in those with CVD, 7.4-49.8% in those with chronic respiratory disease and 12.2-54.5% for those with diabetes. The prevalence of a range of other physical, cognitive and psychological impairments (systemic or structural) was additionally described for each disease. CONCLUSION: Substantial proportions of people with cancer, CVD, chronic respiratory disease or diabetes experience some form of disability - although there was great variance in prevalence and definitions. The findings of this review support the evidence base of global impact associated with NCD, indicate frequency measures for specific disabilities and inabilities associated with each NCD and provide direction for future systematic reviews. WHAT IS KNOWN ABOUT THE TOPIC: WHAT THIS ARTICLE ADDS.

Effectiveness of primary surgery versus primary radiotherapy on unknown primary head and neck squamous cell carcinoma: a systematic review protocol.

REVIEW QUESTION: The review question is: what is the effectiveness of primary surgery versus primary radiotherapy on disease-free survival and quality of life in adults with an unknown primary, head and neck squamous cell carcinoma?

End User and Implementer Experiences of mHealth Technologies for Noncommunicable Chronic Disease Management in Young Adults: Systematic Review.

BACKGROUND: Chronic noncommunicable diseases (NCDs) such as asthma, diabetes, cancer, and persistent musculoskeletal pain impose an escalating and unsustainable burden on young people, their families, and society. Exploring how mobile health (mHealth) technologies can support management for young people with NCDs is imperative. OBJECTIVE: The aim of this study was to identify, appraise, and synthesize available qualitative evidence on users' experiences of mHealth technologies for NCD management in young people. We explored the perspectives of both end users (young people) and implementers (health policy makers, clinicians, and researchers). METHODS: A systematic review and meta-synthesis of qualitative studies. Eligibility criteria included full reports published in peer-reviewed journals from January 2007 to December 2016, searched across databases including EMBASE, MEDLINE (PubMed), Scopus, and PsycINFO. All qualitative studies that evaluated the use of mHealth technologies to support young people (in the age range of 15-24 years) in managing their chronic NCDs were considered. Two independent reviewers identified eligible reports and conducted critical appraisal (based on the Joanna Briggs Institute Qualitative Assessment and Review Instrument: JBI-QARI). Three reviewers independently, then collaboratively, synthesized and interpreted data through an inductive and iterative process to derive emergent themes across the included data. External validity checking was undertaken by an expert clinical researcher and for relevant content, a health policy expert. Themes were subsequently subjected to a meta-synthesis, with findings compared and contrasted between user groups and policy and practice recommendations derived. RESULTS: Twelve studies met our inclusion criteria. Among studies of end users (N=7), mHealth technologies supported the management of young people with diabetes, cancer, and asthma. Implementer studies (N=5) covered the management of cognitive and communicative disabilities, asthma, chronic self-harm, and attention deficit hyperactivity disorder. Quality ratings were higher for implementer compared with end user studies. Both complementary and unique user themes emerged. Themes derived for end users of mHealth included (1) Experiences of functionality that supported self-management, (2) Acceptance (technical usability and feasibility), (3) Importance of codesign, and (4) Perceptions of benefit (self-efficacy and empowerment). For implementers, derived themes included (1) Characteristics that supported self-management (functional, technical, and behavior change); (2) Implementation challenges (systems level, service delivery level, and clinical level); (3) Adoption considerations for specific populations (training end users; specific design requirements); and (4) Codesign and tailoring to facilitate uptake and person-centered care. CONCLUSIONS: Synthesizing available data revealed both complementary and unique user perspectives on enablers and barriers to designing, developing, and implementing mHealth technologies to support young people's management of their chronic NCDs. TRIAL REGISTRATION: PROSPERO CRD42017056317; http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD 42017056317 (Archived by WebCite at http://www.webcitation.org/6vZ5UkKLp).

Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis.

This systematic review investigated whether the insulin sensitiser metformin has a geroprotective effect in humans. Pubmed and Embase were searched along with databases of unpublished studies. Eligible research investigated the effect of metformin on all-cause mortality or diseases of ageing relative to non-diabetic populations or diabetics receiving other therapies with adjustment for disease control achieved. Overall, 260 full-texts were reviewed and 53 met the inclusion criteria. Diabetics taking metformin had significantly lower all-cause mortality than non-diabetics (hazard ratio (HR)=0.93, 95%CI 0.88-0.99), as did diabetics taking metformin compared to diabetics receiving non-metformin therapies (HR=0.72, 95%CI 0.65-0.80), insulin (HR=0.68, 95%CI 0.63-0.75) or sulphonylurea (HR=0.80, 95%CI 0.66-0.97). Metformin users also had reduced cancer compared to non-diabetics (rate ratio=0.94, 95%CI 0.92-0.97) and cardiovascular disease (CVD) compared to diabetics receiving non-metformin therapies (HR=0.76, 95%CI 0.66-0.87) or insulin (HR=0.78, 95%CI 0.73-0.83). Differences in baseline characteristics were observed which had the potential to bias findings, although statistical adjustments were made. The apparent reductions in all-cause mortality and diseases of ageing associated with metformin use suggest that metformin could be extending life and healthspans by acting as a geroprotective agent.

Optimum Tools for Predicting Clinical Outcomes in Prostate Cancer Patients Undergoing Radical Prostatectomy: A Systematic Review of Prognostic Accuracy and Validity.

Prostate cancer is a heterogeneous disease whose therapies frequently have adverse effects. Informed patient counseling regarding likely clinical outcomes is therefore important. In this systematic review we aimed to identify all external validations of tools that are used to predict clinical outcomes in patients undergoing radical prostatectomy and evaluate which are optimum for clinical implementation. PubMed and EMBASE were searched from 2007 to 2016. Search terms related to the inclusion criteria were: prostate cancer, clinical outcomes, radical prostatectomy, and prognosis. Titles and abstracts were screened and relevant studies were advanced to full-text review. Reference lists were reviewed for further studies. The Centre for Evidence Based Medicine prognostic tool was used for critical appraisal. Seventy-three studies externally validated 13 pre- and 41 postoperative tools for the prediction of biochemical recurrence (BCR), aggressive BCR, metastasis, and prostate cancer-specific mortality (PCSM). Recommendations for clinical implementation were made on the basis of accuracy, cohort sizes, and consistency. The accuracy of recommended tools ranged from 68% to 79% and 72% to 92% among the largest validation cohorts for pre- and postoperative tools. For preoperative prognosis we recommended the Cancer of the Prostate Risk Assessment (CAPRA) and Stephenson nomograms for BCR, the CAPRA nomogram for aggressive BCR as well as metastasis, and the D'Amico criteria for PCSM. For postoperative prognosis we recommended the CAPRA-Surgery (CAPRA-S), Stephenson, Kattan, Duke prostate cancer (DPC), and the Suardi nomograms for the prediction of BCR, the DPC nomogram for aggressive BCR, the CAPRA-S and Eggener nomograms for metastasis, and the Eggener nomogram for PCSM. Use of these tools should help clinicians deliver accurate, evidence-based counseling to patients undergoing prostatectomy.

Tools for Predicting Clinical and Patient-reported Outcomes in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Systematic Review of Prognostic Accuracy and Validity.

Androgen deprivation therapy (ADT) can result in a range of adverse symptoms that reduce patients' quality of life. Careful patient counseling on the likely clinical outcomes and adverse effects is therefore vital. The present systematic review was undertaken to identify and characterize all the tools used for the prediction of clinical and patient-reported outcome measures (PROMs) in patients with prostate cancer undergoing ADT. PubMed and EMBASE were systematically searched from 2007 to 2016. Search terms related to the inclusion criteria were: prostate cancer, clinical outcomes, PROMs, ADT, and prognosis. Titles and abstracts were reviewed to find relevant studies, which were advanced to full-text review. The reference lists were screened for additional studies. The Centre for Evidence Based Medicine critical appraisal of prognostic studies tool was applied. The search strategy identified 8755 studies. Of the 8755 studies, 22 on clinical outcomes were identified. However, no studies of PROMs were found. Nine tools could be used to predict clinical outcomes in treatment-naive patients and 10 in patients with recurrence. The Japan Cancer of the Prostate Risk Assessment (J-CAPRA) nomogram was the best performing and validated tool for the prediction of clinical outcomes in treatment-naive patients, and the Chi and Shamash prognostic indexes have been validated for use in patients with castration-resistant disease in different clinical contexts. Using the J-CAPRA nomogram should help clinicians deliver accurate, evidence-based counseling to patients undergoing primary ADT. A strong need exists for primary studies that derive and validate tools for the prediction of PROMs in patients undergoing ADT under any circumstance because these are currently absent from the literature.

Patient-Reported Outcomes After Radiation Therapy in Men With Prostate Cancer: A Systematic Review of Prognostic Tool Accuracy and Validity.

PURPOSE: To identify, through a systematic review, all validated tools used for the prediction of patient-reported outcome measures (PROMs) in patients being treated with radiation therapy for prostate cancer, and provide a comparative summary of accuracy and generalizability. METHODS AND MATERIALS: PubMed and EMBASE were searched from July 2007. Title/abstract screening, full text review, and critical appraisal were undertaken by 2 reviewers, whereas data extraction was performed by a single reviewer. Eligible articles had to provide a summary measure of accuracy and undertake internal or external validation. Tools were recommended for clinical implementation if they had been externally validated and found to have accuracy ≥70%. RESULTS: The search strategy identified 3839 potential studies, of which 236 progressed to full text review and 22 were included. From these studies, 50 tools predicted gastrointestinal/rectal symptoms, 29 tools predicted genitourinary symptoms, 4 tools predicted erectile dysfunction, and no tools predicted quality of life. For patients treated with external beam radiation therapy, 3 tools could be recommended for the prediction of rectal toxicity, gastrointestinal toxicity, and erectile dysfunction. For patients treated with brachytherapy, 2 tools could be recommended for the prediction of urinary retention and erectile dysfunction. CONCLUSIONS: A large number of tools for the prediction of PROMs in prostate cancer patients treated with radiation therapy have been developed. Only a small minority are accurate and have been shown to be generalizable through external validation. This review provides an accessible catalogue of tools that are ready for clinical implementation as well as which should be prioritized for validation.

The effects of curcuminoids on musculoskeletal pain: a systematic review.

BACKGROUND: Western countries are increasingly using complementary and alternative medicine (CAM) to assist with relieving ailments. Turmeric, from the ginger family Zingiberaceae, has a history of use for medicinal purposes. The polyphenols found in turmeric (curcuminoids) have demonstrated anti-inflammatory and pain relieving properties. With the use of CAMs increasing, it is important for the effectiveness of curcuminoids to be established. OBJECTIVES: To identify the effectiveness of the use of curcuminoids for the amelioration of musculoskeletal pain. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Persons experiencing musculoskeletal pain, including experimentally induced musculoskeletal pain. TYPES OF INTERVENTION(S)/PHENOMENA OF INTEREST: The current review considered studies that evaluated the use of curcuminoids. TYPES OF CONTROLS: Any form including placebo, treatment as usual or before and after measurements. TYPES OF STUDIES: Both experimental and epidemiological study designs including randomized controlled trials (RCTs), non-RCTs, quasi-experimental and before and after studies were eligible for consideration in this review. Studies published in English were considered without date restriction. OUTCOMES: The current review considered studies that included measurement of pain. Outcome measures included visual analog scales, and/or pain questionnaires. Secondary outcome measures of functionality (activities of daily living and range of motion) were included. Any data provided on adverse events were considered. SEARCH STRATEGY: The databases PubMed, CINAHL, Embase and ProQuest were searched in March 2015 (and updated in April 2016) using the Joanna Briggs Institute (JBI) three-step search strategy. The reference lists of identified articles were reviewed for additional studies. METHODOLOGICAL QUALITY: Papers selected were assessed by two independent reviewers using standardized instruments from the JBI Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). DATA EXTRACTION: Data were extracted using the data extraction tool from JBI-MAStARI. Data extracted included details about the populations, interventions, study methods and outcomes. DATA SYNTHESIS: Narrative and tabular synthesis was conducted. Meta-analysis was precluded due to methodological and clinical heterogeneity across all included studies. RESULTS: Thirteen studies with a combined total of 1101 participants were included. Three studies of limited sample size examined the effects of curcuminoids compared with the use of placebo on musculoskeletal pain, with one study showing a statistically significant effect. Four studies examined the effects of curcuminoids compared with non-selective non-steroidal anti-inflammatory drugs on musculoskeletal pain. Two of these four studies were non-inferiority studies showed that the use of both curcuminoids and ibuprofen were associated with a similar significant reduction in pain over the study durations of four and six weeks, respectively, with curcuminoid use non-inferior to the use of ibuprofen over the study durations. Six studies investigated presentations of curcuminoid-containing herbomineral mixtures versus placebo or active controls. CONCLUSION: There is insufficient evidence to recommend that curcuminoids be considered for relieving pain and improving function in musculoskeletal pain conditions. This finding needs to be considered in the context of limitations imposed by the variability in the quality of studies, small sample sizes, short duration of interventions, a gender-bias toward females, absence of long-term data extraction and small number of relevant studies.

Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

PURPOSE: Methotrexate chemotherapy is associated with various toxicities which can result in the interruption or discontinuation of treatment and a subsequently raised risk of relapse. This umbrella systematic review was conducted to synthesize the results of all existing systematic reviews that investigate the pharmacogenetics of methotrexate-induced toxicity, with the aim of developing a comprehensive reference for personalized medicine. METHODS: Databases searched were PubMed, Embase, JBI Database of Systematic Reviews and Implementation Reports, DARE, and ProQuest. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool. RESULTS: Three systematic reviews on methotrexate-induced toxicity were included in the review. Meta-analyses were reported across Asian, Caucasian, pediatric and adult patients for the MTHFR C677T and A1298C polymorphisms. Toxicity outcomes included different forms of hematologic, ectodermal and hepatic toxicities. Results varied considerably depending on the patient groups and subgroups investigated in the different systematic reviews, as well as the genetic models utilized. However, significant associations were found between the MTHFR C677T allele and; hepatic toxicity, myelosuppression, oral mucositis, gastrointestinal toxicity, and skin toxicity. Additionally, limited evidence suggests that the MTHFR A1298C polymorphism may be associated with decreased risk of skin toxicity and leukopenia. CONCLUSION: This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of methotrexate toxicity. The next step in making personalized medicine for methotrexate therapy a clinical reality is research on the effectiveness and cost-effectiveness of MTHFR genotype testing to enable the close monitoring of at-risk patients for the timely initiation of rescue therapies.

Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps.