Response to “Evaluating the Prognostic Role of Body Fat Density in Colorectal Cancer: A Critical Appraisal”

Colorectal cancer is one of the most common cancers and pancreatic cancer is among the most fatal and difficult to treat. New prognostic biomarkers are urgently needed to improve the treatment of colorectal and pancreatic cancer. Protein regulating cytokinesis 1 (PRC1), kinesin family member 14 (KIF14) and citron Rho-interacting serine/threonine kinase (CIT) serve important roles in cytokinesis, are strongly associated with cancer progression and have prognostic potential. The present study aimed to investigate the prognostic relevance of the PRC1, KIF14 and CIT genes in colorectal and pancreatic cancer. PRC1, KIF14 and CIT transcript expression was assessed by reverse transcription-quantitative PCR in tumors and paired distant unaffected mucosa from 67 patients with colorectal cancer and tumors and paired non-neoplastic control tissues from 48 patients with pancreatic cancer. The extent of transcript dysregulation between tumor and control tissues and between groups of patients divided by main clinical characteristics, namely patients' age and sex, disease stage, localization and grade, was determined. Finally, the associations of transcript levels in tumors with disease-free interval and overall survival time were evaluated. PRC1, KIF14 and CIT transcripts were upregulated in tumors compared with control tissues. PRC1, KIF14 and CIT levels strongly correlated to each other in both colorectal and pancreatic tumor and control tissues after correction for multiple testing. However, no significant associations were found among the transcript levels of PRC1, KIF14 and CIT and disease-free interval or overall survival time. In summary, the present study demonstrated mutual correlation of PRC1, KIF14 and CIT cytokinesis regulators with no clear prognostic value in pancreatic and colorectal cancers. Hence, according to the results of the present study, transcript levels of these genes cannot be clinically exploited as prognostic biomarkers in colorectal or pancreatic cancer patients.

Rationale: The disproportionate burden of obesity among minority populations is hypothesized to contribute to racial/ethnic disparities in cancer mortality rates (1). However, several studies note differences by race/ethnicity in the relationship of higher BMI to cancer survival, with the strongest adverse associations often seen among non-Hispanic white patients and the weakest among black patients (2-6). A potential explanation is that BMI is an imperfect proxy for total adiposity that does not distinguish muscle from fat mass. Further, data from noncancer patients suggests that body composition at a given BMI may vary by race/ethnicity, underscoring the need for more accurate measures of fat and lean mass to understand the contribution of the body habitus to disparities in cancer survival. Methods: We will summarize the existing literature and present new data on: (1) differences in the BMI-mortality relationship by race/ethnicity, (2) differences in body composition by race/ethnicity, and (3) associations of body composition with mortality among survivors of breast and colorectal cancer by race/ethnicity. For brevity, we will focus on black-white differences in overall survival from a cohort of ~5,000 nonmetastatic breast or colorectal cancer patients at Kaiser Permanente Northern California. Body composition was quantified using clinically-acquired computed tomography (CT) scans, a gold standard to assess adiposity and muscle mass. Results: Body composition at a given BMI differs by race/ethnicity in the general population and among cancer survivors. Among 234 black and 2,290 white breast cancer patients, BMI was not associated with survival. By contrast, higher total adiposity and lower skeletal muscle were both associated with increased risk of death after breast cancer: the HR (95% CI) comparing the highest (versus lowest) tertile of total adiposity index was 2.43 (1.20, 4.92) among black and 1.48 (1.13, 1.93) among white women, respectively, and the HR comparing the lowest (versus highest) tertile of skeletal muscle index was 1.67 (0.82, 3.41) among black and 1.37 (1.05, 1.80) among white women, respectively. Among 243 black and 2,192 white colorectal cancer patients, BMI was associated with survival only among white patients (overweight was associated with a 22% reduction in mortality). By contrast, higher visceral adiposity and lower skeletal muscle were associated with increased risk of death after colorectal cancer diagnosis in both groups: the HR (95% CI) comparing the highest (versus lowest) tertile of visceral adiposity index was 2.64 (1.39, 4.99) among black patients and 1.35 (1.07, 1.70) among white patients, respectively, and the HR comparing the lowest (versus highest) tertile of skeletal muscle index was 2.13 (1.17, 3.88) among black and 1.71 (1.39, 2.12) among white patients, respectively. Conclusion: Body composition assessed via CT scans produces measures of adiposity and muscle that associate with survival across racial/ethnic groups where BMI does not. Accurate assessment of body composition is critical for equitable prognostic assessments and for making appropriate lifestyle recommendations to diverse groups of survivors (e.g., recommending weight loss through caloric restriction only when beneficial and offering complementary interventions, such as building muscle mass through resistance training or physical activity, when appropriate).

The significance of the internet as a source of healthcare information for professionals and public is widely recognized. Access to good quality information is very important for informed decisions making on healthcare issues. This is an introduction to the critical appraisal of clinical information on the internet, discussion of the significance of quality checking of healthcare internet resources and the application of critical appraisal tools to selected internet resources on colorectal cancer care. Internet resources were identified on the basis of a general criterion that it provides information on colorectal cancer and selected on the basis of explicit inclusion and exclusion criteria. Each selected website is assessed for quality of information with validated criteria. The search strategy identified 10 well known internet resources on healthcare information (e.g. Cochrane, NICE) and 12 websites which are dedicated to cancer related information (e.g. CancerBacup, cancer.gov). The websites of NHS Direct, cancerBACUP, cancer.gov, NICE and Cancer Survivors Network were qualified as resources providing good quality information. The critical appraisal process assures quality of the available information and the tool is applicable to all healthcare related internet resources. The process is discussed with respect to colorectal cancer information resources and will be equally useful to healthcare professional and public. The healthcare professionals can apply the tool in practice and advise the public more confidently on internet information.

Associations Between Obesity and Cancer: The Role of Fatty Acid Synthase

Review objective The review objective is to synthesise the best available evidence on exposure to chlorinated water and risk of cancer. Risks associated with colorectal or bladder cancers have already been established and therefore will not be considered in this systematic review. Inclusion criteria Types of participants This review will consider studies that include males and females of all ages. Types of intervention(s)/phenomena of interest This review will consider studies that evaluate exposure to chlorine disinfection by-products by drinking (ingesting), bathing, showering, swimming, cooking, cleaning and dishwashing (dermal and inhalation) and identify incidence and mortality outcomes of cancer (excluding colorectal and bladder) compared with exposure without chemical disinfection (chlorine) or alternative disinfection processes. Types of outcomes This review will consider studies that include the following outcome measures. Incidence, mortality and specifically measures of risk between exposure and outcome of cancers with the exception of bowel and bladder. For example the following cancers have been associated with chlorine disinfection by products, kidney/adrenal, liver, thyroid, pituitary, lymphoma and leukaemia, pancreatic, gastrointestinal (other than colorectal), testicular, breast and lung cancer. These and any other cancers identified as relevant eg. skin cancers will be included.

667 Background: The prognostic role of CpG Island Methylator Phenotype (CIMP) in colorectal cancer (CRC) is still controversial, especially in metastatic CRC. Methods: We retrospectively analyzed the CpG island methylator phenotype (CIMP) in stage I to IV CRC specimens, which were diagnosed during 2005-2013. CIMP status was determined using a 5- gene MethyLight-based assay ( p16, MINT1, MINT2, MINT31, and MLH1). Tumors were designated as CIMP if 3 or more of 5 genes gave percent of methylated reference value ≧ 10. The clinicopatholoical characteristics, anti-cancer therapies, and the overall survival outcome were reviewed. Overall survival (OS) was compared between patients with CIMP CRC and those with non-CIMP CRC. Results: Among 450 patients with successfully determined CIMP status, 259 (57.56%) were male, 312 (70.31%) were stages I-III, 316 (70.69%) were left-sided CRC. In the survival analyses in stages I-IV patients, there was no significant difference in OS between those with or without CIMP (long rank test, p = 0.4526). Importantly, patients with metastatic CIMP CRC had poor OS than those with metastatic non-CIMP CRC (median survival, CIMP vs. non-CIMP: 1.36 vs. 3.11 years, log rank test, p = 0.0047). In a multivariate analysis, which adjusted prognostic variables such as: KRAS and BRAF mutations, microsatellite instability status, age, sex, grade, primary site, metastatic site number, chemotherapies and targeted therapies, CIMP remained an independent poor prognostic factor for OS (HR = 6.213, 95% confidence interval: 2.443 to 15.799, p = 0.0001) in metastatic CRC. In an exploratory analysis, there were more tumors with liver metastases at diagnosis in CIMP CRC than in non-CIMP CRC (94.4% vs. 71.3%, p = 0.0416). Conclusions: Our data demonstrated CIMP might independently predict poor survival in metastatic CRC in a large East Asian cohort.

Cancer‐associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer in recent literature. The SLR was conducted following PRISMA guidelines. Embase® and PubMed were searched to identify articles published in English between 1 January 2016 and 10 October 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by international consensus (IC) diagnostic criteria or a broader definition of any weight loss. Included publications were studies in ≥100 patients with colorectal or pancreatic cancer. Thirteen publications in patients with colorectal cancer and 13 with pancreatic cancer met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 (58%) reported any weight loss. An association between survival and cachexia or weight loss was assessed across studies using multivariate (n = 23) or univariate (n = 3) analyses and within each study across multiple weight loss categories. Cachexia/weight loss was associated with a statistically significantly poorer survival in at least one weight loss category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Cachexia or weight loss was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two‐thirds of the studies. The classification of weight loss varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could help inform prognosis and influence early disease management strategies.

Purpose: To critically appraise existing clinical practice guidelines (CPGs) for colorectal cancer (CRC) and synthesize evidence-based recommendations from a rehabilitation perspective. Methods: Comprehensive literature search was conducted using health databases, CPG clearinghouse/developer websites, and grey literature up to October 2024. All CRC CPGs published in the last decade that reported systematic methods for evidence search, and clearly defined recommendations supporting evidence for rehabilitation interventions were included. Two authors independently selected potential CPGs and assessed their methodological quality using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. Recommendations from included CPGs were qualitatively summarized from a rehabilitation perspective. Results: Twelve of 65 CPGs met the inclusion criteria. The majority of CRC CPGs were of low-moderate quality (AGREE scores of 2–6/7). The recommendations were generic, with only the American Cancer Society (ACS) guidelines providing detailed recommendations on rehabilitation interventions for longer-term issues in CRC survivors. Existing CPGs recommend coordinated multidisciplinary survivorship care, monitoring of longer-term issues, and follow-up support for patients with CRC. However, supporting evidence for these management strategies remains limited. Detailed comparison between the CPGs was not possible due to inconsistent recommendations, making it difficult to summarize the optimal rehabilitation approaches. Conclusion: Despite rehabilitation being an integral component of the management of CRC, it is notably absent in many published CPGs. Future CPGs should explicitly incorporate rehabilitation-specific interventions for improved clinical outcomes tailored to the needs of this population.

In this issue, we have a special supplement focusing on contemporary reviews in cancer care. Literature reviewing as a method has grown exponentially over recent decades, with the inception of most research underpinned by a good quality review. As a result of the proliferation and types of evidence to synthesise, varying approaches have been developed and refined including, and not limited to the following: > scoping reviews (not analysing, but describing and incorporating different kinds of evidence, not just research) > integrative reviews (both quantitative and qualitative) > systematic reviews (which may include meta‐analysis) > narrative reviews > meta‐ethnography/meta‐synthesis (qualitative)

Background CT-derived measures of body composition have been shown to have prognostic value in patients with cancer. However, few studies have compared these observations across tumor types and stages of disease. The aim of the present study was to compare body composition measures between two types of cancers, i.e. colorectal cancer (CRC), which is less inflammatory and patients maintain body composition over a longitudinal study period, whereas lung cancer (LC) is proinflammatory and patients lose more fat and muscle mass using a standard methodology. Methods Clinicopathological characteristics, including those pertaining to nutritional risk/status and systemic inflammation in patients with colorectal cancer (CRC, n = 1047) and lung cancer (LC, n = 662), were compared. The CT image at L3 was used to assess body composition. Comparison of these cohorts was carried out using the chi-square test. Binary logistic regression analysis was performed to assess the impact of clinico-pathological variables on body composition, and scatter plots were used to examine the relationship between body mass index (BMI) and CT-derived measures of body composition. Results According to CT-derived body composition, high subcutaneous (SFI) and visceral fat index (VFI) were common (>70%) in both CRC and LC. Also, low skeletal muscle index (SMI) and density (SMD) were approximately 40–50% and 60–70% in both CRC and LC. Compared with CRC, patients with LC had a higher American Society of Anaesthesia (ASA) (P < 0.001), Malnutrition Universal Screening Tool (MUST) (P < 0.001), modified frailty index (mFI) (P < 0.001), modified Glasgow Prognostic Score (mGPS) (P < 0.001), and neutrophil lymphocyte ratio (NLR) (P < 0.001) scores. On binary logistic regression analysis, MUST, mFI, and NLR were predictors of subcutaneous adiposity (P < 0.05); type of cancer, MUST, and mFI were predictors of visceral obesity (P < 0.001); age, type of cancer, MUST, and mGPS were predictors of low SMI (P < 0.001); and age, type of cancer, mFI, and mGPS were predictors of low SMD (P < 0.05). There was a similar relationship between BMI and other measures of CT-derived body composition across two types of cancers. Conclusion Obesity and low skeletal muscle mass were common in both CRC and LC cohorts despite large differences in comorbidity, nutritional risk, systemic inflammation, and survival, even when normalized for TNM stage. These observations would support the hypothesis that, although prognostic, CT derived body composition analysis primarily reflects patient constitution rather than the effect of tumor stage in patients with cancer. The systemic inflammatory response, as evidenced by mGPS, can be considered as an important therapeutic target and loss of muscle mass in patients with advanced cancer is related to the systemic inflammatory response.

87 Background: Cancer-associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (WL, skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer. Methods: The SLR was conducted following PRISMA guidelines. Embase and PubMed were searched to identify articles published in English between 1 Jan 2016 and 10 Oct 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by International Consensus (IC) diagnostic criteria (Fearon et al., Lancet Oncol 2011;12:489–95) or a broader definition of any WL. Included publications were of studies in ≥100 patients with colorectal or pancreatic cancer. Results: Twenty-six publications in patients with colorectal (n=13) or pancreatic cancer (n=13) met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 studies (58%) reported any WL. An association between survival and cachexia/WL was assessed across studies using multivariate (n=23) or univariate (n=3) analyses and within each study across multiple WL categories. Cachexia/WL was associated with a statistically significantly poorer survival in at least one WL category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Conclusions: Cachexia/WL was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two-thirds of the studies. The classification of WL varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could inform early disease management strategies that may improve prognosis.

Simple SummaryC-X-C chemokine receptor type 4 (CXCR4), a G-protein-coupled receptor, has been demonstrated to stimulate proliferation and invasiveness of many different tumors, including colorectal cancer. Through in vitro evidence, overexpression of CXCR4 has been identified as a negative prognostic factor in colorectal cancer. The identification of prognostic biomarkers can improve the prediction of disease evolution and disease characterization, and guide treatment efforts. This systematic review with a meta-analysis was conducted to pool hazard ratios from prognostic studies on CXCR4, provide an updated estimate of prognostic power of CXCR4, and analyze modalities of evaluating and reporting CXCR4 expression.Background: This study was conducted to provide an updated estimate of the prognostic power of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC), and analyze modalities of evaluating and reporting its expression. Methods: A systematic review with meta-analysis was performed and described according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Studies were identified through PubMed and Google Scholar. The pooled hazard ratios (HRs) for overall survival (OS) or progression-free survival (PFS) with 95% confidence interval (CI) were estimated with the random-effect model. Results: Sixteen studies were selected covering a period from 2005 to 2020. An immunohistochemical evaluation of CXCR4 was performed in all studies. Only in three studies assessment of mRNA through RT–PCR was correlated with prognosis; in the remaining studies, the authors identified prognostic categories based on immunohistochemical expression. In pooled analyses, significant associations were found between positive or high or strong expression of CXCR4 and T stage ≥3 (P = 0.0001), and positive or high or strong expression of CXCR4 and left side primary tumor localization (P = 0.0186). The pooled HR for OS was 2.09 (95% CI: 1.30–2.88) in favor of high CXCR4 expression; for PFS, it was 1.42 (95% CI: 1.13–1.71) in favor of high CXCR4 expression. Conclusion: High CXCR4 expression is clearly associated with increased risk of death and progression in CRC. However, strong methodologic heterogeneity in CXCR4 assessment hinders direct translation into clinical practice; thus, a consensus to streamline detection and scoring of CXCR4 expression in CRC is indicated.

Diet is a complex environmental exposure. Evidence from epidemiologic studies and experimental studies in animal models has indicated that diet and components of diet have an important role in modulating risk of colorectal cancer (CRC). The WCRF/AICR Continuous Update Project Report routinely evaluates epidemiologic studies of diet and cancer risk. In the 2011 report on diet and CRC, the reviewers determined that the evidence was convincing that consumption of foods containing dietary fiber protect against CRC and intake of red meat, processed meat, ethanol from alcoholic beverages are causes of CRC. The evidence that physical activity protects against colon cancer and that body fatness and abdominal fatness (consequences of diet and inactivity) contribute to CRC was also labeled as convincing. Consumption of garlic, milk, and calcium was reported as probably protective, while the evidence was limited that non-starchy vegetables, fruits and foods containing vitamin D protect against CRC, or that foods containing iron, and also cheese, foods containing animal fats, and foods containing sugars are causes of CRC. Experimental studies in animals and randomized controlled trials in humans have helped to expand our understanding of the wide array of mechanisms by which dietary constituents may cause or prevent CRC, including through modulation of inflammation and immune function, carcinogen metabolism, hormone and growth-factor regulation, DNA repair capacity, cell-cycle control, and proliferation and apoptosis. Increasingly, the importance of diet-gut microbe interactions are being recognized; diet can influence the amount and types of microbes present in the gut, and gut microbial metabolism of dietary constituents produces compounds that may have positive or adverse effects on CRC risk. In the past decade, there has been a growing emphasis on identifying dietary patterns associated with lower cancer risk, with the recognition that, although many dietary constituents have been suggested to have preventive effects, they are not consumed in isolation and the role of diet in cancer prevention might be maximized when dietary patterns are considered versus any one single component. Diet quality has been studied using statistical clustering or factor analysis within a data set, an agnostic approach that can potentially identify new patterns important to CRC risk. Another approach is to use diet quality scoring systems defined a priori. These are derived based on emerging evidence of diet and disease risk, have algorithms that can be applied across multiple data sets, and provide the potential for more direct translation to public health messages. A variety of diet quality indices have been developed, including Healthy Eating Index (HEI-2005; HEI-2010), Alternative Healthy Eating Index 2010 (AHEI), the Dietary Approaches to Stop Hypertension (DASH) index, and indices based on the Mediterranean diet. A role for diet quality in CRC risk has been reported in the context of several prospective cohort studies. Reedy et al. (Am. J. Epidemiol., 2008), testing associations between scores on 4 diet quality indices and CRC risk in the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study, reported that higher scores on all 4 indices were associated with a lower risk of CRC in men, but that, in women, only the HEI-2005 score showed an association. In the same NIH-AARP population, 4 different methods of indexing adherence to the DASH diet were associated with lower risk of CRC in men, but only 2 of the DASH indexing methods were associated with a significantly lower CRC risk in women (Miller et al, Am. J. Clin Nutr., 2013). Recently, in the Women's Health Initiative Observational Study, a cohort of postmenopausal US women, higher HEI-2010 diet quality index scores were associated with lower risk of CRC and, similarly, higher DASH diet quality index scores were associated with a 22%–28% lower risk of CRC (Vargas et al, Am. J. Epidemiol., 2016). In these studies, indices of Mediterranean-diet adherence have been less consistently associated with CRC risk. Future use of experimental diets in animal studies that capture the complexity of the human diets may help to further characterize the effectiveness of these diet patterns and the components of them. Understanding the impact of the totality of complex diet patterns is needed further inform approaches for CRC prevention. Citation Format: Johanna W. Lampe. Food and nutrition and colorectal cancer: Patterns for prevention. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA12.

BackgroundThe clinical relevance of mismatch repair (MMR) status in patients with nonmetastatic cancer across tumour types remains unclear. Our goal was to investigate the prognostic role of MMR deficiency in patients with stage I-III colorectal and endometrial cancer.MethodsPatients with nonmetastatic colorectal and endometrial cancer with tumour tissue available for analysis were identified through the Hellenic Cooperative Oncology Group (HeCOG)’s tumour repository. Patients had been referred to Departments of Medical Oncology affiliated with HeCOG. MMR protein expression was evaluated by immunohistochemistry. The primary outcome measure was overall survival (OS).ResultsFrom May 1990 to September 2012, 1158 patients with nonmetastatic colorectal (N = 991) and endometrial cancer (N = 167) were identified (median age: 64 years, men: 544). All patients with colorectal and 109 (65%) with endometrial cancer had received adjuvant treatment. MMR deficiency was observed in 114 (11.5%) of colorectal and 80 (47.9%) of endometrial tumours. More commonly deficient proteins were PMS2 (69 patients, 7%) and MLH1 (63 patients, 6.5%) in colorectal cancer and MSH2 (58 patients, 34.7%) in endometrial cancer. Colorectal MMR-deficient (dMMR) tumours were more likely to be right sided (65 % dMMR vs 27 % proficient MMR, pMMR; p < 0.001), high grade (31% vs 15%, χ2, p < 0.001) and with a mucinous component (64% vs 42%, p < 0.001). Endometrial dMMR tumours were more often of endometrioid histology (51.4 % endometrioid vs 20 % serous/clear cell, p = 0.020). Compared with MMR proficiency, MMR deficiency was associated with improved OS in patients with endometrial cancer (HR = 0.38, 95% CI 0.20 to 0.76, p = 0.006), but not in patients with colorectal cancer (HR = 0.73, 95% CI 0.49 to 1.09, p = 0.130). After adjusting for age, stage and grade, MMR deficiency maintained its favourable prognostic significance in patients with endometrial cancer (HR = 0.42, 95% CI 0.20 to 0.88, p = 0.021).ConclusionsDMMR was associated with improved outcomes in patients with nonmetastatic endometrial cancer, but not in patients with nonmetastatic colorectal cancer who received adjuvant chemotherapy.

Effectiveness of patient-targeted interventions to inform decision making and improve uptake of colorectal cancer genetic evaluation for at-risk individuals: A systematic review