C-Reactive Protein and C-Reactive Protein-Based Scores to Predict Survival in Esophageal and Junctional Adenocarcinoma: Systematic Review and Meta-Analysis.

BACKGROUND: Esophageal adenocarcinoma (EAC) has a poor prognosis; predictive markers of prognosis would facilitate advances in personalized therapy. C-reactive protein (CRP) and CRP-based scores are increasingly recommended across oncology; however, their role and value in EAC is unclear. This systematic review and meta-analysis examined CRP cut-point and scores and how they may best be applied in predicting survival in EAC. METHODS: A systematic literature search was conducted in EMBASE, Medline, Web of Science, Cochrane, Scopus and CINAHL databases, from inception to 1st October 2020. Studies reporting data from adults with EAC including adenocarcinoma of the gastro-esophageal junction (AEG), pre-treatment CRP or CRP-based score and Hazard Ratio (HR) for survival were included. QUIPS tool assessed risk of bias. Meta-analysis was undertaken. RESULTS: A total of 819 records were screened. Eight papers were included, with data for 1475 people. CRP cut-points ranged from 2.8 to 10 mg/L. The Glasgow Prognostic Score (GPS) and modified GPS were the most commonly reported scores. On meta-analysis, elevated preoperative GPS/mGPS was significantly associated with worse overall survival (hazards ratio [HR] 1.81, 95% confidence interval [CI] 1.25-2.62, p = 0.002); results were similar in subgroup analyses of multimodal treatment, M0 disease, and R0 resection. CONCLUSIONS: This is the first review to evaluate comprehensively the evidence for CRP and CRP-based scores in EAC. Meta-analysis demonstrated that elevated preoperative GPS or mGPS was significantly associated with reduced overall survival in EAC, including AEG. There is insufficient evidence to support use of CRP alone. Future studies should examine GPS/mGPS in EAC prospectively, alone and combined with other prognostic markers.

Late referral of cancer patients with malnutrition to dietitians: a prospective study of clinical practice.

PURPOSE: Malnutrition (MN) in cancer is common but underdiagnosed. Dietitian referrals may not occur until MN is established. We investigated cancer patient characteristics (demographics, nutritional status, and nutrition barriers) on referral to oncology dietitians. We also examined referral practices and prevalence of missed referral opportunities. METHODS: This was a naturalistic multi-site study of clinical practice. Data from consecutive referrals were collected in inpatient and outpatient settings. Demographics, nutritional status (weight, body mass index (BMI), weight loss in the preceding 3-6 months, oral intake, nutrition barriers), referral reasons, and use of screening were recorded. Missed opportunities for earlier referral were also noted. RESULTS: Two hundred patients were included (60% male, 51% inpatients). Half had gastrointestinal and hepatobiliary cancers. The majority were on antitumor treatment. Two-thirds had lost ≥ 5% body weight. Forty percent were overweight or obese. Seventy percent had ≥ 2 nutritional barriers. Most common nutrition barriers were anorexia, nausea, and early satiety. Greater weight loss and lower food intake were associated with ≥ 2 barriers. Weight loss was the most common referral reason. Screening was used in 35%. Referrals should have occurred sooner in nearly half (45%, n = 89). CONCLUSIONS: Cancer patients were referred late to a dietitian, with multiple nutritional barriers. Most referrals were for established weight loss (WL). WL may be masked by pre-existing obesity. Almost half had missed earlier referral opportunities; screening was infrequent. Over one-quarter should have been re-referred sooner. There is a clear need for clinician education. Future research should investigate the optimal timing of dietitian referral and the best nutrition screening tools for use in cancer.

Application of the 2011 international consensus cancer cachexia classification in routine oncology dietetic practice: An observational study.

BACKGROUND: Cancer cachexia (CC) is highly prevalent and associated with significant morbidity and mortality, yet underrecognized. In 2011, an international cachexia consensus (ICC) proposed a definition, assessment framework, and stages for classification: cancer precachexia, cachexia, and refractory cachexia. The authors anticipated that a "more practical classification approach for clinical practice" would be required, which we interpreted as a bedside assessment based on clinical data. We investigated whether the ICC classification could be employed in routine dietetic practice without access to objective muscle mass measures. METHODS: Data from 200 consecutive patients with solid tumors were collected as part of clinical practice by oncology dietitians in five tertiary referral hospitals. Dietitians used information gathered during their routine assessment and applied the ICC framework to assign a stage. When the dietitian was unable to assign a stage, the reason was noted. RESULTS: Based on available data, classification was possible in 177 (88%); 23 (12%) could not be staged. The reasons cited were as follows: unknown C-reactive protein (n = 14), complex clinical situation (n = 5), unknown weight loss (n = 2), and acute illness (n = 2). Thirty (17%) of the 177 participants were judged to be noncachectic.  One hundred twelve (83%) met the criteria for 1 of the 3 ICC stages: 92 (52%) were cachectic; 35 (20%) precachectic, and 20 (11%) refractory. CONCLUSIONS: CC staging based on the ICC classification was feasible and practical in routine dietetic practice even without access to objective muscle mass measures. Once validated and operationalized, expert clinical assessment by a dietitian could be a cost-effective means to identify and stage CC, with more resource-intensive means used when there is clinical doubt.

Identification of plasma proteins associated with oesophageal cancer chemotherapeutic treatment outcomes using SWATH-MS.

Oesophageal adenocarcinoma (OAC) is an aggressive cancer with a five-year survival of <15%. Current chemotherapeutic strategies only benefit a minority (20-30%) of patients and there are no methods available to differentiate between responders and non-responders. We performed quantitative proteomics using Sequential Window Acquisition of all THeoretical fragment-ion spectra-Mass Spectrometry (SWATH-MS) on albumin/IgG-depleted and non-depleted plasma samples from 23 patients with locally advanced OAC prior to treatment. Individuals were grouped based on tumour regression (TRG) score (TRG1/2/3 vs TRG4/5) after chemotherapy, and differentially abundant proteins were compared. Protein depletion of highly abundant proteins led to the identification of around twice as many proteins. SWATH-MS revealed significant quantitative differences in the abundance of several proteins between the two groups. These included complement c1q subunit proteins, C1QA, C1QB and C1QC, which were of higher abundance in the low TRG group. Of those that were found to be of higher abundance in the high TRG group, glutathione S-transferase pi (GSTP1) exhibited the lowest p-value and highest classification accuracy and Cohen's kappa value. Concentrations of these proteins were further examined using ELISA-based assays. This study provides quantitative information relating to differences in the plasma proteome that underpin response to chemotherapeutic treatment in oesophageal cancers. SIGNIFICANCE: Oesophageal cancers, including oesophageal adenocarcinoma (OAC) and oesophageal gastric junction cancer (OGJ), are one of the leading causes of cancer mortality worldwide. Curative therapy consists of surgery, either alone or in combination with adjuvant or neoadjuvant chemotherapy or radiation, or combination chemoradiotherapy regimens. There are currently no clinico-pathological means of predicting which patients will benefit from chemotherapeutic treatments. There is therefore an urgent need to improve oesophageal cancer disease management and treatment strategies. This work compared proteomic differences in OAC patients who responded well to chemotherapy as compared to those who did not, using quantitative proteomics prior to treatment commencement. SWATH-MS analysis of plasma (with and without albumin/IgG-depletion) from OAC patients prior to chemotherapy was performed. This approach was adopted to determine whether depletion offered a significant improvement in peptide coverage. Resultant datasets demonstrated that depletion increased peptide coverage significantly. Additionally, there was good quantitative agreement between commonly observed peptides. Data analysis was performed by adopting both univariate as well as multivariate analysis strategies. Differentially abundant proteins were identified between treatment response groups based on tumour regression grade. Such proteins included complement C1q sub-components and GSTP1. This study provides a platform for further work, utilising larger sample sets across different treatment regimens for oesophageal cancer, that will aid the development of 'treatment response prediction assays' for stratification of OAC patients prior to chemotherapy.

Serum C-reactive protein is an important and powerful prognostic biomarker in most adult solid tumors.

INTRODUCTION: Prognostication in cancer is challenging and inaccurate. C-Reactive Protein (CRP), a cheap and sensitive marker of inflammation may help. This study investigated the relationship between CRP and prognosis in a large cohort of solid tumors with mixed cancer diagnoses and stages. METHODS: Electronic medical records of 4931 adults with solid tumors who attended the Taussig Cancer Institute from 2006-2012 were reviewed. Demographic and clinical characteristics were recorded. Maximum CRP (mCRP) was identified for each individual. CRP was analysed as a time-dependent, continuous and categorical variable for association with survival. RESULTS: Two thirds of patients had a high mCRP. This was consistently associated with shorter survival, even after correction for time from diagnosis, and when analysed as a continuous or a categorical variable. When mCRP values above 10 mg/L were subcategorized, a higher mCRP was always worse. Even among those with normal values, statistically and clinically significant shorter survival was noted at mCRP levels >5 mg/L. CONCLUSIONS: In a large representative cohort of consecutive solid tumor patients the risk of death was clinically and statistically significantly greater with a high mCRP. This was independent of other variables and regardless of statistical method from both dates of diagnosis and test. CRP appeared to be underutilized. Our results support the routine use of CRP as a universal cost-effective independent prognostic indicator in most solid tumors.

C-Reactive Protein Is an Important Biomarker for Prognosis Tumor Recurrence and Treatment Response in Adult Solid Tumors: A Systematic Review.

PURPOSE: A systematic literature review was done to determine the relationship between elevated CRP and prognosis in people with solid tumors. C-reactive protein (CRP) is a serum acute phase reactant and a well-established inflammatory marker. We also examined the role of CRP to predict treatment response and tumor recurrence. METHODS: MeSH (Medical Subject Heading) terms were used to search multiple electronic databases (PubMed, EMBASE, Web of Science, SCOPUS, EBM-Cochrane). Two independent reviewers selected research papers. We also included a quality Assessment (QA) score. Reports with QA scores <50% were excluded. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) methodology was utilized for this review (S1 PRISMA Checklist). RESULTS: 271 articles were identified for final review. There were 45% prospective studies and 52% retrospective. 264 had intermediate QA score (≥50% but <80%); Seven were adequate (80% -100%); A high CRP was predictive of prognosis in 90% (245/271) of studies-80% of the 245 studies by multivariate analysis, 20% by univariate analysis. Many (52%) of the articles were about gastrointestinal malignancies (GI) or kidney malignancies. A high CRP was prognostic in 90% (127 of 141) of the reports in those groups of tumors. CRP was also prognostic in most reports in other solid tumors primary sites. CONCLUSIONS: A high CRP was associated with higher mortality in 90% of reports in people with solid tumors primary sites. This was particularly notable in GI malignancies and kidney malignancies. In other solid tumors (lung, pancreas, hepatocellular cancer, and bladder) an elevated CRP also predicted prognosis. In addition there is also evidence to support the use of CRP to help decide treatment response and identify tumor recurrence. Better designed large scale studies should be conducted to examine these issues more comprehensively.