David G. Watt

Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: A systematic review

BACKGROUND Operative injury to the body from all procedures causes a stereotypical cascade of neuroendocrine, cytokine, myeloid, and acute phase responses. This response has been examined commonly by the use of cortisol, interleukin-6 (IL-6), white cell count, and C-reactive protein (CRP). We aimed to determine which markers of the systemic inflammatory response were useful in determining the magnitude of injury after elective operations. METHODS A systematic review of the literature was performed using surgery, endocrine response, systemic inflammatory response, cortisol, IL-6, white cell count, and CRP. For each analyte the studies were grouped according to whether the operative injury was considered to be minor, moderate, or major and then by the operative procedure. RESULTS A total of 164 studies were included involving 14,362 patients. The IL-6 and CRP responses clearly were associated with the magnitude of operative injury and the invasiveness of the operative procedure. For example, the peak CRP response increased from 52 mg/L with cholecystectomy to 123 mg/L with colorectal cancer resection, 145 mg/L with hip replacement, 163 mg/L after abdominal aortic aneurysm repair, and 189 mg/L after open cardiac surgery. There also appeared to be a difference between minimally invasive/laparoscopic and open procedures such as cholecystectomy (27 vs 80 mg/L), colorectal cancer resection (97 vs 133 mg/L), and aortic aneurysm repair (132 vs 180 mg/L). CONCLUSION Peak IL-6 and CRP concentrations consistently were associated with the magnitude of operative injury and operative procedure. These markers may be useful in the objective assessment of which components of Enhanced Recovery after Surgery are likely to improve patient outcome and to assess the possible impact of operative injury on immune function.

Colorectal Cancer, Systemic Inflammation, and Outcome: Staging the Tumor and Staging the Host.

Objective:This study aims to examine the clinical utility of the combination of TNM stage and modified Glasgow Prognostic Score (mGPS) in patients undergoing potentially curative resection of colorectal cancer (CRC). Background:Of measures of the systemic inflammatory response, the mGPS has been most extensively validated in patients with cancer. Methods:Data from 1000 consecutive patients undergoing potentially curative CRC resection from a single institution (January 1997–May 2013) were included. The relationship between mGPS [0–C-reactive protein (CRP) ⩽ 10 mg/L, 1—CRP > 10 mg/L and albumin ≥35 g/L, 2—CRP > 10 mg/L and albumin < 35 g/L], TNM stage, and cancer-specific survival (CSS) and overall survival (OS) was examined using Kaplan-Meier log-rank survival analysis and multivariate Cox regression analysis. Results:An mGPS of 0, 1, and 2 was observed in 63%, 21%, and 16% of patients, respectively. Median follow-up was 56 months (interquartile range: 28–107 months). TNM and mGPS were independently associated with CSS and OS (all P < 0.001). In all patients, TNM and mGPS stratified 5-year CSS and OS from 97% and 87% (stage I, mGPS = 0) to 32% and 26% (stage III, mGPS = 2), respectively. In patients undergoing elective resection of colon cancer (n = 575), 5-year CSS and OS ranged from 100% and 87% (stage I, mGPS = 0) to 37% and 30% (stage III, mGPS = 2), respectively. Conclusions:This study shows how the combination of TNM and mGPS effectively stratifies outcome in patients undergoing potentially curative resection of CRC. These data support routine staging of both the tumor and the host in patients with CRC.

Enhanced Recovery After Surgery: Which Components, If Any, Impact on The Systemic Inflammatory Response Following Colorectal Surgery?: A Systematic Review

AbstractEnhanced Recovery or Fast Track Recovery after Surgery protocols (ERAS) have significantly changed perioperative care following colorectal surgery and are promoted as reducing the stress response to surgery.The present systematic review aimed to examine the impact on the magnitude of the systemic inflammatory response (SIR) for each ERAS component following colorectal surgery using objective markers such as C-reactive protein (CRP) and interleukin-6 (IL-6).A literature search was performed of the US National Library of Medicine (MEDLINE), EMBASE, PubMed, and the Cochrane Database of Systematic Reviews using appropriate keywords and subject headings to February 2015.Included studies had to assess the impact of the selected ERAS component on the SIR using either CRP or IL-6.Nineteen studies, including 1898 patients, were included. Fourteen studies (1246 patients) examined the impact of laparoscopic surgery on the postoperative markers of SIR. Ten of these studies (1040 patients) reported that laparoscopic surgery reduced postoperative CRP. One study (53 patients) reported reduced postoperative CRP using opioid-minimising analgesia. One study (142 patients) reported no change in postoperative CRP following preoperative carbohydrate loading. Two studies (108 patients) reported conflicting results with respect to the impact of goal-directed fluid therapy on postoperative IL-6. No studies examined the effect of other ERAS components, including mechanical bowel preparation, antibiotic prophylaxis, thromboprophylaxis, and avoidance of nasogastric tubes and peritoneal drains on markers of the postoperative SIR following colorectal surgery.The present systematic review shows that, with the exception of laparoscopic surgery, objective evidence of the effect of individual components of ERAS protocols in reducing the stress response following colorectal surgery is limited.

The Neutrophil-Platelet Score (NPS) Predicts Survival in Primary Operable Colorectal Cancer and a Variety of Common Cancers.

Introduction Recent in-vitro studies have suggested that a critical checkpoint early in the inflammatory process involves the interaction between neutrophils and platelets. This confirms the importance of the innate immune system in the elaboration of the systemic inflammatory response. The aim of the present study was to examine whether a combination of the neutrophil and platelet counts were predictive of survival in patients with cancer. Methods Patients with histologically proven colorectal cancer who underwent potentially curative resection at a single centre between March 1999 and May 2013 (n = 796) and patients with cancer from the Glasgow Inflammation Outcome Study, who had a blood sample taken between January 2000 and December 2007 (n = 9649) were included in the analysis. Results In the colorectal cancer cohort, there were 173 cancer and 135 non-cancer deaths. In patients undergoing elective surgery, cancer-specific survival (CSS) at 5 years ranged from 97% in patients with TNM I disease and NPS = 0 to 57% in patients with TNM III disease and NPS = 2 (p = 0.019) and in patients undergoing elective surgery for node-negative colon cancer from 98% (TNM I, NPS = 0) to 65% (TNM II, NPS = 2) (p = 0.004). In those with a variety of common cancers there were 5218 cancer and 929 non-cancer deaths. On multivariate analysis, adjusting for age and sex and stratified by tumour site, incremental increase in the NPS was significantly associated with poorer CSS (p<0.001). Conclusion The neutrophil-platelet score predicted survival in a variety of common cancers and highlights the importance of the innate immune system in patients with cancer.

Neutrophil count is the most important prognostic component of the differential white cell count in patients undergoing elective surgery for colorectal cancer

BACKGROUND Systemic inflammatory scoring systems such as the NLR have been reported to have prognostic value in many solid organ cancers. The aim of this study was to examine the relationships between the components of the white cell count (WCC) and survival in patients undergoing elective surgery for colorectal cancer. METHODS Patients undergoing elective resection at a single center (1997 to 2008) were identified from a prospective database (n = 508). Patient demographics and preoperative laboratory measurements including the differential WCC and their association with cancer-specific survival (CSS) and overall survival were examined. RESULTS There were 172 cancer deaths and 120 noncancer deaths. On Kaplan-Meier analysis of the whole cohort, age, Tumor, Nodal, and Metastasis stage, venous invasion, margin involvement, peritoneal involvement and tumor perforation, and white cell and neutrophil count (all P < .05) were associated with CSS. In those with node-negative colon cancer (n = 226), on multivariate analysis, age, venous invasion, modified Glasgow Prognostic Score, and neutrophil count (all P < .05) were independently associated with CSS. CONCLUSION Of the components of a differential WCC, only the neutrophil count was independently associated with survival, particularly in node-negative colon cancer.

A Survey of Attitudes towards the Clinical Application of Systemic Inflammation Based Prognostic Scores in Cancer

Introduction. The systemic inflammatory response (SIR) plays a key role in determining nutritional status and survival of patients with cancer. A number of objective scoring systems have been shown to have prognostic value; however, their application in routine clinical practice is not clear. The aim of the present survey was to examine the range of opinions internationally on the routine use of these scoring systems. Methods. An online survey was distributed to a target group consisting of individuals worldwide who have reported an interest in systemic inflammation in patients with cancer. Results. Of those invited by the survey (n = 238), 65% routinely measured the SIR, mainly for research and prognostication purposes and clinically for allocation of adjuvant therapy or palliative chemotherapy. 40% reported that they currently used the Glasgow Prognostic Score/modified Glasgow Prognostic Score (GPS/mGPS) and 81% reported that a measure of systemic inflammation should be incorporated into clinical guidelines, such as the definition of cachexia. Conclusions. The majority of respondents routinely measured the SIR in patients with cancer, mainly using the GPS/mGPS for research and prognostication purposes. The majority reported that a measure of the SIR should be adopted into clinical guidelines.

A national survey of attitudes to research in Scottish General Surgery Trainees.

Introduction Given the importance placed on awareness and participation in research by Speciality and Training organisations, we sought to survey Scottish trainee attitudes to exposure to research practice during training and research in or out of programme. Methods An online survey was distributed to core and specialist trainees in general surgery in Scotland. Results Over a 4-month period, 108 trainees (75 ST/SPRs and 33 CTs) completed the survey. In their current post, most were aware of ongoing research projects (77%) and 55% were aware of trial recruitment. Only 47% attend regular journal clubs. Most believe that they are expected to present (89%) and publish (82%) during training. Most (59%) thought that participation in research is well supported. 57% were advised to undertake time out of programme research, mostly by consultants (48%) and training committee (36%). Of the 57 with time out of programme research experience, most did so in early training (37%) or between ST3-5 (47%). 28 out of the 36 (78%) without a national training number secured one after starting research. Most undertook research in a local academic unit (80%) funded by small grants (47%) or internally (33%). Most research (69%) was clinically orientated (13/55 clinical, 25/55 translational). 56% of those completing time out of programme research obtained an MD or PhD. About 91% thought that research was relevant to a surgical career. Conclusions Most trainees believe that research is an important part of training. Generally, most trainees are exposed to research practices including trial recruitment. However, <50% attend regular journal clubs, a pertinent point, given the current ‘exit exam’ includes the assessment of critical appraisal skills.

Post-operative C-reactive protein concentration: A potential therapeutic target following surgery for colorectal cancer?

597 Background: Post-operative C-reactive protein concentrations (CRP) have been reported to be associated with the development of complications following surgery for colorectal cancer (CRC). The development of complications and an exaggerated post-op CRP are associated with poor long term survival. However, whether this is due to the complication or to the CRP concentration remains unclear. Therefore, the aim of the present study was to determine whether post-op CRP concentrations, independent of post-op complications, were associated with poor long term survival following surgery for CRC. Methods: Included patients were obtained from a prospectively maintained database of CRC resections from a single institution (1999-2013). The relationship between post-op CRP concentrations and overall survival (OS) was examined using Cox regression analysis. Results: 813 patients were included. The majority of patients were > 65 yrs (67%), male (55%) and underwent elective surgery (90%). 257 patients (32%) suffered a...

Comment on "prognostic performance of inflammation-based prognostic indices in patients with resectable colorectal liver metastases".

We read with interest the recent article by Neal and colleagues on the comparison of a number of systemic inflammation-based prognostic scores including the neutrophil–lymphocyte ratio (NLR), derived neutrophil– lymphocyte ratio (dNLR), platelet–lymphocyte ratio (PLR), lymphocyte–monocyte ratio (LMR), combination of platelet count and neutrophil–lymphocyte ratio (COP– NLR) and prognostic nutritional index (PNI) and their prognostic value in patients with resectable colorectal liver metastases [1]. This well-documented study in 302 patients who underwent surgery between 2006 and 2010 concluded that, of these haematological indices, only the NLR or the dNLR had independent prognostic significance. In their study, it was notable that the neutrophil-based scores had superior prognostic significance compared with the lymphocyte-based scores and therefore questions the value of the lymphocyte count. Although, on univariate survival analysis, the lymphocyte count had prognostic value, it was not clear whether this was independent of the neutrophil count. Indeed, we have reported that, in patients with colorectal cancer, the lymphocyte count makes little contribution to the prognostic value of the NLR [2, 3]. Also, the recent report of Kumar et al. [4] shows clearly that, compared with the neutrophil count, the lymphocyte count has relatively little prognostic value in patients treated in phase 1 trials. This highlights the problem of using a ratio to predict outcome since it is not clear how the components contribute to the prognostic value. Indeed, compared with other systemic inflammation-based prognostic scores, such as the GPS, the NLR has had a wide range of thresholds (from 2 to 5) reported to have prognostic value [5, 6]. Therefore, despite the potential clinical utility and numerous reports of prognostic value, such heterogeneity of NLR thresholds makes it difficult to make recommendations for routine use. A clearer approach to the use of components of a white cell count as prognostic factors would be to form cumulative prognostic scores in a similar fashion to the GPS. Indeed, we have recently added neutrophil and platelet counts to the GPS in order to ‘‘optimise’’ its prognostic value in patients with cancer [7]. Therefore, in the light of the above comments, the authors and other workers may wish to reconsider their analysis.

The relationship between red cell distribution width (RDW), markers of systemic inflammation and survival in patients undergoing curative surgery for colorectal cancer.

589 Background: There is increasing evidence that red blood cell distribution width (RDW) has prognostic value in cardiovascular and autoimmune disease. It may reflect, in part, the systemic inflammatory response (SIR), a recently recognised prognostic factor in cancer. However, no studies have examined this hypothesis and prognostic value in cancer. The aim was to examine the relationship between pre-op RDW, markers of the SIR and survival in patients undergoing curative surgery for colorectal cancer (CRC). Methods: Data from consecutive patients (n=408) from a single institution (March 2008 to May 2013) were studied. The relationship between RDW (>14.5%) and markers of the SIR (modified Glasgow Prognostic Score (mGPS) and neutrophil-lymphocyte ratio (NLR)) and survival (cancer specific, CSS and overall, OS) were analysed using Spearman’s rank correlation and Cox regression analysis respectively. Results: The majority of patients were male (54%), had node negative disease (65%) and did not receive adjuva...