Paul G. Horgan

A novel technique for parenchymal division during hepatectomy

The major complication in the performance of hepatic rectional surgery is hemorrhage. This report describes a novel technique to achieve hepatic parenchymal division. Preliminary use of the ultrasonic dissector results in the fracture of hepatocytes and leaves bridging arteries, veins, and ducts intact. The use of the Ligasure clamp heat-seals these bridging structures, allowing their bloodless transection with surgical scissors. Six consecutive liver resections were performed in this fashion. The range of blood loss was 425 to 700 mL. This paper describes a simple technique to achieve rapid safe parenchymal division of the liver during hepatectomy resulting in minimal blood loss.

The systemic inflammation-based neutrophil–lymphocyte ratio: Experience in patients with cancer

There is increasing and consistent evidence that cancer-associated inflammation is a key determinant of outcome in patients with cancer. Various markers of inflammation have been examined over the past decade in an attempt to refine stratification of patients to treatment and predict survival. One routinely available marker of the systemic inflammatory response is the neutrophil-lymphocyte ratio (NLR), which is derived from the absolute neutrophil and absolute lymphocyte counts of a full blood count. To date, over 60 studies (>37,000 patients) have examined the clinical utility of the NLR to predict patient outcomes in a variety of cancers. The present systematic review examines and comments on the clinical utility of the NLR. The NLR had independent prognostic value in (a) unselected cohorts (1 study of >12,000 patients), (b) operable disease (20 studies, >4000 patients), (c) patients receiving neoadjuvant treatment and resection (5 studies, >1000 patients), (d) patients receiving chemo/radiotherapy (12 studies, >2000 patients) and (e) patients with inoperable disease (6 studies, >1200 patients). These studies originated from ten different countries, in particular UK, Japan, and China. Further, correlative studies (15 studies, >8500 patients) have shown that NLR is elevated in patients with more advanced or aggressive disease evidenced by increased tumour stage, nodal stage, number of metastatic lesions and as such these patients may represent a particularly high-risk patient population. Further studies investigating the tumour and host-derived factors regulating the systemic inflammatory response, in particular the NLR, may identify novel treatment strategies for patients with cancer.

A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study

INTRODUCTION Components of the systemic inflammatory response, combined to form inflammation-based prognostic scores (modified Glasgow Prognostic Score (mGPS), Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Prognostic Index (PI), Prognostic Nutritional Index (PNI)) have been associated with cancer specific survival. The aim of the present study was to compare the prognostic value of these scores. METHODS Patients (n=27,031) who had an incidental blood sample taken between 2000 and 2007 for C-reactive protein, albumin, white cell, neutrophil, lymphocyte and platelet counts, as well as a diagnosis of cancer (Scottish Cancer Registry) were identified. Of this group 8759 patients who had been sampled within two years following their cancer diagnosis were studied. RESULTS On follow up, there were 5163 deaths of which 4417 (86%) were cancer deaths. The median time from blood sampling to diagnosis was 1.7 months. An elevated mGPS, NLR, PLR, PI and PNI were predictive of a reduced cancer specific survival independent of age, sex and deprivation and tumour site (all p<0.001). The area under the receiver operator curves was greatest for mGPS and PI. Specifically, in colorectal cancer, an elevated mGPS and PI were predictive of a reduced cancer specific survival independent of age, sex, deprivation and tumour stage (both p<0.001). CONCLUSION The results of the present study show that systemic inflammation-based scores, in particular the mGPS and PI, have prognostic value in cancer independent of tumour site. Based on the present results and the existing validation literature, the mGPS should be included in the routine assessment of all patients with cancer.

Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer

There is increasing evidence that the presence of a systemic inflammatory response plays an important role in predicting survival in patients with colorectal cancer. However, it is not clear what components of the systemic inflammatory response best predict survival. The aim of the present study was to compare the prognostic value of an inflammation-based prognostic score (modified Glasgow Prognostic Score (Mgps) 0=C-reactive protein <10 mg l−1, 1=C-reactive protein >10 mg l−1, and 2=C-reactive protein >10 mg l−1 and albumin<35 g l−1) with that of components of the white cell count (neutrophils, lymphocytes, monocytes and platelets using standard thresholds) in patients with colorectal cancer. Two patient groups were studied: 149 patients who underwent potentially curative resection for colorectal cancer and 84 patients who had synchronous unresectable liver metastases. In those patients who underwent potentially curative resection the minimum follow-up was 36 months and 20 patients died of their cancer. On multivariate survival analysis only TNM stage (HR 3.75, 95% CI 1.54–9.17, P=0.004), monocyte count (HR 3.79, 95% CI 1.29–11.12, P=0.015) and mGPS (HR 2.21, 95% CI 1.11–4.41, P=0.024) were independently associated with cancer-specific survival. In patients with synchronous unresectable liver metastases the minimum follow-up was 6 months and 71 patients died of their cancer. On multivariate survival analysis only single liver metastasis >5 cm (HR 1.78, 95% CI 0.99–3.21, P=0.054), extra-hepatic disease (HR 2.09, 95% CI 1.05–4.17, P=0.036), chemotherapy treatment (HR 2.40, 95% CI 1.82–3.17, P<0.001) and mGPS (HR 1.44, 95% CI 1.01–2.04, P=0.043) were independently associated with cancer-specific survival. In summary, markers of the systemic inflammatory response are associated with poor outcome in patients with either primary operable or synchronous unresectable colorectal cancer. An acute-phase protein-based prognostic score, the mGPS, appears to be a superior predictor of survival compared with the cellular components of the systemic inflammatory response.

An inflammation-based prognostic score (mGPS) predicts cancer survival independent of tumour site: a Glasgow Inflammation Outcome Study

Introduction:A selective combination of C-reactive protein and albumin (termed the modified Glasgow Prognostic Score, mGPS) has been shown to have prognostic value, independent of tumour stage, in lung, gastrointestinal and renal cancers. It is also of interest that liver function tests such as bilirubin, alkaline phosphatase and γ-glutamyl transferase, as well as serum calcium, have also been reported to predict cancer survival. The aim of the present study was to examine the relationship between an inflammation-based prognostic score (mGPS), biochemical parameters, tumour site and survival in a large cohort of patients with cancer.Methods:Patients (n=21 669) who had an incidental blood sample taken between 2000 and 2006 for C-reactive protein, albumin and calcium (and liver function tests where available) and a diagnosis of cancer were identified. Of this group 9608 patients who had an ongoing malignant process were studied (sampled within 2 years before diagnosis). Also a subgroup of 5397 sampled at the time of diagnosis (sampled within 2 months prior to diagnosis) were examined. Cancers were grouped by tumour site in accordance with International Classification of Diseases 10 (ICD 10).Results:On follow up, there were 6005 (63%) deaths of which 5122 (53%) were cancer deaths. The median time from blood sampling to diagnosis was 1.4 months. Increasing age, male gender and increasing deprivation was associated with a reduced 5-year overall and cancer-specific survival (all P<0.001). An elevated mGPS, adjusted calcium, bilirubin, alkaline phosphatase, aspartate transaminase, alanine transaminase and γ-glutamyl transferase were associated with a reduced 5-year overall and cancer-specific survival (independent of age, sex and deprivation in all patients sampled), as well as within the time of diagnosis subgroup (all P<0.001). An increasing mGPS was predictive of a reduced cancer-specific survival in all cancers (all P<0.001).Conclusion:The results of the present study indicate that the mGPS is a powerful prognostic factor when compared with other biochemical parameters and independent of tumour site in patients with cancer.

Potential Value of Contrast-Enhanced Intraoperative Ultrasonography During Partial Hepatectomy for Metastases: An Essential Investigation Before Resection?

Objective:The aim of the study was to assess the clinical value of contrast-enhanced intraoperative ultrasound (CE-IOUS) as a novel tool in the hepatic staging of patients undergoing liver resection. Methods:Sixty patients scheduled to undergo liver resection for metastatic disease were studied. Preoperative staging with contrast-enhanced CT and/or MR scans was performed within 2 to 6 weeks of operation. Following exploration, intraoperative ultrasound (IOUS) was performed using an HDI-5000 scanner (Philips) and a finger-probe with pulse inversion harmonic (PIH) capability. CE-IOUS in the PIH mode was performed in a standardized protocol (low MI: 0.02–0.04) after intravenous injection of 3–4 mL of SonoVue (Bracco spa, Milan); all detected lesions on precontrast and postcontrast scans were counted and mapped. Any alteration in surgical management was documented following CE-IOUS compared with IOUS. Results:Three patients were excluded due to disseminated disease on exploration. CE-IOUS was significantly more sensitive than CT/MR and IOUS in detecting liver metastases (96.1% versus 76.7% and 81.5%, respectively) (P < 0.05); it altered surgical management in 29.8% (17 of 57) of cases, due to 1) additional metastases in 19.3% (11 of 57), 2) less metastases in 3.5% (2 of 57), 3) benign lesions wrongly diagnosed as metastasis on IOUS/CT in 5.3% (3 of 57), and 4) vascular proximity in 1.8% (1 of 57). Management was unchanged in 70.2% (40 of 57) despite additional lesions detected in 3.5% (2 of 57) and benign lesion wrongly diagnosed on IOUS and CT as metastasis in 1.8% (1 of 57). CE-IOUS altered combined IOUS/CT/MR staging in 35.1%. Conclusion:These preliminary results suggest CE-IOUS is an essential tool prior to liver resection for metastases.

A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer

Background:The neutrophil lymphocyte ratio (NLR) has prognostic value in patients with a variety of cancers. Many chemotherapeutic trial databases hold information on white cell and neutrophil counts only. The aim of the present study was to compare the prognostic value of the NLR with a derived score (dNLR), composed of white cell and neutrophil counts.Methods:Patients (n=27 031) who were sampled incidentally between 2000 and 2007 for neutrophil, lymphocyte and white cell counts, and also had a diagnosis of cancer (Scottish Cancer Registry), were identified. Of this group, 12 118 patients who had been sampled within 2 years of their cancer diagnosis were studied.Results:On follow-up, there were 7366 deaths, of which 6198 (84%) were cancer deaths. The median time from blood sampling to diagnosis was 2.1 months. The area under the receiver-operating characteristic (ROC) curve for cancer-specific survival was 0.650 for the NLR and 0.640 for the dNLR. The NLR and dNLR were independently associated with survival in all cancers studied (all P<0.001). The optimal thresholds, on the basis of hazard ratios and area under the curve, were 4 : 1 for the NLR and 2 : 1 for the dNLR.Conclusion:The results of the present study show that the dNLR has similar prognostic value to the NLR. Therefore, the universally available dNLR is to be commended for use in the risk stratification of patients undergoing chemotherapy.

RE: nab-Paclitaxel Plus Gemcitabine for Metastatic Pancreatic Cancer: Long-Term Survival From a Phase III Trial.

We read with interest the article by Goldstein and colleagues that reports the long-term results of the large phase III randomized trial (IMPACT) of nab-paclitaxel plus gemcitabine or gemcitabine alone in patients with metastatic pancreatic cancer, extending support for the superior efficacy of this combination therapy (1). They reported that the presence of a systemic inflammatory response, as evidenced by an elevated neutrophil lymphocyte ratio (NLR), effectively stratified survival independent of the trial treatment. A pooled treatment analysis demonstrated that patients with an NLR of 5 or less had a statistically significantly prolonged survival compared with patients with an NLR of more than 5 (median = 9.1 vs 5.0 months, P < .001). In the nab-Paclitaxel plus gemcitabine arm there was a statistically significantly longer overall survival vs the gemcitabine arm alone in patients with an NLR of 5 or less (P < .001). Furthermore, when there was evidence of a raised systemic inflammatory response, a trend was evident favoring prolonged survival in the nab-paclitaxel plus gemcitabine arm vs the gemcitabine alone group (P = .079). These results confirm our previous observations in patients with pancreatic adenocarcinoma, that an elevated NLR is an important independent prognostic factor (2). However, there is good evidence that assessment of the systemic inflammatory response using acute phase proteins, in particular C-reactive protein (CRP) and albumin (Glasgow Prognostic Score [GPS]) has superior prognostic value in a variety of common solid tumors (3), including pancreatic cancer both in resectable and nonresectable forms (2). Therefore, it is clear that even in such a poor-prognosis tumor as pancreatic cancer outcomes can be stratified according to the systemic inflammatory response. This new knowledge offers the possibility for simple and effective stratification for patients with this difficult-to-treat cancer. For heterogeneous cancers, in particular pancreatic cancer, a stratified medicine approach offers potential to target an individual’s cancer with the right treatment for the right patient (4). This strategy could improve overall outcomes and quality of life for patients by minimizing unnecessary side effects arising from ineffective therapies. However, as demonstrated in the present study, the concept of stratification should not be limited to tumoror gene-centric aspects but extended to consider patient or host aspects including the burden of the systemic inflammatory response. Moreover, beyond stratification there is also an opportunity for therapeutic targeting of the systemic inflammatory response. Given the role of JAK-STAT signaling in the inflammatory responses of patients with pancreatic cancer (5), it is of interest that a recent randomized phase II trial of the JAK1/JAK2 inhibitor ruxolitinib combined with capecitabine in patients with metastatic pancreatic cancer revealed a statistically significantly prolonged survival for those patients who were administered ruxolitinib with coexisting evidence of an elevated systemic inflammatory response, as measured by CRP and/or the modified GPS (6). It is also of interest that nab-paclitaxel itself has potential to alter the tumor stroma and immune environment (7). In summary, the work of Goldstein and colleagues (1) confirms the prognostic value of the systemic inflammatory response in patients with metastatic pancreatic cancer. Furthermore, it heralds a new era in which the systemic inflammatory response becomes a legitimate target for treatment of these patients.

Observation or Operation for Patients With an Asymptomatic Inguinal Hernia A Randomized Clinical Trial

Objective:Many patients with an inguinal hernia are asymptomatic or have little in the way of symptoms from their hernia. Repair is often associated with long-term chronic pain and has a recurrence rate of 5% to 10%. Our aim was to compare operation with a wait-and-see policy in patients with an asymptomatic hernia. Methods:A total of 160 male patients 55 years or older were randomly assigned to observation or operation. Patients were assessed clinically and sent questionnaires at 6 months and 1 year. The primary endpoint was pain and general health status at 12 months; other outcome measures included costs to the health service and the rate of operation for a new symptom or complication. Results:At 12 months, there were no significant differences between the randomized groups of observation or operation, in visual analogue pain scores at rest, 3.7 mm versus 5.2 mm (mean difference, −1.6; 95% confidence interval (CI), −4.8 to 1.6, P = 0.34), or on moving, 7.6 mm versus 5.7 mm (mean difference, −1.9; 95% CI, −6.1 to 2.4, P = 0.39). Also, the number of patients 29 versus 24 (difference in proportion, 8%; 95% CI, −7% to 23%, P = 0.31), who recorded pain on moving and the number taking regular analgesia, 9 versus 17 (difference in proportion, −10%; 95% CI, −21% to 2%, P = 0.14) was similar. At 6 months, there were significant improvements in most of the dimensions of the SF-36 for the operation group, while at 12 months although the trend remained the same the differences were only significant for change in health (mean difference, 7.3; 95% CI, 0.4 to 14.3, P = 0.039). The rate of crossover from observation to operation 23 patients at a median follow-up of 574 days was higher than predicted. The observation group also suffered 3 serious hernia-related adverse events compared with none in the operation group. Conclusions:Repair of an asymptomatic inguinal hernia does not affect the rate of long-term chronic pain and may be beneficial to patients in improving overall health and reducing potentially serious morbidity.

Comparison of the Prognostic Value of Inflammation-Based Pathologic and Biochemical Criteria in Patients Undergoing Potentially Curative Resection for Colorectal Cancer

Objective:To examine interrelationships between the local inflammatory response (Klintrup and Jass scores) and the systemic inflammatory response (Glasgow prognostic score [GPS]), and compare their prognostic value in patients undergoing curative resection for colorectal cancer. Background:Both localized peritumoral inflammatory cell infiltrate and the host systemic inflammatory response are known to have prognostic value in colorectal cancer. However, the interrelationships of biochemical and cellular components of the systemic inflammatory response and the local inflammatory response are poorly understood. Methods:Retrospective study of 287 patients who underwent surgery between 1997 and 2004. Data were collected from routine preoperative blood tests. Routine pathology specimens were scored according to Jass and Klintrup criteria for peritumoral infiltrate. Results:Increased Dukes stage was associated with less peritumoral infiltrate (Jass criteria: P < 0.001, Klintrup criteria: P < 0.01). Increased modified GPS (mGPS) was associated with increased circulating white cell (P < 0.01) and neutrophil (P < 0.01) counts and low lymphocyte counts (P < 0.01). Increased circulating white cell count was associated with increased neutrophil count (P < 0.001) and low-grade peritumoral infiltrate (P < 0.05, Klintrup criteria). Jass and Klintrup criteria for peritumoral infiltrate were directly associated (P < 0.001). On univariate survival analysis of patients with node-negative disease (Dukes A and B), age (P < 0.01), mGPS (P < 0.01), neutrophil count (P < 0.05), and Klintrup criteria (P < 0.05) were associated with cancer-specific survival. On multivariate survival analysis in node-negative disease, the mGPS (hazard ratio: 2.61, 95% CI: 1.27–5.35, P < 0.01) and Klintrup criteria (hazard ratio: 6.31, 95% CI: 1.40–28.44, P < 0.05) were independently associated with cancer-specific survival. Conclusions:The results of the present study suggest low peritumoral infiltrate (Klintrup criteria) and increased systemic inflammation (mGPS criteria) are linked through the cell-mediated immune system. Furthermore, both pathologic (Klintrup) and biochemical (mGPS) measures of the inflammatory response predict survival after colorectal cancer surgery.