Does the presence of an intact primary increase the risk of nonelective colorectal surgery in patients treated with bevacizumab?

AIM: In patients with incurable metastatic colorectal cancer (mCRC), resection of the primary tumour is debated; however, patients with intact primaries may be at a higher risk of complications requiring surgery when receiving treatment with bevacizumab. Our aim was to estimate the risk of nonelective colorectal surgery in patients undergoing bevacizumab therapy for mCRC and evaluate the association between intact primary tumours and risk of nonelective surgery. METHOD: We designed a population-based, retrospective cohort study using administrative and cancer registry data in Ontario, Canada. We included patients with mCRC who received bevacizumab from 1 January 2008 to 31 December 2014. The primary outcome was nonelective colorectal surgery after initiation of bevacizumab. We determined the cumulative incidence of nonelective colorectal surgery among patients with previously resected and unresected primaries, accounting for the competing risk of death. We explored the relationship between previous resection of the primary and need for nonelective surgery using a cause-specific hazards model, controlling for patient, tumour and treatment factors. RESULTS: We identified 1840 (32.7%) patients with intact primaries and 3784 (67.3%) patients with prior resection. The cumulative incidence of nonelective surgery 1 year after initiating bevacizumab for all patients was 3.9% (95% CI 3.4-4.5%). One-year cumulative incidence was higher in those with intact primaries than in those with resected primaries (6.1% vs 2.9%, P < 0.0001). After adjustment, an intact primary remained strongly associated with nonelective colorectal surgery (hazard ratio = 2.89, 95% CI 2.32-3.61; P < 0.0001). CONCLUSION: Bevacizumab is associated with a low but meaningful risk for serious gastrointestinal complications, necessitating vigilance, particularly among patients with an intact primary tumour.

Organizational guidance for the care of patients with head-and-neck cancer in Ontario.

Background: At the request of the Head and Neck Cancers Advisory Committee of Ontario Health (Cancer Care Ontario), a working group and expert panel of clinicians with expertise in the management of head-and-neck cancer developed the present guideline. The purpose of the guideline is to provide advice about the organization and delivery of health care services for adult patients with head-and-neck cancer. Methods: This document updates the recommendations published in the Ontario Health (Cancer Care Ontario) 2009 organizational guideline The Management of Head and Neck Cancer in Ontario. The guideline development methods included an updated literature search, internal review by content and methodology experts, and external review by relevant health care providers and potential users. Results: To ensure that all patients have access to the highest standard of care available in Ontario, the guideline establishes the minimum requirements to maintain a head-and-neck disease site program. Recommendations are made about the membership of core and extended provider teams, minimum skill sets and experience of practitioners, cancer centre-specific and practitioner-specific volumes, multidisciplinary care requirements, and unique infrastructure demands. Conclusions: The recommendations contained in this document offer guidance for clinicians and institutions providing care for patients with head-and-neck cancer in Ontario, and for policymakers and other stakeholders involved in the delivery of health care services for head-and-neck cancer.

Predictors of Post-operative Pain and Opioid Consumption in Patients Undergoing Liver Surgery.

BACKGROUND: Post-operative pain management is a critical component of perioperative care. Patients at risk of poorly controlled post-operative pain may benefit from early measures to optimize pain management. We sought to identify risk factors for post-operative pain and opioid consumption in patients undergoing liver resection. METHODS: This is a multi-institutional prospective nested cohort study of patients undergoing open liver resection. Opioid consumption and pain scores were collected following surgery. To estimate the effects of patient factors on opioid consumption (oral morphine equivalents-OME) and on pain scores (NRS-11), we used generalized linear models and multivariable linear regression model, respectively. RESULTS: One hundred and fifty-three patients who underwent open liver resection between 2013 and 2016 were included in the study. The mean patient age was 62.2 years, and 43.3% were female. Younger patients were significantly more likely to use more opioids in the early post-operative period (16.7 OME/10 years, p < 0.001). Patient factors that were significantly associated with increased NRS-11 pain scores also included younger patient age (difference in pain score of 0.3/10 years with cough and 0.2/10 years at rest, p < 0.01 for both) as well as a history of analgesic use (difference in pain score of 0.9 with cough and 0.6 at rest, p < 0.01 and p = 0.07, respectively). CONCLUSION: Younger patients and those with a history of analgesic use are more likely to report higher post-operative pain and require higher doses of opioids. Early identification of these patients, and measures to better manage their pain, may contribute to optimal perioperative care.

Patient indications for Mohs micrographic surgery: a clinical practice guideline.

Objective: The purpose of the present work was to develop evidence-based indications for Mohs micrographic surgery in patients with a diagnosis of skin cancer. Methods: The guideline was developed by Cancer Care Ontario's Program in Evidence-Based Care, together with the Melanoma Disease Site Group and the Surgical Oncology Program, through a systematic review of relevant literature, patient- and caregiver-specific consultation, and internal and external reviews. Recommendation 1: Given a lack of high-quality, comparative evidence, surgery (with postoperative or intraoperative margin assessment) or radiation (for those who are ineligible for surgery) should remain the standard of care for patients with skin cancer. Recommendation 2: Mohs micrographic surgery is recommended for patients with histologically confirmed recurrent basal cell carcinoma of the face and is appropriate for primary basal cell carcinomas of the face that are larger than 1 cm, have aggressive histology, or are located on the H zone of the face. Recommendation 3: Mohs micrographic surgery should be performed by physicians who have completed a degree in medicine or equivalent, including a Royal College of Physicians and Surgeons of Canada Specialist Certificate or equivalent, and have received advanced training in Mohs micrographic surgery.

Changes in preoperative endoscopic and percutaneous bile drainage in patients with periampullary cancer undergoing pancreaticoduodenectomy in Ontario: effect on clinical practice of a randomized trial.

Background: In 2010, a multicentre randomized controlled trial reported increased postoperative complications in pancreaticoduodenectomy (pde) patients undergoing preoperative biliary decompression (pbd). We evaluated the effect of that publication on rates of pbd at the population level. Methods: This retrospective observational cohort study identified patients undergoing pde for malignancy, 2005-2013, linking them with administrative health care databases covering medical services for a population of 13.5 million. Patients undergoing pbd within 6 weeks before their surgery were identified using physician billing codes and were divided into those undergoing pde before and after article publication, with a 6-month washout period. Chi-square tests were used to compare rates of pbd. Results: Of 1997 pde patients identified, 963 underwent surgery before article publication, and 911, after (123 during the washout period). The rate of pbd was 47.5% before publication, and 41.6% after (p = 0.01). The lowest pbd rates occurred immediately after publication, in 2010 and 2011. Similar results were observed when the cohort was restricted to patients seen preoperatively by a gastroenterologist (n = 1412). Conclusions: Rates of pbd have declined a small, but significant, amount after randomized trial publication. Persistence of pbd might relate to suboptimal knowledge translation, the role of pbd in diagnosis of periampullary malignancy, and treatment of complications (cholangitis, severe hyperbilirubinemia) or anticipation of delay from diagnosis to surgery. The nadir in pbd rates after article publication and the subsequent rise suggest an element of transience in the effect of article publication on clinical practice. Further investigation into the reasons for persistent pbd is needed.

Surgical process improvement tools: defining quality gaps and priority areas in gastrointestinal cancer surgery.

BACKGROUND: Surgery is a cornerstone of cancer treatment, but significant differences in the quality of surgery have been reported. Surgical process improvement tools (spits) modify the processes of care as a means to quality improvement (qi). We were interested in developing spits in the area of gastrointestinal (gi) cancer surgery. We report the recommendations of an expert panel held to define quality gaps and establish priority areas that would benefit from spits. METHODS: The present study used the knowledge-to-action cycle was as a framework. Canadian experts in qi and in gi cancer surgery were assembled in a nominal group workshop. Participants evaluated the merits of spits, described gaps in current knowledge, and identified and ranked processes of care that would benefit from qi. A qualitative analysis of the workshop deliberations using modified grounded theory methods identified major themes. RESULTS: The expert panel consisted of 22 participants. Experts confirmed that spits were an important strategy for qi. The top-rated spits included clinical pathways, electronic information technology, and patient safety tools. The preferred settings for use of spits included preoperative and intraoperative settings and multidisciplinary contexts. Outcomes of interest were cancer-related outcomes, process, and the technical quality of surgery measures. CONCLUSIONS: Surgical process improvement tools were confirmed as an important strategy. Expert panel recommendations will be used to guide future research efforts for spits in gi cancer surgery.

Outcomes after hepatic resection and subsequent multimodal treatment of recurrence for multifocal hepatocellular carcinoma.

BACKGROUND: The role of liver resection in patients with multifocal hepatocellular carcinoma (HCC) with well preserved liver function is controversial. This study was conducted to evaluate the outcomes of such patients. METHODS: This was a retrospective analysis of patients who underwent liver resection for multifocal HCC between 1992 and 2011. Postoperative outcomes, survival and predictors of outcomes were analysed. RESULTS: Of 46 patients who underwent hepatic resection for multifocal HCC, 38 had Barcelona Clinic Liver Cancer stage B disease. Major hepatectomy was performed in 27 patients, and major complications occurred in nine (20 per cent). The 90-day postoperative mortality rate was 7 per cent. Overall 1-, 2-, 3- and 5-year survival rates were 78, 64, 59 and 53 per cent respectively (median 70 months), whereas corresponding recurrence-free survival rates were 53, 32, 30 and 27 per cent (median 14 months). Recurrence developed in 28 (61 per cent) of the 46 patients, affecting the liver only in 22. Three-quarters of patients with recurrence underwent further therapy. Major hepatectomy (hazard ratio (HR) 0.37, 95 per cent confidence interval 0.14 to 0·95; P = 0·038), microvascular (HR 3·44, 1·35 to 8·74; P = 0·009) and macrovascular (HR 2·68, 1·11 to 6·43; P = 0·028) invasion, and cirrhosis (HR 3·15, 1·12 to 8·86; P = 0·029) were associated with overall survival. Microvascular invasion (HR 2·81, 1·06 to 7·40; P = 0·037), cirrhosis (HR 3·12, 1·41 to 6·88; P < 0·001) and bilobar disease (HR 2·93, 1·09 to 7·88; P = 0·033) were associated with recurrence-free survival. CONCLUSION: In selected patients with multifocal HCC and well preserved liver function, long-term survival is possible after liver resection and subsequent aggressive treatment of recurrence.

Planned versus unplanned portal vein resections during pancreaticoduodenectomy for adenocarcinoma.

BACKGROUND: The management of portal vein (PV) involvement by pancreatic adenocarcinoma during pancreaticoduodenectomy (PD) is controversial. The aim of this study was to compare the outcomes of unplanned and planned PV resections as part of PD. METHODS: An analysis of PD over 11 years was performed. Patients who had undergone PV resection (PV-PD) were identified, and categorized into those who had undergone planned or unplanned resection. Postoperative and oncological outcomes were compared. RESULTS: Of 249 patients who underwent PD for pancreatic adenocarcinoma, 66 (26·5 per cent) had PV-PD, including 27 (41 per cent) planned and 39 (59 per cent) unplanned PV resections. Twenty-five of 27 planned PV resections were circumferential PV-PD, whereas 25 of 39 unplanned PV resections were partial PV-PD. Planned PV resections were performed in slightly younger patients (mean(s.d.) 60(9) versus 65(10) years; P = 0·031), and associated with longer operating times (mean(s.d.) 602(131) versus 458(83) min; P < 0·001) and more major complications (26 versus 5 per cent; P = 0·026). Planned PV resections were associated with a lower rate of positive margins (4 versus 44 per cent; P < 0·001) despite being carried out for larger tumours (mean(s.d.) 3·9(1·4) versus 2·9(1·0) cm; P = 0·002). There was no difference in survival between the two groups (P = 0·998). On multivariable analysis, margin status was a significant predictor of survival. CONCLUSION: Although planned PV resections for pancreatic adenocarcinoma were associated with higher rates of postoperative morbidity than unplanned resections, R0 resection rates were better.

Risk factors for perioperative morbidity and mortality after extended hepatectomy for hepatocellular carcinoma.

BACKGROUND: Extended hepatectomy with resection of more than four segments is a high-risk operation, especially in patients with hepatocellular carcinoma (HCC) associated with chronic liver disease. This study evaluated the risk factors for morbidity and mortality following extended hepatectomy for HCC. METHODS: Preoperative and intraoperative variables of 155 patients who underwent extended hepatectomy for HCC were analysed to identify risk factors for postoperative morbidity and mortality. RESULTS: The overall morbidity rate was 55.5 per cent (n = 86). Most morbidity was due to ascites or pleural effusion. Significant life-threatening complications occurred in 20.0 per cent (n = 31). The perioperative mortality rate was 8.4 per cent (n = 13). Multivariate analysis found that portal clamping (P = 0.023) and perioperative blood transfusion (P < 0.001) were risk factors for morbidity, whereas perioperative blood transfusion (P < 0.001) was the only risk factor for significant morbidity. Co-morbid illness (P = 0.019) and perioperative blood transfusion (P = 0.004) were risk factors for perioperative mortality. CONCLUSION: Meticulous operative techniques to minimize blood loss and transfusion, while avoiding a prolonged Pringle manoeuvre, may help reduce postoperative morbidity. Avoidance of perioperative blood transfusion and careful preoperative selection of patients in terms of overall physiological status are important measures to reduce the postoperative mortality rate.

Delayed treatment with diethyl maleate prevents E-selectin expression in human endothelial cells.

BACKGROUND: Polymorphonuclear leukocyte (PMN) infiltration is a significant contributor to tissue damage in many disease states and is known to occur through an orderly set of events. The endothelial cell adhesion molecule E-selectin is involved in the initial rolling of PMNs on the endothelium at sites of inflammation. We have previously shown that the glutathione depleting agent diethyl maleate (DEM) attenuates lung injury in a rodent model of intratracheal LPS stimulation. We hypothesized that DEM might attenuate E-selectin in LPS-treated human umbilical vein endothelial cells as a mechanism underlying this effect. Further, we investigated the role of delayed treatment with DEM on E-selectin expression. METHODS: Human umbilical vein endothelial cells were treated with DEM (100 to 400 mumol/L) before or after LPS stimulation (1 microgram/mL). Surface expression of E-selectin was examined using a cellular enzyme-linked immunosorbent assay. E-selectin mRNA transcripts were detected by Northern blot analysis. Nuclear factor-kappa B (NF-kappa B) activity was detected with gel shift assays. RESULTS: DEM significantly inhibited LPS-induced E-selectin surface expression and mRNA levels in a dose-dependent fashion, with complete inhibition at 250 mumol/L, without affecting cell viability. This inhibitory effect was seen even if DEM was added up to 60 minutes after LPS. DEM inhibited NF-kappa B nuclear translocation in a manner that mirrored protein and mRNA levels. CONCLUSIONS: Delayed treatment with DEM attenuates NF-kappa B nuclear translocation and E-selectin expression in human umbilical vein endothelial cells up to 60 minutes after the onset of LPS stimulation. Thus, DEM may represent an effective intervention for PMN-mediated organ injury even when given after an inflammatory insult.

Murine hepatitis virus strain 3 induces the macrophage prothrombinase fgl-2 through p38 mitogen-activated protein kinase activation.

The clinical syndrome of acute liver failure produced by fulminant viral hepatitis can be reproduced in mice by infection with murine hepatitis virus strain 3 (MHV-3). Although it is clear that MHV-3-induced hepatitis depends upon macrophage activation and the expression of a specific prothrombinase, fgl-2, the signaling pathways involved in virally stimulated cell activation are unclear. Since we had previously found that MHV-3 induces the tyrosine phosphorylation of cellular proteins, we investigated the roles of the mitogen-activated protein kinase (MAPK) proteins. In a series of Western blots, immunoprecipitation and in vitro kinase assay studies, we found that both the extracellular signal-related kinase (ERK) and p38 MAPK proteins are tyrosine-phosphorylated and activated following exposure of murine peritoneal exudative macrophages (PEM) to MHV-3. Although p38 phosphorylation and activity are induced soon after MHV-3 exposure, peaking by 1-5 min, ERK phosphorylation and activity increase more gradually, peaking at 20-30 min and gradually fading thereafter. Interestingly, whereas selective p38 inhibition with SB203580 (1-20 microM) abolished the virally stimulated induction of fgl-2 mRNA, protein, and functional activity, selective ERK inhibition with PD98059 (1-50 microM) limited fgl-2 functional activity but had little to no effect on fgl-2 mRNA or protein levels. Moreover, whereas inhibition of ERK had no effect on p38 activity, p38 inhibition consistently increased MHV-3-induced ERK activity. To ensure that these pathways were relevant in vivo, MHV-3 was injected intraperitoneally, and peritoneal exudative macrophages were collected. Again, MHV-3 exposure led to increased p38 and ERK tyrosine phosphorylation. These data argue that MHV-3 induces tightly interconnected ERK and p38 MAPK cascades in the macrophage both in vitro and in vivo. Although the ERK and p38 MAPK proteins have discordant effects at the level of fgl-2 expression, both converge at the level of its activity, suggesting that targeted MAPK inhibition may ultimately be useful in the modulation of viral hepatitis.

MAP-kinase dependent induction of monocytic procoagulant activity by beta2-integrins.

beta2-Integrin adhesion molecules play crucial roles in monocyte transmigration and adherence to the inflamed extracellular matrix. While integrin engagement contributes to inflammatory cell activation, little is known about the precise signaling pathways that are important to integrin-dependent monocyte activation. We examined the role of tyrosine phosphorylation and extracellular-signal regulated kinase (ERK) activity in beta2-integrin signaling in monocytes. Cross-linking of the LFA-1 (CD11a/CD18) and MAC-1 (CD11b/CD18) integrins on the surface of THP-1 monocytic cells induced the accumulation of tyrosine phosphoproteins. As part of this signal both ERK-1 and ERK-2 are tyrosine phosphorylated. In vitro kinase assays documented an increase in ERK-2 activity following both LFA-1 and MAC-1 cross-linking. beta2-Integrin cross-linking also led to a marked increase in 4-h procoagulant activity (PCA) in THP-1 cells and purified human monocytes. Inhibition of tyrosine phosphorylation by genistein (10 microg/ml), or selective ERK inhibition with PD98059 (10 microM), was able to block the integrin-dependent induction of PCA in both THP-1 cells and human monocytes. Thus, beta2 integrin signaling in monocytic cells can flow through the tyrosine phosphorylation and activation of the ERK mitogen activated protein kinases, which is essential for the subsequent expression of tissue factor. These results suggest that the ERK proteins likely function to integrate various adhesion-dependent signals during the process of monocyte transmigration.