Fergal J. Fleming

Association between Intraoperative Blood Transfusion and Mortality and Morbidity in Patients Undergoing Noncardiac Surgery

Background:The impact of intraoperative erythrocyte transfusion on outcomes of anemic patients undergoing noncardiac surgery has not been well characterized. The objective of this study was to examine the association between blood transfusion and mortality and morbidity in patients with severe anemia (hematocrit less than 30%) who are exposed to one or two units of erythrocytes intraoperatively. Methods:This was a retrospective analysis of the association of blood transfusion and 30-day mortality and 30-day morbidity in 10,100 patients undergoing general, vascular, or orthopedic surgery. We estimated separate multivariate logistic regression models for 30-day mortality and for 30-day complications. Results:Intraoperative blood transfusion was associated with an increased risk of death (odds ratio [OR], 1.29; 95% CI, 1.03–1.62). Patients receiving an intraoperative transfusion were more likely to have pulmonary, septic, wound, or thromboembolic complications, compared with patients not receiving an intraoperative transfusion. Compared with patients who were not transfused, patients receiving one or two units of erythrocytes were more likely to have pulmonary complications (OR, 1.76; 95% CI, 1.48–2.09), sepsis (OR, 1.43; 95% CI, 1.21–1.68), thromboembolic complications (OR, 1.77; 95% CI, 1.32–2.38), and wound complications (OR, 1.87; 95% CI, 1.47–2.37). Conclusions:Intraoperative blood transfusion is associated with a higher risk of mortality and morbidity in surgical patients with severe anemia. It is unknown whether this association is due to the adverse effects of blood transfusion or is, instead, the result of increased blood loss in the patients receiving blood.

Expression of SRC-1, AIB1, and PEA3 in HER2 mediated endocrine resistant breast cancer; a predictive role for SRC-1

Background: In human breast cancer, the growth factor receptor HER2 is associated with disease progression and resistance to endocrine treatment. Growth factor induced mitogen activated protein kinase activity can phosphorylate not only the oestrogen receptor, but also its coactivator proteins AIB1 and SRC-1. Aim: To determine whether insensitivity to endocrine treatment in HER2 positive patients is associated with enhanced expression of coactivator proteins, expression of the HER2 transcriptional regulator, PEA3, and coregulatory proteins, AIB1 and SRC-1, was assessed in a cohort of patients with breast cancer of known HER2 status. Methods: PEA3, AIB1, and SRC-1 protein expression in 70 primary breast tumours of known HER2 status (HER2 positive, n = 35) and six reduction mammoplasties was assessed using immunohistochemistry. Colocalisation of PEA3 with AIB1 and SRC-1 was determined using immunofluorescence. Expression of PEA3, AIB1, and SRC-1 was correlated with clinicopathological parameters. Results: In primary breast tumours expression of PEA3, AIB1, and SRC-1 was associated with HER2 status (p = 0.0486, p = 0.0444, and p = 0.0012, respectively). In the HER2 positive population, PEA3 expression was associated with SRC-1 (p = 0.0354), and both PEA3 and SRC-1 were significantly associated with recurrence on univariate analysis (p = 0.0345; p<0.0001). On multivariate analysis, SRC-1 was significantly associated with disease recurrence in HER2 positive patients (p = 0.0066). Conclusion: Patients with high expression of HER2 in combination with SRC-1 have a greater probability of recurrence on endocrine treatment compared with those who are HER2 positive but SRC-1 negative. SRC-1 may be an important predictive indicator and therapeutic target in breast cancer.

Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer.

The oestrogen receptor (ER) interacts with coactivator proteins to modulate genes central to breast tumour progression. Oestrogen receptor is encoded for by two genes, ER-α and ER-β. Although ER-α has been well characterized, the role of ER-β as a prognostic indicator remains unresolved. To determine isoform-specific expression of ER and coexpression with activator proteins, we examined the expression and localisation of ER-α, ER-β and the coactivator protein steroid receptor coactivator 1 (SRC-1) by immunohistochemistry and immunofluorescence in a cohort of human breast cancer patients (n=150). Relative levels of SRC-1 in primary breast cultures derived from patient tumours in the presence of β-oestradiol and tamoxifen was assessed using Western blotting (n=14). Oestrogen receptor-β protein expression was associated with disease-free survival (DFS) and inversely associated with the expression of HER2 (P=0.0008 and P<0.0001, respectively), whereas SRC-1 was negatively associated with DFS and positively correlated with HER2 (P<0.0001 and P<0.0001, respectively). Steroid receptor coactivator 1 protein expression was regulated in response to β-oestradiol or tamoxifen in 57% of the primary tumour cell cultures. Protein expression of ER-β and SRC-1 was inversely associated (P=0.0001). The association of ER-β protein expression with increased DFS and its inverse relationship with SRC-1 suggests a role for these proteins in predicting outcome in breast cancer.

Perioperative outcomes among patients with the modified metabolic syndrome who are undergoing noncardiac surgery.

Background:Previous studies have demonstrated that obesity is paradoxically associated with a lower risk of mortality after noncardiac surgery. This study will determine the impact of the modified metabolic syndrome (defined as the presence of obesity, hypertension, and diabetes) on perioperative outcomes. Methods:This study is based on data from 310,208 patients in the American College of Surgeons National Surgical Quality Improvement Program database. We estimated separate multivariate logistic regression models for 30-day mortality and for 30-day complications. Results:Patients with the modified metabolic syndrome who are super obese had a 2-fold increased risk of death (adjusted odds ratio [AOR] 1.99; 95% CI 1.41–2.80). As stratified by body mass index, patients with the modified metabolic syndrome had a 2- to 2.5-fold higher risk of cardiac adverse events (CAE) compared with normal-weight patients: obese (AOR 1.70; 95% CI 1.40–2.07), morbidly obese (AOR 2.01; 95% CI 1.48–2.73), and super obese (AOR 2.66; 95% CI 1.68–4.19). In addition, the risk of acute kidney injury (AKI) was 3- to 7-fold higher in these patients: obese (AOR 3.30; 95% CI 2.75–3.94), morbidly obese (AOR 5.01; 95% CI 3.87–6.49), and super obese (AOR 7.29; 95% CI 5.27–10.1). Conclusion:Patients with the modified metabolic syndrome undergoing noncardiac surgery are at substantially higher risk of complications compared with patients of normal weight.

Neoadjuvant Therapy in Rectal Cancer

BACKGROUND: The optimal type of neoadjuvant therapy regimen in rectal cancer is contentious. OBJECTIVE: This study aimed to review the impact of neoadjuvant therapy on oncological outcomes and complications (short and long term) in patients undergoing total mesorectal excision for rectal cancer. DATA SOURCES: An electronic search of MEDLINE, PubMed, EMBASE, and the Cochrane Database of Collected Reviews was performed through March 2010. STUDY SELECTION: Key-word combinations including rectal cancer, total mesorectal excision, radiotherapy, chemotherapy, endorectal ultrasound, and magnetic resonance imaging were used to identify randomized control trials where chemotherapy and/or radiotherapy were deployed before resectional surgery. INTERVENTION(S): Patients underwent total mesorectal excision for rectal cancer who did and did not receive preoperative chemotherapy and/or radiotherapy. MAIN OUTCOME MEASURES: The main outcome measures comprised the impact of the addition of neoadjuvant therapy to total mesorectal excision on the perioperative complication rate, the pathological complete response rate, the rate of local recurrence, and long-term treatment-related complications. RESULTS: A total of 12 randomized control trials involving 9410 patients were included. Both short-course radiotherapy and long-course chemoradiation can offer a relative risk reduction of 50% in local recurrence in appropriately selected patients with stage II and III rectal cancer. This oncological benefit comes at the cost of a relative risk increase of 50% in both acute treatment-related toxicity and long-term anorectal dysfunction. LIMITATIONS: Preoperative staging provides only an estimate of the “true” tumor stage that can only be determined by histological assessment of the tumor specimen which renders appropriate patient selection challenging. CONCLUSIONS: The current treatment trade-off of a relative risk reduction of local recurrence of 50% at the cost of a relative increase of 50% in treatment-related complications underpins the need for more accurate patient staging and more precise delivery of neoadjuvant therapy.

Factors affecting metastases to non-sentinel lymph nodes in breast cancer.

Aims: Because sentinel lymph node (SLN) biopsy for breast cancer has become well established, one of the challenges now is to determine which patients require a completion axillary dissection following a positive SLN biopsy. Methods: A prospective database of patients who underwent SLN biopsy for invasive breast cancer from July 1999 to November 2002 (n  =  180) was analysed. Fifty four patients (30%) had one or more positive SLN, and all underwent a completion axillary dissection. This subgroup was further analysed to delineate which factors predicted non-SLN metastasis. Results: Twenty six of the 54 patients with a positive SLN had additional metastases in non-SLNs. Significant variables that predicted non-SLN metastasis included extranodal extension (odds ratio (OR), 17.399; 95% confidence interval (CI), 1.69 to 178.96) and macrometastasis within the SLN (OR, 6.985; 95% CI, 1.291 to 37.785). Conclusions: In patients with invasive breast cancer and a positive SLN, extranodal extension or macrometastasis within the SLN were both independent predictors of non-SLN involvement.

Extended Intervals after Neoadjuvant Therapy in Locally Advanced Rectal Cancer: The Key to Improved Tumor Response and Potential Organ Preservation

BACKGROUND Many rectal cancer patients experience tumor downstaging and some are found to achieve a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT). Previous data suggest that there is an association between the time interval from nCRT completion to surgery and tumor response rates, including pCR. However, these studies have been primarily from single institutions with small sample sizes. The aim of this study was to examine the relationship between a longer interval after nCRT and pCR in a nationally representative cohort of rectal cancer patients. STUDY DESIGN Clinical stage II to III rectal cancer patients undergoing nCRT with a documented surgical resection were selected from the 2006 to 2011 National Cancer Data Base. Multivariable logistic regression analysis was used to assess the association between the nCRT-surgery interval time (<6 weeks, 6 to 8 weeks, >8 weeks) and the odds of pCR. The relationship between nCRT-surgery interval, surgical morbidity, and tumor downstaging was also examined. RESULTS Overall, 17,255 patients met the inclusion criteria. An nCRT-surgery interval time >8 weeks was associated with higher odds of pCR (odds ratio [OR] 1.12, 95% CI 1.01 to 1.25) and tumor downstaging (OR 1.11, 95% CI 1.02 to 1.25). The longer time delay was also associated with lower odds of 30-day readmission (OR 0.82, 95% CI 0.70 to 0.92). CONCLUSIONS An nCRT-surgery interval time >8 weeks results in increased odds of pCR, with no evidence of associated increased surgical complications compared with an interval of 6 to 8 weeks. These data support implementation of a lengthened interval after nCRT to optimize the chances of pCR and perhaps add to the possibility of ultimate organ preservation (nonoperative management).

How much do we need to worry about venous thromboembolism after hospital discharge? A study of colorectal surgery patients using the National Surgical Quality Improvement Program database.

PURPOSE: It is well recognized that the increased risk of a postoperative venous thrombotic event extends beyond the inpatient treatment period. The purpose of this study was to determine the 30-day incidence and risk factors associated with the occurrence of early postdischarge symptomatic venous thromboembolic events in patients who have undergone major colorectal surgery. METHODS: The National Surgical Quality Improvement Program database was queried for patients who had undergone a colon or rectal resection during the study period (2005–2008). Patient demographics, preoperative risk factors, and operative variables were recorded. The primary outcomes were occurrence of deep venous thrombosis requiring therapy or pulmonary embolism within 30 days after initial surgery. The occurrence of postdischarge venous thromboembolic events was calculated from the days to primary outcome and days from operation to discharge. Univariate and multivariate linear regression models incorporating pre- and intraoperative variables as well as the occurrence of a major or minor complication were used to evaluate the effect of these clinical factors on the early postdischarge venous thromboembolic event rate. RESULTS: A total of 52,555 patients were included in the initial analysis. A total of 240 deep venous thromboses were diagnosed in the postdischarge setting giving a postdischarge incidence of 0.47%. One hundred thirty cases of a pulmonary embolus were diagnosed (0.26% incidence) with 30 patients having a concurrent deep venous thrombosis and pulmonary embolus. The overall cumulative postdischarge symptomatic venous thromboembolic incidence was 0.67% (n = 340). Obesity, preoperative steroid use, “bleeding disorder,” ASA class III, and postoperative (major and minor) complications were all independently associated with an increased risk of an early postdischarge venous thromboembolic event. CONCLUSION: This study has identified risk factors that may help stratify patients into different risk profiles and offer prolonged prophylaxis to patients at increased risk on the basis of preoperative risk factors and postoperative complications.

A laparoscopic approach does reduce short-term complications in patients undergoing ileal pouch-anal anastomosis.

BACKGROUND: Studies to date examining the impact of laparoscopy in the IPAA have failed to demonstrate a significant, consistent benefit in terms of a reduction in short-term morbidity or length of stay. OBJECTIVE: The aim of this study was to establish the impact of the operative approach (laparoscopic or open) on outcomes after IPAA formation. DESIGN, SETTING, AND PATIENTS: With use of the American College of Surgeons National Surgical Quality Improvement Program participant use file (2005–2008), the records of patients who underwent open or laparoscopic IPAA with diverting ileostomy were examined. MAIN OUTCOME MEASURES: Risk-adjusted 30-day outcomes and length of stay were assessed by use of regression modeling, adjusting for patient characteristics, comorbidities, and operative approach. RESULTS: Six hundred seventy-six cases were included, of which 339 (50.1%) were laparoscopic procedures. After adjustment, a laparoscopic approach was associated with a lower rate of major (OR = 0.67, 95% CI: 0.45–0.99, P = .04) and minor (OR = 0.44, 95% CI: 0.27–0.70, P = .01) complications. Laparoscopy was not associated with a significant reduction in length of postoperative stay compared with open pouch formation (laparoscopic vs open approach, −0.05 ± 0.30 d (P = .87)). LIMITATIONS: The sampling strategy used by the National Surgical Quality Improvement Program means that only a proportion of all relevant cases would have been analyzed and no data are available about the potential impact of surgeon experience on outcome. CONCLUSIONS: A laparoscopic approach to ileal pouch formation was associated with a significant reduction in both major and minor complications compared with the traditional open approach. Given the high financial costs associated with complications arising from this procedure, this study provides support for the adoption of the laparoscopic approach in the formation of an IPAA.

Tobacco Smoking and Postoperative Outcomes After Colorectal Surgery.

Objective: The aim of this study was to delineate the impact of smoking on postoperative outcomes after colorectal resection for malignant and benign processes. Background: Studies to date have implicated smoking as a risk factor for increased postoperative complications. However, there is a paucity of data on the effects of smoking after colorectal surgery and in particular for malignant compared with benign processes. Methods: The American College of Surgeons National Surgical Quality Improvement Program (2005–2010) database was queried for patients undergoing elective major colorectal resection for colorectal cancer, diverticular disease, or inflammatory bowel disease. Risk-adjusted 30-day outcomes were assessed and compared between patient cohorts identified as never-smokers, ex-smokers, and current smokers. Primary outcomes of incisional infections, infectious and major complications, and mortality were evaluated using regression modeling adjusting for patient characteristics and comorbidities. Results: A total of 47,574 patients were identified, of which 26,333 had surgery for colorectal cancer, 14,019 for diverticular disease, and 7222 for inflammatory bowel disease. More than 60% of patients had never smoked, 20.4% were current smokers, and 19.2% were ex-smokers. After adjustment, current smokers were at a significantly increased risk of postoperative morbidity [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.21–1.40] and mortality (OR, 1.5; 95% CI, 1.11–1.94) after colorectal surgery. This finding persisted across malignant and benign diagnoses and also demonstrated a significant dose-dependent effect when stratifying by pack-years of smoking. Conclusions: Smoking increases the risk of complications after all types of major colorectal surgery, with the greatest risk apparent for current smokers. A concerted effort should be made toward promoting smoking cessation in all patients scheduled for elective colorectal surgery.