Arden M. Morris

Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity

The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed on activated CD4+ T lymphocytes. Engagement of the OX-40R, with either OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R+ T cells isolated from inflammatory lesions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R+ T cells within primary tumors and tumor-invaded lymph nodes of patients with cancer and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming resulted in a significant improvement in the percentage of tumor-free survivors (20–55%) in four different murine tumors derived from four separate tissues. This anti-OX-40R effect was dose dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host’s tumor-specific CD4+ T cells. The identification of OX-40R+ T cells clustered around human tumor cells in vivo suggests that engagement of the OX-40R may be a practical approach for expanding tumor-reactive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.

Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis

Background: Increased infertility in women has been reported after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis but reported infertility rates vary substantially. Aims: (1) To perform a systematic review and meta-analysis of the relative risk of infertility post-IPAA compared with medical management; (2) to estimate the rate of infertility post-IPAA; and (3) to identify modifiable risk factors which contribute to infertility. Methods: Medline, EMBASE, Current Contents, meeting abstracts, and bibliographies were searched independently by two investigators. The titles and abstracts of 189 potentially relevant studies were reviewed; eight met the criteria and all data were extracted independently. Consensus was achieved on each data point, and fixed effects meta-analyses, a funnel plot, and sensitivity analyses were performed. Results: The initial meta-analysis of eight studies had significant heterogeneity (p = 0.004) due to one study with very high preoperative infertility (38%). When this study was omitted, the relative risk of infertility after IPAA was 3.17 (2.41–4.18), with non-significant heterogeneity. The weighted average infertility rate in medically treated ulcerative colitis was 15% for all seven studies, and the weighted average infertility rate was 48% after IPAA (50% if all eight studies are included). We were unable to identify any procedural factors that consistently affected the risk of infertility. Conclusions: IPAA increases the risk of infertility in women with ulcerative colitis by approximately threefold. Infertility, defined as achieving pregnancy in 12 months of attempting conception, increased from 15% to 48% in women post-IPAA for ulcerative colitis. This provides a basis for counselling patients considering colectomy with IPAA. Further studies of modifiable risk factors are needed.

Race and Surgical Mortality in the United States

Objective:This study describes racial differences in postoperative mortality following 8 cardiovascular and cancer procedures and assesses possible explanations for these differences. Summary Background Data:Although racial disparities in the use of surgical procedures are well established, relationships between race and operative mortality have not been assessed systematically. Methods:We used national Medicare data to identify all patients undergoing one of 8 cardiovascular and cancer procedures between 1994 and 1999. We used multiple logistic regression to assess differences in operative mortality (death within 30 days or before discharge) between black patients and white patients, controlling for patient characteristics. Adding hospital indicators to these models, we then assessed the extent to which racial differences in operative mortality could be accounted for by the hospital in which patients were cared for. Results:Black patients had higher crude mortality rates than white patients for 7 of the 8 operations, including coronary artery bypass, aortic valve replacement, abdominal aortic aneurysm repair, carotid endarterectomy, radical cystectomy, pancreatic resection, and esophagectomy. Among these 7 procedures, odds ratios of mortality (black versus white) ranged from 1.23 (95% confidence interval, 1.18–1.29) for CABG to 1.61 (95% confidence interval, 1.28–2.03) for esophagectomy. Adjusting for patient characteristics had modest or no effect on odds ratios of mortality by race. However, there remained few clinically or statistically significant differences in mortality by race after we accounted for hospital. Hospitals that treated a large proportion of black patients had higher mortality rates for all 8 procedures, for white as well as black patients. Conclusions:Black patients have higher operative mortality risks across a wide range of surgical procedures, in large part because of higher mortality rates at the hospitals they attend.

Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers.

BACKGROUND The OX-40 antigen is a cell surface glycoprotein in the tumor necrosis factor receptor family that is expressed primarily on activated CD4+ T cells. Selective target organ expression of the OX-40 receptor on autoantigen specific T cells has been found in autoimmune disease. In order to evaluate whether OX-40 is expressed on T cells from patients with nodal-draining carcinomas, OX-40 expression was assessed in tumor infiltrating lymphocytes (TILs), draining lymph node cells (DLNCs), and/or peripheral blood lymphocytes (PBLs) of 13 patients with head and neck squamous cell carcinomas and 9 patients with melanomas. METHODS Cell phenotype was determined by fluorescence cell analysis using a monoclonal antibody to human OX-40, and CD4+ T cell lymphokine production was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS Expression of the OX-40 receptor was found in as many as 31% of the TILs and as many as 28% of the DLNCs tested. Conversely, no OX-40 expression was found in PBLs. In addition, CD4+ T cells isolated from DLNCs (but not from TILs or PBLs) secreted a Th1 pattern of cytokines (IL-2, gamma interferon). Co-culture of autologous CD4+ TILs with an MHC class II+ melanoma cell line transfected with OX-40 ligand cDNA resulted in T cell proliferation and in vitro tumor regression. CONCLUSIONS These findings suggest that OX-40+ CD4+ T cells isolated from tumors and their adjacent draining nodes may represent a tumor-specific population of activated T cells capable of mediating tumor reactivity. These cells may play an exploitable role in future trials of immunotherapy.

Socioeconomic Status and Surgical Mortality in the Elderly

Background:Although racial disparities in the quality of surgical care are well described, the impact of socioeconomic status on operative mortality is relatively unexplored. Methods:We used Medicare data to identify all patients undergoing 1 of 6 common, high risk surgical procedures between 1999 and 2003. We constructed a summary measure of socioeconomic status for each US ZIP code using data from the 2000 US Census linked to the patients ZIP code of residence. We assessed the effects of socioeconomic status on operative mortality rates while controlling for other patient characteristics and then examined the extent to which disparities in operative mortality could be attributed to differences in hospital factors. Results:Socioeconomic status was a significant predictor of operative mortality for all 6 procedures in crude analyses and in those adjusted for patient characteristics. Comparing the lowest quintile of socioeconomic status to the highest, the adjusted odds ratios (OR) and 95% confidence intervals (CI) ranged from OR = 1.17; 95% CI: 1.10–1.25 for colectomy to OR = 1.39; 95% CI: 1.18–1.65 for gastrectomy. After further adjustment for hospital factors, the odds ratio associated with socioeconomic status for coronary artery bypass (OR = 1.14; 95% CI: 1.09–1.19), aortic valve replacement (OR = 1.13; 95% CI: 1.04–1.23), and mitral valve replacement (OR = 1.11; 95% CI: 1.00–1.23) were diminished, and those for lung resection (OR = 0.93; 95% CI: 0.81–1.07), colectomy (OR = 1.04; 95% CI: 0.98–1.12), and gastrectomy (OR = 1.11; 95% CI: 0.90–1.38) were reduced and also were no longer statistically significant. Within hospitals, there were only small differences in adjusted operative mortality by patient socioeconomic status. Conclusions:Patients with lower socioeconomic status have higher rates of adjusted operative mortality than patients with higher socioeconomic status across a wide range of surgical procedures. These disparities in surgical outcomes are largely attributable to differences between the hospitals where patients of higher and lower socioeconomic status tend to receive surgical treatment.

Reoperation as a Quality Indicator in Colorectal Surgery: A Population-Based Analysis

Objective:To describe unplanned procedures following colorectal cancer surgery that might be used as intermediate outcome measures, and to determine their association with mortality and length of stay. Summary Background:Variation in the quality of surgical care, especially for common illnesses like colorectal cancer, has received increasing attention. Nonfatal complications resulting in procedural interventions are likely to play a role in poor outcomes but have not been well explored. Methods:Cohort analysis of 26,638 stage I to III colorectal cancer patients in the 1992 to 1996 SEER-Medicare database. Independent variables: sociodemographics, tumor characteristics, comorbidity, and acuity. Primary outcome: postoperative procedural intervention. Analysis: Logistic regression identified patient characteristics predicting postoperative procedures and the adjusted risk of 30-day mortality and prolonged hospitalization among patients with postoperative procedures. Results:A total of 5.8% of patients required postoperative intervention. Patient characteristics had little impact on the frequency of postoperative procedures, except for acute medical conditions, including bowel perforation (relative risk [RR] = 3.0, 95% confidence interval [CI] = 2.5–3.6), obstruction (RR = 1.6; 95% CI = 1.4–1.8), and emergent admission (RR = 1.3; 95% CI = 1.1–1.4). After a postoperative procedure, patients were more likely to experience early mortality (RR = 2.4; 95% CI = 2.1–2.9) and prolonged hospitalization (RR = 2.2; 95% CI = 2.1–2.4). The most common interventions were performed for abdominal infection (31.7%; RR mortality = 2.9; 95% CI = 2.3–3.7), wound complications (21.1%; RR mortality = 0.7; 95% CI = 0.4–1.3), and organ injury (18.7%; RR mortality = 1.6; 95% CI = 1.1–2.3). Conclusions:Postoperative complications requiring additional procedures among colorectal cancer patients correlate with established measures of surgical quality. Prospective tracking of postoperative procedures as complication markers may facilitate outcome studies and quality improvement programs.

Understanding racial disparities in cancer treatment and outcomes.

o p p f r 2 w i t t t recent report from the Institute of Medicine documents idespread racial disparities in medical treatment and ealth outcomes. Such disparities are particularly apparent mong patients with cancer. For many types of cancer, lack Americans have markedly higher cancer-specific ortality rates than members of other racial and ethnic roups—more than 2-fold higher in some instances. Exess cancer mortality in this group is partly attributable to igher cancer incidence rates. However, increased cancer ortality among black patients is also due in large part to orse prognoses among those already diagnosed. Reasons for higher mortality among minorities encomass both patient factors and provider and health care sysem effects. Patient factors include characteristics associted with decreased longevity, such as socioeconomic status SES), health behaviors, and comorbid conditions. At the rovider level, higher cancer mortality may reflect underse of screening, resulting in later stage at diagnosis, and nderuse of cancer-directed surgery and adjuvant therapy. inally, racial disparities may be associated with differences n the quality of care delivered by providers and by the elected settings where black patients cluster for care. Some f these settings have been associated with higher cancer ortality rates and may be less likely to provide high uality comprehensive, transitional, and follow-up care afer surgery.

Early discharge and hospital readmission after colectomy for cancer

BACKGROUND: Early discharge after colectomy has been shown to be feasible in studies from specialty centers, but we hypothesized that benefits of early discharge might be offset by higher risk of readmission in the surgical community as a whole. Minimizing readmissions is a national health policy priority. OBJECTIVE: This study aimed to determine whether hospitals discharging patients early had increased readmission rates. DESIGN: Patients undergoing colectomy surgery for cancer were studied using national Medicare data (MEDPAR database). Multiple logistic regression was performed to determine whether hospitals with a pattern of early discharge (median length of stay ≤5 d after surgery) had increased readmission rates. Results were adjusted for patient comorbidity, emergency operation, laparoscopic surgery, demographic factors, and complications. A separate analysis at the patient level was conducted to determine risk factors for readmission. SETTINGS: Early discharge rates at US acute care hospitals were investigated. PATIENTS: Patients 65 and older undergoing colectomy surgery for cancer (2003–2008, n = 477,461) were included. MAIN OUTCOME MEASURE: The main outcome measure was 30-day, all hospital readmission rates. RESULTS: Hospitals with a pattern of early discharge (median length of stay ≤5 d) were not found to have a higher risk-adjusted readmission rate than hospitals with the usual median length of stay (16.3% vs 15.7%, P = .077). However, changing the cutoff for “early discharge” to ≤4 days revealed an increased risk for readmission among “very early discharge” hospitals (risk-adjusted readmission rate 21.3% vs 15.7%, P < .001). At the patient level, independent risk factors for readmission included older age, male sex, black race, lower socioeconomic status, urgent/emergent surgery, comorbidities, complications, open (vs laparoscopic) surgery, and longer length of stay for the index hospitalization. LIMITATIONS: Limitations of this study included the limitations of the administrative data and elderly population. CONCLUSIONS: Hospitals with a pattern of early discharge (median length of stay ≤5 d after surgery) do not have a higher risk-adjusted readmission rate than other hospitals. These results support the safety of early discharge programs in the Medicare population.

Hospital Factors and Racial Disparities in Mortality After Surgery for Breast and Colon Cancer

PURPOSE Black patients have worse prognoses than whites with breast or colorectal cancer. Mechanisms underlying such disparities have not been fully explored. We examined the role of hospital factors in racial differences in late mortality after surgery for breast or colon cancer. METHODS Patients undergoing surgery after new diagnosis of breast or colon cancer were identified using the Surveillance Epidemiology and End Results-Medicare linked database (1995 to 2005). The main outcome measure was mortality at 5 years. Proportional hazards models were used to assess relationships between race and late mortality, accounting for patient factors, socioeconomic measures, and hospital factors. Fixed and random effects models were used to account for quality differences across hospitals. RESULTS Black patients, compared with white patients, had lower 5-year overall survival rates after surgery for breast (62.1% v 70.4%, respectively; P < .001) and colon cancer (41.3% v 45.4%, respectively; P < .001). After controlling for age, comorbidity, and stage, black race remained an independent predictor of mortality for breast (adjusted hazard ratio [HR] = 1.25; 95% CI, 1.16 to 1.34) and colon cancer (adjusted HR = 1.13; 95% CI, 1.07 to 1.19). After risk adjustment, hospital factors explained 36% and 54% of the excess mortality for black patients with breast cancer and colon cancer, respectively. Hospitals with large minority populations had higher late mortality rates independent of race. CONCLUSION Hospital factors, including quality, are important mediators of the association between race and mortality for breast and colon cancer. Hospital-level quality improvement should be a major component of efforts to reduce disparities in cancer outcomes.

Residual Treatment Disparities After Oncology Referral for Rectal Cancer

BACKGROUND Black patients with rectal cancer are considerably less likely than white patients to receive adjuvant therapy. We examined the hypothesis that the lower treatment rate for blacks is due to underreferral to medical and radiation oncologists. METHODS We used 1992-1999 Surveillance, Epidemiology, and End Results-Medicare data to identify elderly (> or = 66 years of age) patients who had been hospitalized for resection of stage II or III rectal cancer (n = 2716). We used chi(2) tests to examine associations between race and 1) consultation with an oncologist and 2) receipt of adjuvant therapy. We then used logistic regression to analyze the influence of sociodemographic and clinical characteristics (age at diagnosis, sex, marital status, median income and education in area of residence, comorbidity, and cancer stage) on black-white differences in the receipt of adjuvant therapy. All statistical tests were two-sided. RESULTS There was no statistically significant difference between the 134 black patients and the 2582 white patients in the frequency of consultation with a medical oncologist (73.1% for blacks vs 74.9% for whites, difference = 1.8%, 95% confidence interval [CI] = > 5.9% to 9.5%, P = .64) or radiation oncologist (56.7% vs 64.8%, difference = 8.1%, 95% CI = > 0.5% to 16.7%, P = .06), but blacks were less likely than whites to consult with both a medical oncologist and a radiation oncologist (49.2% vs 58.8%, difference = 9.6%, 95% CI = 0.9% to 18.2%, P = .03). Among patients who saw an oncologist, black patients were less likely than white patients to receive chemotherapy (54.1% vs 70.2%, difference = 16.1%, 95% CI = 6.0% to 26.2%, P = .006), radiation therapy (73.7% vs 83.4%, difference = 9.7%, 95% CI = 0.4% to 19.8%, P = .06), or both (60.6% vs 76.9%, difference = 16.3%, 95% CI = 4.3% to 28.3%, P = .008). Patient and provider characteristics had minimal influence on the racial disparity in the use of adjuvant therapy. CONCLUSION Racial differences in oncologist consultation rates do not explain disparities in the use of adjuvant treatment for rectal cancer. A better understanding of patient preferences, patient-provider interactions, and potential influences on provider decision making is necessary to develop strategies to increase the use of adjuvant treatment for rectal cancer among black patients.