Emily Finlayson

Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments

Th17 cells play an active role in autoimmune diseases. However, the nature of Th17 cells is poorly understood in cancer patients. We studied Th17 cells, the associated mechanisms, and clinical significance in 201 ovarian cancer patients. Tumor-infiltrating Th17 cells exhibit a polyfunctional effector T-cell phenotype, are positively associated with effector cells, and are negatively associated with tumor-infiltrating regulatory T cells. Tumor-associated macrophages promote Th17 cells through interleukin-1beta (IL-1beta), whereas tumor-infiltrating regulatory T cells inhibit Th17 cells through an adenosinergic pathway. Furthermore, through synergistic action between IL-17 and interferon-gamma, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome. Altogether, Th17 cells may contribute to protective human tumor immunity through inducing Th1-type chemokines and recruiting effector cells to the tumor microenvironment. Inhibition of Th17 cells represents a novel immune evasion mechanism. This study thus provides scientific and clinical rationale for developing novel immune-boosting strategies based on promoting the Th17 cell population in cancer patients.

Hospital volume, length of stay, and readmission rates in high-risk surgery.

Objective Aimed at reducing surgical deaths, several recent initiatives have attempted to establish volume-based referral strategies in high-risk surgery. Although payers are leading the most visible of these efforts, it is unknown whether volume standards will also reduce resource use. Methods We studied postoperative length of stay and 30-day readmission rate after 14 cardiovascular and cancer procedures using the 1994-1999 national Medicare database (total n = 2.5 million). We used regression techniques to examine the relationship between length of stay, 30-day readmission, and hospital volume, adjusting for age, gender, race, comorbidity score, admission acuity, and mean social security income. Results Mean postoperative length of stay ranged from 3.4 days (carotid endarterectomy) to 19.6 days (esophagectomy). There was no consistent relationship between volume and mean length of stay; it significantly increased across volume strata for 7 of the 14 procedures and significantly decreased across volume strata for the other 7. Mean length of stay at very-low-volume and very-high-volume hospitals differed by more than 1 day for 6 procedures. Of these, the mean length of stay was shorter in high-volume hospitals for 3 procedures (pancreatic resection, esophagectomy, cystectomy), but longer for other procedures (aortic and mitral valve replacement, gastrectomy). The 30-day readmission rate also varied widely by procedure, ranging from 9.9% (nephrectomy) to 22.2% (mitral valve replacement). However, volume was not related to 30-day readmission rate with any procedure. Conclusion Although hospital volume may be an important predictor of operative mortality, it is not associated with resource use as reflected by length of stay or readmission rates.

FOXP3 Defines Regulatory T Cells in Human Tumor and Autoimmune Disease

Activated T cells may express FOXP3. It is thought that FOXP3 is not a specific marker to determine regulatory T cells (Treg) in humans. Here, we examined the functional phenotype and cytokine profile of the in vitro induced FOXP3(+) T cells, primary FOXP3(+) and FOXP3(-) T cells in patients with ulcerative colitis and tumors including colon carcinoma, melanoma, hepatic carcinoma, ovarian carcinoma, pancreatic cancer, and renal cell carcinoma. We observed similar levels of suppressive capacity of primary FOXP3(+) T cells in blood, tumors, and colitic tissues. Compared with primary FOXP3(-) T cells in the same microenvironment, these primary FOXP3(+) T cells expressed minimal levels of effector cytokines, negligible amount of cytotoxic molecule granzyme B, and levels of suppressive molecules interleukin-10 and PD-1. Although the in vitro activated T cells expressed FOXP3, these induced FOXP3(+) T cells expressed high levels of multiple effector cytokines and were not functionally suppressive. The data reinforce the fact that FOXP3 remains an accurate marker to define primary Tregs in patients with cancer and autoimmune disease. We suggest that the combination of FOXP3 and cytokine profile is useful for further functionally distinguishing primary Tregs from activated conventional T cells.

Preoperative Assessment of the Older Patient: A Narrative Review

IMPORTANCE Surgery in older patients often poses risks of death, complications, and functional decline. Prior to surgery, evaluations of health-related priorities, realistic assessments of surgical risks, and individualized optimization strategies are essential. OBJECTIVE To review surgical decision making for older adult patients by 2 measures: defining treatment goals for elderly patients and reviewing the evidence relating risk factors to adverse outcomes. Assessment and optimization strategies for older surgical patients are proposed. EVIDENCE ACQUISITION A review of studies relating geriatric conditions such as functional and cognitive impairment, malnutrition, facility residence, and frailty to postoperative mortality and complications (including delirium, discharge to an institution, and functional decline). Medline, EMBASE, and Web of Science databases were searched for articles published between January 1, 2000, and December 31, 2013, that included patients older than 60 years. RESULTS This review identified 54 studies of older patients; 28 that examined preoperative clinical features associated with mortality (n = 1,422,433 patients) and 26 that examined factors associated with surgical complications (n = 136,083 patients). There was substantial heterogeneity in study methods, measures, and outcomes. The absolute risk and risk ratios relating preoperative clinical conditions to mortality varied widely: 10% to 40% for cognitive impairment (adjusted hazard ratio [HR], 1.26 [95% CI, 1.06-1.49] to 5.77 [95% CI, 1.55-21.55]), 10% to 17% for malnutrition (adjusted odds ratio [OR], 0.88 [95% CI, 0.78-1.01] to 59.2 [95% CI, 3.6-982.9]), and 11% to 41% for institutionalization (adjusted OR, 1.5 [95% CI, 1.02-2.21] to 3.27 [95% CI, 2.81-3.81]).) Risk ratios for functional dependence relating to mortality ranged from an adjusted HR of 1.02 (95% CI, 0.99-1.04) to an adjusted OR of 18.7 (95% CI, 1.6-215.3) and for frailty relating to mortality, ranged from an adjusted HR of 1.10 (95% CI, 1.04-1.16) to an adjusted OR of 11.7 (95% CI not reported) (P < .001). Preoperative cognitive impairment (adjusted OR, 2.2; 95% CI, 1.4-2.7) was associated with postoperative delirium (adjusted OR, 17.0; 95% CI, 1.2-239.8; P < .05). Frailty was associated with a 3- to 13-fold increased risk of discharge to a facility (adjusted OR, 3.16 [95% CI, 1.0-9.99] to 13.02 [95% CI, 5.14-32.98]). CONCLUSIONS AND RELEVANCE Geriatric conditions may be associated with adverse surgical outcomes. A comprehensive evaluation of treatment goals and communication of realistic risk estimates are essential to guide individualized decision making.

Effects of hospital volume on life expectancy after selected cancer operations in older adults: a decision analysis.

BACKGROUND In addition to lower operative mortality, patients undergoing selected cancer operations at high volume centers have improved longterm survival. We sought to determine the overall effect of hospital volume on life expectancy after cancer surgery. STUDY DESIGN We used a Markov decision analysis model to estimate life expectancy for patients undergoing resection for pancreatic, lung, or colon cancer. Model inputs included probabilities of operative mortality and longterm survival. For input data, we examined operative mortality (in-hospital or within 30 days) stratified by volume in over 400,000 patients undergoing resection for these three cancers using the national Medicare database (1994-1999). Risks of late mortality were abstracted from published studies (MEDLINE, 1966 to present) to model the effect of hospital volume on longterm survival. In analysis, we first calculated life expectancy for patients undergoing surgery at very low, low, medium, high, and very high volume hospitals. We then explored the effects of various regionalization strategies. RESULTS Life expectancy increased steadily with hospital volume for all three cancers. Life expectancy after pancreatic cancer resection increased linearly with hospital volume: from 1.9 years at very low volume centers to 3.6 years at very high volume centers. For lung cancer, life expectancy ranged from 5.4 to 6.6 years. Increases in life expectancy for colon cancer were not as dramatic: from 6.8 at very low volume hospitals to 7.4 years at very high volume hospitals. Differences in life expectancy across volume strata were largely attributable to differences in longterm survival, not operative mortality. From a policy perspective, regionalizing surgery for colon cancer would produce the greatest overall life-expectancy gains, but it would require moving most patients. CONCLUSIONS Patients aged 65 and older with pancreatic, lung, and colon cancer have substantially greater life expectancy after cancer resection at higher volume hospitals. Further work is needed to understand the mechanisms underlying differences in performance across hospitals in cancer care.

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.

Functional Status After Colon Cancer Surgery in Elderly Nursing Home Residents

To determine functional status and mortality rates after colon cancer surgery in older nursing home residents.

Impact of frailty on complications in patients undergoing common urological procedures: a study from the American College of Surgeons National Surgical Quality Improvement database

To evaluate the association of frailty, a measure of diminished physiological reserve, with both major and minor surgical complications among patients undergoing urological surgery.

Advancing Age and 30‐Day Adverse Outcomes After Nonemergent General Surgeries

To determine whether 30‐day postoperative mortality, complications, failure‐to‐rescue (FTR) rates, and postoperative length of stay increase with advancing age.

Major abdominal surgery in nursing home residents: a national study.

Objective:To determine surgical risk in nursing home residents undergoing major abdominal surgery. Background:Recent studies suggest that surgery can be performed safely in the very old. Surgical risk in nursing home residents is poorly understood. Methods:We used national Medicare claims and the nursing home Minimum Data Set (1999–2006) to identify nursing home residents undergoing surgery (surgery for bleeding duodenal ulcer, cholecystectomy, appendectomy, and colectomy, n = 70,719). We compared operative mortality and use of invasive interventions (mechanical ventilation, intravascular hemodynamic monitoring, feeding tube placement, tracheostomy, and vena cava filters) among nursing home residents to rates among noninstitutionalized Medicare enrollees age 65 and older undergoing the same procedures. (n = 1,060,389). We adjusted for patient characteristics using logistic regression. Results:Operative mortality among nursing home residents was substantially higher than among noninstitutionalized Medicare enrollees for all procedures (surgery for bleeding duodenal ulcer, 42% versus 26%, adjusted odds ratio (AOR) 1.79; colectomy, 32% versus 13%, AOR 2.06; appendectomy, 12% versus 2%, AOR 3.27; cholecystectomy, 11% versus 3%, AOR 2.65; P < 0.001 for all comparisons). Overall, invasive interventions were more common among nursing home residents than controls (ranging from 18% and 5%, respectively, for cholecystectomy to 55% and 43%, respectively, for surgery for bleeding duodenal ulcer, P < 0.0001 for all comparisons). Conclusions:Nursing home residents experience substantially higher rates of mortality and invasive interventions after major surgery than other Medicare beneficiaries that are independent of age and measured comorbidities. Our data suggest that the risks of major surgery are substantially higher in nursing home residents and this information should inform decisions of physicians and patients and their families.