John S. Moody

15-Lipoxygenase Metabolism of 2-Arachidonylglycerol GENERATION OF A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α AGONIST

The recent demonstrations that cyclooxygenase-2 and leukocyte-type 12-lipoxygenase (LOX) efficiently oxygenate 2-arachidonylglycerol (2-AG) prompted an investigation into related oxygenases capable of metabolizing this endogenous cannabinoid receptor ligand. We evaluated the ability of six LOXs to catalyze the hydroperoxidation of 2-AG. Soybean 15-LOX, rabbit reticulocyte 15-LOX, human 15-LOX-1, and human 15-LOX-2 oxygenate 2-AG, providing 15(S)-hydroperoxyeicosatetraenoic acid glyceryl ester. In contrast, potato and human 5-LOXs do not efficiently metabolize this endocannabinoid. Among a series of structurally related arachidonyl esters, arachidonylglycerols serve as the preferred substrates for 15-LOXs. Steady-state kinetic analysis demonstrates that both 15-LOX-1 and 15-LOX-2 oxygenate 2-AG comparably or preferably to arachidonic acid. Furthermore, 2-AG treatment of COS-7 cells transiently transfected with human 15-LOX expression vectors or normal human epidermal keratinocytes results in the production and extracellular release of 15-hydroxyeicosatetraenoic acid glyceryl ester (15-HETE-G), establishing that lipoxygenase metabolism of 2-AG occurs in an eukaryotic cellular environment. Investigations into the potential biological actions of 15-HETE-G indicate that this lipid, in contrast to its free-acid counterpart, acts as a peroxisome proliferator-activated receptor α agonist. The results demonstrate that 15-LOXs are capable of acting on 2-AG to provide 15-HETE-G and elucidate a potential role for endocannabinoid oxygenation in the generation of peroxisome proliferator-activated receptor α agonists.

Adult gliosarcoma: epidemiology, natural history, and factors associated with outcome

The epidemiology and natural history of adult gliosarcomas (GSMs), as well as patient and treatment factors associated with outcome, are ill defined. Patients over 20 years of age with GSM diagnosed from 1988 to 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis and Cox models were used to examine outcomes. Similar analyses were conducted for patients diagnosed with glioblastoma (GBM) over the same time period. GSM represented 2.2% of the 16,388 patients identified with either GSM or GBM. No significant differences between GSM and GBM were identified with respect to age, gender, race, tumor size, or use of adjuvant radiation therapy (RT). Patients with GSM were more likely to have temporal lobe involvement and undergo some form of tumor resection. The most important analyzed factors influencing GSM overall survival were age, extent of resection, and use of adjuvant RT. After adjusting for factors impacting overall survival, the prognosis for GSM appears slightly worse than for GBM (HR = 1.17, 95% CI, 1.05-1.31). GSM is a rare malignancy that presents very similarly to GBM with a slightly greater propensity for temporal lobe involvement. Optimal treatment remains to be defined. However, these retrospective findings suggest tumor excision, as opposed to biopsy only, and adjuvant RT may improve outcome. Despite therapy, prognosis remains dismal and outcomes may be inferior to those seen in GBM patients.

Primary cardiac sarcoma.

BACKGROUND The presentation, management, and outcome of patients with primary cardiac sarcomas are not well defined. Furthermore, the role of adjuvant therapy has not been delineated in the management of primary cardiac sarcomas. METHODS Patients with primary cardiac sarcoma and noncardiac sarcoma, diagnosed between 1988 and 2005, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Clinical characteristics and outcomes of primary cardiac sarcoma were defined and compared with the characteristics of noncardiac sarcomas. Univariate and multivariate methods were used to identify factors associated with primary cardiac sarcoma survival. RESULTS Compared with noncardiac sarcomas, primary cardiac sarcomas were found to occur in a younger age group and were more likely to present with advanced disease. Primary cardiac sarcomas were ten times more likely to be vessel-derived (eg, angiosarcoma), comprising almost half of all cases. Median overall survival for cardiac sarcoma patients was 6 months whereas that for noncardiac sarcoma patients was significantly longer at 93 months (p < 0.001). Furthermore, cardiac sarcoma patients who underwent surgery had a median survival of 12 months whereas those who did not undergo surgery had a median survival of 1 month (p < 0.001). CONCLUSIONS Cardiac sarcomas are a distinct, rare subset of soft tissue sarcomas with a poor prognosis. Surgery continues to be the central component of successful management. Future clinical efforts should be directed at developing approaches to permit safe radical excision and, potentially, developing effective adjuvant therapy.

Giant cell glioblastoma: A glioblastoma subtype with distinct epidemiology and superior prognosis

Giant cell glioblastoma (GC) is an uncommon subtype of glioblastoma multiforme (GBM). Consequently, the epidemiology, natural history, and factors associated with outcome are not well defined. Patients diagnosed with GC from 1988 through 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Outcomes were examined with Kaplan-Meier survival analysis and Cox models. For comparison, similar analyses were conducted for patients diagnosed with GBM. GC was identified in 1% of 16,430 patients diagnosed with either GC or GBM. Compared with GBM, GC showed similar gender and racial distributions. Likewise, tumor size and location were not significantly different between the two histologies. GC tended to occur in younger patients with a median age at diagnosis of 51 years, compared with 62 years for GBM. Additionally, patients with GC were more likely to undergo complete resection compared with patients with GBM. For both histologies, young age, tumor size, extent of resection, and the use of adjuvant radiation therapy (RT) were associated with improved survival. Cox modeling suggests the prognosis for GC is significantly superior to that for GBM (hazard ratio = 0.76; 95% confidence interval, 0.59-0.97) even after adjustment for factors affecting survival. GC is an uncommon GBM subtype that tends to occur in younger patients. Prospective data defining optimal treatment for GC are unavailable; however, these retrospective findings suggest that resection, as opposed to biopsy only, and adjuvant RT may improve survival. The prognosis of GC is superior to that of GBM, and long-term survival is possible, suggesting aggressive therapy is warranted.

Angiosarcoma outcomes and prognostic factors: a 25-year single institution experience.

Objective:Angiosarcoma is an aggressive malignancy with endothelial differentiation and notoriously poor prognosis despite aggressive therapy. Limited data are available to guide management decisions. To address this limitation, we present a large retrospective analysis of angiosarcoma patients treated at a single institution over a 25-year period. Methods:To identify factors that impact angiosarcoma outcomes, we reviewed demographic, tumor, and treatment characteristics of angiosarcoma patients evaluated at the University of Wisconsin Hospital between 1987 and 2012. Results:The cohort included 81 patients diagnosed at ages 19 to 90 years (median, 67 y). Fifty-five (68%) patients presented with localized disease, whereas 26 (32%) presented with metastases. The primary sites were visceral/deep soft tissue (42%), head and neck/cutaneous (37%), breast (16%), and limbs in the setting of Stewart-Treves (5%). The 5-year overall survival was 40% with a median of 16 months. By univariate analysis, significant adverse predictors of survival included metastases at presentation, visceral/deep soft tissue tumor location, tumor size>5 cm, tumor necrosis, and the absence of surgical excision. A trend toward prolonged survival was observed with radiation therapy and for chemotherapy in patients with metastases. Age, sex, and prior radiation showed no correlation with survival. Conclusions:Our large single institution series confirms the poor prognosis of angiosarcoma, supports a central role for surgical excision in management, and highlights the need for novel therapies particularly in patients who present with metastatic disease.

Refusal of radiation therapy and its associated impact on survival.

Objectives:Despite evidence that radiation therapy (RT) improves outcome in multiple malignancies, some patients with strong clinical indications still refuse RT. Data on factors associated with RT refusal are limited. Furthermore, the effect of RT refusal on outcome has not been clearly defined. Methods:Patients with nonmetastatic cancer, diagnosed between 1988 and 2005, were identified in the Surveillance, Epidemiology, and End Results database. Univariate and multivariate methods were used to identify factors associated with RT refusal and the impact of refusal on outcomes. Results:On univariate analysis, age, sex, marital status, tumor site, and tumor stage were associated with RT refusal (P < 0.001). On multivariate analysis, sex and tumor stage were not found to be associated with RT refusal. In contrast, age, race, marital status, and tumor location were significantly associated with RT refusal. The median survival of compliant patients was 171 months compared with just 96 months among patients who refused RT. Conclusions:A significant percentage of patients continue to refuse RT despite medical advice and evidence. Subgroups at particular risk of RT refusal include elderly, black and widowed patients. RT refusal is associated with markedly worse clinical outcomes.

Bladder preservation for localized muscle-invasive bladder cancer: the survival impact of local utilization rates of definitive radiotherapy.

PURPOSE This study examines the management and outcomes of muscle-invasive bladder cancer in the United States. METHODS AND MATERIALS Patients with muscle-invasive bladder cancer diagnosed between 1988 and 2006 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified according to three mutually exclusive treatment categories based on the primary initial treatment: no local management, radiotherapy, or surgery. Overall survival was assessed with Kaplan-Meier analysis and Cox models based on multiple factors including treatment utilization patterns. RESULTS The study population consisted of 26,851 patients. Age, sex, race, tumor grade, histology, and geographic location were associated with differences in treatment (all p < 0.01). Patients receiving definitive radiotherapy tended to be older and have less differentiated tumors than patients undergoing surgery (RT, median age 78 years old and 90.6% grade 3/4 tumors; surgery, median age 71 years old and 77.1% grade 3/4 tumors). No large shifts in treatment were seen over time, with most patients managed with surgical resection (86.3% for overall study population). Significant survival differences were observed according to initial treatment: median survival, 14 months with no definitive local treatment; 17 months with radiotherapy; and 43 months for surgery. On multivariate analysis, differences in local utilization rates of definitive radiotherapy did not demonstrate a significant effect on overall survival (hazard ratio, 1.002; 95% confidence interval, 0.999-1.005). CONCLUSIONS Multiple factors influence the initial treatment strategy for muscle-invasive bladder cancer, but definitive radiotherapy continues to be used infrequently. Although patients who undergo surgery fare better, a multivariable model that accounted for patient and tumor characteristics found no survival detriment to the utilization of definitive radiotherapy. These results support continued research into bladder preservation strategies and suggest that definitive radiotherapy represents a viable initial treatment strategy for those who wish to attempt to preserve their native bladder.

External Beam Radiotherapy for Colon Cancer: Patterns of Care

PURPOSE Despite its common and well characterized use in other gastrointestinal malignancies, little is known about radiotherapy (RT) use in nonmetastatic colon cancer in the United States. To address the paucity of data regarding RT use in colon cancer management, we examined the RT patterns of care in this patient population. METHODS AND MATERIALS Patients with nonmetastatic colon cancer, diagnosed between 1988 and 2005, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate methods were used to identify factors associated with RT use. RESULTS On univariate analysis, tumor location, age, sex, race, T stage, N stage, and geographic location were each associated with differences in RT use (all p < 0.01). In general, younger patients, male patients, and patients with more advanced disease were more likely to receive RT. On multivariate analysis, tumor location, age, gender, T and N stage, time of diagnosis and geographic location were significantly associated with RT use (all p < 0.001). Race, however, was not associated with RT use. On multivariate analysis, patients diagnosed in 1988 were 2.5 times more likely to receive RT than those diagnosed in 2005 (p = 0.001). Temporal changes in RT use reflect a responsiveness to evolving evidence related to the therapeutic benefits of adjuvant RT. CONCLUSIONS External beam RT is infrequently used for colon cancer, and its use varies according to patient and tumor characteristics. RT use has declined markedly since the late 1980s; however, it continues to be used for nonmetastatic disease in a highly individualized manner.

Gastric leiomyosarcomas: A SEER analysis.

106 Background: Gastric sarcoma is an uncommon malignancy that represents approximately 1% of gastric malignancies. The presentation and outcomes of these patients remains poorly defined, and a dearth of information is available regarding the management of such patients. METHODS Patients with primary gastric leiomyosarcoma, diagnosed between 1988 and 2008, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Clinical characteristics and outcomes of these patients were defined and compared with the characteristics of gastric adenocarcinoma patients. RESULTS A total of 49,258 patients were identified for analysis, 574 with leiomyosarcoma. Gastric leiomyosarcomas were more likely to occur in younger patients, female patients, and were less likely to present with advanced disease. These tumors were more likely to occur in the gastric fundus or along the greater curvature of the stomach. The incidence of gastric leiomyosarcoma has dramatically decreased over the last decade, consistent with the likelihood that many of these tumors are now considered to represent GIST tumors with current pathologic techniques. Median overall survival for gastric leiomyosarcoma patients was 36 months whereas that for gastric adenocarcinomas was significantly shorter at 10 months (P < 0.001 on Kaplan-Meier analysis). For non-metastatic patients, the median survival of leiomyosarcoma patients was 72 months versus 22 months for gastric adenocarcinoma patients. Cox proportional hazards modeling similarly demonstrated a decreased mortality risk associated with leiomyosarcoma (HR 0.52, 95% CI 0.47-0.57). A multivariable Cox analysis that examined tumor, patient and treatment characteristics demonstrated that leiomyosarcoma was independently associated with improved survival (HR 0.64, 95% CI 0.54-0.76). A Cox analysis for leiomyosarcoma patients alone showed that surgery was associated with improved survival (HR 0.14, 95% CI 0.06 - 0.34). CONCLUSIONS Gastric leiomyosarcomas have been a distinct subset of gastric tumors with a superior prognosis than adenocarcinomas. Surgery has historically been a key component of successful management and is associated with improved survival.