Jonathan Frandsen

Central Leptin Signaling Is Required to Normalize Myocardial Fatty Acid Oxidation Rates in Caloric-Restricted ob/ob Mice

OBJECTIVE ob/ob and db/db mice manifest myocardial hypertrophy, insulin resistance, altered substrate utilization, mitochondrial dysfunction, and lipid accumulation. This study was designed to determine the contribution of central and peripheral leptin signaling to myocardial metabolism and function in ob/ob and db/db mice in the absence of diabetes and morbid obesity. RESEARCH DESIGN AND METHODS Male ob/ob mice (aged 4 weeks) were caloric restricted by pairfeeding to a leptin-treated ob/ob group. In addition to determining glucose tolerance and circulating lipid concentrations, myocardial substrate metabolism and mitochondrial function were determined in saponin-permeabilized cardiac fibers. Second, experiments were performed to determine whether leptin treatment by intraperitoneal injection or intracerebroventricular infusion could normalize myocardial palmitate oxidation in caloric-restricted ob/ob mouse hearts. RESULTS Despite normalizing body weight and glucose tolerance, fat mass and circulating lipid levels remained increased in caloric-restricted ob/ob animals. Palmitate oxidation remained elevated in caloric-restricted ob/ob hearts and was normalized by intraperitoneal or intracerebroventricular leptin. Intraperitoneal and intracerebroventricular treatment also normalized circulating free fatty acid levels, myocardial fatty acid oxidation gene expression, and myocardial insulin sensitivity. CONCLUSIONS These data suggest that impaired hypothalamic leptin signaling is sufficient to increase myocardial fatty acid oxidation by increasing delivery of free fatty acid substrates and peroxisome proliferator–activated receptor-α ligands to the heart.

Determination of cytokine protein levels in oral secretions in patients undergoing radiotherapy for head and neck malignancies

BackgroundCytokines may be elevated in tumor and normal tissues following irradiation. Cytokine expression in these tissues may predict for toxicity or tumor control. The purpose of this pilot study was to determine the feasibility of measuring local salivary cytokine levels using buccal sponges in patients receiving chemo-radiation for head and neck malignancies.Patients and methods11 patients with epithelial malignancies of the head and neck were recruiting to this study. All patients received radiotherapy to the head and neck region with doses ranging between 60 – 67.5 Gy. Chemotherapy was delivered concurrently with radiation in all patients. Salivary samples were obtained from high dose and low dose regions prior to treatment and at three intervals during treatment for assessment of cytokine levels (IL-4, IL-6, IL-8, IL-10, EGF, MCP-1, TNF-α, and VEGF).ResultsCytokine levels were detectable in the salivary samples. Salivary cytokine levels of IL-4, IL-6, IL-8, EGF, MCP-1, TNF- α , and VEGF were higher in the high dose region compared to the low dose region at all time points (p < 0.05). A trend toward an increase in cytokine levels as radiation dose increased was observed for IL-6, IL-8, MCP-1, and TNF-α.ConclusionAssessment of salivary cytokine levels may provide a novel method to follow local cytokine levels during radiotherapy and may provide a mechanism to study cytokine levels in a regional manner.

In the Modern Treatment Era, Is Breast Conservation Equivalent to Mastectomy in Women Younger Than 40 Years of Age? A Multi-Institution Study

PURPOSE Mastectomy is often recommended for women ≤40 years of age with breast cancer, as young women were under-represented in the landmark trials comparing breast conservation therapy (BCT) to mastectomy. We hypothesized that, in the modern treatment era, BCT and mastectomy result in equivalent local control rates in young women. METHODS AND MATERIALS Breast cancer cases arising between 1975 and 2013 in women ≤40 years old were collected from the tumor registries of 2 large healthcare systems in Utah. Kaplan-Meier estimates and Cox proportional hazards models were used to analyze freedom from locoregional recurrence (FFLR), overall survival (OS), and relapse-free survival (RFS). RESULTS This analysis identified 853 BCT candidates. A comparison of BCT to mastectomy after 2000 showed FFLR, RFS, and OS were all similar. Rate for FFLR at 10 years was 94.9% versus 92.1% for BCT and mastectomy, respectively (P=.57). For women whose cancer was diagnosed after 2000, who received BCT, FFLR and RFS rates were improved compared to those whose cancer was diagnosed prior to 2000 (P<.05), whereas OS (P=.46) rates were similar. Among those who underwent mastectomy, FFLR, OS, and RFS were significantly improved (P<.05) with diagnosis after 2000. CONCLUSIONS FFLR rates for young women, ≤40 years of age, have significantly improved for BCT and mastectomy over time. If patients were treated after 2000, BCT appears to be safe and equivalent to mastectomy at 10 years in terms of FFLR, OS, and RFS.

Patterns of Care in Proton Radiation Therapy for Pediatric Central Nervous System Malignancies

PURPOSE Proton beam therapy (PBT) potentially allows for improved sparing of normal tissues, hopefully leading to decreased late side effects in children. Using a national registry, we sought to perform a patterns-of-care analysis for children receiving PBT for primary malignancies of the central nervous system (CNS). METHODS AND MATERIALS Using the National Cancer Data Base, we identified pediatric patients with primary CNS malignancies that were diagnosed between 2004 and 2012. We used a standard t test for comparison of means and χ2 testing to identify differences in demographic and clinical characteristics. Univariate and multivariate logistical regression was applied to identify predictors of PBT use. RESULTS We identified 4637 pediatric patients receiving radiation therapy from 2004 to 2012, including a subset of 267 patients treated with PBT. We found that PBT use increased with time from <1% in 2004 to 15% in 2012. In multivariate logistical regression, we found the following to be predictors of receipt of PBT: private insurance, the highest income bracket, younger age, living in a metropolitan area, and residing >200 miles from a radiation treatment facility (P<.05). CONCLUSIONS We noted the proportion of children receiving PBT to be significantly increasing over time from <1% to 15% from 2004 to 2012. We also observed important disparities in receipt of PBT based on socioeconomic status. Children from higher-income households and with private insurance were more likely to use this expensive technology. As we continue to demonstrate the potential benefits of PBT in children, efforts are needed to expand the accessibility of PBT for children of all socioeconomic backgrounds and regions of the country.

Increased prevalence of depression and anxiety in patients with migraine and interictal photophobia

BackgroundMost patients with migraine report photophobia associated with headache; a subset report interictal photophobia. These patients are light sensitive even during headache-free periods. The objective of this case–control study was to assess the prevalence of symptoms of anxiety and depression in migraine patients with and without interictal photophobia.MethodsWe recruited 16 subjects with migraine and interictal photophobia, 16 age- and gender-matched migraine subjects without interictal photophobia, and 16 age- and gender- matched controls. Migraine subjects met International Headache Society classification criteria. Participants completed a photophobia questionnaire, Beck Depression Inventory (BDI-II), and Beck Anxiety Inventory (BAI). Chi-square analyses and two-tailed Wilcoxon rank sum tests were used for the analyses.ResultsSubjects with interictal photophobia had significantly higher scores on the photophobia questionnaire compared to subjects without interictal photophobia. Subjects with interictal photophobia had significantly higher scores on the BDI-II and BAI compared to subjects without interictal photophobia.ConclusionsMigraine patients with interictal photophobia are more likely to manifest symptoms of depression and anxiety compared to migraine patients without interictal photophobia. Care providers should be aware of increased prevalence of these symptoms in this population and consider appropriate referrals. Future research could assess whether treatment of photophobia leads to improvements in symptoms of depression and anxiety in migraine patients.

Increased risk of death due to heart disease after radiotherapy for esophageal cancer

OBJECTIVE To evaluate the risk of heart disease related death (HDRD) following radiation therapy (RT) for esophageal cancer (EC). METHODS Using the Surveillance, Epidemiology, and End Results (SEER) database, two cohorts of patients with EC were created: (I) patients who received RT with their initial therapy; and (II) those who did not. Heart disease specific survival (HDSS) was analyzed using Kaplan-Meier methods. Cox proportional-hazards regression methods were used for univariate and multivariate analyses. RESULTS We identified 40,778 patients with EC. A total of 26,377 patients received RT and 14,401 did not. HDSS analysis revealed increased risk of HDRD in those receiving RT (P<0.05), with an absolute risk of HDRD of 2.8%, 5.3% and 9.4% at 5-, 10- and 20-year, respectively. Log rank test of HDSS revealed the risk of HDRD became significant at 8 months (P<0.05). The following were associated with HDRD: RT, age, race, stage at presentation, time period of diagnosis, and known comorbid condition keeping one from esophagectomy. On multivariate analysis, RT remained predictive of HDRD [hazard ratio (HR) 1.46, P<0.05]. When considering only candidates for definitive therapy, RT remained predictive of HDRD on univariate (HR 1.53, P<0.0001) and multivariate (HR 1.62, P<0.0001) analyses. CONCLUSIONS The use of RT leads to increased risk of HDRD that is detectable as early as eight months from diagnosis. More research is needed to define optimal dose volume parameters to prevent cardiac death. Consideration should be given to this risk in relation to prognosis and the expected benefits of RT.

Survival analysis of endometrial cancer patients with cervical stromal involvement.

Objective Stage II endometrial cancer is relatively uncommon. There is no consensus for appropriate adjuvant therapy in endometrial cancer patients with cervical stromal involvement (International Federation of Gynecology and Obstetrics [FIGO] stage II). This study investigates how adjuvant treatments and tumor characteristics influence overall survival (OS) and disease-free survival (DFS) in stage II patients in order to establish better treatment guidelines. Methods This multi-institution, Institutional Review Board approved, study is a retrospective review of 40 endometrial cancer patients with cervical stromal involvement treated from 1993 to 2009. Kaplan-Meier estimates were used to evaluate OS and DFS. Results OS was 85% at three years and 67% at five years. There were no significant differences in age, histology, depth of invasion, comorbid conditions, surgical staging or recurrence between patients who received radiation therapy (RT) and those who did not. However, patients with FIGO grade 1 cancers were less likely to receive RT (p=0.007). Patients treated with RT had a similar 5 year OS (n=33, 69%) to those treated with surgery only (n=7, 60%, p=0.746). There were no OS differences when evaluating by grade, histology, or depth of invasion between patients who did and did not receive RT. Four patients recurred: three were locoregional failures only, and one failed locally and distant. Conclusion Patients receiving RT had higher grade tumors. Despite this, OS was comparable between the RT and the no RT cohorts. Local failure was the predominant pattern of failure. Endometrial cancer patients with cervical stromal involvement likely receive better locoregional control with the addition of adjuvant RT and we continue to advocate for RT in most cases.

Anaplastic meningioma: an analysis of the National Cancer Database from 2004 to 2012

OBJECTIVE Anaplastic meningiomas represent 1%-2% of meningioma diagnoses and portend a poor prognosis. Limited information is available on practice patterns and optimal management. The purpose of this study was to define treatment patterns and outcomes by treatment modality using a large national cancer registry. METHODS The National Cancer Database was used to identify patients diagnosed with anaplastic meningioma from 2004 to 2012. Log-rank statistics were used to compare survival outcomes by extent of resection, use of adjuvant radiotherapy (RT), and use of adjuvant chemotherapy. Least-squares linear regression was used to evaluate the utilization of RT over time. Logistic regression modeling was used to identify predictors of receipt of RT. Cox proportional hazards modeling was used to evaluate the effect of RT, gross-total resection (GTR), and chemotherapy on survival. RESULTS A total of 755 adults with anaplastic meningioma were identified. The 5-year overall survival rate was 41.4%. Fifty-two percent of patients received RT, 7% received chemotherapy, and 58% underwent GTR. Older patients were less likely to receive RT (OR 0.98, p < 0.01). Older age (HR 1.04, p < 0.01), high comorbidity score (HR 1.33, p = 0.02), and subtotal resection (HR 1.57, p = 0.02) were associated with increased risk of death on multivariate modeling, while RT receipt was associated with decreased risk of death (HR 0.79, p = 0.04). Chemotherapy did not have a demonstrable effect on survival (HR 1.33, p = 0.18). CONCLUSIONS Anaplastic meningioma portends a poor prognosis. Gross-total resection and RT are associated with improved survival, but utilization of RT is low. Unless medically contraindicated, patients with anaplastic meningioma should be offered RT.

Patterns of care and outcomes in gliosarcoma: an analysis of the National Cancer Database

OBJECTIVE The authors compared presenting characteristics and survival for patients with gliosarcoma (GS) and glioblastoma (GBM). Additionally, they performed a survival analysis for patients who underwent GS treatments with the hypothesis that trimodality therapy (surgery followed by radiation and chemotherapy) would be superior to nontrimodality therapy (surgery alone or surgery followed by chemotherapy or radiation). METHODS Adults diagnosed with GS and GBM between the years 2004 and 2013 were queried from the National Cancer Database. Chi-square analysis was used to compare presenting characteristics. Kaplan-Meier, Cox regression, and propensity score analyses were employed for survival analyses. RESULTS In total, data from 1102 patients with GS and 36,658 patients with GBM were analyzed. Gliosarcoma had an increased rate of gross-total resection (GTR) compared with GBM (19% vs 15%, p < 0.001). Survival was not different for patients with GBM (p = 0.068) compared with those with GS. After propensity score analysis for GS, patients receiving trimodality therapy (surgery followed by radiation and chemotherapy) had improved survival (12.9 months) compared with those not receiving trimodality therapy (5.5 months). In multivariate analysis, GTR, female sex, fewer comorbidities, trimodality therapy, and age < 65 years were associated with improved survival. There was a trend toward improved survival with MGMT promoter methylation (p = 0.117). CONCLUSIONS In this large registry study, there was no difference in survival in patients with GBM compared with GS. Among GS patients, trimodality therapy significantly improved survival compared with nontrimodality therapy. Gross-total resection also improved survival, and there was a trend toward increased survival with MGMT promoter methylation in GS. The major potential confounder in this study is that patients with poor functional status may not have received aggressive radiation or chemotherapy treatments, leading to the observed outcome. This study should be considered hypothesis-generating; however, due to its rarity, conducting a clinical trial with GS patients alone may prove difficult.

Impact on survival with adjuvant radiotherapy for clear cell, mucinous, and endometriod ovarian cancer: the SEER experience from 2004 to 2011

Objective Evaluate the impact of radiotherapy on cause specific survival (CSS) and overall survival (OS) for stage (I–III) clear cell, mucinous, and endometriod ovarian cancer. Methods We analyzed incidence, survival, and treatments from the Surveillance, Epidemiology, and End Results (SEER) Program from 2004 to 2011 for clear cell, mucinous, and endometriod histologies of the ovary for stages (I–III). We examined CSS and OS for all three histologies combined and each histology with relation to the use of adjuvant radiation therapy (RT). Survival analysis was calculated by Kaplan-Meier and log-rank analysis. Results CSS was higher in individuals not receiving RT at 5 years (81% vs. 74%) and 10 years (74% vs. 65%, p=0.003). OS was higher in individuals not receiving RT at 5 years (76% vs. 73%) and 10 years (64% vs. 59%, p=0.039). Stage III patients receiving RT had a higher OS at 5 years (54% vs. 44%) and 10 year intervals (36% vs. 30%, p=0.037). Stage III patients with mucinous histology receiving RT had a higher OS at 5 years (50% vs. 36%) and 10 years (45% vs. 26%, p=0.052). Conclusion Those receiving RT had a lower CSS and OS at 5 and 10 years. However, subgroup analysis revealed a benefit of RT in terms of OS for all stage III patients and for stage III patients with mucinous histology.