The treatment of metastatic uveal melanoma remains a major clinical challenge. Procaspase-3, a proapoptotic protein and precursor to the key apoptotic executioner caspase-3, is overexpressed in a wide range of malignancies, and the drug PAC-1 leverages this overexpression to selectively kill cancer cells. Herein, we investigate the efficacy of PAC-1 against uveal melanoma cell lines and report the synergistic combination of PAC-1 and entrectinib. This preclinical activity, tolerability data in mice, and the known clinical effectiveness of these drugs in human cancer patients led to a small Phase 1b study in patients with metastatic uveal melanoma. The combination of PAC-1 and entrectinib was tolerated with no treatment-related grade ≥3 toxicities in these patients. The pharmacokinetics of entrectinib were not affected by PAC-1 treatment. In this small and heavily pretreated initial cohort, stable disease was observed in four out of six patients, with a median progression-free survival of 3.38 months (95% CI 1.6–6.5 months). This study is an initial demonstration that the combination of PAC-1 and entrectinib may warrant further clinical investigation. Clinical trial registration: Clinical Trials.gov: NCT04589832.
Summary The opioid receptor (OR) antagonist naltrexone inhibits estrogen receptor-α (ER) function in model systems. The goal of this study was to determine the clinical activity of naltrexone in patients with ER-positive metastatic breast cancer. Patients with hormone receptor positive metastatic breast cancer were enrolled on a phase II study of naltrexone. An escalating dose scheme was used to reach the planned dose of 50 mg daily. The primary objective of the study was to evaluate response to therapy as measured by stabilization or reduction of the tumor Maximum Standardized Uptake Value (SUVmax) at 4 weeks by PET-CT scan. The secondary objectives included safety assessment and tumor SUVmax at 8 weeks. Out of 13 patients we enrolled, 8 patients had serial PET-CT scans that were evaluable for response. Of these 8 patients, 5 had stable or decreased SUVmax values at 4 weeks and 3 had clinical or imaging progression. Median time to progression was short at 7 weeks. Naltrexone was well tolerated. There were no discontinuations due to toxicity and no grade 3 or 4 toxicities were noted. Naltrexone showed modest activity in this short study suggesting the contribution of opioid receptors in ER-positive breast cancer. Our data do not support further development of naltrexone in hormone refractory breast cancer. It is possible that more potent peripherally acting OR antagonists may have a greater effect. ( ClinicalTrials.gov Identifier: NCT00379197 September 21, 2006 ).
OBJECTIVE To assess the effectiveness of prophylactic headache treatment in children and adolescents. DATA SOURCES PubMed, EMBASE, Cochrane Database of Clinical Trials, and bibliography of retrieved articles through August 11, 2012. STUDY SELECTION Randomized trials of headache treatment among children and adolescents (<18 years old). INTERVENTION Any placebo-controlled trial or comparisons between 2 or more active medications. MAIN OUTCOME MEASURE Number of headaches per month. RESULTS Among 21 included trials, there were 13 placebo-controlled and 10 active comparator trials (2 also included placebo). Twenty trials focused on episodic migraines and 1 on chronic daily headaches. Drugs more effective than placebo for episodic migraines (<15 headaches per month) included topiramate (difference in headaches per month, -0.71; 95% CI, -1.19 to -0.24) and trazodone (-0.60; 95% CI, -1.09 to -0.11). Ineffective drugs included clonidine, flunarizine, pizotifen, propranolol, and valproate. A single trial of fluoxetine for chronic daily headaches found it ineffective. Patients given placebo experienced a significant (P = .03) decline in headaches, from 5.6 (95% CI, 4.52-6.77; Q = 8.14 [Cochran Q is a measure of the heterogeneity of the included studies]) to 2.9 headaches per month (95% CI, 1.66-4.08; Q = 4.72). Among the 10 active comparator trials, flunarizine was more effective than piracetam (difference in headaches per month, -2.20; 95% CI, -3.93 to -0.47) but no better than aspirin, dihydroergotamine, or propranolol. Propranolol was compared with valproate as well as behavioral treatment, and 2 studies compared different doses of topiramate; none of these trials showed significant differences. CONCLUSIONS Topiramate and trazodone have limited evidence supporting efficacy for episodic migraines. Placebo was effective in reducing headaches. Other commonly used drugs have no evidence supporting their use in children and adolescents. More research is needed.
Results: Among 21 included trials, there were 13 placebocontrolled and 10 active comparator trials (2 also included placebo). Twenty trials focused on episodic migraines and 1 on chronic daily headaches. Drugs more effective than placebo for episodic migraines ( 15 headaches per month) included topiramate (difference in headaches per month, 0.71; 95% CI, 1.19 to 0.24) and trazodone ( 0.60; 95% CI, 1.09 to 0.11). Ineffective drugs included clonidine, flunarizine, pizotifen, propranolol, and valproate. A single trial of fluoxetine for chronic daily headaches found it ineffective. Patients given placebo experienced a significant (P=.03) decline in headaches, from 5.6 (95% CI, 4.52-6.77; Q=8.14 [Cochran Q is a measure of the heterogeneity of the included studies]) to 2.9 headaches per month (95% CI, 1.66-4.08; Q=4.72). Among the 10 active comparator trials, flunarizine was more effective than piracetam (difference in headaches per month, 2.20; 95% CI, 3.93 to 0.47) but no better than aspirin, dihydroergotamine, or propranolol. Propranolol was compared with valproate as well as behavioral treatment, and 2 studies compared different doses of topiramate; none of these trials showed significant differences.
10584 Background: HE are rare vascular soft tissue (ST) tumors with variable clinical biology. Prognostic factors and treatment (rx) options are poorly defined. This study aimed to describe patient (pt) and tumor features of HE and identify predictors of survival using the SEER database (1973-2010). Methods: HE and epithelioid HE (EHE) pts were identified using codes 9130/3, 9133/3. Demographics, tumor features and rx were retrieved. We sorted age cohorts based on Adolescent and Young Adult Oncology Progress Review Groups into children (0-15 yrs), young adults (16-39), adults (40-64), elderly (>65). Overall survival (OS) and disease specific survival (DSS) were compared using multivariate (MVA) proportional hazards methods controlling for age, gender, race, grade, stage, radiation (RT), surgery (S), size, year and histology. Analyses were done using SAS version 9.4. Results: 606 pts (296 EHE) were identified; median age 52 yrs (0-97), 52% female. 72% pts were > 40 yrs and most were white (85%). 443 pts had grade (G) 3 tumors. 36% cases were diagnosed from 2001-10, compared to 20% from 1973-1980. 52% had locoregional disease and 29% were metastatic. ST (38%), liver (18%) and bone (14%) were most common sites affected. 65% underwent S and 24% received RT. Tumor size data available on 406 pts revealed 27% tumors < 5cm. At a median follow-up of 70 months (m), the median OS was 35m (95% CI 27, 46); 5-yr OS was 43%. 5-yr DSS was 58%. In a univariate model on 401 pts (excluding 205 pts with missing data), age > 40, tumor grade 2/3, size > 5cm, distant disease and absence of S predicted for poorer OS. MVA for OS confirmed worse prognosis for adults (HR 3.6; 95% CI 1.3, 9.97), elderly (HR 12.85; 4.57, 36.14), G2 tumors (HR 1.74; 1.01, 3), size 5-10cm (HR 2.92; 1.69, 5.06), size > 10cm (HR 2.45; 1.29, 4.63), distant disease (HR 3.04; 1.97, 4.7) and no S (HR 1.71; 1.22, 2.42); all p-values < 0.05. Females had improved DSS (HR 0.69; 0.48, 0.98; p=0.04) but similar OS. Race, EHE histology and RT did not affect DSS or OS. Conclusions: Recognizing inherent bias using SEER data, age, tumor size and grade were predictive factors for survival in this study, the largest of its kind in HE. Surgical resection is important for improving outcome in HE.
Background: Vascular 18F-Fluorodeoxyglucose (FDG) activity, detected by Positron Emission Tomography (PET) correlates with atherosclerotic inflammation. Here we test the hypothesis that inflammation (measured by FDG-PET) is increased in coronary artery plaques with High Risk Morphological features (HRM) as defined by coronary CT angiography (CTA). Methods: Nineteen patients with stable atherosclerotic disease underwent FDG-PET and CTA imaging. Left main coronary artery (LM) was assessed for presence and morphology of atherosclerotic plaque using CTA imaging. A 10 mm segment adjacent to the LM bifurcation was analyzed. Plaque with HRM was defined by low CT attenuation (<50 HU) and/or presence of spotty calcification. FDG uptake was measured within the center of the LM while blinded to CTA analysis. Target-to-background ratio (TBR) was calculated by dividing the LM by blood activity. TBR of the LM was then compared to the underlying plaque morphology. Results: LM plaques were present on CTA in 14 patients, ...
Introduction: Inflammation plays an important role in the pathobiology of abdominal aortic aneurysms (AAA). Here we compared vascular inflammation in the aortic wall between patients with AAA and age and gender-matched subjects without AAA, using 18-fluorodeoxyglucose-positron emission tomography (FDG-PET). Methods and Materials: Thirty-three patients (Median [IQR] 71[7] years, 82% male), 11 with AAA and 22 age/gender-matched controls without AAA, underwent PET and CT imaging. FDG uptake within the aortic wall was assessed in axial images, from the celiac artery to the iliac bifurcation. Mean target-to-Background ratio (TBR) was determined by dividing aortic wall activity by vena caval blood activity. Additionally, within AAA, TBR was measured in transitional zones of the AAA (the shoulders of the aneurysm) as well as in the opposite wall (figure 1). Results: Vessel wall inflammation (TBR) was higher in AAA vs. controls (2.82 [1.81] vs. 1.84 [0.59], P<0.001), a difference which remained significant after ...
Background: FDG uptake correlates with cardiovascular (CV) events. Here we test the hypothesis that aortic inflammation measured with FDG-PET-CT imaging provides added value to Framingham risk score (FRS). Methods: We screened consecutive clinical data (n= 6,109) for patients with no prior CVD, active cancer, or chronic inflammatory conditions who had clinical follow-up data for up to 5 years after an index FDG-PET. From the 229 (median age[IQR],60[47,68], 38% males) meeting these criteria, 42 had CV events (incident ischemic stroke, TIA, ACS, carotid or coronary revascularization) and 187 did not during the follow-up. FRS 10 year % probability of CHD was calculated. FDG uptake was measured (ascending aorta) and reported as target-to-background ratio (TBR) while blinded to clinical data. Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) were used to compare FRS with and without TBR for CV event prediction. Results: Patients in the highest TBR tertile were substantially more likely to experience CV events (HR[95%CI], 4.85[1.89,12], p=0.001) compared to the lowest tertile after adjusting for FRS, BMI, statin, and diabetes. Further, addition of TBR (tertiles) to FRS variables resulted in an improvement in patient net reclassification, (NRI[95% CI]=26.89%[10%, 47%) across risk categories (<10, 10-20, >20) compared to their initially calculated risk. Adding TBR (tertiles) to FRS variables further improved discrimination of CV risk, (IDI=5.56%[0.27%, 11%]). Conclusions: FDG-PET measured aortic plaque inflammation improves risk discrimination and reclassification. These preliminary data support prospective follow-up studies to evaluate imaging plaque inflammation for CVD risk assessment.
