MDA-9/Syntenin in the tumor and microenvironment defines prostate cancer bone metastasis.

Bone metastasis is a frequent and incurable consequence of advanced prostate cancer (PC). An interplay between disseminated tumor cells and heterogeneous bone resident cells in the metastatic niche initiates this process. Melanoma differentiation associated gene-9 (mda-9/Syntenin/syndecan binding protein) is a prometastatic gene expressed in multiple organs, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), under both physiological and pathological conditions. We demonstrate that PDGF-AA secreted by tumor cells induces CXCL5 expression in BM-MSCs by suppressing MDA-9-dependent YAP/MST signaling. CXCL5-derived tumor cell proliferation and immune suppression are consequences of the MDA-9/CXCL5 signaling axis, promoting PC disease progression. mda-9 knockout tumor cells express less PDGF-AA and do not develop bone metastases. Our data document a previously undefined role of MDA-9/Syntenin in the tumor and microenvironment in regulating PC bone metastasis. This study provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC.

Utilization Practices of Inferior Vena Cava Filters at an Academic Medical Center.

INTRODUCTION:  Anticoagulation is the mainstay of management for patients with venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Inferior vena cava (IVC) filters are indicated in select patients who are not candidates for anticoagulation. There is a lack of quality evidence supporting other indications. In addition, long-term benefits and safety profiles of IVC filters have not been established. We investigated the utilization practice of IVC filters in a contemporary series of patients in a tertiary academic medical center. METHODOLOGY:  A retrospective review of 200 patients who received IVC filters at Virginia Commonwealth University (VCU) Medical Center in the years 2017 and 2018 was conducted. Adult patients 18 years of age or older with or without cancer were included, and patients were selected consecutively until data on 200 patients were collected. Data on patient demographics, an indication of IVC filter placement, filter retrieval rate, and re-thrombosis events over a median follow-up period of nine months were extracted from the electronic medical record and analyzed. RESULTS: A total of 200 patients (105 male and 95 female) were included with a median age of 61 years (range 17-92 years). Of the 200 patients, 97 (48.5%) had a DVT, 28 (14%) had a PE, 73 (36.5%) had both a PE and DVT, and 2 (1%) had thrombosis at other sites. A total of 130 (65%) patients had an IVC filter placed because of a contraindication to anticoagulation, while 70 (35%) had an IVC filter placed for other nonstandard indications, which included new or worsening VTE despite anticoagulation, recent VTE who must have anticoagulation held during surgery, primary prevention in high-risk patients, and extensive disease burden among other reasons. Seventy-two (36%) patients had active malignancy at the time of filter placement, and 64 (32%) were lost to follow-up. Of the 119 patients who were potentially eligible for filter retrieval, 55 (46%) patients had their IVC filters removed at a median of five months after insertion. Of the 55 patients who had IVC filters removed, 8 (14.5%) patients experienced a re-thrombosis event within a median follow-up of 39 months. Of the 145 patients who still had their filter in place at the time of death or last follow-up, 5 (3.4%) patients experienced a re-thrombosis event within a median follow-up of three months. CONCLUSIONS:  One-third of the patients in this series had an IVC filter placed without a standard indication, and less than half of them had the IVC filters removed within one year of placement. Additionally, one-third of the patients were lost to follow-up, highlighting the need for improved structured follow-up programs and education among both patients and providers regarding the indications for placement and retrieval to minimize complications.

Myocardial viability assessment with gated SPECT Tc-99m tetrofosmin % wall thickening: comparison with F-18 FDG-PET.

OBJECT: This study was designed to assess the value of gated SPECT Tc-99m-tetrofosmin (TF) wall thickening (WT) in addition to TF exercise (Ex)/rest myocardial SPECT, in comparison with F-18 fluorodeoxyglucose (FDG)-PET. METHODS: The study population consisted of 33 patients with old myocardial infarction (27 men and 6 women; mean age, 62 +/- 8 years old). All patients underwent Ex/rest TF SPECT and glucose loading FDG-PET. Polar map images of Ex/rest TF were generated and divided into 24 segments for further analysis. We classified LV segments according to the exercise-rest perfusion scintigraphy. LV segments with less than 70% of the maximum TF activity on the exercise image were defined as stress-induced defects. Among these, the segments whose TF activity increased by 10% from exercise to rest images or exceeded 70% of the maximum uptake were defined as reversible (viable) defects. The remaining defects on the rest image were irreversible (non-viable) defect segments, and were considered for viability study on the basis of %WT. %WT was calculated according to the standard method: [(counts ES - counts ED)/counts ED] x 100. A viable segment on gated SPECT was defined as a segment whose %WT exceeded the lower limit of the normal value (mean - SD). PET viability was defined as FDG uptake exceeding 50% of the maximum count. RESULTS: Among the 792 segments evaluated in the 33 patients studied, there were 689 PET viable segments. Of the 689 segments analyzed, 198 (29%) were identified as having defects on Ex images. Among these defects, 55 (8%) were reversible or partially reversible, as evidenced by rest images, and 143 (21%) were irreversible. Of the irreversible segments on Ex/rest images, 106 (15%) demonstrated no apparent WT by gated TF SPECT, whereas 37 (6%) segments with irreversible defects did have apparent WT. Overall, the sensitivity of Ex/rest TF perfusion imaging was 79%. Sensitivity was improved from 79% to 85% by combining %WT and perfusion data, but specificity was reduced from 70% to 56%. CONCLUSION: %WT evaluated from gated TF imaging enhanced myocardial viability assessment in comparison with FDG-PET.

Left ventricular mass index measured by quantitative gated myocardial SPECT with 99mTc-tetrofosmin: a comparison with echocardiography.

OBJECTIVE: Left ventricular mass is an important determinant of diagnosis and prognosis in patients with heart disease. The aim of the present study was to validate measurement of the left ventricular mass index (LVMI) by quantitative gated myocardial SPECT (QGS) with 99mTc-tetrofosmin by comparing it with echocardiography. METHODS: QGS and M-mode echocardiography (Echo) were performed within one month of each other in 179 patients. M-mode echocardiography was carried out according to Devereux's method. QGS images were acquired one hour after injection of 99Tc-tetrofosmin at rest. Myocardial volume was defined as the volume between the endocardial and epicardial surface in the end-diastolic phase. LVMI (g/m2) was defined as myocardial volume divided by myocardial specific density and corrected for body surface area. QGS LVMI measurements were performed twice by the same observer and independently by two different observers. Regional hypoperfusion in the group of patients with old myocardial infarction (n = 26) was evaluated semiquantitatively on the basis of the total defect score on the resting 99mTc-tetrofosmin SPECT images. RESULTS: Among the patients as a whole QGS LVMI was significantly correlated with Echo LVMI (r = 0.96, p < 0.001). Intra-observer and inter-observer analyses showed significant reproducibility (r = 0.99 and r = 0.98, respectively, p < 0.001). In the patients with old myocardial infarction, but QGS LVMI was significantly lower than Echo LVMI (p < 0.001), and the magnitude of the underestimation was closely related to the severity of the perfusion defect on the resting SPECT images. CONCLUSIONS: Measurements of LVMI by 99mTc-tetrofosmin QGS are reproducible and consistent with echocardiograpic estimates. Underestimation in patients with severe perfusion defects must be taken into consideration.

Characteristics of regional myocardial stunning after exercise in gated myocardial SPECT.

BACKGROUND: A number of studies have demonstrated prolonged left ventricular (LV) global dysfunction after exercise-induced ischemia in gated myocardial single photon emission tomography (SPECT) as a manifestation of exercise-induced stunning. This study investigated the residual effects of exercise on postexercise LV regional function and its implications on the detection of stunning in gated SPECT. METHODS AND RESULTS: Fifty-three subjects with known or suspected coronary artery disease and 10 control subjects underwent myocardial SPECT according to a same-day exercise-rest protocol. Both postexercise and resting images were gated and acquired 1 hour after injection of technetium 99m tetrofosmin. The LV global ejection fraction and segmental systolic wall thickening were quantitated with the use of an automatic program. Segmental perfusion was assessed semiquantitatively on summed nongated tomograms. Wall thickening index (WTI), the ratio of systolic wall thickening of a segment to that of a corresponding control segment, was significantly lower after exercise than at rest in the reversible defect (RD) segments (0.66 +/- 0.24 vs 0.78 +/- 0.24; P <.0001). In patients with exercise-induced ischemia, the difference in WTI between rest and after exercise was significantly greater in the RD segments, which represented ischemia, than in the non-RD segments. Postexercise WTIs were not different from the resting values in subjects with no perfusion abnormalities or who had fixed defects (infarction). Significant postexercise dysfunction was present in 44% of the RD segments, compared with 5% of the normal and 3% of the fixed defect segments. Postexercise segmental dysfunction was correlated with the segmental reversibility score, the difference in defect scores between exercise and rest images (n = 82, Spearman rank correlation coefficient = -0.78, P <.0001). Among 19 patients with ischemia, 9 (47%) exhibited concurrent segmental and global dysfunction, but segmental dysfunction persisted in the absence of global dysfunction in 4 additional patients (21%). CONCLUSIONS: Significant postexercise LV regional dysfunction, consistent with the concept of stunning, occurs in the region of severe ischemia. The incidence and magnitude of regional stunning are determined by the severity of ischemia. For the detection of stunning in gated SPECT, LV regional dysfunction may be more sensitive than global dysfunction.