Unification of favourable intermediate‐, unfavourable intermediate‐, and very high‐risk stratification criteria for prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139069/1/bju13903.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139069/2/bju13903_am.pd

Quantification of collagen organization in histopathology samples using liquid crystal based polarization microscopy

Author Posting. © The Optical Society, 2017. This article is posted here by permission of The Optical Society for personal use, not for redistribution. The definitive version was published in Biomedical Optics Express 8 (2017): 4243-4256, doi:10.1364/BOE.8.004243.A number of histopathology studies have utilized the label free microscopy method of Second Harmonic Generation (SHG) to investigate collagen organization in disease onset and progression. Here we explored an alternative label free imaging approach, LC-PolScope that is based on liquid crystal based polarized light imaging. We demonstrated that this more accessible technology has the ability to visualize all fibers of interest and has a good to excellent correlation between SHG and LC-PolScope measurements in fibrillar collagen orientation and alignment. This study supports that LC-PolScope is a viable alternative to SHG for label free collagen organization measurements in thin histology sections.Morgridge Institute for Research and National Institutes of Health (NIH) (U54DK104310 and R01GM114274); The University of Wisconsin Carbone Cancer Center Cancer Center Biocore and Histology core (UWCCC) (P30 CA014520)

Quantitating whole lesion tumor biology in rectal cancer MRI: taking a lesson from FDG-PET tumor metrics

PURPOSE To determine the value of novel whole tumor metrics in DWI-MRI and DCE-MRI of rectal cancer treatment assessment. MATERIALS AND METHODS This retrospective study included 24 uniformly treated patients with rectal adenocarcinoma who underwent MRI including diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) sequences, before and after chemoradiotherapy. Two experienced readers independently measured tumor volume and apparent diffusion coefficient (ADC) on DWI-MRI and tumor volume and transfer constant K on DCE-MRI. In addition, we explored and defined Total Lesion Diffusion (TLD) as Total DWI tumor volume multiplied by mean volumetric ADC and Total Lesion Perfusion (TLP) as the total DCE tumor volume multiplied by the mean volumetric K . These metrics were correlated with histopathologic percent tumor regression in the resected specimen (%TR). Inter-reader agreement was assessed using the concordance correlation coefficient (CCC). RESULTS For both readers, post-treatment TLP revealed comparable correlations with %TR compared with K (reader 1; Spearman's rho = - 0.36 vs. - 0.32, reader 2; Spearman's rho = - 0.32 vs. - 0.28). In addition, TLP afforded the highest inter-reader agreement at post-treatment among TLP, DCE vol, and K (CCC: 0.64 vs. 0.36 vs. 0.35). Post-treatment TLD showed similar correlation with %TR as DWI volume in reader 1 and superior correlation with %TR for reader 2 (reader 1; Spearman's rho - 0.56 vs. - 0.57, reader 2; Spearman's rho - 0.59 vs. - 0.45). CONCLUSION The novel tumor metrics TLD and TLP revealed similar results to established metrics for correlation with tumor response with equivalent or superior inter-reader agreements and we recommend that these be studied in larger trials

Combined gadoxetic acid and gadobenate dimeglumine enhanced liver MRI: a parameter optimization study

PURPOSE To demonstrate the feasibility of combined delayed-phase gadoxetic acid (GA) and gadobenate dimeglumine (GD) enhanced liver MRI for improved detection of liver metastases, and to optimize contrast agent dose, timing, and flip angle (FA). METHODS Fourteen healthy volunteers underwent liver MRI at 3.0T at two visits during which they received two consecutive injections: 1. GA (Visit 1 = 0.025 mmol/kg; Visit 2 = 0.05 mmol/kg) and 2. GD (both visits = 0.1 mmol/kg) 20 min after GA administration. Two sub-studies were performed: Experiment-1 Eight subjects underwent multi-phase breath-held 3D-fat-saturated T1-weighted spoiled gradient echo (SGRE) imaging to determine the optimal imaging window for the combined GA + GD protocol to create a homogeneously hyperintense liver and vasculature ("plain-white-liver") with maximum contrast to muscle which served as a surrogate for metastatic lesions in both experiments. Experiment-2 Six subjects underwent breath-held 3D-fat-saturated T1-weighted SGRE imaging at three different FA to determine the optimal FA for best image contrast. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were evaluated. RESULTS Experiment-1 The combined GA + GD protocol created a homogeneously hyperintense liver and vasculature with maximum CNR liver/muscle at approximately 60-120 s after automatic GD-bolus detection. Experiment-2 Flip angles between 25° and 35° at a dose of 0.025 mmol/kg GA provided the best combination that minimized liver/vasculature CNR, while maximizing liver/muscle CNR. CNR performance to achieve a "plain-white-liver" was superior with 0.025 mmol/kg GA compared to 0.05 mmol/kg. CONCLUSION Combined GA + GD enhanced T1-weighted MRI is feasible to achieve a homogeneously "plain-white-liver". Future studies need to confirm that this protocol can improve sensitivity of liver lesion detection in patients with metastatic liver disease

Pharmacokinetics of Ferumoxytol in the Abdomen and Pelvis: A Dosing Study with 1.5- and 3.0-T MRI Relaxometry

Background The off-label use of ferumoxytol (FE), an intravenous iron preparation for iron deficiency anemia, as a contrast agent for MRI is increasing; therefore, it is critical to understand its pharmacokinetics. Purpose To evaluate the pharmacokinetics of FE in the abdomen and pelvis, as assessed with quantitative 1.5- and 3.0-T MRI relaxometry. Materials and Methods R2*, an MRI technique used to estimate tissue iron content in the abdomen and pelvis, was performed at 1.5 and 3.0 T in 12 healthy volunteers between April 2015 and January 2016. Volunteers were randomly assigned to receive an FE dose of 2 mg per kilogram of body weight (FE$_{2mg}$) or 4 mg/kg (FE$_{4mg}$). MRI was repeated at 1.5 and 3.0 T for each volunteer at five time points: days 1, 2, 4, 7, and 30. A radiologist experienced in MRI relaxometry measured R2* in organs of the mononuclear phagocyte system (MPS) (ie, liver, spleen, and bone marrow), non-MPS anatomy (kidney, pancreas, and muscle), inguinal lymph nodes (LNs), and blood pool. A paired Student t test was used to compare changes in tissue R2*. Results Volunteers (six female; mean age, 44.3 years ± 12.2 [standard deviation]) received either FE$_{2 mg}$ (n = 5) or FE$_{4 mg}$ (n = 6). Overall R2* trend analysis was temporally significant (P < .001). Time to peak R2* in the MPS occurred on day 1 for FE$_{2mg}$ and between days 1 and 4 for FE$_{4mg}$ (P < .001 to P < .002). Time to peak R2* in non-MPS anatomy, LNs, and blood pool occurred on day 1 for both doses (P < .001 to P < .09). Except for the spleen (at 1.5 T) and liver, MPS R2* remained elevated through day 30 for both doses (P = .02 to P = .03). Except for the kidney and pancreas, non-MPS, LN, and blood pool R2* returned to baseline levels between days 2 and 4 at FE$_{2mg}$ (P = .06 to P = .49) and between days 4 and 7 at FE$_{4mg}$ (P = .06 to P = .63). There was no difference in R2* change between non-MPS and LN R2* at any time (range, 1-71 sec$^{-1}$ vs 0-50 sec$^{-1}$; P = .06 to P = .97). Conclusion The pharmacokinetics of ferumoxytol in lymph nodes are distinct from those in mononuclear phagocyte system (MPS) organs, parallel non-MPS anatomy, and the blood pool. © RSNA, 2019 Online supplemental material is available for this article

The tumoral and stromal immune microenvironment in malignant pleural mesothelioma: A comprehensive analysis reveals prognostic immune markers

Antitumor immune responses against solid malignancies correlate with improved patient survival. We conducted a comprehensive investigation of immune responses in tumor and tumor-associated stroma in epithelioid malignant pleural mesothelioma with the goal of characterizing the tumor immune microenvironment and identifying prognostic immune markers. We investigated 8 types of tumor-infiltrating immune cells within the tumor nest and tumor-associated stroma, as well as tumor expression of 5 cytokine/chemokine receptors in 230 patients. According to univariate analyses, high densities of tumoral CD4- and CD20-expressing lymphocytes were associated with better outcomes. High expression of tumor interleukin-7 (IL-7) receptor was associated with worse outcomes. According to multivariate analyses, stage and tumoral CD20 detection were independently associated with survival. Analysis of single immune cell infiltration for CD163(+) tumor-associated macrophages did not correlate with survival. However, analysis of immunologically relevant cell combinations identified that: (1) high CD163(+) tumor-associated macrophages and low CD8(+) lymphocyte infiltration had worse prognosis than other groups and (2) low CD163(+) tumor associated macrophages and high CD20(+) lymphocyte infiltration had better prognosis than other groups. Multivariate analyses demonstrated that CD163/CD8 and CD163/CD20 were independent prognostic factors of survival. With a recent increase in immunotherapy investigations and clinical trials for malignant pleural mesothelioma patients, our observations that CD20(+) B lymphocytes and tumor-associated macrophages are prognostic markers provide important information about the tumor microenvironment of malignant pleural mesothelioma

Analysis of VDT-PACE Utilization in Multiple Myeloma Patients Treated at MSKCC for Relapsed Disease or Cytoreduction and Stem Cell Mobilization after Initial Induction Therapy

Abstract Background: The total therapy 3 protocol for multiple myeloma (MM) introduced the use of intensive induction with VDT-PACE, a combination of bortezomib, dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, and etoposide for newly diagnosed MM patients. This regimen, which demonstrated rapid responses in the first-line setting, has also been used in relapsed disease, to rescue induction failures or for stem cell mobilization. We evaluated the efficacy and toxicity of using VDT-PACE in these clinical settings. Patients and Methods: We identified 84 patients through pharmacy profile review who received at least one cycle of VDT-PACE for the treatment of MM between 1/2007 and 8/2013 at our institution. Patients were grouped into a stem cell collection cohort (C) if stem cell pheresis was performed following VDT-PACE. Remaining patients were analyzed in the relapsed cohort (RR). The primary objective of this study was to determine the overall response rate with combination VDT-PACE. Secondary Objectives include progression-free survival (PFS), overall survival (OS), stem cell collection in patients that underwent chemomobilization, and the extent of toxicity. Results: In the RR group, 45 patients received VDT-PACE after a median of 4 prior therapies (range 1-8) including autologous stem cell transplantation (ASCT) in 79%. The median time between diagnosis and first cycle of VDT-PACE treatment was 35.4 months (range 1.3-163.4). 47% of patients had adverse cytogenetics defined as presence of complex karyotype or FISH with del 17p, t4;14, or t14;16. Patients received a median of 2 cycles of VDT-PACE (range 1-4) with a response rate after all cycles of 51% (2% CR, 22% VGPR, 27% PR). Additional therapy was administered in 82% within 6 months (18% allogeneic SCT, 35% ASCT, 29% chemotherapy regimens). 18% of patients died without additional therapy (13% from disease progression, 5% from toxicity), all within 5 months of their last VDT-PACE cycle. PFS and OS for the RR group was 8.8 months (95% CI 4.6, 13.1) and 10.3 months (95% CI 8.8, 17.4), respectively. Patients that received subsequent lines of therapy following VDT-PACE achieved a median PFS and OS of 9.5 months (95% CI 5.6, 13.3) and 9.5 months (95% CI 7.5, 32.1), respectively, measured from the time of next therapy. In the C group, 39 patients received a median of 2 prior regimens (range 1-4) before starting VDT-PACE and 31% of patients had adverse cytogenetics. Reasons for using VDT-PACE for mobilization included residual or progressive disease (64%), provider discretion (33%), and failure of a prior attempt at collection (3%). The median time between diagnosis and first cycle of VDT-PACE treatment was 7 months (range 2.3-122.7). Patients received a median of 2 cycles (range 1-4) of VDT-PACE. The median number of cells collected was 12.3x106CD34 cells/kg (range 0.21-43.74) and the median number of collection session required was 2 (range 1-6), with 21% of patients requiring plexirafor. Two patients (5%) from this group failed collection. The response rate after all cycles of VDT-PACE was 59% (3% CR, 13% VGPR, 44% PR). 35 out of the 39 patients went to transplant following VDT-PACE (34 ASCT, 1 allogeneic SCT). Of the 4 patients who did not receive transplant, 2 were for toxicity attributed to VDT-PACE, 1 for failure to mobilize, and 1 for personal reasons. The post-transplant response rate was 91% (17% CR, 34% VGPR, 40% PR) with 1 patient (3%) experiencing disease progression immediately after transplant. Median PFS and OS for the C group patients was 34.5 months (95% CI 20.2, n.r.) and 64.8 months (95% CI 26.0, n.r.), respectively. Reported toxicities following treatment included infection (20%), fatigue (19%), nausea (17%), renal complications (6%), thrombosis (4%), and edema (4%), which were seen in 67% and 62% of the RR and C groups, respectively. Hospital readmission for management of side effects occurred in 30% of patients. Conclusions: VDT-PACE is an effective therapy for RR patients and for stem cell mobilization in patients with residual or progressive disease following initial therapy. Importantly, it is also associated with significant morbidity and requires careful monitoring. VDT-PACE does not appear to adversely affect stem cell collection or SCT outcomes. At our institution, this regimen is commonly used for stem cell collection in patients with unfavorable outcomes following initial therapy. Disclosures No relevant conflicts of interest to declare

Ovarian vein thrombosis after debulking surgery for ovarian cancer: epidemiology and clinical significance

OBJECTIVE: Ovarian vein thrombosis is associated with pregnancy and pelvic surgery. Postpartum ovarian vein thrombosis is associated with infection and a high morbidity rate, and is treated with anticoagulant and intravenous antibiotic therapy. The natural history of such thrombotic events after debulking surgery for ovarian cancer has not been well described. Our objective was to characterize the presentation and outcomes for patients with this condition at our institution. STUDY DESIGN: We conducted a retrospective study of patients who underwent surgical debulking for ovarian cancer at Memorial Sloan Kettering Cancer Center between the years 2001 and 2010. Patients were included if contrast computed tomography scans of the abdomen and pelvis were performed both within 12 weeks before and 12 weeks after the surgery. The images were reviewed to assess for the presence and extent of a new post-operative ovarian vein thrombosis. When available, subsequent studies were assessed for thrombus progression. Medical records were reviewed to determine if anticoagulation was used for treatment of the thrombotic episode and to record the occurrence of any new significant venous thromboembolic event in the following year. RESULTS: 159 patients had satisfactory imaging. New ovarian vein thrombosis was a common complication of debulking surgery, as found in 41 (25.8%) of patients. Only 5 women with ovarian vein thrombosis were started on anticoagulation, of which 2 individuals had an independent venous thromboembolic event as indication for treatment. Only 2 (4.9%) of the ovarian vein thromboses progressed to the inferior vena cava or left renal vein on subsequent scan. The estimated cumulative incidence of venous thromboembolism one year after the first post-operative scan was 17.1% for patients in the new ovarian vein thrombosis group, versus 15.3% of individuals for the group without a post-operative ovarian vein thrombosis (p=0.78). CONCLUSION: Ovarian vein thrombosis is commonly encountered after debulking surgery for ovarian cancer. Anticoagulation is usually not indicated and clinically meaningful thrombus progression rarely occurs