Prognostic value of DCE-CT-derived blood volume and flow compared to core biopsy microvessel density in patients with metastatic renal cell carcinoma.

BACKGROUND: Angiogenesis is prominent in metastatic renal cell carcinoma (mRCC). We compared two angiogenesis assessment methods: dynamic contrast-enhanced computed tomography (DCE-CT)-derived blood volume (BV) and blood flow (BF) and core biopsy microvessel density (MVD). METHODS: As planned in DaRenCa Study-1 study, DCE-CT and core biopsy were performed from the same tumour/metastasis at baseline. MVD was assessed by CD34 immunostaining in tumour (CD34-indexT) or tumour including necrosis (CD34-indexTN). BV and BF were assessed using the DCE-CT software. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier analysis. Spearman coefficient (rho) tested the correlation between MVD and BV, BF, or CT density (HU). RESULTS: At baseline, 25 patients had analysable scans and tissue. BVdeconv, BVPatlak, and BFdeconv > median were associated with favourable OS (43.2 versus 14.6 months, p = 0.002; 31.6 versus 20.2 months, p = 0.015; and 31.6 versus 24.5 months, p = 0.019). CD34-indexT and CD34-indexTN did not correlate with age (p = 0.543), sex (p = 0.225), treatment (p = 0.848), International mRCC Database Consortium category (p = 0.152), synchronous versus metachronous metastatic disease (p = 0.378), or tumour volume (p = 0.848). CD34-indexT or CD34-indexTN > median was not associated with PFS (p = 0.441 and p = 0.854, respectively) or OS (p = 0.987 and p =0.528, respectively). CD34-indexT or CD34-indexTN was not correlated with BV, BF, or HU (rho 0.20-0.26). CONCLUSIONS: Differently from MVD, DCE-CT-derived BV and BF had prognostic impact and may better reflect angiogenesis in mRCC. TRIAL REGISTRATION: NCT01274273.

Use of patient outcome endpoints to identify the best functional CT imaging parameters in metastatic renal cell carcinoma patients.

OBJECTIVE: To use the patient outcome endpoints overall survival and progression-free survival to evaluate functional parameters derived from dynamic contrast-enhanced CT. METHODS: 69 patients with metastatic renal cell carcinoma had dynamic contrast-enhanced CT scans at baseline and after 5 and 10 weeks of treatment. Blood volume, blood flow and standardized perfusion values were calculated using deconvolution (BVdeconv, BFdeconv and SPVdeconv), blood flow and standardized perfusion values using maximum slope (BFmax and SPVmax) and blood volume and permeability surface area product using the Patlak model (BVpatlak and PS). Histogram data for each were extracted and associated to patient outcomes. Correlations and agreements were also assessed. RESULTS: The strongest associations were observed between patient outcome and medians and modes for BVdeconv, BVpatlak and BFdeconv at baseline and during the early ontreatment period (p < 0.05 for all). For the relative changes in median and mode between baseline and weeks 5 and 10, PS seemed to have opposite associations dependent on treatment. Interobserver correlations were excellent (r ≥ 0.9, p < 0.001) with good agreement for BFdeconv, BFmax, SPVdeconv and SPVmax and moderate to good (0.5 < r < 0.7, p < 0.001) for BVdeconv and BVpatlak. Medians had a better reproducibility than modes. CONCLUSION: Patient outcome was used to identify the best functional imaging parameters in patients with metastatic renal cell carcinoma. Taking patient outcome and reproducibility into account, BVdeconv, BVpatlak and BFdeconv provide the most clinically meaningful information, whereas PS seems to be treatment dependent. Standardization of acquisition protocols and post-processing software is necessary for future clinical utilization. Advances in knowledge: Taking patient outcome and reproducibility into account, BVdeconv, BVpatlak and BFdeconv provide the most clinically meaningful information. PS seems to be treatment dependent.

Dynamic Contrast-Enhanced Computed Tomography-Derived Blood Volume and Blood Flow Correlate With Patient Outcome in Metastatic Renal Cell Carcinoma.

OBJECTIVES: The aim was to explore the potential for using dynamic contrast-enhanced computed tomography as a noninvasive functional imaging biomarker before and during the early treatment of metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Dynamic contrast-enhanced computed tomography scans were performed at baseline and after 5 and 10 weeks' treatment in 69 prospectively included mRCC patients receiving treatment with interferon alpha and interleukin 2 (n = 26); interferon alpha, interleukin 2, and bevacizumab (n = 24); sunitinib (n = 7); pazopanib (n = 5); or temsirolimus (n = 7). Using a prototype software program (Advanced Perfusion and Permeability Application, Philips Healthcare, Best, the Netherlands), blood volume (BV), blood flow (BF), and permeability surface area product (PS) were calculated for each tumor at baseline, week 5, and week 10. These parameters as well as relative changes between baseline and weeks 5 and 10 were tested for associations with progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. RESULTS: Using the 25th percentile as the cutoff, baseline BV for all patients independent of subsequent treatment was statistically significantly associated with PFS (10.8 vs 5.3 months, P = 0.007) and OS (35.2 vs 13.3 months, P = 0.001), and baseline BF was significantly associated with OS (31.7 vs 14.6 months, P = 0.024) with high values for both parameters being associated with significantly longer PFS and OS. Baseline PS was not associated with PFS or OS.In patients treated with angiogenesis inhibitors (bevacizumab, sunitinib, pazopanib, or temsirolimus), the relative change in BV from baseline to week 5 using 25th percentile as the cutoff was associated with PFS (5.6 vs 24.8 months, P = 0.001) and OS (19.1 months vs not reached, P = 0.008) and from baseline to week 10 with PFS (8.1 vs 16.4 months, P = 0.014) and OS (15.5 months vs not reached, P = 0.002). The relative change in BF from baseline to week 5 using medians as the cutoff was associated with PFS (5.5 vs 14.3 months, P = 0.018) and OS (14.6 vs 31.7 months, P = 0.027). The relative change in BF from baseline to week 10 using 25th percentile as the cutoff was associated with PFS (8.3 vs 46.9 months, P = 0.011) and OS (19.1 vs 53.0 months, P = 0.006). For both parameters, the largest reductions during early treatment were associated with increased PFS and OS.In patients receiving immunotherapy only (interferon alpha and interleukin 2), relative changes in PS between baseline and weeks 5 and 10 were significantly associated with PFS with larger increases associated with longer PFS. In patients receiving angiogenesis inhibitors, the relative changes in PS between baseline and week 10 were significantly associated with PFS and OS with larger reductions associated with favorable outcomes. CONCLUSIONS: In patients with mRCC treated with angiogenesis inhibitors, the largest reductions in BV and BF between baseline and weeks 5 and 10 were associated with favorable outcomes. At baseline, the lowest BV and BF were associated with the poorest outcomes regardless of the subsequent treatment. Early reductions in PS were associated with favorable outcomes for those treated with angiogenesis inhibitors and with poor outcomes for those treated with immunotherapies.

Intralymphatic immunotherapy induces allergen specific plasmablasts and increases tolerance to skin prick testing in a pilot study.

BACKGROUND: Allergen Immunotherapy is a promising treatment of allergy. Seven patients with rhinoconjunctivitis to grass allergen were treated with intralymphatic immunotherapy (ILIT) to explore whether this treatment could be performed. Effect of treatment was assessed as change in symptom medication score, response in skin prick test and nasal allergen provocation. ILIT deposits allergen in an inguinal lymph node to elicit a strong immune stimulus. This allowed us to monitor appearance of allergen specific plasmablasts 7 days after allergen injection. FINDINGS: In an open trial of seven patients with a history of symptomatic allergic rhinoconjunctivitis due to grass pollen, three injections of allergen into inguinal lymph nodes were performed with monthly intervals. Allergen injections induced grass allergen specific plasmablasts expressing other isotypes than IgE after 7 days, induced a trend toward improvement in symptom and medication score and rhinoconjunctivitis-related quality of life during the grass pollen season 2013 and significantly raised the threshold in nasal allergen challenge and titrated skin prick testing. Mild side-effects were recorded after 3 of the 21 of injections (14 %). CONCLUSIONS: This pilot study shows that ILIT may induce allergen specific plasmablasts, and confirms an effect on provocation of mast cells in skin and nasal mucosa during the ensuing winter.

Fas ligand expression in metastatic renal cell carcinoma during interleukin-2 based immunotherapy: no in vivo effect of Fas ligand tumor counterattack.

PURPOSE: It has been hypothesized that tumor cells expressing Fas ligand (FasL) might be able to counterattack and neutralize tumor-infiltrating lymphocytes. We assessed the effect of FasL tumor counterattack on the clinical outcome of interleukin-2 (IL-2)-based immunotherapy in metastatic renal cell carcinoma. EXPERIMENTAL DESIGN: Tumor core needle biopsies were obtained before IL-2-based immunotherapy in 86 patients and repeated within the first cycle in 57 patients. Tumor cells expressing FasL and intratumoral lymphocyte subsets expressing CD4, CD8, CD56, and CD57 were analyzed by immunohistochemistry. RESULTS: At baseline, negative FasL staining in tumor cells was seen in 10 of 86 (12%) biopsies, whereas intense FasL staining was seen (a) in fewer than 10% of tumor cells in 26 (30%) biopsies; (b) in 11 to 50% of tumor cells in 25 (29%) biopsies; (c) in 51 to 90% of tumor cells in 18 (21%) biopsies; and (d) in >90% of tumor cells in 7 (8%) biopsies. On treatment, tumor FasL expression did not change from baseline levels. Moreover, tumor FasL expression was not correlated with objective response or survival whereas the absolute number of CD4(+), CD8(+), CD56(+), and CD57(+) cells per mm(2) tumor tissue at baseline was significantly higher in responding patients compared with nonresponding patients (P = 0.01, P = 0.008, P = 0.015, and P < 0.001, respectively). During the first course of immunotherapy, the absolute number of CD4(+), CD8(+), and CD57(+) cells per mm(2) tumor tissue was significantly higher in responding patients compared with nonresponding patients (P = 0.034, P < 0.001, and P < 0.001, respectively). However, no correlation was observed between the number of intratumoral lymphocytes and tumor FasL expression level. CONCLUSION: These observations do not support the hypothesis that FasL tumor "counterattack" has an effect on the clinical outcome in metastatic renal cell carcinoma during IL-2-based immunotherapy.

Malignant ascites in patients with terminal cancer is effectively treated with permanent peritoneal catheter.

BACKGROUND: Malignant ascites is a pathological condition caused by intra- or extra-abdominal disseminated cancer. The object of treatment is palliation. In search of an effective and minimally invasive palliative treatment of malignant ascites placement of a permanent intra peritoneal catheter has been suggested. PURPOSE: To evaluate our experiences with treatment of malignant ascites by implantation of a permanent PleurX catheter. MATERIAL AND METHODS: A retrospective study was conducted, comprising 20 consecutive patients with terminal cancer, who had a permanent PleurX catheter implanted because of malignant ascites in the period from February to November 2014. Using the patients' medical records, we retrieved data on patients and procedures. RESULTS: The technical success rate was 100%. Catheter patency was 95.2%, one catheter was removed due to dislocation. Ten patients (50.0%) experienced minor adverse events. No procedural difficulties were reported and there was no need for additional treatment of malignant ascites after catheter implantation. Median residual survival after catheter implantation was 27 days. CONCLUSION: Implantation of a permanent PleurX catheter is a minimally invasive and effective procedure with only minor adverse events and a high rate of catheter patency in patients with malignant ascites caused by terminal cancer disease.

Dynamic contrast-enhanced computed tomography as a potential biomarker in patients with metastatic renal cell carcinoma: preliminary results from the Danish Renal Cancer Group Study-1.

OBJECTIVES: The aim of this study was to explore the impact of dynamic contrast-enhanced (DCE) computer tomography (CT) as a biomarker in metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Twelve patients with favorable or intermediate Memorial Sloan Kettering Cancer Center risk group and clear cell mRCC participating in an ongoing prospective randomized phase II trial comprising interleukin-2-based immunotherapy and bevacizumab were included in this preliminary analysis. All patients had a follow-up time of at least 2 years. Interpretation of DCE-CT (max slope method) was performed blinded to treatment group. The DCE-CT scans were performed at baseline, at weeks 5 and 10, and thereafter every third month. Blood flow (BF; mL/min/100 mL), peak enhancement (Hounsfield units), time to peak (seconds), and blood volume (BV; mL/100 g) were calculated. Parameters for DCE-CT were correlated with sum of diameters (defined by Response Evaluation Criteria in Solid Tumors 1.1), progression-free survival (PFS), and overall survival (OS) using Wilcoxon, Man-Whitney, Kaplan-Meier, and log rank statistics, as appropriate. RESULTS: Blood flow at baseline ranged from 4.9 to 148.1 mL/min/100 mL (median, 62.2; 25th percentile, 25.8; 75th percentile, 110.0). Patients with high baseline BF (using quartiles as cutoffs) had significantly longer OS (not reached vs 5.2 months, P = 0.011) and longer PFS (not reached vs 3.9 months, P = 0.026). Blood volume at baseline ranged from 8.8 to 74.1 mL/100 g tissue (median, 21.5), and at week 5, from 4.9 to 34.7 mL/100 g (median, 17.2). Relative changes in BV between baseline and week 5 ranged from -64% to +68% (median, -16%; 25th percentile, -41%; 75th percentile, +2%) and were significantly associated with OS using quartiles as cutoffs (5.2 months vs not reached, P = 0.038) and PFS using the median as cutoff (5.3 months vs not reached, P = 0.009), with larger reductions associated with longer survival. Using medians as cutoffs, relative changes in both BF and BV between baseline and week 10 were significantly associated with OS (for both, 8.6 months vs not reached, P = 0.031). CONCLUSIONS: Dynamic contrast-enhanced CT is a potential biomarker in patients with mRCC. High baseline BF and reductions in BF and BV during early treatment are associated with improved outcome. Large-scale studies are required.

Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma.

With the objective of evaluating leukocyte orchestration in situ, serial blood samples and tumour tissue core needle biopsies were obtained at baseline and repeated after 1 month of therapy, among 49 consecutive single-institution patients with metastatic renal cell carcinoma (mRCC). Patients were treated with outpatient low-dose subcutaneous interleukin 2 (IL-2) and interferon alpha (IFN-alpha) alone (n = 23) or in combination with histamine dihydrochloride (n = 26). Objective responses were achieved in ten of 49 patients (20%) with an overall median survival of 14 months and an estimated 1- to 4-year survival rate of 57, 35, 24 and 22%, respectively. Toxicity was mild to moderate with no treatment-related deaths. High numbers of blood monocytes and neutrophils were significantly correlated to short survival. By contrast, high numbers of intratumoural CD3+, CD4+, CD8+ and CD57+ lymphocytes were positively correlated to objective response and/or long-term survival. Intratumoural lymphocytes showed low zeta expression, whereas blood lymphocytes showed almost normal levels of zeta expression. Neutrophils, the most frequent peripheral blood leukocyte subset, were scarce within the tumour tissue. Intratumoural eosinophils were not observed. In progressing patients, both the absolute number and the relative composition of leukocyte subsets in blood and tumour tissue remained unaffected by cytokine therapy. However, in responding patients, cytokine therapy was followed by an absolute and relative increase in T cells in blood as well as tumour tissue, an absolute and relative reduction in neutrophils in peripheral blood and a relative reduction of intratumoural macrophages. Histamine did not influence levels of intratumoural or blood leukocyte numbers, zeta-chain expression or cytotoxicity. In conclusion, the present regimen of outpatient low-dose subcutaneous IL-2 and IFN-alpha in mRCC should attract interest based on response, survival and toxicity. In responding patients, cytokine therapy was followed by substantial changes in the blood and tumour tissue leukocyte composition, correlated to response and survival. No discernable differences in immunologic parameters studied could be detected between histamine- and nonhistamine-treated patients.