Response to Anti-PD1/L1 Antibodies in Advanced Urothelial Cancer in the 'Real-Life' Setting.

Immune checkpoint inhibitors (ICIs) are now the standard of care for metastatic urothelial carcinoma (mUC) patients. Our aim was to describe the activity of ICIs in mUC and find the clinical parameters associated with response. This is a retrospective, single-center chart review of mUC patients receiving ICIs. The overall survival (OS) was plotted using the Kaplan-Meier method and was compared using a log-rank test. Associations between the variables and responses were analyzed by univariate and multivariable analyses, using either logistic regression or a Chi-square/Fisher's exact test. Ninety-four patients received ICIs, 85% of which were in the second line or beyond; the median age was 71.8 years, and 82% were men. Six (6.4%), 11 (11.7%), 7 (7.4%) and 70 (74.5%) patients achieved a complete response (CR), partial response (PR), mixed response/stable disease (M/SD) or progressive disease (PD), respectively. The median overall survival was 3.2 months for the entire cohort and was significantly different according to the response pattern-not reached, 32.3, 6.4 and 2.0 months for CR, PR, M/SD and PD, respectively. The response was not significantly associated with the line of treatment. 'Site of metastasis' was associated with the response, and the absolute neutrophil count was borderline associated with the response. In summary, we found a substantial variance in the potential benefit from ICIs in mUC, emphasizing the need for predictive biomarkers and frequent monitoring of mUC patients receiving ICIs.

Very low-dose computerized tomography for confirmation of urinary stone presence.

PURPOSE: To determine whether a modified non-contrast very low-dose computed tomography (VLD-CT) protocol is applicable for confirmation of known urolithiasis. METHODS AND MATERIALS: Consecutive adult patients with a CT scan showing urinary tract stone(s) between 6/2017-12/2018 were included. They were referred to a modified VLD-CT protocol if stone presence was equivocal or if stone location needed reassessment before an endourological interventional procedure. The scanned area was limited to the level of initial stone location caudally. Data on patients' demographics andbody mass index, were collected. The scanned length and radiation dose were calculated. Images were reviewed by two radiologists who assessed stone size and location. Follow-up reference standard included stone passage, surgical removal, and other imaging and clinical information. RESULTS: Sixty-three patients [63 stones, mean BMI 28.7 (range 19-41.9)] were included. VLD-CTs revealed 31 stones in 31 patients, with a mean stone length of 5.5 mm. Fifteen stones remained at the same location, and 16 had migrated, of which two appeared in the bladder. Thirty-two stones were not observed on VLD-CT. The mean span scanned on the VLD-CT was 274 mm (± 80). The average radiation exposure was 1.47 mGy (range 1.09-3.3), and the absorbed dose was 0.77 mSv (range 0.39-1.43), compared to 10.24 mGy (range 1.75-28.9) and 7.87 mSv (range 1.44-18.5) in the previous scan. The mean radiation dose reduction between scans was 89%. On follow-up, all VLD-CT findings were confirmed. CONCLUSION: A modified imaging protocol is applicable for confirmation of stone presence and location by utilizing very low-dose radiation exposure.

Clinical significance of perifissural nodules in the oncologic population.

PURPOSE: To evaluate for stability of perifissural nodules (PFNs) in a dedicated oncologic population. METHODS: A retrospective review of 500 computed tomography (CT) chests from oncologic patients at our tertiary care cancer center with at least a three year follow up yielded 76 patients with PFNs. Patients with metastases on baseline CT chest were excluded (n = 14) as the presence of a PFN would not be clinically relevant, thus our final patient cohort was 62 patients with a total of 112 PFNs. PFN features, clinical features, and ancillary information was recorded from the CT and the electronic medical record for all patients. The two patient cohorts-stable or decreased PFN vs. increased PFN-were then compared. RESULTS: 112 PFNs were examined in 62 patients with a median follow up interval of 5.7 years. Of 62 patients, 59 (95.2%, 95% CI: 86.5, 99.0) had decreased/stable PFNs on follow up scan (median follow up 5.6 years) and 3 (4.8%, 95% CI: 1.0, 13.5%) had enlarged PFNs (median follow up 6.3 years). None of the PFN features, clinical features, nor ancillary information from the CT proved to be statistically significant. CONCLUSIONS: Despite the lack of statistically significant distinguishing features to predict growth, our results are reassuring, since the majority of PFNs in our oncology patients were decreased or unchanged in size which is comparable to previously published data on PFNs in non-oncologic patients. Thus, we can similarly presume these nodules are most likely benign and can provide reassurance to our oncologic colleagues and our patients. Larger studies are warranted to further evaluate PFNs in the oncologic population which also examines the nodules by cancer type.

Computed Tomographic Appearance of Organizing Pneumonia in an Oncologic Patient Population.

OBJECTIVE: The aims of this study were to describe the computed tomographic features of organizing pneumonia (OP) in an oncologic patient population and to also identify features associated with lung cancer and patients undergoing hematopoietic stem cell transplant (HSCT). METHODS: In retrospective computed tomographies from 151 patients with pathologically confirmed OP between January 2009 and September 2014, number of lesions, location, size, margin type, and consistency, as well as volume of lymphadenopathy and the presence and size of pleural effusions, were recorded. Associated malignancy was noted. RESULTS: Organizing pneumonia most commonly presented as a diffuse process (n = 62, 41%), frequently occupied both a central and peripheral location (n = 79, 53%), and commonly presented with a solid appearance (n = 67, 44%) or with ground glass opacity (n = 80, 53%). Pleural effusions were seen in 68 patients (45%). Organizing pneumonia less frequently contained air bronchograms, cavitation, necrosis, surrounding ground glass opacity, or adjacent bronchiectasis. In patients with lung cancer (n = 25, 17%), OP more likely presented as discrete lesions and occupied a peripheral location as compared with patients with other malignancies (Ps = 0.025 and 0.002). In HSCT patients (n = 29, 19%), a diffuse process was more commonly seen than in non-HSCT patients (P = 0.038). CONCLUSIONS: Organizing pneumonia more commonly presents as discrete lesions with a peripheral location in patients with lung cancer and as a diffuse process in patients who had undergone HSCT.

Prostate cancer bone metastases on staging prostate MRI: prevalence and clinical features associated with their diagnosis.

PURPOSE: Bone lesions on prostate MRI often raise concern about metastases. This study aimed to evaluate the prevalence of bone metastases on staging prostate MRI and evaluate associations between their MRI features and clinical/pathologic characteristics. METHODS: Retrospective, IRB-approved study of 3765 patients undergoing prostate MRI for newly diagnosed PCa between 2000 and 2014. The reference standard to calculate the prevalence of bone metastases was bone biopsy and/or ≥1-year follow-up after MRI. In a subsample of 228 patients, the MRI characteristics of bone lesions were recorded by two radiologists independently. Associations between MRI and clinical/pathologic findings, including National Comprehensive Cancer Network (NCCN) risk categories, were calculated. RESULTS: 57/3765 patients (1.5%, 95% CI 1.2-2.0%) had bone metastases. No patient with NCCN low-risk PCa (Gleason < 7, PSA < 10 ng/mL, cT1-2a) had bone metastases. In the subsample, ≥1 bone lesion was present on MRI in 74% (95% CI 0.67-0.79) and 72% (95% CI 0.66-0.78) of patients (R1 and R2). Larger lesion diameter (OR 1.33/1.19; p < 0.001 for both readers) and the absence of intralesional fat (OR 0.07/0.11; p = 0.004/0.002 for R1/R2) were significantly associated with bone metastases. CONCLUSION: Bone lesions are common in prostate MRI, but only rarely represent metastases. MRI should be interpreted in the context of clinical features that influence the likelihood of metastatic disease.

CT appearance of the pelvis after Cesarean delivery--what is considered normal?

OBJECTIVE: To describe the normal computed tomography (CT) appearance of the pelvis after uncomplicated Cesarean section (C-section). PATIENTS AND METHODS: Pelvic CT examinations of 31 patients after uncomplicated C-section were reviewed. RESULTS: Higher postoperative day (POD) correlated well with decreases in the uterine long axis and endometrial width but did not correlate to scar width. Full thickness defect of the uterine wall was revealed in 48% of patients. Small volumes of intrauterine gas presented in half of patients at POD 1-26. Free pelvic fluid appeared in 74%. Pelvic collections were rare and small. CONCLUSION: There is wide variability in pelvic CT appearance following uncomplicated C-section.

Resistance of renal cell carcinoma to sorafenib is mediated by potentially reversible gene expression.

PURPOSE: Resistance to antiangiogenic therapy is an important clinical problem. We examined whether resistance occurs at least in part via reversible, physiologic changes in the tumor, or results solely from stable genetic changes in resistant tumor cells. EXPERIMENTAL DESIGN: Mice bearing two human RCC xenografts were treated with sorafenib until they acquired resistance. Resistant 786-O cells were harvested and reimplanted into naïve mice. Mice bearing resistant A498 cells were subjected to a 1 week treatment break. Sorafenib was then again administered to both sets of mice. Tumor growth patterns, gene expression, viability, blood vessel density, and perfusion were serially assessed in treated vs control mice. RESULTS: Despite prior resistance, reimplanted 786-O tumors maintained their ability to stabilize on sorafenib in sequential reimplantation steps. A transcriptome profile of the tumors revealed that the gene expression profile of tumors upon reimplantation reapproximated that of the untreated tumors and was distinct from tumors exhibiting resistance to sorafenib. In A498 tumors, revascularization was noted with resistance and cessation of sorafenib therapy and tumor perfusion was reduced and tumor cell necrosis enhanced with re-exposure to sorafenib. CONCLUSIONS: In two RCC cell lines, resistance to sorafenib appears to be reversible. These results support the hypothesis that resistance to VEGF pathway therapy is not solely the result of a permanent genetic change in the tumor or selection of resistant clones, but rather is due to a great extent to reversible changes that likely occur in the tumor and/or its microenvironment.

Liposomal doxorubicin increases radiofrequency ablation-induced tumor destruction by increasing cellular oxidative and nitrative stress and accelerating apoptotic pathways.

PURPOSE: To determine if oxidative and nitrative stress and/or apoptosis contribute to increased coagulation when combining radiofrequency (RF) ablation with liposomal doxorubicin. MATERIALS AND METHODS: Animal care committee approval was obtained. R3230 mammary adenocarcinomas in Fischer rats were treated with either RF ablation (n = 43), 1 mg of intravenously injected liposomal doxorubicin (n = 26), or combined therapy (n = 30) and were compared with control subjects (n = 11). A subset of animals receiving combination therapy (n = 24) were treated in the presence or absence of N-acetylcysteine (NAC) administered 24 hours and 1 hour before RF ablation. Tumors were analyzed 2 minutes to 72 hours after treatment to determine the temporal range of response by using immunohistochemical staining of the apoptosis marker cleaved caspase-3, phosphorylated gammaH2AX, and HSP70 and of markers of oxidative and nitrative stress (8-hydroxydeoxyguanosine [8-OHdG], 4-hydroxynonenal [4-HNE]-modified proteins, and nitrotyrosine [NT]). Statistical analyses, including t tests and analysis of variance for comparisons where appropriate, were performed. RESULTS: By 4 hours after RF ablation alone, a 0.48-mm +/- 0.13 (standard deviation) peripheral band with 57.0% +/- 7.3 cleaved caspase-3 positive cells was noted at the ablation margin, whereas a 0.73-mm +/- 0.18 band with 77.7% +/- 6.3 positivity was seen for combination therapy (P < .03 for both comparisons). Combination therapy caused increased and earlier staining for 4-HNE-modified proteins, 8-OHdG, NT, and gammaH2AX with colocalization to cleaved caspase-3 staining. A rim of increased HSP70 was identified peripheral to the area of cleaved caspase-3. Parameters of oxidative and nitrative stress were significantly inhibited by NAC 1 hour following RF ablation, resulting in decreased cleaved caspase-3 positivity (0.28-mm +/- 0.09 band of 25.9% +/- 7.4 positivity vs 0.59-mm +/- 0.11 band of 62.9% +/- 6.0 positivity, P < .001 for both comparisons). CONCLUSION: Combining RF ablation with liposomal doxorubicin increases cell injury and apoptosis in the zone of increased coagulation by using a mechanism that involves oxidative and nitrative stress that leads to accelerated apoptosis.

Does arterial spin-labeling MR imaging-measured tumor perfusion correlate with renal cell cancer response to antiangiogenic therapy in a mouse model?

PURPOSE: To determine whether arterial spin-labeling (ASL) magnetic resonance (MR) imaging findings at baseline and early during antiangiogenic therapy can predict later resistance to therapy. MATERIALS AND METHODS: Protocol was approved by an institutional animal care and use committee. Caki-1, A498, and 786-0 human renal cell carcinoma (RCC) xenografts were implanted in 39 nude mice. Animals received 80 mg sorafenib per kilogram of body weight once daily once tumors measured 12 mm. ASL imaging was performed at baseline and day 14, with additional imaging performed for 786-0 and A498 (3 days to 12 weeks). Mean blood flow values and qualitative differences in spatial distribution of blood flow were analyzed and compared with histopathologic findings for viability and microvascular density. t Tests were used to compare differences in mean tumor blood flow. Bonferroni-adjusted P values less than .05 denoted significant differences. RESULTS: Baseline blood flow was 80.1 mL/100 g/min +/- 23.3 (standard deviation) for A498, 75.1 mL/100 g/min +/- 28.6 for 786-0, and 10.2 mL/100 g/min +/- 9.0 for Caki-1. Treated Caki-1 showed no significant change (14.9 mL/100 g/min +/- 7.6) in flow, whereas flow decreased in all treated A498 on day 14 (47.9 mL/100 g/min +/- 21.1) and in 786-0 on day 3 (20.3 mL/100 g/min +/- 8.7) (P = .003 and .03, respectively). For A498, lowest values were measured at 28-42 days of receiving sorafenib. Regions of increased flow occurred on days 35-49, 17-32 days before documented tumor growth and before significant increases in mean flow (day 77). Although 786-0 showed new, progressive regions with signal intensity detected as early as day 5 that correlated to viable tumor at histopathologic examination, no significant changes in mean flow were noted when day 3 was compared with all subsequent days (P > .99). CONCLUSION: ASL imaging provides clinically relevant information regarding tumor viability in RCC lines that respond to sorafenib.

Body tumor CT perfusion protocols: optimization of acquisition scan parameters in a rat tumor model.

PURPOSE: To evaluate the effects of total scanning time (TST), interscan delay (ISD), inclusion of image at peak vascular enhancement (IPVE), and selection of the input function vessel on the accuracy of tumor blood flow (BF) calculation with computed tomography (CT) in an animal model. MATERIALS AND METHODS: All animal protocols and experiments were approved by the institutional animal care and use committee prior to study initiation. After injection of 0.2 or 0.4 mL of iodinated contrast material, six rats with mammary adenocarcinoma (three tumors each) were scanned in the axial mode for 5 minutes with 1-second ISD (reference scan), 2.5-mm section thickness, 2.5-mm interval, pitch of 1.3, 120 kV, 240 mA, and 0.5-second rotation time. A total of 126 dynamic data sets were created with commercial software by varying TST and ISD, including or excluding the IPVE, and using the aorta or inferior vena cava (IVC) as the input function. Comparative analyses were used to test for significant differences (t test, Wilcoxon signed rank test). Regression analysis was performed to assess the relationship between attenuation of the input function vessel and BF. RESULTS: No significant difference was observed (P > .05) when TST was as short as 30 seconds (range, 20-23 mL/100 g). In sequences performed with an ISD longer than 8 seconds, BF was significantly elevated (P < .01). Inclusion of the IPVE eliminated this difference (P > .10). Use of the IVC as the input function resulted in significantly higher BF (P < .02), with a correlation between peak attenuation and BF (R(2) = 0.43). CONCLUSION: To reduce radiation dose in tumor perfusion with CT, TST can be reduced without causing significant changes in BF calculation in an animal model. Scanning the aortic reference with peak contrast enhancement reduces variability sufficiently to allow for longer ISDs.

Perfusion MDCT enables early detection of therapeutic response to antiangiogenic therapy.

OBJECTIVE: The objective of our study was to determine whether perfusion CT can be used to detect early changes in therapeutic response to antiangiogenic therapy in an animal tumor model. MATERIALS AND METHODS: Twenty-five rats implanted with R3230 mammary adenocarcinoma (diameter, 1.2-2.0 cm) randomly received 7.5 or 30 mg/kg of an antiangiogenic agent, sorafenib, by daily gavage for 4 (n = 4), 9 (n = 9), or 14 (n = 5) days. Seven untreated animals served as a control group. Perfusion MDCT was performed at days 0, 4, 9, and 14 with 0.4 mL of ioversol (350 mg/mL) and included four 5-mm slices covering the entire tumor volume. Changes in tumor growth were determined by volumetric analysis of CT data. Serial changes in tumor volume and blood flow were assessed and correlated with pathology findings. RESULTS: All control tumors grew larger (from 2.0 +/- 0.7 cm(3) at day 0 to 5.9 +/- 1.0 cm(3) at day 14), whereas all treated tumors shrank (from 2.5 +/- 1.1 to 2.1 +/- 1.0 cm(3)), with a statistically significant rate of growth or shrinkage in both groups (p < 0.05). Although perfusion in the control tumors changed little from day 0 to day 14 (day 0, 18.1 +/- 9.2 mL/min/100 g; day 4, 15.8 +/- 5.6; day 9, 21.7 +/- 12.2; day 14, 27.7 +/- 34), in the sorafenib group, the mean blood flow was significantly lower at day 4 (5.2 +/- 3.2 mL/min/100 g, 77% decrease), day 9 (6.4 +/- 4.0 mL/min/100 g, 66% decrease), and day 14 (6.3 +/- 5.2 mL/min/100 g, 83% decrease) compared with day 0 (23.8 +/- 11.6 mL/min/100 g) (p < 0.05). Poor correlation was seen between changes in blood flow and tumor volume for days 0-9 (r(2) = 0.34), 4-9 (r(2) = 0.0004), and 9-14 (r(2) = 0.16). However, when comparing day 4 images with days 9 and 14 images, seven of 14 (50%) sorafenib-treated tumors had focal areas of new perfusion that correlated with areas of histopathologic viability despite the fact that these tumors were shrinking in size from day 4 onward (day 4, 2.18 +/- 0.8 cm(3); day 9, 1.98 +/- 0.8 cm(3)). CONCLUSION: Perfusion MDCT can detect focal blood flow changes even when the tumor is shrinking, possibly indicating early reversal of tumor responsiveness to antiangiogenic therapy. Given that changes in tumor volume after antiangiogenic therapy do not necessarily correlate with true treatment response, physiologic imaging of tumor perfusion may be necessary.