Differences in sensitivity to new therapies between primary and metastatic breast cancer: A need to stratify the tumor response?

OBJECTIVE: We compared therapeutic response of Varlitinib + Capecitabine (VC) versus Lapatinib + Capecitabine (LC) in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer after trastuzumab therapy by assessing changes in target lesion (TL) diameter and volume per location. METHODS: We retrospectively analyzed the CT data of the ASLAN001-003 study (NCT02338245). We analyzed TL size and number at each location focusing on therapeutic response from baseline to Week 12. We used TL diameter and volume to conduct an inter-arm comparison of the response according to: RECIST 1.1; stratified per TL location and considering TLs independently. Multiple pairwise intra-arm comparisons of therapeutic responses were performed. Considering TL independently, weighted models were designed by adding weighted mean TL responses grouped by location. RESULTS: We evaluated 42 patients (88 TL) and 35 patients (74 TL), respectively, at baseline and Week 12. We found reductions in breast TL burden in the VC arm compared to the LC arm (p = 0.002 (diameter), p < 0.001 (volume)). Responses and TL sizes at baseline were not correlated. Explained variabilities of volume change per TL location, patient and patient:TL interaction were 36%, 10% and 4% (VC), and 13%, 1% and 23%, (LC). A test of inter-arm difference of responses yielded p = 0.07 (diameter), and p < 0.001 (volume). CONCLUSIONS: The therapeutic responses differed across tumors' locations; the magnitude of the differences of responses across the tumors' locations were drug-dependent. Stratified analysis of the response by tumor location improved drug comparisons and is a powerful tool to understand TL heterogeneity.

Enhanced vertebra to disk ratio as a new semi-quantitative imaging biomarker for Gaucher disease patients.

PURPOSE: Gaucher disease (GD) is an inherited lysosomal storage disorder. The Vertebral Disk Ratio (VDR) is a semi-quantitative imaging biomarker designed to diagnose and monitor GD. Computed from standard T1 MRI images, the VDR is derived from 2D segmentations. This study aimed to evaluate the 3D version of VDR, namely eVDR, and analyze the performances of two eVDR-derived response criteria for GD patients. METHODS: Three datasets were used: 8 longitudinal GD patients, 13 non-GD patients, and 2 longitudinal GD patients with known Bone Marrow Burden (BMB) scores. Two eVDR-derived response criteria were tested: 1) a parametric version (PeVDR) averaging all eVDR measures recorded for the 5 lumbar vertebrae; and 2) a non-parametric version (NPeVDR), considering all eVDR measures as independent and evaluating therapeutic response in a paired fashion. Analyses included assessment of reader variability in eVDR (3D) versus VDR (2D) and comparison with BMB response criteria. RESULTS: The repeatability of eVDR (3D) versus VDR (2D) demonstrated no difference in mean values but a lower variance (p < 0.004). The PeVDR intra-reader variability had a standard deviation < 0.1 with a coefficient of variation < 5%; the inter-reader variability featured a Limit of Agreement < 5% and a Bias < 3%. Observational comparison of eVDR and BMB scoring and sensitivity indicated a correlation between PeVDR and BMB, with an improved sensitivity with the NPeVDR version. CONCLUSIONS: Based on a standard MRI sequence, the eVDR imaging biomarker and its derived response criteria improved GD assessments and could help assessing other bone marrow diseases.

BIRADS 3 MRI lesions: Was the initial score appropriate and what is the value of the blooming sign as an additional parameter to better characterize these lesions?

OBJECTIVE: To investigate whether there were suspicious criteria on the initial MRI in BIRADS 3 lesions. To analyze the value of "blooming sign" as an additional criterion for malignancy. MATERIALS AND METHODS: In this retrospective study the lesion morphological and enhancement characteristics were analyzed. The "blooming sign" (BS), defined as the lesion size increase between the early and the late phase after gadolinium was assessed. We determined the optimal cut-off value for the BS to distinguish benign and malignant breast lesions. RESULTS: 100 lesions were classified BIRADS 3 in 75 patients (12%). Four of the five malignant lesions had suspicious BIRADS criteria on the index MRI. 45 lesions were stable and 30 lesions resolved spontaneously during the follow-up MRI. The optimal cut-off value for the BS was 8.54% with 100% sensitivity, 94% specificity, 44% positive and 100% negative predictive values. Using reclassification rule to upgrade benign BIRADS lesions with suspicious BS feature and downgrade suspicious BIRADS lesions with benign BS feature increased MRI specificity (89%), sensitivity (100%) while preserving NPV (100%). CONCLUSIONS: This study showed the suggestive part of classified BIRADS 3 lesions. The blooming sign seems to be a good additional parameter to increase MRI specificity when associated to BIRADS criteria.

Improved surgical management through optimized imaging of pelvic endometriosis.

Deep infiltrating endometriosis is a frequent benign pathology that is found in 10-15% of fertile women and in 20% of infertile women. It has an impact on fertility but also on everyday life. In case of failure of medical treatment, surgical treatment can be offered to the patient. To provide adequate treatment and give the clearest information to patients, it seems essential to achieve optimal preoperative imaging. The aim of this work was to define for each compartment the surgeon's expectations and the indications of iconographic work-ups before surgical management of pelvic endometriosis. We do not discuss technical examinations nor surgical indications and techniques.

Shear Wave Elastography (SWE): An Analysis of Breast Lesion Characterization in 83 Breast Lesions.

Qualitative and quantitative shear wave elastography (SWE) criteria were assessed to differentiate between malignant and benign breast lesions. This prospective study included 83 lesions. SWE features measured included maximal stiffness values inside the lesion (E(lesion)) and in the peri-lesion area (E(perilesion)) and ratio values (R(lesion) and R(perilesion)) according to the formula E(lesion) or E(perilesion)/E(fat), with E(fat) corresponding to normal fatty tissue. We compared ultrasonography (B-mode), SWE and histologic sizes. With qualitative and quantitative SWE analysis, sensitivity was 94% and specificity 73%. Malignant lesions appeared more heterogeneous, with higher stiffness and ratio values than benign lesions (p < 0.001). For malignant lesions, SWE size was better correlated to histologic size than B-mode size. Using benign SWE signs to selectively downgrade category 4a and 4b lesions, the specificity improved from 13% to 51% without loss in sensitivity (100%) compared to ultrasound.

Antitumoral Effect of Mural Cells Assessed With High-Resolution MRI and Fluorescence Microscopy.

OBJECTIVE: The purpose of this study was to detect labeled mural cells in vivo and study their therapeutic effect on tumor growth and on functional changes in the vascular network by use of MRI and fibered confocal fluorescence microscopy (FCFM). MATERIALS AND METHODS: Twenty-eight mice were allocated to the following three groups 7 days after injection of TC1 tumor cells (C157 black 6): control, no injection (n = 7); sham, injection of phosphate-buffered saline solution (n = 10); and treated, injection of human mural cells (n = 11). Tumor growth was measured with calipers. Labeled mural cells were tracked with high-resolution MRI and FCFM. Microvessel density was assessed with MRI and FCFM, and the findings were compared with the histologic results. RESULTS: Tumor growth was significantly slowed in the treated group starting on day 10 (p = 0.001). Round signal-intensity voids were observed in the center of six of seven tumors treated with magnetically labeled mural cells. Positive staining for iron was observed in histologic sections of two of five of these tumors. Microvessel density measured with FCFM was greater in the treated mice (p = 0.03). Flow cytometry revealed viable human mural cells only in treated tumors. CONCLUSION: In this study, imaging techniques such as high-resolution MRI and FCFM showed the therapeutic effect of mural cell injection on tumor growth and microvessel function.

Multiparametric optical and MR imaging demonstrate inhibition of tumor angiogenesis natural history by mural cell therapy.

PURPOSE: To determine whether functional imaging using MRI and fibered confocal fluorescence microscopy (FCFM) could be used to monitor cell therapy by mural progenitor cells (MPC). METHODS: Fifty mice bearing TC1 murine xenograft tumors were allocated into: control (n = 17), sham (phosphate buffer saline, n = 16), and MPC-treated (MPC, n = 17) groups. MRI was performed before (D0 ) and 7 days (D7 ) after injection measuring tumor size, R2 * under air, oxygen, and carbogen using blood oxygen level dependent (BOLD) and f (fraction linked to microcirculation), D* (perfusion related coefficient) and Dr (restricted diffusion coefficient) using diffusion-weighted sequences based on the IVIM (intravoxel incoherent motion) method. FCFM was performed at D7 measuring "index leakage" (capillary permeability). RESULTS: Tumor growth was significantly slowed down in the MPC-treated animals (P = 0.002) on D7 . R2 *air significantly decreased in controls between D0 and D7 (P = 0.03), reflecting a decrease in tumor oxygenation. ΔR2 *O2CO2 significantly increased in controls between D0 and D7 (P = 0.01) reflecting loss of vessel response to carbogen. D* significantly decreased in controls between D0 and D7 (P = 0.03). Finally, "index leakage" was lower in the MPC-treated tumors (P = 0,009). CONCLUSION: Treatment by MPC resulted in slowing down of tumor growth, capillary permeability decrease, and stabilization of tumor angiogenesis.

In vivo imaging of tumor angiogenesis using fluorescence confocal videomicroscopy.

Fibered confocal fluorescence in vivo imaging with a fiber optic bundle uses the same principle as fluorescent confocal microscopy. It can excite fluorescent in situ elements through the optical fibers, and then record some of the emitted photons, via the same optical fibers. The light source is a laser that sends the exciting light through an element within the fiber bundle and as it scans over the sample, recreates an image pixel by pixel. As this scan is very fast, by combining it with dedicated image processing software, images in real time with a frequency of 12 frames/sec can be obtained. We developed a technique to quantitatively characterize capillary morphology and function, using a confocal fluorescence videomicroscopy device. The first step in our experiment was to record 5 sec movies in the four quadrants of the tumor to visualize the capillary network. All movies were processed using software (ImageCell, Mauna Kea Technology, Paris France) that performs an automated segmentation of vessels around a chosen diameter (10 µm in our case). Thus, we could quantify the 'functional capillary density', which is the ratio between the total vessel area and the total area of the image. This parameter was a surrogate marker for microvascular density, usually measured using pathology tools. The second step was to record movies of the tumor over 20 min to quantify leakage of the macromolecular contrast agent through the capillary wall into the interstitium. By measuring the ratio of signal intensity in the interstitium over that in the vessels, an 'index leakage' was obtained, acting as a surrogate marker for capillary permeability.

Diffusion-weighted imaging for evaluation of uterine arterial embolization of fibroids.

PURPOSE: To determine whether diffusion-weighted imaging (DWI) characteristics could predict the effectiveness of uterine arterial embolization in treatment of fibroids. METHODS: This retrospective study included 17 women (27 fibroids) who underwent uterine arterial embolization for fibroids. MR imaging (1.5 T) was performed before, 1 week and 6 months after uterine arterial embolization. The volume, T2 signal, T1 signal, enhancement after contrast media injection, DWI signal (b = 500 s/mm(2) ) and apparent diffusion coefficient (ADC) were assessed for fibroids. RESULTS: DWI signal or ADC, whether before or 1 week after the procedure, did not show a statistical relationship to success of uterine arterial embolization. On the 1-week follow-up, 22% of fibroids enhanced vs. 85% on baseline, P < 0.0001 and DW signal intensity increased. ADC values in fibroids decreased between baseline and 1-week (1.61 vs. 1.53 × 10(-3) mm(2) /s, P = 0.13). On 6-months, ADC continued to decrease compared with baseline (1.27 × 10(-3) mm(2) /s, P = 0.002), but with a lower signal on DWI. No changes were observed in myometrium ADC at any time point. CONCLUSION: Our study demonstrated that DWI and ADC reflected early and delayed changes in fibroids after embolization; however, we were not able to demonstrate a statistically significant relationship with outcome.

Macromolecular capillary leakage is involved in the onset of anaphylactic hypotension.

BACKGROUND: The role of the hypovolemic component secondary to the microcirculatory changes in the onset of inaugural anaphylactic hypotension remains debated. We investigated the microcirculatory permeability in a model of anaphylactic shock using a fluorescence confocal microscopy imaging system. METHODS: Ovalbumin-sensitized anesthetized Brown Norway rats were randomly allocated into two groups (n = 6/group): control and anaphylaxis, respectively induced by intravenous saline or ovalbumin at time 0 (T0). The mesentery was surgically exposed. Macromolecular fluorescein isothiocyanate-dextran was intravenously injected (T0-5min) allowing in vivo visualization of the mesenteric microvascular network by fluorescence microscopy. After a period of stabilization of the contrast agent concentration, a 5-s movie was recorded to obtain baseline signal intensity. Following T0, 5-s movies were recorded every 30 s for 30 min. Capillary leakage of fluorescein isothiocyanate-dextran was assessed in interstitium and compared between groups. Data are expressed as mean ± SD. RESULTS: Following anaphylactic shock onset, an early, progressive, and global signal intensity increase over time was detected in the interstitium. Mean index leakage differed between control and anaphylaxis (respectively 20 ± 11 vs. 170 ± 127%; P < 0.0001), starting at 2 min after shock onset and progressively increasing. Index leakage correlated with the drop in arterial blood pressure until T0 + 10 min (r = -0.75, P = 0.0001). CONCLUSIONS: During anaphylaxis, interstitial capillary leakage occurs within minutes after shock onset. Compared with controls, the mesenteric microcirculation showed at least 8-fold-increased macromolecular capillary leakage. The inflammation-induced microcirculatory changes with subsequent intravascular fluid transfer might be involved in the onset of the inaugural hypotension during anaphylactic shock.

Placental perfusion and permeability: simultaneous assessment with dual-echo contrast-enhanced MR imaging in mice.

PURPOSE: To assess placental perfusion and permeability in mice with magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was conducted according to French law and National Institutes of Health recommendations for animal care. Twenty-two pregnant BALB/c mice were examined at 1.5 T with a single-section dual-echo fast spoiled gradient-echo sequence. Two injection protocols were used: monophasic injection (double the clinical dose of contrast agent) and biphasic injection (quadruple the clinical dose). Signal intensities (SIs) were measured in the maternal left ventricle, placenta, and fetus (n = 16). At these high gadolinium doses, a T2* effect correction was used. SIs were converted to gadolinium concentrations and were analyzed by using a three-compartment model. Quantitative microcirculation parameters were calculated. Results with the monophasic and biphasic protocols were compared, and final arterial concentrations determined with MR imaging were compared with those determined with atomic emission spectrophotometry by using the unpaired Student t test. RESULTS: Perfusion and permeability parameters for monophasic and biphasic injections were similar: Mean placental blood flow was 180 mL/min/100 g, mean permeability surface coefficient from maternal placental to fetal placental compartment was 10.3 x 10(-4) sec(-1) +/- 6.81 (standard deviation), mean permeability surface coefficient from fetal placental to maternal placental compartment was 4.65 x 10(-4) sec(-1) +/- 4.37, and mean fractional volume of the maternal vascular placental compartment was 36.5% +/- 0.9. Placental (146 vs 105 micromol/L, P < .004) and fetal (33.3 vs 19.1 micromol/L, P < .001) gadolinium concentrations were higher with the biphasic than with the monophasic protocol. Arterial gadolinium concentrations at MR imaging did not differ significantly from those at spectrophotometry for the monophasic (P = .254) or biphasic (P = .776) injection protocol. CONCLUSION: Placental perfusion and permeability can be measured in vivo by using high gadolinium doses and a dual-echo MR imaging sequence.

Imaging of burned-out testis tumor: five new cases and review of the literature.

OBJECTIVE: Burned-out tumors of the testis are extremely rare. From 5 new cases, the clinical and radiologic findings are discussed in light of a review of the literature. METHODS: Over a 13-year period, 5 patients 17 to 50 years old were admitted with metastatic germ cell neoplasms. All were explored by thoracic and abdominal computed tomography and scrotal sonographic examination. RESULTS: The disease was revealed by the presence of lymphadenopathies in 4 of these patients: retroperitoneal in 3 and supraclavicular in the other. Scrotal sonography revealed abnormalities in all cases. CONCLUSIONS: Burned-out tumors may cause some confusion in the diagnosis, because secondary tumors can often be mistaken for primary tumors. Careful evaluation of the testis is crucial for identifying the primary lesion site; all abnormalities shown on clinical or sonographic scrotal examination call for orchidectomy.