Evaluation Of Therapeutic Response Research Articles

Noninvasive assessment of regulable transferred-p53 gene expression and evaluation of therapeutic response with FDG–PET in tumor model

The use of tumor-suppressor gene p53 as an anticancer therapeutic has been vigorously investigated. However, progress has met with limited success to date. Some major drawbacks are the difficulty in achieving controllable and efficient gene transfer as well as in analyzing the transferred gene expression in real time and the treatment response in a timely manner. Thus, development of novel gene transfer vector with a regulative gene expression system coupled with the reporter gene, by which transgene can be monitored simultaneously, is critical. Moreover, noninvasive imaging-based assessment of the therapeutic response to exogenous wild-type p53 gene transfer is crucial for refining treatment protocols. In this study, as a simple preclinical model, we constructed a doxycycline-regulated bidirectional vector harboring a reporter gene encoding red fluorescence protein and p53. Then, we determined the controllable and simultaneously coordinated expression of both proteins and the p53-mediated anticancer effects in vitro and in vivo. Next, we observed that cells or tumors with induced p53 overexpression exhibited decreased uptake of [(14)C]FDG in cellular assay and [(18)F]FDG in positron emission tomography (PET) imaging. Thus, by coupling with bidirectional vector, controllable p53 transfer was achieved and the capability of fluoro-2-deoxy-D-glucose (FDG)-PET to assess the therapeutic response to p53 gene therapy was evidently confirmed, which may have an impact on the improvement of p53 gene therapy.

Abstract ED4-3: PET tracer for therapy monitoring

Abstract Molecular or metabolic imaging with PET plays a crucial role not only for the individual patient management but also for further validation of new therapies. The concept of using PET and [18F]fluorodeoxyglucose (FDG) for assessment of response is based on early changes in tumor glucose use which correlate to the effectiveness of a specific treatment. However, FDG-PET is a suitable surrogate marker for response prediction only in intensely FDG-avid tumors. For imaging in the context of planning of a chemotherapeutic intervention and for therapy monitoring, tracers with higher specificity are required. With the advent of molecular imaging, tumor tissue can be non-invasively characterized by imaging probes targeting biological processes such as metabolism, cell growth and migration as well as vascularization and oxygen tension. Based on such measurements signals can be defined which detect and quantitatively describe pharmacologic effects in tumor tissues within a few days after initiation of therapy. Initial results suggest that therapeutic strategies can be successfully adapted based on molecular imaging results, which are able to identify responders with improved clinical outcome. These specific and sensitive imaging signals are needed to match therapeutic targets with imaging agents addressing the same or corresponding biologic processes. Inhibiting neoangiogenesis, for example, represents an attractive therapeutic option, which benefits from imaging probes addressing molecular targets such as integrins and VEGF receptors as well as measuring perfusion and blood volume. Prior to treatment, these tracers enable to define the expression of a specific target. Alternative probes for molecular cancer imaging address metabolic key processes, such as cell proliferation ([18F]FLT), protein biosynthesis ([18F]FET, [11C]MET), neoangiogenesis ([18F]Galacto-RGD), hypoxia ([18F]FAZA), somatostatin receptor expression ([68Ga]DOTATOC), estrogen receptor expression ([18F]FES) or new concepts, such as cytokine / chemokine receptor expression ([68Ga]CPCR4). For response evalu ation, the tracer uptake has to correlate with the therapeutic effect at all imaging time points. Here, tracers with high sensitivity are required, allowing for the early assessment of therapeutic effects and response evaluation. Citation Information: Clin Cancer Res 2010;16(7 Suppl):ED4-3

Predictive value of 18F-FDG hybrid PET/CT for the clinical outcome in patients with non-Hodgkin's lymphoma prior to and after autologous stem cell transplantation

Objective: Evaluation of therapeutic response in non-Hodgkin's lymphoma (NHL) patients with autologous stem cell transplantation (ASCT) is of great clinical significance. But the exact role of 18F-fluorodeoxyglucose (FDG) imaging in NHL associated with ASCT is unclear. This study assessed the predictive value of 18F-FDG hybrid PET/CT imaging for the clinical outcome such as progression-free survival (PFS) in patients with NHL prior to and after ASCT.Methods: 18F-FDG hybrid PET/CT was performed in 31 patients (24 male and 7 female) with pathologically confirmed NHL prior to and after ASCT. Mean age was 43·1±13·8 years. No patients were lost to follow-up earlier than 1 year from ASCT. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 18F-FDG hybrid PET/CT before ASCT were compared to the results after ASCT. The results of pre- and post-ASCT FDG hybrid PET/CT findings were correlated to PFS using Kaplan–Meier survival analysis. Regression analyses were employed to test for independence of established prognostic factors.Results: Sixteen of 31 patients (52%) progressed/relapsed or died after a median follow-up of 7 months, the remaining 15 patients (48%) were disease free after a median follow-up of 24 months. Both pre- and post-ASCT, 18F-FDG hybrid PET/CT findings showed high PPV, NPV and accuracy (85·7 versus 92·3%, 76·5 versus 77·8% and 80·6 versus 83·9%). Both pre- and post-ASCT, 18F-FDG hybrid PET/CT findings were strongly correlated with PFS (P<0·0005, significant). Of pre- ASCT FDG finding, the 1-year PFS rate for FDG-negative and FDG-positive patients was 88·2 and 28·6%. Of post-ASCT FDG finding, the 1-year PFS rate for FDG-negative patients and FDG-positive patients was 88·9 and 23·1%. The regression model showed that the predictive value of FDG imaging owed its significance to the very high hazard ratio between patients with positive FDG imaging and negative FDG imaging (P<0·005) both pre- and post-ASCT.Conclusions: 18F-FDG hybrid PET/CT imaging prior to and following autologous stem cell transplantation in NHL contains predictive information on the long-term clinical outcome.

Biomarkers in systemic sclerosis.

Systemic sclerosis is an autoimmune inflammatory disorder of unknown etiologycharacterized b y pronounced fibroproliferative alterations in the microvasculature, and frequent cellular and humoral immunity abnormalities, culminating in a severe and often progressive fibrotic process. Numerous biomarkers reflecting the three main pathogenetic mechanisms in systemic sclerosis have been described; however, aside from several disease-specific autoantibodies, other biomarkers have not been thoroughly validated and require further study. Thus, there is an unmet need for validated biomarkers for diagnosis, disease classification, and evaluation of organ involvement and therapeutic response in systemic sclerosis.

The history of erosions in rheumatoid arthritis: Are erosions history?

Small joint periarticular erosions have occupied center stage in the understanding of the pathogenesis of rheumatoid arthritis (RA) for well over 50 years (1). Such erosions have diagnostic and prognostic significance and have served as a valuable outcome measure in the evaluation of therapeutic responses to drugs for disease (2). The RA erosion paradigm extends well beyond these immediately clinically relevant issues. An understanding of the proinflammatory milieu at the cartilage–pannus junction, the putative site where erosion formation was thought to be initiated, was considered to represent a key event toward the development of biologic therapies in RA (3). Ongoing efforts seek to link the immunopathogenetic basis for erosion formation to emergent genome-wide association studies to further elucidate the basis for joint disease in RA. The importance of erosions in the immunopathogenesis of RA is almost dwarfed by the importance that their early detection has assumed. Erosions represent 1 of the 3 diagnostic criteria for RA when combined with clinical and serologic parameters (2). With the advent of more sophisticated imaging techniques, most notably, magnetic resonance imaging (MRI) and ultrasound (US), rheumatologists are increasingly interested in detecting these seemingly diagnostic and prognostic features in early RA to facilitate a definitive diagnosis and to initiate the most appropriate therapy, at the earliest possible opportunity. Why this is the case and why it merits reconsideration based on work reported by Stach et al in this issue of Arthritis & Rheumatism (4) and based on other recent data are the subjects of this perspective. History of erosion immunopathogenesis

Functional evaluation of therapeutic response for a mouse model of medulloblastoma

Medulloblastoma is an aggressive childhood cerebellar tumor. We recently reported a mouse model with conditional deletion of Patched1 gene that recapitulates many characteristics of the human medulloblastoma. Qualitative symptoms observed in the mouse model include irregular stride length, impaired cranial nerve function and decreased motor coordination and performance. In our current study, several quantitative behavioral assays including a mouse rotarod, a forced air challenge, a screen inversion test, a horizontal wire test, and stride length analysis were evaluated to determine the most sensitive and cost-effective functional assay for impaired neuromotor behavior associated with disease progression. Magnetic resonance imaging (MRI) was used to confirm and monitor tumor growth and as an anatomical biomarker for therapeutic response. Wild type mice or medulloblastoma-prone, conditional Patched1 knockout mice were observed by behavioral assays and MRI from postnatal weeks 3-6. Bortezomib treatment was administered during this period and therapeutic response was assessed using cerebellar volumes at the end of treatment. Of the behavioral tests assessed in this study, stride length analysis was best able to detect differences between tumor-prone mice and wild type mice as early as postnatal day 37 (P=0.003). Significant differences between stride lengths of bortezomib treated and control tumor-bearing mice could be detected as early as postnatal day 42 (P=0.020). Cerebellar volumes measured by MRI at the end of treatment validated the therapeutic effects seen by behavioral tests (P=0.03). These findings suggest that stride length analysis may serve as one of the more sensitive and cost-effective method for assessing new therapeutic compounds in this and other preclinical model of brain tumors.

F-18 FDG PET/CT evaluation of radiotherapy response in rare case of mucosa-associated lymphoid tissue lymphoma

We experienced two cases of mucosa-associated lymphoid tissue (MALT) lymphoma arising at unusual locations and used F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to evaluate their response to radiation therapy (RT). A 62-year-old male with proven prostatic MALT lymphoma and a 43-year-old woman with proven duodenal MALT lymphoma had diffuse FDG uptake in the lesion. Both cases were treated with RT; following FDG, PET/CT showed decreased FDG uptake in each lesion. Neither patient had evidence of recurrence at more than 18 months after RT. FDG PET/CT is useful for indicating the treatment site in MALT lymphoma and in evaluation of therapeutic response following RT.

Computer-Assisted Quantitative Evaluation of Therapeutic Responses for Lymphoma Using Serial PET/CT Imaging

Molecular imaging modalities such as positron emission tomography (PET)/computed tomography (CT) have emerged as an essential diagnostic tool for monitoring treatment response in lymphoma patients. However, quantitative assessment of treatment outcomes from serial scans is often difficult, laborious, and time consuming. Automatic quantization of longitudinal PET/CT scans provides more efficient and comprehensive quantitative evaluation of cancer therapeutic responses. This study develops and validates a Longitudinal Image Navigation and Analysis (LINA) system for this quantitative imaging application. LINA is designed to automatically construct longitudinal correspondence along serial images of individual patients for changes in tumor volume and metabolic activity via regions of interest (ROI) segmented from a given time point image and propagated into the space of all follow-up PET/CT images. We applied LINA retrospectively to nine lymphoma patients enrolled in an immunotherapy clinical trial conducted at the Center for Cell and Gene Therapy, Baylor College of Medicine. This methodology was compared to the readout by a diagnostic radiologist, who manually measured the ROI metabolic activity as defined by the maximal standardized uptake value (SUVmax). Quantitative results showed that the measured SUVs obtained from automatic mapping are as accurate as semiautomatic segmentation and consistent with clinical examination findings. The average of relative squared differences of SUVmax between automatic and semiautomatic segmentation was found to be 0.02. These data support a role for LINA in facilitating quantitative analysis of serial PET/CT images to efficiently assess cancer treatment responses in a comprehensive and intuitive software platform.

Novel anti‐filamin‐A antibody detects a secreted variant of filamin‐A in plasma from patients with breast carcinoma and high‐grade astrocytoma

Identification of tumor-derived proteins in the circulation may allow for early detection of cancer and evaluation of therapeutic responses. To identify circulating tumor-derived proteins, mice were immunized with concentrated culture medium conditioned by human breast cancer cells. Antibodies generated by hybridomas were screened against conditioned media from both normal epithelial cells and tumor cells. Antibody selectively reacting with tumor cell-conditioned media was further characterized. This led to the development of a monoclonal antibody (Alper-p280) that reacts with a newly identified 280-kDa secreted variant of human filamin-A. Circulating filamin-A was detected in patient plasma samples using Alper-p280 in an ELISA assay. Human plasma samples from 134 patients with brain, breast, or ovarian cancer, 15 patients with active arthritis, and 76 healthy controls were analyzed. Filamin-A protein levels in human cell lines and tissues were analyzed by western blotting, immunohistochemistry, and electron and confocal microscopy. Circulating filamin-A was detected in the plasma of 109 of 143 patients with breast cancer and primary brain tumors. Plasma levels of filamin-A showed 89.5% sensitivity (95% confidence interval [CI] = 0.67% to 0.99%) and 97.8% specificity (95% CI = 0.88% to 0.99%) for glioblastoma at a cut-off of 21.0 ng/mL. Plasma levels of filamin-A (>36.0 ng/mL) had 96.7% sensitivity (95% CI = 0.80% to 0.99%) and 67.8% specificity (95% CI = 0.54% to 0.79%) for metastatic breast cancer. Filamin-A levels were increased in malignant breast or brain tissues, but not in normal control tissues. Filamin-A localized to lysosomes in MDA.MB.231 breast cancer cells, but not in normal human mammary epithelial cells, suggesting that filamin-A may undergo cancer-specific processing. Plasma filamin-A appears to be a specific and sensitive marker for patients with high-grade astrocytoma or metastatic breast cancer. Additional novel cancer biomarkers have been identified and are being developed alongside Alper-p280 for use in diagnosis of breast carcinoma and high-grade astrocytoma, and for use in the evaluation of therapeutic responses.

Prognostic values of serum LDH and β2-MG in patients with non-Hodgkin’s lymphoma

To evaluate the clinical significance of quantitative determination of serum lactic dehydrogenase (LDH) and beta 2-microglobulin (β2-MG) in patients with non-Hodgkin’s lymphoma (NHL). Date of the 65 patients from 2003 to 2004 were retrospectively analyzed, relationship between LDH and β2-MG activities and tumor phase, effect of treatment as well as prognosis were studied. The levels of LDH and β2-MG in the advanced stage, B group and bone marrow involvement were obviously higher than their comparison counterpart and the difference was significant (P < 0.05). There was no significant difference between the high LDH group and normal LDH group in the two-year survival rate. But the difference in the four-year survival rate was significance. The level of LDH and β2-MG are valuable for clinical stage, prognosis and evaluation of therapeutic response in patients with NHL.

WE‐D‐210A‐04: Novel PET Probes to Image the Immune System and Cancer — From Discovery to Clinical Applications

Monitoring immune function using molecular imaging could significantly impact the diagnosis and treatment evaluation of immunological disorders and therapeutic immune responses. Positron Emission Tomography (PET) is a molecular imaging modality with applications in cancer and other diseases. PET studies of immune function have been limited by a lack of specialized probes. We identified [18F]FAC (1‐(2′‐deoxy‐2′‐[18F]fluoroarabinofuranosyl) cytosine) by differential screening as a new PET probe for the deoxyribonucleotide salvage pathway. [18F]FAC PET enabled visualization of lymphoid organs and was sensitive to localized immune activation in a mouse model of anti‐tumor immunity. [18F]FAC microPET also detected early changes in lymphoid mass in systemic autoimmunity and allowed evaluation of immunosuppressive therapy. We have also developed a series of [18F]FAC analogs with improved pharmacokinetic properties. Data in animal models and preliminary studies in humans support the use of [18F]FAC and its analogs for immune monitoring by PET and suggest a wide range of clinical applications in immune disorders and in certain types of cancer.Research sponsored in part by Sofie Biosciences through a UC Discovery grant.

MR-based biomarkers in the diagnosis and the evaluation of the therapeutic response to radiotherapy (ETRR) in prostatic carcinoma (PCa): Implementation of clinical and experimental approaches

e16136 Background: ETRR in PCa remains a challenging task. New biomarkers in the form of metabolites, detected with Proton Magnetic Resonance Spectroscopy (1H-MRS), and quantitative Apparent Diffusion Coefficient (ADC), determined with Diffusion-Weighted Magnetic Resonance Imaging, could be of value in the ETRR for PCa. Methods: Twenty-one men with biopsy proven localized PCa were examined before external radiotherapy. 3D-1H-MRS was performed at 3.0T without endorectal coils. The delivered radiotherapy dose was 78 Gy in 39 fractions with 6 MV photons. MR follow-up examinations up to 36 months post-radiotherapy were performed. For the pre-clinical study, healthy rat prostate was studied in 3 nude rats. PC3-MM2 and PAC-120 tumors were subcutaneously (SC) and orthotopically (OT) xenografted in 5 nude rats, respectively. Radiotherapy anti-tumor efficacy administered as HDR-brachytherapy (SC) or X6 external beam irradiation (OT) delivering 10 Gy/5 fractions was evaluated. 1H-MRS was performed at 4.7 T using SVS. Results: Twelve men received the 3-month examination, 8 patients are at 6-months, 4 are at 9 months and 1 has been followed for 1 year. At baseline, healthy prostate shows a low Choline (Cho)/Citrate ratio, whereas the presence of cancer considerably increases this ratio. At 3 months, we observed metabolic atrophy except for Cho. Although, higher ADC values are normally found in peripheral zone than in central gland, these differences disappear after radiotherapy. In healthy rat prostate high levels of Cho without citrate were noted. Cho and free lipids were detected in PC3-MM2 and PAC120 SC-grafted tumors, with a higher Cho content in PC3-MM2. Radiotherapy induced significant antitumor activity in PC3-MM2 (SC) (T/C% = 38%) and OT (ILS% = 58%) tumors, but was not efficient in PAC120 SC-grafted tumors (T/C% = 90%). Radiotherapy slightly modified Cho content 4 days after the end of treatment but no modification on overall metabolic profile was observed before, during and after radiotherapy. Conclusions: Combined ADC and Cho are powerful biomarkers for the detection of PCa in men and could be useful for ETRR.The use of Cho in ETRR for PCa in rats appears to be promising. No significant financial relationships to disclose.

Chronic Myeloid Leukemia Patients Present Elevation of the Circulating Endothelial Cells

The increase of the angiogenesis is a prognostic factor in solid tumors. In oncho-hemathology, it is associated to the Myelodysplastic syndromes, Acute Leukaemia and Multiple myeloma. The impact of the raise in the expression of the growing endothelial (VEGF) in the course of chronic myeloid leukaemia (CML) is yet unknown. Yet, there are reports that those patients have presented a higher vascular density in bone marrow (BM) than healthy individuals, specially in blastic phase. Some authors suggest that abnormalities in the angiogenesis may be involved in the phatogenesis in the CML, as well as to its transformation in blastic phase. The increase of the circulating endothelial cells (CEC) is associated to the phatogenesis and to the prognostic of breast cancer and Non-Hodgkin lymphoma, but there are no studies in CML. Thus, we have elaborated a study in order to quantify the CEC in patients with CML in accelerated, chronic and blast phases for flow cytometry. Up to the moment, samples of 46 patients with CML (15 in accelerated phase, 24 in chronic phase and 7 in blastic phase) have been evaluated. Thirty six platelet donors for apheresis with negative sorology were used as a control group. The samples were processed at the same day of the collection, using monoclonal antibodies (MoAb) previously validated in cell of lineage HUV-EC. For the research of the CEC, we used the MoAb CD146 FITC, CD34 PE, CD133 APC e CD62E PE. O AcMo CD45 PC5 was used as a gate strategy for the analysis. The samples were acquired in flow cytometry FACS-Calibur G5 (100.000 events) and analysed in software CellQuest Pro. We noticed an increase statistically significant of CEC in the chronic (p< 0,01), accelerated (p = 0,02) and blastic (p = 0,01) phases of the CML in comparison to the control group, given that these endothelial cells were found in a mature stage. The precursor endothelial cells did not present any statistically significant difference. Patients with LMC present an increment in the amount of CEC in all the phases. The quantification of these cells can be used in the evaluation of therapeutic response, of prognostics and as potential therapeutic target in LMC. The mechanisms involved in the increase of the CEC must be evaluated in future studies. Financial Support: FAPESP

Diagnostic and prognostic role of matrix metalloproteases in cancer

Matrix metalloproteases (MMPs) are key players in the progression and metastasis of cancer. MMPs cleave extracellular matrix components and in this way promote tumor growth, invasion and vascularization. MMPs also affect tumor progression by regulating availability and activity of growth factors, inflammatory cytokines and chemokines. Accordingly, several MMPs have been found to serve as prognostic indicators in solid tumors. Usually the increased levels of MMPs in patients' tumor tissue or serum/plasma are associated with poor outcome. Interestingly, recent results show that certain MMPs also serve as tumor suppressors. This review discusses the latest view on MMPs as diagnostic and prognostic indicators in cancer patients. Studies with clinical samples of 70 or more patients are included in particular. In addition, the possible roles of MMPs in future molecular diagnostics and in the evaluation of therapeutic responses are discussed. MMP-9 in particular has shown prognostic value in various types of tumor, and its measurement in circulation, urine or tumor tissue might help in clinical surveillance of otherwise problematic patient cases. There is upcoming new knowledge on MMPs in therapy response evaluation, in which MMPs might be useful together with CT scans and other clinically more established prognostic factors. Certain MMPs have a dual role in terms of cancer-modulating properties and thus it is essential to evaluate their expression and function in tumor cells and host environment to select validated therapy targets but spare MMP antitargets.

Molecular imaging of lymphoid organs and immune activation by positron emission tomography with a new [18F]-labeled 2′-deoxycytidine analog

Monitoring immune function using molecular imaging could significantly impact the diagnosis and treatment evaluation of immunological disorders and therapeutic immune responses. Positron Emission Tomography (PET) is a molecular imaging modality with applications in cancer and other diseases. PET studies of immune function have been limited by a lack of specialized probes. We identified [18F]FAC (1-(2′-deoxy-2′-[18F]fluoroarabinofuranosyl) cytosine) by differential screening as a new PET probe for the deoxyribonucleotide salvage pathway. [18F]FAC enabled visualization of lymphoid organs and was sensitive to localized immune activation in a mouse model of anti-tumor immunity. [18F]FAC microPET also detected early changes in lymphoid mass in systemic autoimmunity and allowed evaluation of immunosuppressive therapy. These data support the use of [18F]FAC PET for immune monitoring and suggest a wide range of clinical applications in immune disorders and in certain types of cancer.

Role of Power Doppler Sonography in Evaluation of Therapeutic Response of the Knee in Juvenile Rheumatoid Arthritis

Role of Power Doppler Sonography in Evaluation of Therapeutic Response of the Knee in Juvenile Rheumatoid Arthritis

ELISA in the evaluation of therapeutic response to albendazole in neurocysticercosis

Immunological tests are frequently used in the diagnosis of neurocysticercosis (NC), but scant literature is available on the efficacy of these tests in the assessment of therapeutic response. An ELISA using the Cysticercus fasciolaris larval stage of T. taeniaeformis has been evaluated in the post-treatment follow-up of NC in a cohort of 165 cases. Cases (n=165) with at least one active cyst documented by computed tomography and a positive pre-treatment serum ELISA for IgG and/or IgM antibodies were treated with albendazole. CT scan and ELISA tests were repeated at 6 months in 148 cases who returned for follow-up. A radiological response was observed in 132 of 148 cases at follow-up. Sixteen cases were non-responders. Amongst the responders, 111/128 (IgG) and 93/117 (IgM) respectively had converted to negative antibody titers at 6 months. Thirteen of 16 and 12 of 15 non-responders continued to show high anti-Cysticercus IgG and IgM titers. IgG ELISA, IgM ELISA and combined IgG and IgM results exhibited a sensitivity (%) of 81.3, 80.0 and 100, a specificity (%) of 86.7, 79.5 and 72.0, a positive predictive value (PV%) of 97.4, 96.9 and 30.2, and a negative PV(%) of 97.4, 96.9, 100 respectively. IgG ELISA is a sensitive and specific tool to assess treatment response. A negative ELISA result for both IgG and IgM antibodies denotes a cure. While ELISA cannot replace the visual confirmation provided by radiological imaging in follow-up, the addition of an ELISA test may help overcome the limitations in interpretation of CT scans.

Role of Power Doppler sonography in evaluation of therapeutic response of the knee in juvenile rheumatoid arthritis

The objective is to study the role of power Doppler sonography (PDS) in assessment of therapeutic response in juvenile rheumatoid arthritis (JRA) of knee joint. Thirty patients (age range 3-11 years) of JRA with knee joint involvement were selected for this study. Clinical assessment and ultrasound was done on the same day and repeated at the end of second and sixth month of therapy. All patients received naproxen (15-20 mg/kg/day) for a period of 6 months. Total clinical score (TCS) was calculated as sum of scores of pain, articular swelling and functional impairment. PDS was performed and degree of vascularity was assessed and graded. Total USG score was obtained by adding sum of scores of synovial effusion, synovial thickening and PDS. Results were compared between the total clinical score and the total ultrasound score and between clinical groups at baseline, end of second month and end of sixth month. There were statistically significant differences between clinical and ultrasound indices and confirmed that PDS is more sensitive in detection and follow-up of clinically silent cases of JRA. PDS holds great promise for detection of active synovial inflammatory disease in sub-clinical cases of JRA and is useful in objective assessment of therapeutic response.

Magnetic resonance imaging for detection and determination of tumor volume in a genetically engineered mouse model of ovarian cancer

Our laboratory developed a transgenic mouse model of spontaneous epithelial ovarian cancer (EOC) in which tumors are initiated by expression of the early region of the Simian Virus 40 (SV40) under transcriptional control of the 5’ upstream regulatory region of the Müllerian inhibiting substance type II receptor (MISIIR) gene. Female TgMISIIR-TAg-DR26 transgenic mice develop bilateral ovarian tumors with variable latency and survive an average of 152 days. In the absence of reliable methods for disease detection and evaluation of therapeutic response, preclinical studies of this transgenic mouse model of EOC would be limited to longitudinal experiments involving large numbers of animals with euthanasia as the endpoint. Therefore, a non-invasive method for detecting tumors, measuring tumor volume and calculating parameters relevant to the evaluation of therapeutic or preventive interventions (i.e., tumor growth rates, tumor initiation, tumor regression and the time for tumors to reach a given size) is required. We developed and optimized a non-invasive Magnetic Resonance Imaging (MRI) scanning protocol to obtain high resolution abdominal images that is well tolerated by mice. Superior contrast and contrast to noise ratio (CNR) was found with Gd-DTPA contrast enhanced T1-weighted sequences. Image sets in both the axial and coronal orientations for redundant measurements of normal ovary and ovarian tumor volume can be acquired in approximately 20 minutes. Accuracy of MRI-based ovary and tumor volume determinations was verified by standard volume measurements at necropsy. Serial imaging studies were performed on 41 ovarian cancer bearing TgMISIIR-TAg-DR26 transgenic mice to quantitate tumor progression over time in this model. A chemotherapy study was conducted on TgMISIIR-TAg-DR26 transgenic mice using a standard combination therapy consisting of cisplatin and paclitaxel. Our results demonstrate that MRI is well tolerated and can be repeated in serial imaging studies, permitting quantitative analysis of tumor growth and progression and response to therapeutic interventions.

Développements récents en imagerie ultrasonore de contraste à visée oncologique

The combined use of high-end ultrasound units and sonographic contrast agents provide valuable information for lesion characterization and follow-up of patients under targeter treatments, especially oncologic patients. Early published results for liver pathology have created a place for this technique as a reference method leading to the publication of European guidelines. New oncologic applications have emerged over the last several years for lesions accessible by ultrasound with varied diagnostic value based on each target organ. Contrast-enhanced sonography is rapidly gaining ground for the follow-up of patients under targeted treatment, physical or drug induced, with major implications for the validation of concepts, and management of patients based on reliable early evaluation of therapeutic response to treatment. The purpose of this paper is to review recent advances in this field of sonographic imaging to better understand the role of ultrasound in oncologic pathology.