Therapy Response Evaluation Research Articles

Early Metabolic Response at Mid-Radiation Therapy FDG-PET Imaging Predicts Patterns of Treatment Failure in Locally Advanced Oropharyngeal Cancer

Imaging with 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) is used for staging, radiation treatment planning, and evaluation of therapy response. The purpose of this work was to assess early metabolic response at mid-radiotherapy (RT) FDG-PET imaging obtained at 30-36 Gy and investigate its ability to predict patterns of treatment failure in locally advanced oropharyngeal cancer. We retrospectively collected data for oropharyngeal squamous cell carcinoma patients who were treated with definitive chemoradiotherapy from 2009 to 2015 at our institution and who have available pre- and mid-RT PET-CT scans. Three types of PET image features were analyzed, including SUV maximum, metabolic tumor volume (defined at a threshold of 50% of SUVmax), and total lesion glycolysis. All three features were calculated on both pre- and mid-RT PET scans. Additionally, the longitudinal change between the two scans was also computed for all image features. Cox proportional hazard regression analysis was used to evaluate the prognostic value of individual PET image features for predicting locoregional recurrence and distant metastasis. We further adjusted for clinicopathologic factors including tumor and nodal stage, HPV and smoking status in multivariate Cox regression analysis A total of 104 patients with a median follow-up of 30 months were analyzed. On univariate analysis, mid-RT MTV was the only PET imaging parameter associated with locoregional recurrence (hazard ratio [HR] = 9.6, 95% confidence interval [CI]: 1.2-76.6, P = 0.0005). On multivariate analysis, mid-RT MTV remained a significant predictor (HR = 1.5; 95% CI: 1.02-2.3, P = 0.039) for locoregional recurrence, in addition to nodal stage (HR = 7.6; 95% CI: 1.2-49.0, P = 0.032), HPV positivity (HR = 0.14; 95% CI: 0.03-0.79, P = 0.025). Both pre-RT SUVmax and the change between SUVmax pre- and mid-RT scans were associated with distant metastasis (HR = 4.1, 95% CI: 1.2-14.4, P = 0.016, HR = 3.4, 95% CI: 1.1-10.5, P = 0.026, respectively) on univariate analysis. However, there were no significant predictors for distant metastasis on multivariate analysis. MTV at mid-RT PET was an independent predictor of locoregional recurrence. If validated, it may aid with individualized risk-adaptive therapy for oropharyngeal cancer.

Evaluation of Simulated Lesions as Surrogates to Clinical Lesions for Thoracic CT Volumetry: The Results of an International Challenge

To evaluate a new approach to establish compliance of segmentation tools with the computed tomography volumetry profile of the Quantitative Imaging Biomarker Alliance (QIBA); and determine the statistical exchangeability between real and simulated lesions through an international challenge. The study used an anthropomorphic phantom with 16 embedded physical lesions and 30 patient cases from the Reference Image Database to Evaluate Therapy Response with pathologically confirmed malignancies. Hybrid datasets were generated by virtually inserting simulated lesions corresponding to physical lesions into the phantom datasets using one projection-domain-based method (Method 1), two image-domain insertion methods (Methods 2 and 3), and simulated lesions corresponding to real lesions into the Reference Image Database to Evaluate Therapy Response dataset (using Method 2). The volumes of the real and simulated lesions were compared based on bias (measured mean volume differences between physical and virtually inserted lesions in phantoms as quantified by segmentation algorithms), repeatability, reproducibility, equivalence (phantom phase), and overall QIBA compliance (phantom and clinical phase). For phantom phase, three of eight groups were fully QIBA compliant, and one was marginally compliant. For compliant groups, the estimated biases were -1.8 ± 1.4%, -2.5 ± 1.1%, -3 ± 1%, -1.8 ± 1.5% (±95% confidence interval). No virtual insertion method showed statistical equivalence to physical insertion in bias equivalence testing using Schuirmann's two one-sided test (±5% equivalence margin). Differences in repeatability and reproducibility across physical and simulated lesions were largely comparable (0.1%-16% and 7%-18% differences, respectively). For clinical phase, 7 of 16 groups were QIBA compliant. Hybrid datasets yielded conclusions similar to real computed tomography datasets where phantom QIBA compliant was also compliant for hybrid datasets. Some groups deemed compliant for simulated methods, not for physical lesion measurements. The magnitude of this difference was small (<5.4%). While technical performance is not equivalent, they correlate, such that, volumetrically simulated lesions could potentially serve as practical proxies.

OA203] Assessment of radiation exposure in a newly formed nuclear medicine department

Purpose In an oncology nuclear medicine department, radioisotopes are not only used for tumor detecting, staging, evaluation of therapy response but also for therapeutic purposes. This study documents the radiation exposure of departmental staff, related to cyclotron operation and service during the production and injection of 18F radiopharmaceuticals for PET/CT examination. In addition, it investigates exposure in a multiple holding tank system used for the storage of 131I waste generated from patients undergoing thyroid therapy, in order to optimize environmental protection procedures. Methods Measurements for the dose rates of neutrons and photons in the room of ABT-BG-75 self-shielded mini-cyclotron were recorded during bombardment for 18F-FDG production using a neutron detector and a scintillation dosimeter. The correlation between the duration of bombardment and required time to reach a dose rate equal to background level was investigated. An electronic dosimeter was used to record staff exposure for 18F production, dispensing, administration and imaging using PET-CT. Finally, the decay rate of 131I waste was measured using a dose rate meter positioned in the decay tank system of the radioactive iodine isolation ward. Results The time required for the cyclotron room to reach background level following completion of bombardment (3 × 50 min each) was approximately 2 h. The dose rate from neutrons was found to be negligible and from photons was less than 7.5 μ Sv/h. Therefore, personnel can safely enter the room during bombardment. The staff mean whole-body dose per 18F-administered patient was 1–2 μ Sv, depending on patient condition. The values obtained from the 131I radioactive waste stored in a delay tank system were comparable with theoretical values. Conclusion This study is useful for optimizing radiation exposure in an oncology nuclear medicine department. It is shown that during 18F production exposure is mostly attributed to photons. The level of the dose permits staff entry into the cyclotron room. Staff responsible for administration received 1–2 μ Sv per 18F-patient, considered to be on the lower end of the acceptable limit for a radiation worker. The study also documents the decay rate of 131I waste over the period which the suggested activity level for release in the environment is reached.

Cytokines and MMPs levels in gingival crevicular fluid from patients with chronic periodontitis before and after non-surgical periodontal therapy

The study of host response in periodontal disease may provide a mechanism to monitor disease progression. The purpose of the present research was to determine the levels of IL-1α, IL-1β, TNF-α, IL-6, IL-6sR, IL-8, IL-10, MMP-3 and MMP-8 in gingival crevicular fluid (GCF), before and after non-surgical periodontal treatment (NSPT) in order to evaluate therapy response. Methodology: Eleven patients diagnosed with chronic periodontitis and eleven healthy subjects were selected for this study. Clinical measurements, including probing depth (PD) and clinical attachment loss (CAL) were carried out in patients diagnosed with chronic periodontitis and periodontal healthy controls. The clinical indexes evaluated were: gingival index (GI) and plaque index (PI). Samples of GCF were taken from one tooth per quadrant before and 45 days after NSPT. The levels of inflammatory mediators were measured by ELISA. Results: The values of all clinical parameters decreased significantly after treatment. The concentration levels of all cytokines and MMP-3 and MMP-8 in the GCF sample were higher in patients diagnosed with chronic periodontitis compared to the healthy group. All inflammatory mediators decreased after therapy, but did not reach control values; IL-6, Il-6sR, IL-10 and TNF-α, attained the highest reduction (70% -54%); the vales of MMP3, IL-1α, IL-1β and IL-8 were reduced between 50% - 34%; and MMP-8 showed the lowest decrease (28%). Conclusion: All clinical parameters and cytokines levels decreased after NSPT. The mediators TNF-α IL-6, IL-6sR, and IL-10 showed the largest variation between before and after NSPT and could thus be used to evaluate therapy response.

EOSINOFIL PASCA MENGEROK MUKOSA HIDUNG DAN PEMERIKSAAN DARAH RUTIN DI RINITIS ALERGI

Diagnostic of rhinitis allergy was based on anamnesis, physical examinations. Examine including anterior rhinoscopy, nasal endoscope, skin test and laboratory assay of nasal cytology, eosinofil count in the blood. Eosinofil mucosal nasal brushing assay andeosinofil routine hematology can be used as other examination to diagnose rhinitis allergy and to evaluate therapy response. The aimof the study was to know the correlation between eosinofil level on mucosal nasal brushing and routine hematology in suspect allergyrhinitis. The study used cross sectional methods, and was done among 37 suspected Rhinitis Allergy patients in the Clinical PathologyLaboratory, and the Clinic of Ears, Nose and Throat at Wahidin Sudirohusodo hospital Makasar, during the period of March - August2008. Eosinofil mucosal nasal brushing assay used Hansel stain and routine hematology assay used automatic blood cell counter Sysmex1800i. The data were analyzed with Pearson Correlation test using SPSS for Windows version 12,0. In the results were found from the37 samples by a correlation test the mean eosinofil level of mucosal nasal brushing. In men was 12.9/HPF and in women was 5/HPF.While eosinofil in routine hematology in men was 1595/µl and in women was 551/µl, with p &lt; 0.000 and r = 0.930. The conclusionso far from this study that the correlation of eosinofil count between mucosal nasal brushing and hematology routine in those patients suspect rhinitis allergy was very strong. So this test can be used as an alternative examination to diagnose rhinitis allergy.

Melanoma & nuclear medicine: new insights & advances.

The contribution of nuclear medicine to management of melanoma patients is increasing. In intermediate-thickness N0 melanomas, lymphoscintigraphy provides a roadmap for sentinel node biopsy. With the introduction of single-photon emission computed tomography images with integrated computed tomography (SPECT/CT), 3D anatomic environments for accurate surgical planning are now possible. Sentinel node identification in intricate anatomical areas (pelvic cavity, head/neck) has been improved using hybrid radioactive/fluorescent tracers, preoperative lymphoscintigraphy and SPECT/CT together with modern intraoperative portable imaging technologies for surgical navigation (free-hand SPECT, portable gamma cameras). Furthermore, PET/CT today provides 3D roadmaps to resect 18F-fluorodeoxyglucose-avid melanoma lesions. Simultaneously, in advanced-stage melanoma and recurrences, 18F-fluorodeoxyglucose-PET/CT is useful in clinical staging and treatment decision as well as in the evaluation of therapy response. In this article, we review new insights and recent nuclear medicine advances in the management of melanoma patients.

Perianal inflammatory diseases : Classification and imaging

During the past 30years, classifications and scoring systems have been developed in order to evaluate and objectify the degree and activity of anorectal fistulas. Only afew of these disease-specific instruments have been adopted into daily clinical routine. Generally, clinicians tend to use global medical judgement rather than numeric activity indices, which often seem complex and time consuming. Activity scores in Crohn disease, however, appeared to be very useful in clinical trials regarding evaluation of therapy response. Thus, activity indices must be simple and reproducible. The years 1976 and 1995, in which the Parks Classification and Perianal Disease Activity Index (PDAI) were established, can be considered milestone years for classifying patients with anorectal fistulizing disease. These instruments should be recognized at present as the gold standard for evaluating the complexity as well as the severity of anorectal fistulas and perianal Crohn disease.

Individualized threshold for tumor segmentation in 18F-FDG PET/CT imaging: The key for response evaluation of neoadjuvant chemoradiation therapy in patients with rectal cancer?

The standard treatment for locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiation followed by radical surgery. Regardless the extensive use of SUVmax in 18F-FDG PET tumor uptake as representation of tumor glycolytic consumption, there is a trend to apply metabolic volume instead. Thus, the aim of the present study was to evaluate a noninvasive method for tumor segmentation using the 18F-FDG PET imaging in order to predict response to neoadjuvant chemoradiation therapy in patients with rectal cancer. The sample consisted of stage II and III rectal cancer patients undergoing 18F-FDG PET/CT examination before and eight weeks after neoadjuvant therapy. An individualized tumor segmentation methodology was applied to generate tumor volumes (SUV2SD) and compare with standard SUVmax and fixed threshold (SUV40%, SUV50% and SUV60%) pre- and post-therapy. Therapeutic response was assessed in the resected specimens using Dworak's protocol recommendations. Several variables were generated and compared with the histopathological results. Seventeen (17) patients were included and analyzed. Significant differences were observed between responders (Dworak 3 and 4) and non-responders for SUVmax-2 (p<0.01), SUV2SD-2 (p<0.05), SUV40%-2 (p<0.05), SUV50%-2 (p<0.05) and SUV60%-2 (p<0.05). ROC analyses showed significant areas under the curve (p<0.01) for the proposed methodology with sensitivity and specificity varying from 60% to 83% and 73% to 82%, respectively. The present study confirmed the predictive power of the variables using a noninvasive individualized methodology for tumor segmentation based on 18F-FDG PET/CT imaging for response evaluation in patients with rectal cancer after neoadjuvant chemoradiation therapy.

Advances in exosome-related biomarkers for glioblastoma: Basic research and clinical application

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median survival rate of GBM patients is approximately 14 months and tumor recurrence is almost inevitable. With the increased use of immunotherapy, immune response and edema found on posttreatment magnetic resonance imaging (MRI) may be misinterpreted as tumor progression. Distinguishing the true radiographic progression from pseudo-progression by MRI is often difficult. Peripheral biomarkers are needed to identify the true tumor recurrence and evaluate therapy response. Exosomes isolated from both blood and cerebrospinal fluid are cargo containers utilized by eukaryotic cells to exchange biomolecules such as proteins, mRNA, and microRNA (miRNA). These biomolecules participate in cell-cell communication, cell migration, angiogenesis, and tumor growth. Isolation of RNA (including miRNA) from exosomes can yield a greater concentration compared with circulating mRNA directly taken from body fluid as molecules within exosomes are not degraded by nucleases and proteases. Not only are exosomes a novel approach to biomarker detection, but they may also provide potential therapeutic interventional targets. In addition, exosomes are critical in miRNA replacement therapy as they can act as a carrier for anticancer drug delivery. This review focuses on the advances in basic research of exosome-related potential biomarkers and discusses their potential application in the diagnosis, prognosis, and treatment of GBM.

EBONI: A Tool for Automated Quantification of Bone Metastasis Load in PSMA PET/CT.

Prostate-specific membrane antigen (PSMA) PET/CT has a high diagnostic accuracy for lesion detection in metastatic prostate cancer, including bone metastases. Novel therapeutic approaches require valid biomarkers for standardized disease staging and for evaluation of progression and therapy response. Here, we introduce EBONI (Evaluation of Bone Involvement), a software tool to automatically quantify the bone metastasis load in PSMA PET/CT. Lesion quantity, mean and maximum lesional SUV, z score, and percentage of affected bone volume are determined. EBONI is open source and freely available. Methods: To validate EBONI, the results of automated quantification of 38 PSMA PET/CT scans with different levels of bone involvement were compared with visual expert reading. The influence of SUV threshold and Hounsfield unit thresholds was analyzed. Results: A high correlation between bone lesion quantity as determined visually and automatically was found (SUVmax, r2 = 0.97; SUVmean, r2 = 0.88; lesion count, r2 = 0.97). The Hounsfield unit threshold had no significant influence, whereas an SUV threshold of 2.5 proved optimal for automated lesion quantification. The systematic error of false-positive tissue misclassification was low, occurred mainly around the salivary and lacrimal glands, and could easily be corrected. There were no false-negative ratings. Conclusion: EBONI analysis is robust, quick (<3 min per scan), and 100% reproducible. It allows rater-independent quantification of bone metastasis in metastatic prostate cancer. It provides lesion quantification equivalent to that of visual assessment, as well as providing complementary information. It can be easily implemented as an add-on to visual analysis of PSMA PET/CT scans and has the potential to reduce turnaround time.

Apparent Diffusion Coefficient (ADC) predicts therapy response in pancreatic ductal adenocarcinoma

Recent advances in molecular subtyping of Pancreatic Ductal Adenocarcinoma (PDAC) support individualization of therapeutic strategies in this most aggressive disease. With the emergence of various novel therapeutic strategies and neoadjuvant approaches in this quickly deteriorating disease, robust approaches for fast evaluation of therapy response are urgently needed. To this aim, we designed a preclinical imaging-guided therapy trial where genetically engineered mice harboring endogenous aggressive PDAC were treated with the MEK targeting drug refametinib, which induces rapid and profound tumor regression in this model system. Multi-parametric non-invasive imaging was used for therapy response monitoring. A significant increase in the Diffusion-Weighted Magnetic Resonance Imaging derived Apparent Diffusion Coefficient (ADC) was noted already 24 hours after treatment onset. Histopathological analyses showed increased apoptosis and matrix remodeling at this time point. Our findings suggest the ADC parameter as an early predictor of therapy response in PDAC.

Use of imaging techniques in large vessel vasculitis and related conditions.

Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are large vessel vasculitis (LVV) primarily affecting the aorta and its major branches, mainly differentiated by the onset age (>50 years GCA and <40 years TA). In addition, temporal artery involvement and polymyalgia rheumatica are typical features of GCA, but not TA. Imaging techniques are required to secure the diagnosis of large-vessel vasculitides, and to monitor the disease course. Both morphological and metabolic imaging are involved. Morphological imaging is represented mainly by computerized tomography (CT), CT angiography, magnetic resonance (MR), MR angiography, color-Doppler sonography (CDS) and high-resolution CDS. Metabolic aspects of inflammatory process in LVV can be well studied by positron emission tomography/computed tomography with [18F]deoxyglucose ([18F]FDG PET/CT). It has an important increasing role in diagnosis, extent assessment and disease activity and therapy response evaluation. In the near future the concomitant development of increasingly powerful PET/CT scanners, of new radiopharmaceuticals more specific for inflammation, and of new PET/MRI hybrid scanners probably will lead to a further new step forward in the diagnosis and clinical management of LVV.

Contrast-enhanced spectral mammography in patients with MRI contraindications.

Background Contrast-enhanced spectral mammography (CESM) is a novel breast imaging technique providing comparable diagnostic accuracy to breast magnetic resonance imaging (MRI). Purpose To show that CESM in patients with MRI contraindications is feasible, accurate, and useful as a problem-solving tool, and to highlight its limitations. Material and Methods A total of 118 patients with MRI contraindications were examined by CESM. Histology was obtained in 94 lesions and used as gold standard for diagnostic accuracy calculations. Imaging data were reviewed retrospectively for feasibility, accuracy, and technical problems. The diagnostic yield of CESM as a problem-solving tool and for therapy response evaluation was reviewed separately. Results CESM was more accurate than mammography (MG) for lesion categorization (r = 0.731, P < 0.0001 vs. r = 0.279, P = 0.006) and for lesion size estimation (r = 0.738 vs. r = 0.689, P < 0.0001). Negative predictive value of CESM was significantly higher than of MG (85.71% vs. 30.77%, P < 0.0001). When used for problem-solving, CESM changed patient management in 2/8 (25%) cases. Superposition artifacts and timing problems affected diagnostic utility in 3/118 (2.5%) patients. Conclusion CESM is a feasible and accurate alternative for patients with MRI contraindications, but it is necessary to be aware of the method's technical limitations.

PrediCTC, liquid biopsy in precision oncology: a technology transfer experience in the Spanish health system.

Management of metastatic disease in oncology includes monitoring of therapy response principally by imaging techniques like CT scan. In addition to some limitations, the irruption of liquid biopsy and its application in personalized medicine has encouraged the development of more efficient technologies for prognosis and follow-up of patients in advanced disease. PrediCTC constitutes a panel of genes for the assessment of circulating tumor cells (CTC) in metastatic colorectal cancer patients, with demonstrated improved efficiency compared to CT scan for the evaluation of early therapy response in a multicenter prospective study. In this work, we designed and developed a technology transfer strategy to define the market opportunity for an eventual implementation of PrediCTC in the clinical practice. This included the definition of the regulatory framework, the analysis of the regulatory roadmap needed for CE mark, a benchmarking study, the design of a product development strategy, a revision of intellectual property, a cost-effectiveness study and an expert panel consultation. The definition and analysis of an appropriate technology transfer strategy and the correct balance among regulatory, financial and technical determinants are critical for the transformation of a promising technology into a viable technology, and for the decision of implementing liquid biopsy in the monitoring of therapy response in advanced disease.

Abstract 2868: 18F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal therapy

Abstract Aim: Nanoparticle-assisted photothermal therapy is a new promising therapeutic strategy that utilizes photo-absorbing nanoparticles irradiated with near infrared light to generate a local temperature increase in tumor tissue. Here we used small animal 18F-FDG PET/CT to evaluate the treatment response of silica-gold nanoshell (NS)-assisted photothermal therapy in human tumor xenografts in mice. Method: NMRI nude mice had ~ 106 human neuroendocrine tumor cells (H727) inoculated into the left flank. After 4-5 weeks, animals were divided into three groups: one receiving NS and laser irradiation (NS group, n = 9), one receiving saline and laser irradiation (saline group, n = 9), and one receiving NS but no laser irradiation (sham group, n = 5). All animals were PET scanned with 18F-FDG one day before treatment (baseline), followed by iv administration of either NS or saline. Approximately 24 hours after injection, the animals were placed on a laser treatment platform and the tumors were irradiated with an 807 nm diode laser for 5 minutes using a laser intensity of 1.8 W/cm2. During irradiation, the temperature at the surface of the tumor was measured using thermographic imaging. The mice were 18F-FDG PET scanned again at day 1 after treatment and tumor growth was followed by caliper measurements with the humane endpoint defined as a tumor volume of 1,000 mm3. PET and CT images were co-registered, and regions of interest were manually drawn on whole tumor regions. 18F-FDG uptake was quantified as mean percentage of injected dose per grams of tissue (%ID/g) and the treatment response was evaluated based on the reduction in tumor uptake of 18F-FDG between baseline and day 1. Results: Thermographic imaging showed that the tumor surface on average reached 49.2 ± 3.3 °C in the NS group. In comparison, the average temperatures reached 44.5 ± 1.9 °C in the saline group and 33 ± 1.0 °C in the sham group. This was consistent with an overall inhibited tumor growth, as well as improved survival in the NS group compared to the sham and saline groups. The tumor accumulation of 18F-FDG uptake was comparable between groups at baseline but PET imaging revealed a significant reduction in tumor uptake at day 1 in the NS group ( 84 ± 8 % (day 1/baseline)) compared to the saline (= 108 ± 21 %; p &amp;lt; 0.01) and sham (= 110 ± 11 %; p &amp;lt; 0.05) groups. Moreover, the change in 18F-FDG tumor uptake (day 1/baseline), was used to stratify animals into responders and non-responders, where the responding group matched inhibited tumor growth and improved survival. Conclusion: In this study we showed that 18F-FDG PET could be used for early response monitoring of the therapeutic outcome of nanoparticle-assisted photothermal therapy in human tumor xenografts in mice. Based on this, we suggest that PET can also be used for optimization of therapy, both for guiding treatment planning and early identification of non-responders for which the treatment strategy should then be changed. Citation Format: Jesper Tranekjaer Joergensen, Kamilla Norregaard, Marina Simón Martín, Fredrik Melander, Lotte K. Kristensen, Pól Martin Bendix, Thomas L. Andresen, Lene B. Oddershede, Andreas Kjaer. 18F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2868. doi:10.1158/1538-7445.AM2017-2868

Imaging Spectrum of Invasive Fungal and Fungal-like Infections.

Invasive fungal and fungal-like infections contribute to substantial morbidity and mortality in immunocompromised individuals. The incidence of these infections is increasing-largely because of rising numbers of immunocompromised patients, including those with neutropenia, human immunodeficiency virus, chronic immunosuppression, indwelling prostheses, burns, and diabetes mellitus, and those taking broad-spectrum antibiotics. Invasive fungal pathogens include primary mycotic organisms such as Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, and Paracoccidioides brasiliensis, which are true pathogens and inherently virulent. Secondary mycotic organisms such as Candida and Aspergillus species, Cryptococcus neoformans, Pneumocystis jirovecii, and Mucorales fungi are opportunistic, less virulent pathogens. Nocardia and Actinomyces species are gram-positive bacteria that behave like fungi in terms of their growth pattern and cause fungal-like invasive indolent infections; thus, these organisms are included in this review. Fungal and fungal-like infections can affect a variety of organ systems and include conditions such as meningitis, sinusitis, osteomyelitis, and enteritis. As awareness of these infections increases, timely diagnosis and treatment will become even more important. Imaging has a critical role in the evaluation of disease activity, therapy response, and related complications. Using an organ-based approach with computed tomography, magnetic resonance imaging, and ultrasonography to gain familiarity with the appearances of these infections enables timely and accurate diagnoses. ©RSNA, 2017.

18F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal cancer therapy.

Within the field of nanoparticle-assisted photothermal cancer therapy, focus has mostly been on developing novel heat-generating nanoparticles with the right optical and dimensional properties. Comparison and evaluation of their performance in tumor-bearing animals are commonly assessed by changes in tumor volume; however, this is usually a late-occurring event. This study implements 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography imaging to perform early evaluation of the treatment outcome of photothermal therapy. Silica-gold nanoshells (NS) are administered intravenously to nude mice bearing human neuroendocrine tumor xenografts and the tumors are irradiated by a near-infrared laser. The animals are positron emission tomography scanned with 2-deoxy-2-[F-18]fluoro-D-glucose one day before and one day after treatment. Using this setup, a significant decrease in tumor uptake of 2-deoxy-2-[F-18]fluoro-D-glucose is found already one day after therapy in the group receiving NS and laser treatment compared to control animals. At this time point no change in tumor volume can be detected. Moreover, the change in tumor uptake, is used to stratify the animals into responders and non-responders, where the responding group matched improved survival. Overall, these findings support the use of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography imaging for preclinical and clinical evaluation and optimization of photothermal therapy.

Abstract IA07: Genetic determinants of tumor development, therapy response and resistance in mouse models of BRCA-deficient breast cancer

Abstract Heterozygous germline mutations in BRCA1 or BRCA2 strongly predispose to development of breast and ovarian cancer (as well as other cancer types) via loss of the remaining wildtype allele. BRCA1/2-deficient cancers are defective in DNA double-strand break (DSB) repair via homologous recombination (HR) and therefore hypersensitive to DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors. However, these treatments do not result in tumor eradication and eventually resistance develops. To maximize therapeutic efficacy of these drugs and achieve durable remissions, it is important to unravel the mechanisms by which these tumors acquire resistance to platinum drugs and PARP inhibitors, in order to develop combination therapies that prevent development of resistance or re-sensitize resistant tumors. To study therapy response and resistance in a realistic in vivo setting, we have established several genetically engineered mouse models (GEMMs) and patient-derived tumor xenograft (PDX) models for BRCA-deficient breast cancer. These mice develop mammary tumors that are characterized by genomic instability and hypersensitivity to DNA-damaging agents, including platinum drugs and PARP inhibitors. Using cross-species oncogenomics and reverse genetics, we have identified several cancer genes including p53, MYC and RB as critical drivers in BRCA1-associated breast cancer. In addition, we have used these mammary tumor models for preclinical evaluation of therapy response and elucidation of mechanisms of acquired drug resistance. Using functional genetic screens, reverse genetics and genomic analysis of therapy-resistant tumors, we found that therapy response and resistance of BRCA1-deficient mammary tumors to cisplatin and the clinical PARP inhibitor olaparib is affected by several factors, including drug efflux transporter activity, type of BRCA1 founder mutation and restoration of HR repair via loss of 53BP1 or REV7. Also BRCA1 re-activation via genetic or epigenetic mechanisms contributes to therapy resistance in PDX models of BRCA1-deficient breast cancer. Importantly, pharmacokinetic or HR-related mechanisms underlie olaparib-resistance in only a fraction of BRCA1/2-deficient mammary tumors, indicating the existence of additional, unknown mechanisms. Citation Format: Jos Jonkers. Genetic determinants of tumor development, therapy response and resistance in mouse models of BRCA-deficient breast cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA07.

18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography for Other Thyroid Cancers: Medullary, Anaplastic, Lymphoma and So Forth.

Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) is used in staging, restaging, and evaluation of therapy response in many cancers as well as differentiated thyroid carcinomas especially in non-iodine avid variants. Its potential in less frequent thyroid tumors like medullary, anaplastic thyroid cancers, thyroid lymphoma and metastatic tumors of the thyroid however, is not well established yet. The aim of this review is to provide an overview on the recent applications and indications of 18F-FDG PET/CT in these tumors and to focus on the controversies in the clinical setting.

Value of the “Standing Test” in the Diagnosis and Evaluation of Beta-blocker Therapy Response in Long QT Syndrome

Introduction and objectivesPatients with congenital long QT syndrome (LQTS) have an abnormal QT adaptation to sudden changes in heart rate provoked by standing. The present study sought to evaluate the standing test in a cohort of LQTS patients and to assess if this QT maladaptation phenomenon is ameliorated by beta-blocker therapy. MethodsElectrographic assessments were performed at baseline and immediately after standing in 36 LQTS patients (6 LQT1 [17%], 20 LQT2 [56%], 3 LQT7 [8%], 7 unidentified-genotype patients [19%]) and 41 controls. The corrected QT interval (QTc) was measured at baseline (QTcsupine) and immediately after standing (QTcstanding); the QTc change from baseline (ΔQTc) was calculated as QTcstanding – QTcsupine. The test was repeated in 26 patients receiving beta-blocker therapy. ResultsBoth QTcstanding and ΔQTc were significantly higher in the LQTS group than in controls (QTcstanding, 528 ± 46ms vs 420 ± 15ms, P < .0001; ΔQTc, 78 ± 40ms vs 8 ± 13ms, P < .0001). No significant differences were noted between LQT1 and LQT2 patients. Typical ST-T wave patterns appeared after standing in LQTS patients. Receiver operating characteristic curves of QTcstanding and ΔQTc showed a significant increase in diagnostic value compared with the QTcsupine (area under the curve for both, 0.99 vs 0.85; P < .001). Beta-blockers attenuated the response to standing in LQTS patients (QTcstanding, 440 ± 32ms, P < .0001; ΔQTc, 14 ± 16ms, P < .0001). ConclusionsEvaluation of the QTc after the simple maneuver of standing shows a high diagnostic performance and could be important for monitoring the effects of beta-blocker therapy in LQTS patients.