Assessment Of Tumor Burden Research Articles

Differential Mutation Detection Capability Through Capture-Based Targeted Sequencing in Plasma Samples in Hepatocellular Carcinoma

Circulating tumor DNA (ctDNA) is a promising biomarker for accurate monitoring and less invasive assessment of tumor burden and treatment response. Here, targeted next-generation sequencing (NGS) with a designed gene panel of 176 cancer-relevant genes was used to assess mutations in 90 ctDNA samples from 90 patients with multiple types of liver disease and 10 healthy donor samples for control. Using our ctDNA detection panel, we identified mutations in 98.89% (89/90) of patient plasma biopsy samples, and 19 coding variants located in 10 cancer-related genes [ACVR2A, PCLO, TBCK, adhesion G protein-coupled receptor (ADGRV1), COL1A1, GABBR1, MUC16, MAGEC1, FASLG, and JAK1] were identified in 96.7% of patients (87/90). The 10 top mutated genes were tumor protein p53 (TP53), ACVR2A, ADGRV1, MUC16, TBCK, PCLO, COL11A1, titin (TTN), DNAH9, and GABBR1. TTN and TP53 and TTN and DNAH9 mutations tended to occur together in hepatocellular carcinoma samples. Most importantly, we found that most of those variants were insertions (frameshift insertions) and deletions (frameshift deletions and in-frame deletions), such as insertion variants in ACVR2A, PCLO, and TBCK; such mutations were detected in almost 95% of patients. Our study demonstrated that the targeted NGS-based ctDNA mutation profiling was a useful tool for hepatocellular carcinoma (HCC) monitoring and could potentially be used to guide treatment decisions in HCC.

Preliminary Analysis of Liquid Biopsy after Hepatectomy for Colorectal Liver Metastases

Liquid biopsies are increasingly tested in patients with colorectal cancer to assess tumor burden, response to therapy, and prognosis. The significance of liquid biopsy results after resection of colorectal liver metastases (CLMs) is not well-defined. Sixty-three patients undergoing CLM resection between 2016 and 2018 had plasma drawn postoperatively for liquid biopsy evaluation. Next-generation sequencing analysis was performed to detect somatic mutations in 70 genes. Liquid biopsy after CLM resection was positive in 42 of 63 patients (67%). Eleven patients (18%) had 1 gene mutation, 14 patients (22%) had 2 to 3 mutations, and 17 patients (27%) had 4 or more mutations. The most common mutation was APC, detected in 32 patients (76%), followed by TP53 (74%) and KRAS (38%). Two-year overall survival rate from date of liver resection was significantly worse among patients with a positive liquid biopsy (70% vs 100%; p= 0.005), particularly for those with 4 or more gene mutations detected, whose 2-year overall survival rate was 41%. Sixteen of the 63 patients underwent serial liquid biopsies, resulting in 100 liquid biopsies with matched serum CEA and CT scan results. Metastases were identified in 74 CT scans, which correlated with positive liquid biopsy in 77% of samples (p < 0.001) and CEA > 3 ng/mL in 45% of samples (p < 0.22). Liquid biopsy results provide information about disease burden and prognosis that is complementary to serum CEA and CT imaging. A positive liquid biopsy after CLM resection is associated with worse overall survival, particularly when multiple gene mutations are detected.

Abstract PO-086: Detection of cancer lesions in histopathological lung images using a sparse PCA network

Abstract Purpose: Lung cancer has been the leading cause of cancer-related deaths worldwide. To address the clinical need for efficacious treatments, genetically engineered mouse models (GEMMs) have become integral in identifying and evaluating unique pathways that may be exploited as therapeutic targets. Assessment of GEMM tumor burden on histopathological sections performed by manual inspection is both time consuming and prone to subjective bias. Therefore, an interplay of needs and challenges exists for computer aided detection tools, for the accurate and efficient analysis of these histopathology images. Our work demonstrates a simple machine learning approach called sparse principal component analysis (PCA) network, for automated detection of cancerous lesions on histological lung slides stained by hematoxylin and eosin (H&amp;E). Methods: Our method comprises four steps: 1) cascaded sparse PCA; 2) graph-based PCA hashing; 3) block-wise histograms; and 4) support vector machine (SVM) classification. In our proposed architecture, sparse PCA is employed to learn the filter banks of the multiple stages. This is followed by a graph-based PCA hashing and block histograms for indexing and pooling. The meaningful features extracted from this sparse PCA are then fed to an SVM classifier. We tested the proposed sparse PCA network on H&amp;E slides obtained from an inducible KrasG12D lung cancer mouse model. Our dataset consists of N = 21 whole slide histopathology lung images with 9 non-tumor bearing control mice and 12 mice with visible lung tumors. Tumor lesions from 12 lung images with visible tumors were visually identified by three trained individuals, which served as ground truth. The size of each image in our dataset is 2048 × 2048 pixels. Each image was divided into non-overlapping image patches of size 20 × 20 pixels consisting of a total of 12,361 cancer lesion patches and 207,839 non-cancer patches. We used 50% of the data for training and 50% of the data for testing our proposed sparse PCA network. We evaluated our algorithm using conventional metrics that have been used for evaluation of classification algorithms, namely precision (P), recall (R), and coverage measure (F-score). Results: The automatic cancer lesion detection results were compared with manually annotated ground truth. The proposed method achieves a cancer lesion detection accuracy of 97.98% with P = 0.8624, R = 0.9062 and F-score = 0.8790. The proposed method was found to take on average 17 minutes to train and learn a good representation for accurate and efficient classification of cancerous lesions within the images. Conclusion: We demonstrated a simple machine learning methodology for detection of cancerous lesions within histopathological lung images. Experimental results show that the proposed method is able to classify the regions of interest both efficiently and accurately. Future work will focus on feature extraction of individual tumors and tumor location within lungs. Citation Format: Sundaresh Ram, Wenfei Tang, Alexander J. Bell, Cara Spencer, Alexander Buschhuas, Charles R. Hatt, Marina P. di Magliano, Stefanie Galban, Craig J. Galban. Detection of cancer lesions in histopathological lung images using a sparse PCA network [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-086.

Comparison of Solid Tumor Treatment Response Observed in Clinical Practice With Response Reported in Clinical Trials

In clinical trials supporting the regulatory approval of oncology drugs, solid tumor response is assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Calculation of RECIST-based responses requires sequential, timed imaging data, which presents challenges to the method's application in real-world evidence research. To evaluate the feasibility and validity of a novel real-world RECIST method in assessing tumor burden associated with therapy for a large heterogeneous patient population undergoing treatment in routine clinical practice. This cohort study used physician-abstracted data pooled from retrospective, multisite electronic health record (EHR) review studies of patients treated with anticancer drugs at US oncology practices from 2014 through 2017. Included patients were receiving first-line treatment for thyroid cancer, breast cancer, or metastatic melanoma. Data were analyzed from March through August 2020. Undergoing treatment with immunotherapy or targeted therapy. Tumor response was classified according to RECIST guidelines (ie, change in sum diameter of target lesions) post hoc with measurements derived from imaging scans and reports. Among 1308 completed electronic case report forms, 956 forms (73.1%) had adequate data to classify real-world RECIST response. The greatest difference between physician-recorded responses and real-world RECIST-based responses was found in the proportion of complete responses: 118 responses (12.3%) vs 46 responses (4.8%) (P < .001). Among 609 patients in the metastatic melanoma population, complete responses were reported in 112 physician-recorded responses (18.4%) vs 44 real-world RECIST-based responses (7.2%) (P < .001), compared with 11 of 247 responses (4.5%) to 31 of 192 responses (16.1%) across pivotal trials of the same melanoma therapies. These findings suggest that comparing tumor lesion sizes and categorizing treatment response according to RECIST guidelines may be feasible using real-world data. This study found that physician-recorded assessments were associated with overestimation of treatment response, with the largest overestimation among complete responses. Real-world RECIST-based assessments were associated with better approximations of tumor response reported in clinical trials compared with those reported in EHRs.

Time to focus on circulating nucleic acids for diagnosis and monitoring of gliomas: A systematic review of their role as biomarkers.

Gliomas are diffusely growing tumours arising from progenitors within the central nervous system. They encompass a range of different molecular types and subtypes, many of which have a well-defined profile of driver mutations, copy number changes and DNA methylation patterns. A majority of gliomas will require surgical intervention to relieve raised intracranial pressure and reduce tumour burden. A proportion of tumours, however, are located in neurologically sensitive areas and a biopsy poses a significant risk of a deficit. A majority of gliomas recur after surgery, and monitoring tumour burden of the recurrence is currently achieved by imaging. However, most imaging modalities have limitations in assessing tumour burden and infiltration into adjacent brain, and sometimes imaging is unable to discriminate between tumour recurrence and pseudo-progression. Liquid biopsies, obtained from body fluids such as cerebrospinal fluid or blood, contain circulating nucleic acids or extracellular vesicles containing tumour-derived components. The studies for this systematic review were selected according to PRISMA criteria, and suggest that the detection of circulating tumour-derived nucleic acids holds great promises as biomarker to aid diagnosis and prognostication by monitoring tumour progression, and thus can be considered a pathway towards personalized medicine.

Total diffusion volume in MRI vs. total lesion glycolysis in PET/CT for tumor volume evaluation of multiple myeloma.

This study compared the tumor burden and prognostic impact of total diffusion volume (tDV) and total lesion glycolysis (TLG) in the same patients with newly diagnosed multiple myeloma (NDMM) simultaneously. We also examined the relationship between these imaging tumor volumes (TVs) and plasma cell (PC) TV in bone marrow (BM) specimens. We retrospectively reviewed the data of 63 patients with newly diagnosed multiple myeloma (NDMM) from April 2016 to March 2018. tDV was calculated from whole-body diffusion-weighted imaging and TLG was calculated from the average standard uptake value and the metabolic tumor volume, respectively. Cellularity of BM hematopoietic tissue and the percentage of BM PCs were used as a reference of PC volume in the BM. The Spearman correlation coefficient between tDV and TLG was moderate (ɤs = 0.588, p < 0.001) when PET false-negative patients were excluded. There were positive correlations between the BM plasma cell volume (BMPCV) and the imaging TVs (ɤs = 0.505, vs. tDV; and 0.464, vs. TLG). Patients with high tDV and high TLG, as determined by the receiver operating characteristic curve, had worse survival; moreover, patients with both high tDV and high TLG showed the worst prognosis (median progression-free and overall survival: 13.2 and 28.9 months, respectively). Although tDV and TLG each reflected the total TV, in several cases, tDV and TLG were discrepant due to the biological features of each MM. It is important to use both modalities for complementary assessment of total tumor burden and biological characteristics in MM. • Total diffusion volume (tDV) and total lesion glycolysis (TLG) reflect the total tumor volume and have prognostic value in patients with multiple myeloma (MM). • tDV and TLG could assess MM from different biological perspectives and should be considered for each patient individually.

Mutational Landscape and Tumor Burden Assessed by Cell-free DNA in Diffuse Large B-Cell Lymphoma in a Population-Based Study.

We analyzed the utility of cell-free DNA (cfDNA) in a prospective population-based cohort to determine the mutational profile, assess tumor burden, and estimate its impact in response rate and outcome in patients with diffuse large B-cell lymphoma (DLBCL). A total of 100 patients were diagnosed with DLBCL during the study period. Mutational status of 112 genes was studied in cfDNA by targeted next-generation sequencing. Paired formalin-fixed, paraffin-embedded samples and volumetric PET/CT were assessed when available. Appropriate cfDNA to perform the analyses was obtained in 79 of 100 cases. At least one mutation could be detected in 69 of 79 cases (87%). The sensitivity of cfDNA to detect the mutations was 68% (95% confidence interval, 56.2-78.7). The mutational landscape found in cfDNA samples was highly consistent with that shown in the tissue and allowed genetic classification in 43% of the cases. A higher amount of circulating tumor DNA (ctDNA) significantly correlated with clinical parameters related to tumor burden (elevated lactate dehydrogenase and β2-microglobulin serum levels, advanced stage, and high-risk International Prognostic Index) and total metabolic tumor volume assessed by PET/CT. In patients treated with curative intent, high ctDNA levels (>2.5 log hGE/mL) were associated with lower complete response (65% vs. 96%; P < 0.004), shorter progression-free survival (65% vs. 85%; P = 0.038), and overall survival (73% vs. 100%; P = 0.007) at 2 years, although it did not maintain prognostic value in multivariate analyses. In a population-based prospective DLBCL series, cfDNA resulted as an alternative source to estimate tumor burden and to determine the tumor mutational profile and genetic classification, which have prognostic implications and may contribute to a future tailored treatment.

Droplet digital PCR-based detection of circulating tumor DNA from pediatric high grade and diffuse midline glioma patients.

BackgroundThe use of liquid biopsy is of potential high importance for children with high grade (HGG) and diffuse midline gliomas (DMG), particularly where surgical procedures are limited, and invasive biopsy sampling not without risk. To date, however, the evidence that detection of cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA) could provide useful information for these patients has been limited, or contradictory.MethodsWe optimized droplet digital PCR (ddPCR) assays for the detection of common somatic mutations observed in pediatric HGG/DMG, and applied them to liquid biopsies from plasma, serum, cerebrospinal fluid (CSF), and cystic fluid collected from 32 patients.ResultsAlthough detectable in all biomaterial types, ctDNA presented at significantly higher levels in CSF compared to plasma and/or serum. When applied to a cohort of 127 plasma specimens from 41 patients collected from 2011 to 2018 as part of a randomized clinical trial in pediatric non-brainstem HGG/DMG, ctDNA profiling by ddPCR was of limited use due to the small volumes (mean = 0.49 mL) available. In anecdotal cases where sufficient material was available, cfDNA concentration correlated with disease progression in two examples each of poor response in H3F3A_K27M-mutant DMG, and longer survival times in hemispheric BRAF_V600E-mutant cases.ConclusionTumor-specific DNA alterations are more readily detected in CSF than plasma. Although we demonstrate the potential of the approach to assessing tumor burden, our results highlight the necessity for adequate sample collection and approach to improve detection if plasma samples are to be used.

PCN126 A Cost IMPACT Analysis of Clonoseq® As a Valid and CE-Certified Minimal Residual Disease (MRD) Diagnostic in Multiple Myeloma in Germany

The measurement of minimal residual disease (MRD) with clonoSEQ®-Assay is being used in the assessment of residual lymphoid B-cell tumor burden throughout treatment with increased accuracy, higher sensitivity and objective assessment compared to traditional cytomorphological approaches. With more targeted therapies and immunotherapies in lymphoid cancers, standardized MRD assessment methods with higher sensitivity and specificity are becoming increasingly important. The primary aim of this analysis is to estimate the cost-effectiveness of MRD testing with clonoSEQ® compared to no MRD testing for patients with multiple myeloma (MM) on maintenance drug therapy in Germany. The cost impact of clonoSEQ® was analyzed from the German statutory health insurance perspective. Clinical data were derived from literature and expert opinions. Cost input was utilized based on publicly available data and literature. Patients in the MRD arm were assumed to be tested every 6 months. The deterministic Markov model consists of six health states and every patient begins at the start of their drug maintenance therapy. Included therapies are RVD (lenalidomide, bortezomib, dexamethasone), bone marrow transplantation / stem cell transfusion, lenalidomide and for the relapsed health state carfilzomib, lenalidomide and dexamethasone. For a time horizon of ten years, the cost impact analysis shows total cost of € 336’056 for patients with MRD testing using the clonoSEQ® in comparison to € 364’576 for simulated patients without an MRD test. The cost savings per patients are calculated to be € 28’520 per patient in Germany. Cost savings after 3 years are 25’224 € per patient. The main drivers for the cost differences are the saved cost of unnecessary drug therapies. Based on the underlying health economic model, the clonoSEQ® MRD test can support health insurance funds in Germany to more efficiently use high cost drugs in the treatment of multiple myeloma.

Total Diffusion Volume Estimated By Whole-Body Diffusion Magnetic Resonance Imaging for the Assessment of Tumor Burden in Multiple Myeloma

Introduction: Whole-body diffusion-weighted magnetic resonance imaging (wbDWI) is an emerging imaging technique for assessing the tumor burden of patients with multiple myeloma (MM). Total diffusion volume (tDV) is a potential parameter to quantify the tumor volume of bone marrow (BM) images obtained by wbDWI. The apparent diffusion coefficient (ADC) value, also calculated with wbDWI, has the potential to accurately evaluate the treatment response of MM; however, correlation between tDV and the treatment response of MM remains poorly studied. Methods: We retrospectively selected patients with newly-diagnosed, symptomatic MM who were treated at Kameda Medical Center, Japan, from January 2016 to November 2019; we analyzed the tDV obtained by wbDWI before and after treatment. We used the BD score software (PixSpace, Japan) to analyze tDV. Briefly, the regions of interest, including areas with abnormally high signal intensity of diffusion weighted imaging considered to contain myeloma lesions in the BM or extramedullary tissue, were automatically obtained with a b-value of 900 s/mm2. Physiological areas with high signal intensity were removed manually. Threshold values for distinguishing diseased areas from the background were manually adjusted to cover all bone lesions. Diagnosis and response were assessed using the International Myeloma Working Group criteria. We compared tDV before and after treatment, and in each response category. Comparison of continuous variables between the two categories and between three or more sets were analyzed using Wilcoxon test and Kruskal-Wallis test, respectively. All statistical analyses were performed using R (version 4.0.2; R Foundation, Vienna, Austria). Results: We analyzed 42 patients (18 men; median age, 71.5 years; interquartile range [IQR]: 65.0-77.0) whose pre- and post-treatment tDV values were available. The type of myeloma at diagnosis included immunoglobulin G (IgG) (n=21, 50%), immunoglobulin A (IgA) (n=12, 28%), and light chain alone (n=9, 21.4%). Three patients (7.1%) underwent wbDWI when they achieved partial response (PR); 6 patients (14.2%) achieved very good partial response (VGPR), 3 patients (7.1%) achieved complete response (CR), and 30 patients (71.4%) achieved stringent complete response (sCR). In all patients, median tDV decreased significantly before and after the treatment (median, 464.24 mL [IQR: 152.99-929.23] and 108.2 mL [IQR: 27.76-368.85], respectively; p&amp;lt;0.001) (Figure 1). Median tDV after treatment trended to be progressively low for patients who achieved PR, VGPR, CR, and sCR (tDV: 381.33 mL, 218.85 mL, 19.26 mL, and 63.97 mL, respectively; p=0.12). However, these values were not statistically significant. We also compared the tDV before and after treatment for patients who achieved less than CR (PR and VGPR) and those who achieved CR or better (≥CR). The median tDV of the patients who achieved less than CR was 298.24 mL [IQR: 147.88-381.33] and for those who achieved ≥CR was 62.65 mL [IQR: 19.26-279.79] (p=0.02) (Figure 2). We also compared the decreasing rate of tDV before and after treatment between patients who achieved less than CR and those who achieved ≥CR. The median decreasing rate of tDV was 61.0% 72.0% for patients who achieved less than CR and ≥CR, respectively. Although this result was not statistically significant, the data suggests that patients who achieved a deeper response tended to have a larger decreasing rate of tDV. Conclusions: Our data shows that tDV correlates with the depth of treatment response, and thus, is a potentially useful marker for evaluating the treatment response in patients with MM. Disclosures No relevant conflicts of interest to declare.

Quantitative in vivo bioluminescence imaging of orthotopic patient-derived glioblastoma xenografts

Despite extensive research, little progress has been made in glioblastoma therapy, owing in part to a lack of adequate preclinical in vivo models to study this disease. To mitigate this, primary patient-derived cell lines, which maintain their specific stem-like phenotypes, have replaced established glioblastoma cell lines. However, due to heterogenous tumour growth inherent in glioblastoma, the use of primary cells for orthotopic in vivo studies often requires large experimental group sizes. Therefore, when using intracranial patient-derived xenograft (PDX) approaches, it is advantageous to deploy imaging techniques to monitor tumour growth and allow stratification of mice. Here we show that stable expression of near-infrared fluorescent protein (iRFP) in patient-derived glioblastoma cells enables rapid, direct non-invasive monitoring of tumour development without compromising tumour stemness or tumorigenicity. Moreover, as this approach does not depend on the use of agents like luciferin, which can cause variability due to changing bioavailability, it can be used for quantitative longitudinal monitoring of tumour growth. Notably, we show that this technique also allows quantitative assessment of tumour burden in highly invasive models spreading throughout the brain. Thus, iRFP transduction of primary patient-derived glioblastoma cells is a reliable, cost- and time-effective way to monitor heterogenous orthotopic PDX growth.

Abstract 5451: Longitudinal proteomic assessment of patient with metastatic apocrine adenocarcinoma reveals evolutionary selection for androgen-receptor-dependence and therapeutic response

Abstract Combined use of new molecular diagnostic and imaging methods could improve care of individual patients with rare cancers. A 57-year-old developed apocrine adenocarcinoma of the left axilla with regional lymph node metastasis detected at initial surgery. After adjuvant regional radiotherapy, metastases developed and over the subsequent 7 years he received serial systemic therapy with 11 different regimens. Expression of 128 proteins/phosphoproteins was evaluated in 8 tissue samples from diagnosis, progressive adenopathy at 45 months, brain metastases at 60 months, and abdominal metastases at 63 months by CLIA-standardized reverse phase phosphoprotein arrays (RPPA). Tumor burden was estimated by quantifying the volume of individual lesions with semi-automated segmentation algorithms on serially collected CT images. Next-generation sequencing (NGS) revealed a PIK3CA K111T mutation, prompting treatment with sirolimus 28 months after diagnosis. Seventeen months later, new neoplastic adenopathy emerged. NGS revealed a new PIK3CA M610V mutation. Semiquantitative scoring of RPPA demonstrated relative increase in AKT (from 0.72 to 0.9) and mTOR (from 0.55 to 0.8) pathway activation. The relative estimated tumor burden (RETB) was 21,145 mm3. Over 6 months of docetaxel therapy the RETB decreased to 12,077 mm3. The patient subsequently received pembrolizumab with increased RETB (71,308 mm3). Gemcitabine appeared to stabilize the RETB (73,168 mm3), but brain metastases emerged. The patient underwent craniotomy, began paclitaxel therapy, and then RETB declined to 35,623 mm3. But new symptomatic abdominal metastases prompted surgical resection. The patient then received the PI3K inhibitor taselisib; however, after an initial decrease, RETB rose to 31,208 mm3. At this point, the patient began bicalutamide therapy. NGS of the primary mass and the initial metastatic adenopathy revealed no amplification of the androgen receptor (AR). But RPPA demonstrated inversion of the ratio of measured phosphorylated AR S81 to AR S650, suggesting primarily cytoplasmic AR in tumor through 45 months but nuclear AR in samples resected at 60 and 63 months. Immunohistochemistry revealed 3+ nuclear AR expression in the latter metastatic tissue. After 9 months of bicalutamide, enzalutamide and leuprolide were administered for 7 months (final RETB = 1,555 mm3). Treatment continued beyond the study period. Tumor burden assessment by new CT imaging measurement methods, combined with RPPA could improve adaptive, responsive, therapy for patients with rare tumors. We identified the phenotypic evolution of androgen-driven growth of apocrine adenocarcinoma after cytotoxic and PI3K-mTOR inhibitor therapy. Protein-based diagnostics revealed an effective treatment strategy in late metastatic disease that was not indicated by NGS testing. Citation Format: Erik Dvergsten, Anthony Serritella, Danielle Kimble, Malcom McIver, Sanja Karovic, Vasiliki Thomeas-McEwing, Hao Yang, Manish R. Sharma, Thomas P. Conrads, Mariaelena Pierobon, Peter Pytel, Binsheng Zhao, Lawrence H. Schwartz, Emanuel F. Petricoin, Russell Szmulewitz, Michael L. Maitland. Longitudinal proteomic assessment of patient with metastatic apocrine adenocarcinoma reveals evolutionary selection for androgen-receptor-dependence and therapeutic response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5451.

Spectral photon-counting CT imaging of colorectal peritoneal metastases: initial experience in rats

Computed tomography imaging plays a major role in the preoperative assessment of tumor burden by providing an accurate mapping of the distribution of peritoneal metastases (PM). Spectral Photon Counting Computed Tomography (SPCCT) is an innovative imaging modality that could overcome the current limitations of conventional CT, offering not only better spatial resolution but also better contrast resolution by allowing the discrimination of multiple contrast agents. Based on this capability, we tested the feasibility of SPCCT in the detection of PM at different time of tumor growth in 16 rats inoculated with CC531 cells using dual-contrast injection protocols in two compartments (i.e. intravenous iodine and intraperitoneal gadolinium or the reverse protocol), compared to surgery. For all peritoneal regions and for both protocols, sensitivity was 69%, specificity was 100% and accuracy was 80%, and the correlation with surgical exploration was strong (p = 0.97; p = 0.0001). No significant difference was found in terms of diagnostic performance, quality of peritoneal opacification or diagnostic quality between the 2 injection protocols. We also showed poor vascularization of peritoneal metastases by measuring low concentrations of contrast agent in the largest lesions using SPCCT, which was confirmed by immunohistochemical analyses. In conclusion, SPCCT using dual-contrast agent injection protocols in 2 compartments is a promising imaging modality to assess the extent of PM in a rat model.

Ewing sarcoma family of tumors-derived small extracellular vesicle proteomics identify potential clinical biomarkers

Purpose: Ewing Sarcoma Family of Tumors (ESFT), the second most common pediatric osseous malignancy, are characterized by the pathognomonic chromosomal EWS-ETS translocation. Outside of tumor biopsy, no clinically relevant ESFT biomarkers exist. Additionally, tumor burden assessment at diagnosis, monitoring of disease responsiveness to therapy, and detection of disease recurrence are limited to radiographic imaging. To identify new, clinically relevant biomarkers we evaluated the proteome of a subset of ESFT-derived small extracellular vesicles (sEVs).Materials and Methods: We performed the first high quality proteomic study of ESFT-derived sEVs from 5 ESFT cell lines representing the most common EWS-ETS fusion types and identified 619 proteins composing the core ESFT sEV proteome. We compared these core proteins to databases of common plasma-based proteins and sEV-associated proteins found within healthy plasma to identify proteins unique or enriched within ESFT.Results: From these analyses, two membrane bound proteins with biomarker potential were selected, CD99/MIC2 and NGFR, to develop a liquid-based assay enriching of ESFT-associated sEVs and detection of sEV mRNA cargo (i.e., EWS-ETS transcripts). We employed this immuno-enrichment approach to diagnosis of ESFT utilizing plasma (250 μl) from both localized and metastatic ESFT pediatric patients and cancer-free controls, and showed significant diagnostic power [AUC = 0.92, p = 0.001 for sEV numeration, with a PPV = 1.00, 95% CI = (0.63, 1.00) and a NPV = 0.67, 95% CI = (0.30, 0.93)].Conclusions: In this study, we demonstrate utilization of circulating ESFT-associated sEVs in pediatric patients as a source of minimally invasive diagnostic and potentially prognostic biomarkers.

Immuno-oncology : No longer a need for interventional radiology?

Hepatocellular carcinoma (HCC) is associated with ahigh mortality rate. For many years, sorafenib was the only, and frequently poorly tolerated systemic treatment option, which lead to the unreflected recurrent use of locoregional treatment modalities, such as transarterial chemoembolization (TACE). Based on recent positive phaseIII trial results, we now have three systemic therapeutic options available in the first and second line of treatment, respectively. This development enables us to design sequential treatments concepts for patients with advanced HCC. Beyond the assessment of tumor burden, the liver function of HCC patients needs to be closely monitored under therapy. High response rates, including complete remissions have been documented for immuno-oncology-based combination regimens in HCC patients. Already today, a median overall survival (mOS) above 20months can been achieved through the sequential application of systemic therapies in phaseII studies in patients with advanced HCC and preserved liver function. Local therapies will remain an integral component of HCC therapy. However, recent advancements will shift the focus towards systemic treatment concepts. The rigorous implementation of validated scoring systems can contribute towards an improved selection of patients that are suited to locoregional therapies. Longitudinal monitoring of liver function is fundamental to ensure that the optimal point in time for aswitch towards systemic therapies is not missed.

Grossing Breast Cancer Specimens: A Comprehensive Review

Abstract Grossing breast specimens presents a unique challenge in the anatomic pathology laboratory, because the approach varies with the type of specimen received, the preoperative diagnosis, and the administration of neoadjuvant therapy. Furthermore, careful attention to preanalytic variables, such as time of fixation, is required. The specimen often lacks orienting anatomic landmarks, and accurately documenting margins in 3 dimensions requires a deliberate approach that is easily understood for future reference. This article will provide a comprehensive source for grossing commonly received breast specimens, ranging from surgical biopsies to modified radical mastectomies and will describe the proper care of preanalytical measures to avoid compromise of biomarkers, methods to ensure adequate sampling of tissue for diagnosis, and assessment of tumor burden following neoadjuvant treatment.

Spinal manifestations of Neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) patients may present a wide spectrum of spinal pathologies. Osseous changes may lead to severe deformities with significant implications on growth and quality of life. Neurogenic tumors and soft tissue abnormalities may cause neuropathic pain and dysfunction ranging from minor paresthesias to profound motor and sensory deficits. Advanced imaging such as whole-body MRI, and volumetric tumor burden assessment have an evolving role in the evaluation and follow-up of patients with high spinal tumor load. Novel biological agents that target the hyperactivated ras pathway are currently under investigation and are reshaping current and future treatment paradigms. Surgical interventions for benign and malignant tumors, as well as deformity correction remain pivotal in treatment frameworks and require careful assessment by a dedicated multidisciplinary team. In this manuscript we review the various spinal manifestations of NF1 patients, indication for surgical intervention and oncological treatments.

99mTc-MIP-1404 SPECT/CT for Assessment of Whole-Body Tumor Burden and Treatment Response in Patients With Biochemical Recurrence of Prostate Cancer.

This study aims to investigate the value of Tc-MIP-1404 SPECT/CT for assessment of whole-body tumor burden and treatment response in patients with biochemical recurrence of prostate cancer who undergo androgen deprivation therapy (ADT) or external beam radiation therapy (EBRT). A total of 125 patients with biochemical recurrence of prostate cancer underwent Tc-MIP-1404 SPECT/CT. All 364 prostate-specific membrane antigen (PSMA)-positive lesions in the field of view were assessed quantitatively to calculate PSMA-derived metabolic tumor parameters, including whole-body PSMA tumor volume and whole-body total lesion PSMA. These metrics were correlated with serum prostate-specific antigen (PSA) levels and Gleason scores. In a subset of 50 patients who underwent Tc-MIP-1404 SPECT/CT before the initiation of ADT or EBRT, TL-PSMA and SUVmax were compared with radiographic response assessment by CT based on RECIST 1.1 and to biochemical response (BR) determined by changes in serum PSA levels. Serum PSA levels correlated with SUVmax, whole-body PSMA tumor volume, and whole-body total lesion PSMA in patients with 1 and in those with more than 1 PSMA-positive lesion (P < 0.05). The correlations were significant for both well-differentiated (Gleason score ≤7) and poorly differentiated tumors (Gleason score ≥8) (P < 0.05). The agreement between TL-PSMA derived from SPECT and BR in patients who underwent Tc-MIP-1404 SPECT/CT before and after initiation of ADT was 80% (95% confidence interval [CI], 0.43-0.91; Cohen κ = 0.68; P < 0.05); in these patients, the agreement between TL-PSMA and CT was 60% (95% CI, 0.20-0.72; Cohen κ = 0.46; P < 0.05) and the agreement between BR and CT was 52% (0.07-0.61; Cohen κ = 0.34; P < 0.05). Comparable results were found for patients who underwent SPECT/CT before and after initiation of EBRT, with the strongest agreement between TL-PSMA and BR (80%; 95% CI, 0.38-0.93; Cohen κ = 0.66; P < 0.05) compared with the agreement between TL-PSMA and CT (60%; 95% CI, 0.13-0.69; Cohen κ = 0.69; P < 0.05) and between BR and CT (48%; 95% CI, 0-0.54; Cohen κ = 0.26; P = 0.11). Discordant findings between SPECT and CT were most likely due to limitations in the assessment of small lymph node metastases and bone involvement, which were detectable on SPECT but not on CT. The results of our study show that Tc-MIP-1404 SPECT/CT is a promising method for the evaluation of treatment response in patients with biochemical recurrence of prostate cancer who undergo either ADT or EBRT. TL-PSMA for assessment of treatment response has the strongest correlation with serum PSA levels, superior to SUVmax-based evaluation and response assessment based on CT data and RECIST 1.1.

Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer

PurposeThe CellSearch® system has been used to identify circulating tumor cells (CTCs) in cerebrospinal fluid (CSF) to diagnose leptomeningeal metastasis (LM) in patients with epithelial cancers. Using this system, we prospectively explored sequential CSF CTC enumeration in patients with LM from HER2+ cancers receiving intrathecal (IT) trastuzumab to capture dynamic changes in CSF CTC enumeration.MethodsCSF from patients enrolled in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was obtained on day 1 of each cycle and was evaluated by the CellSearch® platform for CTC enumeration. The results were correlated with CSF cytology from the same sample, along with clinical and radiographic response.ResultsFifteen out of 34 patients with HER2+ LM were enrolled in CSF CTC analysis; 14 were women. Radiographic LM was documented in 14 (93%) patients; CSF cytology was positive in 6 (40%) and CSF CTCs were identified in 13 (87%). Median CSF CTC was 22 CTCs (range 0–200 +) per 3 ml. HER2/neu expression analysis of CTCs was performed in 8 patients; 75% had confirmed expression of HER2/neu positivity in CSF and HER2/neu expression was absent in 25%. Four of 10 patients received 7 or more cycles of IT trastuzumab; in 3 of these patients, increase in CSF CTCs enumeration from baseline was detected 2–3 months prior to changes seen on MRI, and while CSF cytology remained negative.ConclusionOur study demonstrates that enumeration of CSF CTCs may provide dynamic, quantitative assessment of tumor burden in the central nervous system compartment during treatment for LM and prior to changes on MRI or CSF cytology.Trial Registration: Clinicaltrials.gov: NCT01325207; registered March 29th, 2011.

The use of multiparametric 18F-fluoro-L-3,4-dihydroxy-phenylalanine PET/MRI in post-therapy assessment of patients with gliomas.

To determine the utility of F-fluoro-L-3,4-dihydroxy-phenylalanine (F-DOPA) PET/MRI versus cross-sectional MRI alone in glioma response assessment and identify whether the two techniques demonstrate different tumour features. F-DOPA PET/MRI studies from 40 patients were analysed. Quantitative PET parameters and conventional MRI features were recorded. Tumour volume was assessed on both PET and MRI. Using dynamic susceptibility contrast perfusion-weighted imaging, maps of cerebral blood flow (CBF) and cerebral blood volume (CBV) were obtained. Within volume of tumours of tumour features and normal-appearing white matter (NAWM) drawn on MRI, standardised uptake value (SUV)max, CBF and CBV were recorded. Presence of residual active tumour was assessed by qualitative visual assessment. Receiver operating characteristic analysis was performed univariately and on parameter combination to analyse ability to determine presence/absence of disease. Reference standard for presence of viable tissue was biopsy or clinical follow-up. Median SUVmax was 3.4 for low-grade glioma (LGG) and 3.3 for high-grade glioma (HGG). There was a significant correlation between PWI parameters and WHO grade (P < 0.001), but no correlation with SUVmax. Median F-DOPA volume was 8216.88 mm for HGG and 6284.94 mm for LGG; MRI volume was 6316.57 mm and 5931.55 mm, respectively. SUVmax analysis distinguished enhancing and nonenhancing components from necrosis and NAWM and demonstrated active disease in nonenhancing regions. Visually, the modalities were concordant in 37 patients. Combining the multiparametric PET/MRI approach with all available data-enhanced detection of the presence of tumour (area under the curve 0.99, P < 0.01). MRI and F-DOPA are complementary modalities for assessment of tumour burden. Matching F-DOPA and MRI in assessing residual tumour volume may better delineate the radiotherapy target volume.