Quality Improvement Report: Design and Implementation of a Radiology E-Consult Service.

Electronic consultations (e-consults) mediated through an electronic health record system or web-based platform allow synchronous or asynchronous physician-to-physician communication. E-consults have been explored in various clinical specialties, but relatively few instances in the literature describe e-consults to connect health care providers directly with radiologists.The authors outline how a radiology department can implement an e-consult service and review the development of such a service in a large academic health system. They describe the logistics, workflow, turnaround time expectations, stakeholder management, and pilot implementation and highlight challenges and lessons learned.

Repeatability and Reproducibility Assessment of the Apparent Diffusion Coefficient in the Prostate: A Trial of the ECOG-ACRIN Research Group (ACRIN 6701).

BACKGROUND: Uncertainty regarding the reproducibility of the apparent diffusion coefficient (ADC) hampers the use of quantitative diffusion-weighted imaging (DWI) in evaluation of the prostate with magnetic resonance imaging MRI. The quantitative imaging biomarkers alliance (QIBA) profile for quantitative DWI claims a within-subject coefficient of variation (wCV) for prostate lesion ADC of 0.17. Improved understanding of ADC reproducibility would aid the use of quantitative diffusion in prostate MRI evaluation. PURPOSE: Evaluation of the repeatability (same-day) and reproducibility (multi-day) of whole-prostate and focal-lesion ADC assessment in a multi-site setting. STUDY TYPE: Prospective multi-institutional. SUBJECTS: Twenty-nine males, ages 53 to 80 (median 63) years, following diagnosis of prostate cancer, 10 with focal lesions. FIELD STRENGTH/SEQUENCE: 3T, single-shot spin-echo diffusion-weighted echo-planar sequence with four b-values. ASSESSMENT: Sites qualified for the study using an ice-water phantom with known ADC. Readers performed DWI analyses at visit 1 ("V1") and visit 2 ("V2," 2-14 days after V1), where V2 comprised scans before ("V2pre") and after ("V2post") a "coffee-break" interval with subject removal and repositioning. A single reader segmented the whole prostate. Two readers separately placed region-of-interests for focal lesions. STATISTICAL TESTS: Reproducibility and repeatability coefficients for whole prostate and focal lesions derived from median pixel ADC. We estimated the wCV and 95% confidence interval using a variance stabilizing transformation and assessed interreader reliability of focal lesion ADC using the intraclass correlation coefficient (ICC). RESULTS: The ADC biases from b0 -b600 and b0 -b800 phantom scans averaged 1.32% and 1.44%, respectively; mean b-value dependence was 0.188%. Repeatability and reproducibility of whole prostate median pixel ADC both yielded wCVs of 0.033 (N = 29). In 10 subjects with an evaluable focal lesion, the individual reader wCVs were 0.148 and 0.074 (repeatability) and 0.137 and 0.078 (reproducibility). All time points demonstrated good to excellent interreader reliability for focal lesion ADC (ICCV1  = 0.89; ICCV2pre  = 0.76; ICCV2post  = 0.94). DATA CONCLUSION: This study met the QIBA claim for prostate ADC. Test-retest repeatability and multi-day reproducibility were largely equivalent. Interreader reliability for focal lesion ADC was high across time points. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2 TOC CATEGORY: Pelvis.

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. METHODS: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. FINDINGS: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. INTERPRETATION: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation.

BACKGROUND: Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined. METHODS: Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS. RESULTS: The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068). CONCLUSION: Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.

Effect of contrast dose on diagnostic performance in DCE-MR breast imaging.

OBJECTIVE: To assess the diagnostic performance of breast magnetic resonance (MR) imaging as a function of gadolinium contrast dose using a retrospective reader study. MATERIAL AND METHODS: IRB approval was obtained prior to the start of this study and was HIPAA compliant. One-hundred and fifty MR breast examinations were included that were acquired between January 2001 and December 2006. Seventy-five patients received contrast doses (gadopentetate dimeglumine) by weight of 0.10 mmol/kg and 75 patients were imaged using fixed volumes of 20 ml. The images were assessed by two radiologists with performance calculated for each reader as well as a combined assessment. Dose response was measured by comparing performance between cases binned by dose: <=0.10; >0.10; and >0.13 mmol/kg. Statistical significance was calculated using a one-sided Z-test for differences in proportions with interobserver agreement calculated using Cohen's kappa statistics. RESULTS: In the combined reader assessment with equivocal lesions classified as negative, sensitivity rose from 66% (19/29) to 92% (24/26, P < 0.01) and 95% (18/19, P < 0.01) with the specificity also increasing from 65% (32/49) to 87% (40/46, P < 0.01) and 86% (32/37, P = 0.01) corresponding to doses <=0.10, >0.10, >0.13 mmol/kg. With equivocal lesions classified as positive, sensitivity rose from 79% (23/29) to 92% (24/26, P < 0.10) and 95% (18/19, P < 0.10) Specificity also increased from 53% (26/49) to 72% (33/46, P < 0.05) and 70% (26/37, P = 0.05) with increasing dose. Interobserver agreement also improved at the higher doses.

Test-retest repeatability and reproducibility of ADC measures by breast DWI: Results from the ACRIN 6698 trial.

BACKGROUND: Quantitative diffusion-weighted imaging (DWI) MRI is a promising technique for cancer characterization and treatment monitoring. Knowledge of the reproducibility of DWI metrics in breast tumors is necessary to apply DWI as a clinical biomarker. PURPOSE: To evaluate the repeatability and reproducibility of breast tumor apparent diffusion coefficient (ADC) in a multi-institution clinical trial setting, using standardized DWI protocols and quality assurance (QA) procedures. STUDY TYPE: Prospective. SUBJECTS: In all, 89 women from nine institutions undergoing neoadjuvant chemotherapy for invasive breast cancer. FIELD STRENGTH/SEQUENCE: DWI was acquired before and after patient repositioning using a four b-value, single-shot echo-planar sequence at 1.5T or 3.0T. ASSESSMENT: A QA procedure by trained operators assessed artifacts, fat suppression, and signal-to-noise ratio, and determine study analyzability. Mean tumor ADC was measured via manual segmentation of the multislice tumor region referencing DWI and contrast-enhanced images. Twenty cases were evaluated multiple times to assess intra- and interoperator variability. Segmentation similarity was assessed via the Sørenson-Dice similarity coefficient. STATISTICAL TESTS: Repeatability and reproducibility were evaluated using within-subject coefficient of variation (wCV), intraclass correlation coefficient (ICC), agreement index (AI), and repeatability coefficient (RC). Correlations were measured by Pearson's correlation coefficients. RESULTS: In all, 71 cases (80%) passed QA evaluation: 44 at 1.5T, 27 at 3.0T; 60 pretreatment, 11 after 3 weeks of taxane-based treatment. ADC repeatability was excellent: wCV = 4.8% (95% confidence interval [CI] 4.0, 5.7%), ICC = 0.97 (95% CI 0.95, 0.98), AI = 0.83 (95% CI 0.76, 0.87), and RC = 0.16 * 10-3 mm2 /sec (95% CI 0.13, 0.19). The results were similar across field strengths and timepoint subgroups. Reproducibility was excellent: interreader ICC = 0.92 (95% CI 0.80, 0.97) and intrareader ICC = 0.91 (95% CI 0.78, 0.96). DATA CONCLUSION: Breast tumor ADC can be measured with excellent repeatability and reproducibility in a multi-institution setting using a standardized protocol and QA procedure. Improvements to DWI image quality could reduce loss of data in clinical trials. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1617-1628.

Comparing radiomic classifiers and classifier ensembles for detection of peripheral zone prostate tumors on T2-weighted MRI: a multi-site study.

BACKGROUND: For most computer-aided diagnosis (CAD) problems involving prostate cancer detection via medical imaging data, the choice of classifier has been largely ad hoc, or been motivated by classifier comparison studies that have involved large synthetic datasets. More significantly, it is currently unknown how classifier choices and trends generalize across multiple institutions, due to heterogeneous acquisition and intensity characteristics (especially when considering MR imaging data). In this work, we empirically evaluate and compare a number of different classifiers and classifier ensembles in a multi-site setting, for voxel-wise detection of prostate cancer (PCa) using radiomic texture features derived from high-resolution in vivo T2-weighted (T2w) MRI. METHODS: Twelve different supervised classifier schemes: Quadratic Discriminant Analysis (QDA), Support Vector Machines (SVMs), naïve Bayes, Decision Trees (DTs), and their ensemble variants (bagging, boosting), were compared in terms of classification accuracy as well as execution time. Our study utilized 85 prostate cancer T2w MRI datasets acquired from across 3 different institutions (1 for discovery, 2 for independent validation), from patients who later underwent radical prostatectomy. Surrogate ground truth for disease extent on MRI was established by expert annotation of pre-operative MRI through spatial correlation with corresponding ex vivo whole-mount histology sections. Classifier accuracy in detecting PCa extent on MRI on a per-voxel basis was evaluated via area under the ROC curve. RESULTS: The boosted DT classifier yielded the highest cross-validated AUC (= 0.744) for detecting PCa in the discovery cohort. However, in independent validation, the boosted QDA classifier was identified as the most accurate and robust for voxel-wise detection of PCa extent (AUCs of 0.735, 0.683, 0.768 across the 3 sites). The next most accurate and robust classifier was the single QDA classifier, which also enjoyed the advantage of significantly lower computation times compared to any of the other methods. CONCLUSIONS: Our results therefore suggest that simpler classifiers (such as QDA and its ensemble variants) may be more robust, accurate, and efficient for prostate cancer CAD problems, especially in the context of multi-site validation.

Diffusion-weighted MRI Findings Predict Pathologic Response in Neoadjuvant Treatment of Breast Cancer: The ACRIN 6698 Multicenter Trial.

Purpose To determine if the change in tumor apparent diffusion coefficient (ADC) at diffusion-weighted (DW) MRI is predictive of pathologic complete response (pCR) to neoadjuvant chemotherapy for breast cancer. Materials and Methods In this prospective multicenter study, 272 consecutive women with breast cancer were enrolled at 10 institutions (from August 2012 to January 2015) and were randomized to treatment with 12 weekly doses of paclitaxel (with or without an experimental agent), followed by 12 weeks of treatment with four cycles of anthracycline. Each woman underwent breast DW MRI before treatment, at early treatment (3 weeks), at midtreatment (12 weeks), and after treatment. Percentage change in tumor ADC from that before treatment (ΔADC) was measured at each time point. Performance for predicting pCR was assessed by using the area under the receiver operating characteristic curve (AUC) for the overall cohort and according to tumor hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) disease subtype. Results The final analysis included 242 patients with evaluable serial imaging data, with a mean age of 48 years ± 10 (standard deviation); 99 patients had HR-positive (hereafter, HR+)/HER2-negative (hereafter, HER2-) disease, 77 patients had HR-/HER2- disease, 42 patients had HR+/HER2+ disease, and 24 patients had HR-/HER2+ disease. Eighty (33%) of 242 patients experienced pCR. Overall, ΔADC was moderately predictive of pCR at midtreatment/12 weeks (AUC = 0.60; 95% confidence interval [CI]: 0.52, 0.68; P = .017) and after treatment (AUC = 0.61; 95% CI: 0.52, 0.69; P = .013). Across the four disease subtypes, midtreatment ΔADC was predictive only for HR+/HER2- tumors (AUC = 0.76; 95% CI: 0.62, 0.89; P < .001). In a test subset, a model combining tumor subtype and midtreatment ΔADC improved predictive performance (AUC = 0.72; 95% CI: 0.61, 0.83) over ΔADC alone (AUC = 0.57; 95% CI: 0.44, 0.70; P = .032.). Conclusion After 12 weeks of therapy, change in breast tumor apparent diffusion coefficient at MRI predicts complete pathologic response to neoadjuvant chemotherapy. © RSNA, 2018 Online supplemental material is available for this article.

MRI, Clinical Examination, and Mammography for Preoperative Assessment of Residual Disease and Pathologic Complete Response After Neoadjuvant Chemotherapy for Breast Cancer: ACRIN 6657 Trial.

OBJECTIVE: The objective of our study was to determine the accuracy of preoperative measurements for detecting pathologic complete response (CR) and assessing residual disease after neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer. SUBJECTS AND METHODS: The American College of Radiology Imaging Network 6657 Trial prospectively enrolled women with ≥ 3 cm invasive breast cancer receiving NACT. Preoperative measurements of residual disease included longest diameter by mammography, MRI, and clinical examination and functional volume on MRI. The accuracy of preoperative measurements for detecting pathologic CR and the association with final pathology size were assessed for all lesions, separately for single masses and nonmass enhancements (NMEs), multiple masses, and lesions without ductal carcinoma in situ (DCIS). RESULTS: In the 138 women with all four preoperative measures, longest diameter by MRI showed the highest accuracy for detecting pathologic CR for all lesions and NME (AUC = 0.76 and 0.84, respectively). There was little difference across preoperative measurements in the accuracy of detecting pathologic CR for single masses (AUC = 0.69-0.72). Longest diameter by MRI and longest diameter by clinical examination showed moderate ability for detecting pathologic CR for multiple masses (AUC = 0.78 and 0.74), and longest diameter by MRI and longest diameter by mammography showed moderate ability for detecting pathologic CR for tumors without DCIS (AUC = 0.74 and 0.71). In subjects with residual disease, longest diameter by MRI exhibited the strongest association with pathology size for all lesions and single masses (r = 0.33 and 0.47). Associations between preoperative measures and pathology results were not significantly influenced by tumor subtype or mammographic density. CONCLUSION: Our results indicate that measurement of longest diameter by MRI is more accurate than by mammography and clinical examination for preoperative assessment of tumor residua after NACT and may improve surgical planning.

MR spectroscopy of breast cancer for assessing early treatment response: Results from the ACRIN 6657 MRS trial.

PURPOSE: To estimate the accuracy of predicting response to neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer using MR spectroscopy (MRS) measurements made very early in treatment. MATERIALS AND METHODS: This prospective Health Insurance Portability and Accountability Act (HIPAA)-compliant protocol was approved by the American College of Radiology and local-site institutional review boards. One hundred nineteen women with invasive breast cancer of ≥3 cm undergoing NACT were enrolled between September 2007 and April 2010. MRS measurements of the concentration of choline-containing compounds ([tCho]) were performed before the first chemotherapy regimen (time point 1, TP1) and 20-96 h after the first cycle of treatment (TP2). The change in [tCho] was assessed for its ability to predict pathologic complete response (pCR) and radiologic response using the area under the receiver operating characteristic curve (AUC) and logistic regression models. RESULTS: Of the 119 subjects enrolled, only 29 cases (24%) with eight pCRs provided usable data for the primary analysis. Technical challenges in acquiring quantitative MRS data in a multi-site trial setting limited the capture of usable data. In this limited data set, the decrease in tCho from TP1 to TP2 had poor ability to predict either pCR (AUC = 0.53, 95% confidence interval [CI]: 0.27-0.79) or radiologic response (AUC = 0.51, 95% CI: 0.27-0.75). CONCLUSION: The technical difficulty of acquiring quantitative MRS data in a multi-site clinical trial setting led to a low yield of analyzable data, which was insufficient to accurately measure the ability of early MRS measurements to predict response to NACT. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:290-302.

Neoadjuvant Chemotherapy for Breast Cancer: Functional Tumor Volume by MR Imaging Predicts Recurrence-free Survival-Results from the ACRIN 6657/CALGB 150007 I-SPY 1 TRIAL.

PURPOSE: To evaluate volumetric magnetic resonance (MR) imaging for predicting recurrence-free survival (RFS) after neoadjuvant chemotherapy (NACT) of breast cancer and to consider its predictive performance relative to pathologic complete response (PCR). MATERIALS AND METHODS: This HIPAA-compliant prospective multicenter study was approved by institutional review boards with written informed consent. Women with breast tumors 3 cm or larger scheduled for NACT underwent dynamic contrast-enhanced MR imaging before treatment (examination 1), after one cycle (examination 2), midtherapy (examination 3), and before surgery (examination 4). Functional tumor volume (FTV), computed from MR images by using enhancement thresholds, and change from baseline (ΔFTV) were measured after one cycle and before surgery. Association of RFS with FTV was assessed by Cox regression and compared with association of RFS with PCR and residual cancer burden (RCB), while controlling for age, race, and hormone receptor (HR)/ human epidermal growth factor receptor type 2 (HER2) status. Predictive performance of models was evaluated by C statistics. RESULTS: Female patients (n = 162) with FTV and RFS were included. At univariate analysis, FTV2, FTV4, and ΔFTV4 had significant association with RFS, as did HR/HER2 status and RCB class. PCR approached significance at univariate analysis and was not significant at multivariate analysis. At univariate analysis, FTV2 and RCB class had the strongest predictive performance (C statistic = 0.67; 95% confidence interval [CI]: 0.58, 0.76), greater than for FTV4 (0.64; 95% CI: 0.53, 0.74) and PCR (0.57; 95% CI: 0.39, 0.74). At multivariate analysis, a model with FTV2, ΔFTV2, RCB class, HR/HER2 status, age, and race had the highest C statistic (0.72; 95% CI: 0.60, 0.84). CONCLUSION: Breast tumor FTV measured by MR imaging is a strong predictor of RFS, even in the presence of PCR and RCB class. Models combining MR imaging, histopathology, and breast cancer subtype demonstrated the strongest predictive performance in this study.

Macroscopic optical physiological parameters correlate with microscopic proliferation and vessel area breast cancer signatures.

INTRODUCTION: Non-invasive diffuse optical tomography (DOT) and diffuse correlation spectroscopy (DCS) can detect and characterize breast cancer and predict tumor responses to neoadjuvant chemotherapy, even in patients with radiographically dense breasts. However, the relationship between measured optical parameters and pathological biomarker information needs to be further studied to connect information from optics to traditional clinical cancer biology. Thus we investigate how optically measured physiological parameters in malignant tumors such as oxy-, deoxy-hemoglobin concentration, tissue blood oxygenation, and metabolic rate of oxygen correlate with microscopic histopathological biomarkers from the same malignant tumors, e.g., Ki67 proliferation markers, CD34 stained vasculature markers and nuclear morphology. METHODS: In this pilot study, we investigate correlations of macroscopic physiological parameters of malignant tumors measured by diffuse optical technologies with microscopic histopathological biomarkers of the same tumors, i.e., the Ki67 proliferation marker, the CD34 stained vascular properties marker, and nuclear morphology. RESULTS: The tumor-to-normal relative ratio of Ki67-positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy-hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01). In a subset of the Ki67-negative group (defined by the 15 % threshold), an inverse correlation between Ki67 expression level and mammary metabolic rate of oxygen was observed (R = -0.95, p-value: 0.014). Further, CD34 stained mean-vessel-area in tumor is positively correlated with tumor-to-normal total-hemoglobin and oxy-hemoglobin concentration. Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments. CONCLUSIONS: Collectively, the pilot data are consistent with the notion that increased blood is supplied to breast cancers, and it also suggests that less conversion of oxy- to deoxy-hemoglobin occurs in more proliferative cancers. Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information.

Phase 2 trial of the cyclin-dependent kinase 4/6 inhibitor palbociclib in patients with retinoblastoma protein-expressing germ cell tumors.

BACKGROUND: Alterations in the retinoblastoma pathway in germ cell tumors (GCTs) have been described. In the phase 1 trials of the selective cyclin-dependent kinase 4/6 inhibitor palbociclib, 3 patients with unresectable, growing, mature teratoma syndrome achieved prolonged disease stabilization. The authors conducted an open-label, phase 2 study to determine the efficacy and safety of palbociclib in patients with incurable, refractory, retinoblastoma protein (pRB)-expressing GCTs. METHODS: Patients who had incurable, refractory GCTs that demonstrated pRB expression by immunohistochemistry received oral palbociclib 125 mg daily for 21 days followed by a 7-day break. The primary endpoint was the 24-week progression-free survival (PFS) rate. A 24-week PFS rate ≥15% was considered promising, and a PFS rate ≤5% was not considered promising. RESULTS: Thirty patients received treatment, and 29 were evaluable for the primary endpoint. The estimated 24-week PFS rate was 28% (90% exact confidence interval, 15%-44%). Patients who had teratoma and teratoma with malignant transformation had significantly better PFS than patients who had nonteratomatous GCTs. Toxicity was manageable and was principally hematologic. CONCLUSIONS: Treatment with palbociclib was associated with a favorable 24-week PFS rate in patients with refractory, pRB-expressing GCTs. Benefit was mainly observed in patients who had unresectable teratomas and teratomas with malignant transformation.

Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers.

BACKGROUND: Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis. PATIENTS AND METHODS: We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks. RESULTS: A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors. CONCLUSION: Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients.

Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer.

BACKGROUND: Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed. METHODS: A total of 29 patients were randomized to a run-in of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m(2) loading, 250 mg/m(2) maintenance) weekly, followed by the combination in this dose-escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [(18)F]Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed as an indicator of tumor perfusion changes, at 3 time points. RESULTS: Everolimus and cetuximab were tolerable at full doses, with an expected toxicity profile. Dose-limiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patient. Of 16 patients evaluable for response, 5 had stable disease lasting 4 to 19 months. Mean change in maximum standardized uptake value (SUV(max)) for those treated initially with everolimus was -24% (2% to -54%), and with cetuximab was -5% (-23 to 36%). The K(trans) measured by DCE-MRI did not decrease, regardless of run-in drug. CONCLUSIONS: Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommended phase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population.

Computerized image analysis for identifying triple-negative breast cancers and differentiating them from other molecular subtypes of breast cancer on dynamic contrast-enhanced MR images: a feasibility study.

PURPOSE: To determine the feasibility of using a computer-aided diagnosis (CAD) system to differentiate among triple-negative breast cancer, estrogen receptor (ER)-positive cancer, human epidermal growth factor receptor type 2 (HER2)-positive cancer, and benign fibroadenoma lesions on dynamic contrast material-enhanced (DCE) magnetic resonance (MR) images. MATERIALS AND METHODS: This is a retrospective study of prospectively acquired breast MR imaging data collected from an institutional review board-approved, HIPAA-compliant study between 2002 and 2007. Written informed consent was obtained from all patients. The authors collected DCE MR images from 65 women with 76 breast lesions who had been recruited into a larger study of breast MR imaging. The women had triple-negative (n = 21), ER-positive (n = 25), HER2-positive (n = 18), or fibroadenoma (n = 12) lesions. All lesions were classified as Breast Imaging Reporting and Data System category 4 or higher on the basis of previous imaging. Images were subject to quantitative feature extraction, feed-forward feature selection by means of linear discriminant analysis, and lesion classification by using a support vector machine classifier. The area under the receiver operating characteristic curve (Az) was calculated for each of five lesion classification tasks involving triple-negative breast cancers. RESULTS: For each pair-wise lesion type comparison, linear discriminant analysis helped identify the most discriminatory features, which in conjunction with a support vector machine classifier yielded an Az of 0.73 (95% confidence interval [CI]: 0.59, 0.87) for triple-negative cancer versus all non-triple-negative lesions, 0.74 (95% CI: 0.60, 0.88) for triple-negative cancer versus ER- and HER2-positive cancer, 0.77 (95% CI: 0.63, 0.91) for triple-negative versus ER-positive cancer, 0.74 (95% CI: 0.58, 0.89) for triple-negative versus HER2-positive cancer, and 0.97 (95% CI: 0.91, 1.00) for triple-negative cancer versus fibroadenoma. CONCLUSION: Triple-negative cancers possess certain characteristic features on DCE MR images that can be captured and quantified with CAD, enabling good discrimination of triple-negative cancers from non-triple-negative cancers, as well as between triple-negative cancers and benign fibroadenomas. Such CAD algorithms may provide added diagnostic benefit in identifying the highly aggressive triple-negative cancer phenotype with DCE MR imaging in high-risk women.

Comparison of polyvinyl alcohol microspheres and tris-acryl gelatin microspheres for uterine fibroid embolization: results of a single-center randomized study.

PURPOSE: To assess the efficacy of two embolic agents in the treatment of symptomatic uterine leiomyomas. MATERIALS AND METHODS: A randomized, prospective, single-center study enrolled 60 women with symptomatic uterine leiomyomas. Uterine artery embolization (UAE) with spherical polyvinyl alcohol (SPVA) microspheres (n = 30; 700-900 µm and 900-1,200 µm; near-stasis or stasis endpoint) and tris-acryl gelatin (TAG) microspheres (n = 30; 500-700 µm; "pruned-tree" endpoint) was performed. Infarction rates were calculated for the dominant tumor and for small (< 2 cm) and large (> 2 cm) nondominant tumors. The primary endpoint was tumor infarction at 24 hours measured by contrast-enhanced magnetic resonance imaging assessed by a blinded reviewer. RESULTS: Baseline characteristics were similar between groups. The primary endpoint was similar in both treatments (≥ 91% dominant tumor infarction; SPVA. 86.2%; TAG, 93.3%, P = .35). Complete infarction (100%) was also similar between arms at 24 hours and 3 months. Symptom severity was reduced and quality of life improved equally at 3 and 12 months in each treatment group. Complications were minor in both groups. CONCLUSIONS: Uterine leiomyoma infarction at 24 hours and 3 months after treatment with SPVA or TAG microspheres was comparable when using near-stasis as a procedural endpoint with SPVA microspheres. Symptom relief was maintained for as long as 12 months for both embolic agents.

MRI assessment of early tumor response in metastatic renal cell carcinoma patients treated with sorafenib.

OBJECTIVE: The purpose of this study was to examine early MRI changes in renal cell carcinoma (RCC) treated with the antiangiogenic agent sorafenib and to identify MRI biomarkers of RCC response to sorafenib. MATERIALS AND METHODS: Sixteen patients with RCC were evaluated by MRI before and 3-12 weeks after commencing treatment with sorafenib. Two experienced MR radiologists, blinded to treatment status, independently graded tumor appearance on T1-weighted, T2-weighted, and gadolinium-enhanced images. The proportional odds mixed model was used to compare qualitative appearance of tumors before and after therapy. Time-to-progression was correlated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and MR-modified Choi criteria, incorporating changes in both tumor enhancement and size. RESULTS: After sorafenib therapy, there was a significant increase in T1 signal intensity of tumors (p < 0.0001) and a significant decrease in degree of tumor enhancement (p < 0.0001). The sum of unidimensional tumor diameters decreased significantly after therapy (p = 0.005). However, the average decrease in size at early follow-up was 13%, and all patients except one had stable disease by RECIST 1.0. Early responders defined by MR-modified Choi criteria had increased time-to-progression compared with nonresponders, whereas early RECIST evaluation did not predict clinical outcome. CONCLUSION: Decreased enhancement and T1 shortening of tumors on MRI may be useful biomarkers of RCC response to angiogenesis inhibitors. Response criteria combining early changes in size and enhancement lead to better correlation with clinical outcome compared with size decrease alone.