Development and Evaluation of Machine Learning in Whole-Body Magnetic Resonance Imaging for Detecting Metastases in Patients With Lung or Colon Cancer: A Diagnostic Test Accuracy Study

OBJECTIVES: Whole-body magnetic resonance imaging (WB-MRI) has been demonstrated to be efficient and cost-effective for cancer staging. The study aim was to develop a machine learning (ML) algorithm to improve radiologists' sensitivity and specificity for metastasis detection and reduce reading times. MATERIALS AND METHODS: A retrospective analysis of 438 prospectively collected WB-MRI scans from multicenter Streamline studies (February 2013-September 2016) was undertaken. Disease sites were manually labeled using Streamline reference standard. Whole-body MRI scans were randomly allocated to training and testing sets. A model for malignant lesion detection was developed based on convolutional neural networks and a 2-stage training strategy. The final algorithm generated lesion probability heat maps. Using a concurrent reader paradigm, 25 radiologists (18 experienced, 7 inexperienced in WB-/MRI) were randomly allocated WB-MRI scans with or without ML support to detect malignant lesions over 2 or 3 reading rounds. Reads were undertaken in the setting of a diagnostic radiology reading room between November 2019 and March 2020. Reading times were recorded by a scribe. Prespecified analysis included sensitivity, specificity, interobserver agreement, and reading time of radiology readers to detect metastases with or without ML support. Reader performance for detection of the primary tumor was also evaluated. RESULTS: Four hundred thirty-three evaluable WB-MRI scans were allocated to algorithm training (245) or radiology testing (50 patients with metastases, from primary 117 colon [n = 117] or lung [n = 71] cancer). Among a total 562 reads by experienced radiologists over 2 reading rounds, per-patient specificity was 86.2% (ML) and 87.7% (non-ML) (-1.5% difference; 95% confidence interval [CI], -6.4%, 3.5%; P = 0.39). Sensitivity was 66.0% (ML) and 70.0% (non-ML) (-4.0% difference; 95% CI, -13.5%, 5.5%; P = 0.344). Among 161 reads by inexperienced readers, per-patient specificity in both groups was 76.3% (0% difference; 95% CI, -15.0%, 15.0%; P = 0.613), with sensitivity of 73.3% (ML) and 60.0% (non-ML) (13.3% difference; 95% CI, -7.9%, 34.5%; P = 0.313). Per-site specificity was high (>90%) for all metastatic sites and experience levels. There was high sensitivity for the detection of primary tumors (lung cancer detection rate of 98.6% with and without ML [0.0% difference; 95% CI, -2.0%, 2.0%; P = 1.00], colon cancer detection rate of 89.0% with and 90.6% without ML [-1.7% difference; 95% CI, -5.6%, 2.2%; P = 0.65]). When combining all reads from rounds 1 and 2, reading times fell by 6.2% (95% CI, -22.8%, 10.0%) when using ML. Round 2 read-times fell by 32% (95% CI, 20.8%, 42.8%) compared with round 1. Within round 2, there was a significant decrease in read-time when using ML support, estimated as 286 seconds (or 11%) quicker (P = 0.0281), using regression analysis to account for reader experience, read round, and tumor type. Interobserver variance suggests moderate agreement, Cohen κ = 0.64; 95% CI, 0.47, 0.81 (with ML), and Cohen κ = 0.66; 95% CI, 0.47, 0.81 (without ML). CONCLUSIONS: There was no evidence of a significant difference in per-patient sensitivity and specificity for detecting metastases or the primary tumor using concurrent ML compared with standard WB-MRI. Radiology read-times with or without ML support fell for round 2 reads compared with round 1, suggesting that readers familiarized themselves with the study reading method. During the second reading round, there was a significant reduction in reading time when using ML support

Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer

Abstract: Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1–15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6–15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC

Whole-body diffusion-weighted MRI in malignant lymphoma: staging and early treatment response assessment

Malignant lymphoma is the 5th most common tumor type, comprising a large group of cancers with distinct histopathological features, which translates into different treatment plans and prognosis. Two main categories can be identified, Hodgkin (HL) and non-Hodgkin lymphoma (NHL), the latter of which can be subdivided in aggressive and indolent lymphoma based on the clinical behavior. The lymphatic system is a circulatory system throughout the body consisting of lymph nodes and lymphatic vessels, which explains why disease can arise virtually anywhere in the body and typically has a systemic spreading pattern. Therefore, a whole-body imaging technique is required to capture the full disease extent (=staging). Currently, 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) is the standard imaging technique not only to stage lymphoma, but also to assess treatment response during and at the end of treatment. However, FDG-PET/CT is expensive and exposes patients to a significant amount of ionizing radiation, which is an increasing area of concern due to improving survival rates, particularly in young patients requiring lifelong follow-up. Furthermore, not all lymphoma subtypes are FDG-avid, while the addition of immunotherapy to the standard chemotherapy regimens has notably decreased the technique’s specificity due to a treatment-induced confounding inflammatory response. To counteract the disadvantages of FDG-PET/CT, the purpose of this doctoral thesis was to evaluate the potential of diffusion-weighted magnetic resonance imaging (DWI/MRI) as an alternative imaging method. By probing the motion of water molecules on a microstructural level, malignancy can be detected with high sensitivity. Diffusion-restricting lesions can be appreciated on the DWI/MR images, but quantified as well by calculating the apparent diffusion coefficient (ADC), a measure which correlates inversely with cellularity. As such ADC is useful for pretreatment lesion characterization, while treatment response can be monitored by ADC changes during and after treatment. Technical advancements in the last decade have allowed clinical implementations of DWI/MRI in a whole-body protocol, making it now suitable to assess systemic diseases such as malignant lymphoma. The first chapter of this doctoral thesis consists of two pilot studies performed in patients with aggressive NHL. In the first pilot study, whole-body DWI/MRI (WB-DWI/MRI) was found to be a feasible method to stage patients. Visual analysis of the images sufficed to detect the vast majority of malignant bone and soft tissue lesions, while accurate lymph node characterization required additional quantitative analysis, consisting of ADC calculations. A second pilot study focused on the role of WB-DWI/MRI in the assessment of treatment response and its ability to predict treatment outcome. Interval ADC changes between the pretreatment scan and the scan performed 2 and 4 weeks after the start of therapy were significantly different for responding and non-responding lesions and correlated significantly with patient’s progression-free-survival (PFS). Subsequent studies are categorized in two sections: staging and early treatment response assessment. For the staging section of this doctoral thesis, a larger-scale, prospective staging study was performed including both HL and NHL patients. Diagnostic performance of CT and visual analysis of WB-MRI with and without DWI were compared with the reference standard, namely FDG-PET/CT in combination with bone marrow biopsy (BMB) results. For Ann Arbor staging, WB-MRI with DWI showed the closest to the reference standard, and its accuracy was further improved by adding ADC calculations to the visual analysis. In an additional study, the quantitative analysis consisting of conventional ADC mean calculations of lymph nodes was extended with ADC histogram analysis. This approach allowed the identification of ADC skewness - a measure of histogram asymmetry - as a more accurate and robust parameter for lymph node characterization than the commonly used mean ADC. In the following treatment response section, the potential of WB-DWI/MRI for early treatment response assessment and outcome prediction was explored in both aggressive NHL and HL. A larger-scale study in aggressive NHL patients showed that quantitative WB-DWI/MRI after only one cycle of immunochemotherapy was an accurate and independent prognostic factor of treatment outcome in comparison with interim and end-of-treatment FDG-PET/CT as well as several prognostic histopathological parameters. Taking into account the low tumor cell density in HL, lesion ADC histogram analysis was complemented with 3D (ADC) texture analysis. In contrast to interval changes of ADC histogram analysis parameters, texture analysis parameters reflecting tumor heterogeneity, namely ADC energy, ADC local homogeneity and ADC entropy, were significantly different between responding and non-responding lesions and correlated with PFS. In conclusion, this doctoral thesis demonstrated that WB-DWI/MRI may be feasible for staging malignant lymphoma and may be a valuable tool to assess and predict treatment response after only 1 cycle of (immuno)chemotherapy without the burden of ionizing radiation or contrast injection.status: publishe

The clinical value of the hepatic venous pressure gradient in patients undergoing hepatic resection for hepatocellular carcinoma with or without liver cirrhosis.

Peer reviewed: TrueAcknowledgements: We would like to thank Dr Keno K. Bressem for his earlier efforts in creating the Kaplan–Meier survival curves. We would also like to thank the Interventional Radiology Team (Drs Andrew Winterbottom, Nadeem Shaida, Nicholas Hilliard, Amir Helmy, Sharmini Desigan, and Simon Hilliard), the Hepatocellular Carcinoma Multidisciplinary Team, the Hepatology Team, and the Liver Resection Team for their clinical involvement in this cohort of patients.Publication status: PublishedThe role of hepatic venous pressure gradient (HVPG) measurement in risk stratification before liver resection is an ongoing area of debate. This study examines the impact of preoperative HVPG levels on overall survival (OS)/time to recurrence (TTR) and postoperative complications after hepatic resection of hepatocellular carcinoma (HCC). Thirty-eight HCC patients undergoing HVPG measurement before liver resection at Cambridge University Hospitals NHS Foundation Trust between January 2014 and April 2022 were retrospectively analysed. Statistical analysis comprised univariable/multivariable Cox/logistic regression to identify risk factors of reduced OS/TTR or 90-day post-resection complications and Kaplan-Meier estimator, log-rank, chi-squared, Fisher's exact, and Mann-Whitney U test, or Student's t-test for survival/subgroup analysis. The median HPVG was 6 (range: 0-14) mmHg. The HVPG was an independent risk factor for poorer TTR in the overall cohort (cut-off: ≥7.5 mmHg (17.18/43.81 months; P = 0.009)). In the subgroup analysis of cirrhotic patients (N = 29 (76%)), HVPG was additionally an independent risk factor for lower OS (cut-off: ≥8.5 mmHg [44.39/76.84 months; P = 0.012]). The HVPG had no impact on OS/TTR in non-cirrhotic patients (N = 9 (24%)), nor was it associated with postoperative complications in any cohort. In conclusion, preoperative HVPG levels are useful predictors for TTR and OS in cirrhotic HCC patients undergoing hepatic resection

Improving lymph node characterization in staging malignant lymphoma using first-order ADC texture analysis from whole-body diffusion-weighted MRI

Correct staging and treatment initiation in malignant lymphoma depends on accurate lymph node characterization. However, nodal assessment based on conventional and diffusion-weighted (DWI) MRI remains challenging, particularly in smaller nodes.status: accepte

Prospective comparison of ⁶⁸Ga-PSMA PET/CT, ¹⁸F-sodium fluoride PET/CT and diffusion weighted-MRI at for the detection of bone metastases in biochemically recurrent prostate cancer

PurposeTo prospectively compare diagnostic accuracies for detection of bone metastases by Ga-68-PSMA PET/CT, F-18-NaF PET/CT and diffusion-weighted MRI (DW600-MRI) in prostate cancer (PCa) patients with biochemical recurrence (BCR).MethodsSixty-eight PCa patients with BCR participated in this prospective study. The patients underwent Ga-68-PSMA PET/CT, a F-18-NaF PET/CT and a DW600-MRI (performed in accordance with European Society of Urogenital Radiology guidelines, with b values of 0 and 600s/mm(2)). Bone lesions were categorized using a three-point scale (benign, malignant or equivocal for metastases) and a dichotomous scale (benign or metastatic) for each imaging modality by at least two experienced observers. A best valuable comparator was defined for each patient based on study-specific imaging, at least 12months of clinical follow-up and any imaging prior to the study and during follow-up. Diagnostic performance was assessed using a sensitivity analysis where equivocal lesions were handled as non-metastatic and then as metastatic.ResultsTen of the 68 patients were diagnosed with bone metastases. On a patient level, sensitivity, specificity and the area under the curve (AUC) by receiver operating characteristic analysis were, respectively, 0.80, 0.98-1.00 and 0.89-0.90 for Ga-68-PSMA PET/CT (n=68 patients); 0.90, 0.90-0.98 and 0.90-0.94 for (NaF)-Na-18 PET/CT (n=67 patients); and 0.25-0.38, 0.87-0.92 and 0.59-0.62 for DW600-MRI (n=60 patients). The diagnostic performance of DW600-MRI was significantly lower than that of Ga-68-PSMA PET/CT and (NaF)-Na-18 PET/CT for diagnosing bone metastases (p<0.01), and no significant difference in the AUC was seen between Ga-68-PSMA PET/CT and (NaF)-Na-18 PET/CT (p=0.65).Conclusion(68)Ga-PSMA PET/CT and F-18-NaF PET/CT showed comparable and high diagnostic accuracies for detecting bone metastases in PCa patients with BCR. Both methods performed significantly better than DW600-MRI, which was inadequate for diagnosing bone metastases when conducted in accordance with European Society of Urogenital Radiology guidelines

Quantitative Whole-Body Diffusion-weighted MRI after One Treatment Cycle for Aggressive Non-Hodgkin Lymphoma Is an Independent Prognostic Factor of Outcome.

To evaluate the prognostic utility of apparent diffusion coefficient (ADC) changes at whole-body diffusion-weighted (WB-DW) MRI after one treatment cycle for aggressive non-Hodgkin lymphoma (NHL) compared with response assessment at interim and end-of-treatment fluorine 18 (F) fluorodeoxyglucose (FDG) PET/CT. This was a secondary analysis of a prospective study (ClinicalTrials.gov identifier: NCT01231269) in which participants with aggressive NHL were recruited between March 2011 and April 2015 and underwent WB-DW MRI before and after one cycle of immunochemotherapy. Volunteers were recruited for test-retest WB-DW MRI (ClinicalTrials.gov identifier: NCT01231282) to assess ADC measurement repeatability. Response assessment was based on ADC change after one treatment cycle at WB-DW MRI and Deauville criteria at F-FDG PET/CT. To evaluate prognostic factors of disease-free survival (DFS), Kaplan-Meier survival analysis and univariable and multivariable Cox regression were performed; intraclass correlation coefficient (ICC) and mean difference with limits of agreement were calculated to determine inter- and intraobserver repeatability of ADC measurements. Forty-five patients (mean age, 58 years ± 17 [standard deviation]; 31 men) and nine volunteers (mean age, 22 years ± 3; seven men) were enrolled. Median DFS was 48 months (range, 2-48 months). Outcome prediction accuracy was 86.7% (39 of 45), 71.4% (30 of 42), and 73.8% (31 of 42) for WB-DW MRI and interim and end-of-treatment F-FDG PET/CT, respectively. WB-DW MRI (hazard ratio [HR], 17.8; < .001) and interim (HR, 5; = .008) and end-of-treatment (HR, 4.3; = .017) F-FDG PET/CT were prognostic of DFS. After multivariable analysis, WB-DW MRI remained an independent predictor of outcome (HR, 26.8; = .002). Intra- and interobserver agreement for ADC measurements were excellent (ICC = 0.85-0.99). Quantitative WB-DW MRI after only one cycle of immunochemotherapy predicts DFS in aggressive NHL and is noninferior to routinely performed interim and end-of-treatment F-FDG PET/CT. MR-Diffusion Weighted Imaging, Lymphoma, Oncology, Tumor Response, Whole-Body Imaging© RSNA, 2021

Low tendon stiffness and abnormal ultrastructure distinguish classic Ehlers-Danlos syndrome from benign joint hypermobility syndrome in patients

There is a clinical overlap between classic Ehlers-Danlos syndrome (cEDS) and benign joint hypermobility syndrome (BJHS), with hypermobility as the main symptom. The purpose of this study was to investigate the role of type V collagen mutations and tendon pathology in these 2 syndromes. In patients (cEDS, n=7; BJHS, n=8) and controls (Ctrl, n=8), we measured patellar tendon ultrastructure (transmission electron microscopy), dimensions (magnetic resonance imaging), and biomechanical properties (force and ultrasonographic measurements during a ramped isometric knee extension). Mutation analyses (COL5A1 and COL5A2) were performed in the patients. COL5A1 mutations were found in 3 of 4 of the patients with cEDS. Patellar tendon dimensions were similar between the groups, but large, irregular collagen fibrils were in 4 of 5 patients with cEDS. In the cEDS group, tendon stiffness and Young's modulus were reduced to approximate to 50% of that in BJHS and Ctrl groups (P<0.05). The nonhypermobile, healthy controls were matched with the patients in age, sex, body weight, and physical activity, to compare outcomes. COL5A1 mutations led to structural tendon pathology and low tendon stiffness in cEDS, explaining the patients' hypermobility, whereas no tendon pathology was found that explained the hypermobility in BJHS

68Ga-PSMA PET/CT compared with MRI/CT and diffusion-weighted MRI for primary lymph node staging prior to definitive radiotherapy in prostate cancer: a prospective diagnostic test accuracy study

BACKGROUND: The aim was to compare the diagnostic accuracy of 68Ga-PSMA PET/CT with conventional cross-sectional imaging and diffusion-weighted MRI (DW-MRI) for detecting lymph node metastasis (LNM) to stage prostate cancer patients. Twenty consecutive, newly- diagnosed prostate cancer patients were prospectively enrolled and underwent 68Ga-PSMA-11 PET/CT, anatomical MRI or contrast-enhanced CT, and DW-MRI prior to laparoscopic, template-based, extended lymph node dissection. Histopathological findings served as the reference test. RESULTS: Histopathology showed LNM in 13 of 20 patients (19 high-risk, 1 intermediate risk). Five patients had metastasis-suspected lymph nodes on 68Ga-PSMA PET/CT. Patient-based analysis showed that the sensitivity and specificity for detecting LNM were 39% and 100% with 68Ga-PSMA PET/CT, 8% and 100% with MRI/CT, and 36% and 83% with DW-MRI, respectively. The positive and negative predictive values were 100% and 49% with 68Ga-PSMA PET/C, 100% and 37% with MRI/CT, and 80% and 42% with DW-MRI. Of 573 dissected lymph nodes, 33 were LNM from 26 regions. True-positive LNM on 68Ga-PSMA PET/CT was 9-11 mm in diameter, whereas false-negative LNM had a median diameter of 4 mm, with only 3 of 30 lymph nodes being larger than 10 mm. LNM were positive for PSMA by immunostaining. CONCLUSIONS: The sensitivity of 68Ga-PSMA PET/CT was notably better than that of MRI/CT and comparable to that of DW-MRI. Some false positive findings with DW-MRI reduced its specificity and positive predictive value compared with those of 68Ga-PSMA PET/CT and MRI/CT