Effect of bead size and doxorubicin loading on tumor cellular injury after transarterial embolization and chemoembolization in a rat model of hepatocellular carcinoma.

Embolic agents used in transarterial embolization for intermediate stage hepatocellular carcinoma reduce blood flow into tumors and can deliver anticancer drugs. Tumor blood supply can be interrupted using doxorubicin-eluting beads (DEB-TACE) or non-loaded beads (TAE) of different calibers. In this preclinical study, we characterized the extent of remaining stressed tumor cells after treatment, hypoxia within the surviving tumor regions, and inflammatory immune cell infiltrates after embolization with 40-60 or 70-150 µm with non-loaded or doxorubicin-loaded beads at 3 and 7 days after treatment. TAE-treated tumors had more stressed and surviving tumor cells after 3 days, irrespective of bead size, compared with DEB-TACE-treated tumors. Hypoxic stress of residual cells increased after treatment with 70-150 µm beads without or with doxorubicin. Treatment with DEB-TACE of 70-150 µm resulted in increased inflammation and proliferation in the adjacent parenchyma. Inflammatory cell infiltrates were reduced at the periphery of tumors treated with 40-60 µm DEB-TACE.

Automated Volumetric Assessment of Hepatocellular Carcinoma Response to Sorafenib: A Pilot Study.

PURPOSE: This pilot study evaluates the feasibility of automated volumetric quantification of hepatocellular carcinoma (HCC) as an imaging biomarker to assess treatment response for sorafenib. METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, a training database of manually labeled background liver, enhancing and nonenhancing tumor tissue was established using pretherapy and first posttherapy multiphasic computed tomography images from a registry of 13 HCC patients. For each patient, Hounsfield density and geometry-based feature images were generated from registered multiphasic computed tomography data sets and used as the input for a random forest-based classifier of enhancing and nonenhancing tumor tissue. Leave-one-out cross-validation of the dice similarity measure was applied to quantify the classifier accuracy. A Cox regression model was used to confirm volume changes as predictors of time to progression (TTP) of target lesions for both manual and automatic methods. RESULTS: When compared with manual labels, an overall classification accuracy of dice similarity coefficient of 0.71 for pretherapy and 0.66 posttherapy enhancing tumor labels and 0.45 for pretherapy and 0.59 for posttherapy nonenhancing tumor labels was observed. Automated methods for quantifying volumetric changes in the enhancing lesion agreed with manual methods and were observed as a significant predictor of TTP. CONCLUSIONS: Automated volumetric analysis was determined to be feasible for monitoring HCC response to treatment. The information extracted using automated volumetrics is likely to reproduce labor-intensive manual data and provide a good predictor for TTP. Further work will extend these studies to additional treatment modalities and larger patient populations.

Cancer Genomics and Important Oncologic Mutations: A Contemporary Guide for Body Imagers.

The field of cancer genomics is rapidly evolving and has led to the development of new therapies. Knowledge of commonly involved cellular pathways and genetic mutations is now essential for radiologists reading oncology cases. Radiogenomics is an emerging area of research that seeks to correlate imaging features with cancer genotypes. Such knowledge may extend the utility of multiparametric imaging to yield information regarding cancer prognosis and likelihood of therapeutic response. To date, only a handful of radiogenomics studies have been performed to evaluate solid tumors of the body, and there is much to explore. Before doing so, however, it behooves us to have adequate background knowledge of clinical cancer genomics to design meaningful radiogenomics projects and explore imaging phenotypes. Herein, an up-to-date, detailed overview is provided of well-known and common mutations of solid body tumors (such as human epithelial growth factor receptor 2, breast cancer susceptibility protein), newer genomic alterations with potential for clinical relevance, and a discussion of known related imaging findings, including existing radiogenomics data and other radiologic patterns of disease. © RSNA, 2017 Online supplemental material is available for this article.

Evaluation of Abdominal Computed Tomography Image Quality Using a New Version of Vendor-Specific Model-Based Iterative Reconstruction.

PURPOSE: To qualitatively and quantitatively compare abdominal computed tomography (CT) images reconstructed with a new version of model-based iterative reconstruction (Veo 3.0; GE Healthcare) to those created with Veo 2.0. MATERIALS AND METHODS: This retrospective study was approved by our institutional review board and was Health Insurance Portability and Accountability Act compliant. The raw data from 29 consecutive patients who had undergone CT abdomen scanning was used to reconstruct 4 sets of 3.75-mm axial images: Veo 2.0, Veo 3.0 standard, Veo 3.0 5% resolution preference (RP), and Veo 3.0 20% RP. A slice thickness optimization of 3.75 mm and texture feature was selected for Veo 3.0 reconstructions.The images were reviewed by 3 independent readers in a blinded, randomized fashion using a 5-point Likert scale and 5-point comparative scale.Multiple 2-dimensional circular regions of interest were defined for noise and contrast-to-noise ratio measurements. Line profiles were drawn across the 7 lp/cm bar pattern of the CatPhan 600 phantom for spatial resolution evaluation. RESULTS: The Veo 3.0 standard image set was scored better than Veo 2.0 in terms of artifacts (mean difference, 0.43; 95% confidence interval [95% CI], 0.25-0.6; P < 0.0001), overall image quality (mean difference, 0.87; 95% CI, 0.62-1.13; P < 0.0001) and qualitative resolution (mean difference, 0.9; 95% CI, 0.69-1.1; P < 0.0001). Although the Veo 3.0 standard and RP05 presets were preferred across most categories, the Veo 3.0 RP20 series ranked best for bone detail. Image noise and spatial resolution increased along a spectrum with Veo 2.0 the lowest and RP20 the highest. CONCLUSION: Veo 3.0 enhances imaging evaluation relative to Veo 2.0; readers preferred Veo 3.0 image appearance despite the associated mild increases in image noise. These results provide suggested parameters to be used clinically and as a basis for future evaluations, such as focal lesion detection, in the oncology setting.

Ovarian Cancer, the Revised FIGO Staging System, and the Role of Imaging.

OBJECTIVE: It is now recognized that ovarian cancer includes a heterogeneous group of malignant epithelial tumors originating from the ovaries, fallopian tubes, or peritoneum. This development has prompted the International Federation of Gynecology and Obstetrics (FIGO) to issue a revised staging system that can provide prognostic information and guidance on personalized management of ovarian cancer. CONCLUSION: We review the epidemiology of ovarian cancer, the new FIGO staging system, and the role of imaging in the assessment, staging, and follow-up of ovarian cancer.

CAIPIRINHA-VIBE and GRAPPA-VIBE for liver MRI at 1.5 T: a comparative in vivo patient study.

OBJECTIVE: Three-dimensional T1-weighted (T1W) gradient recall echo volumetric interpolated breath-hold examination (VIBE) using generalized autocalibrating partially parallel acquisitions (GRAPPA) is one of the key sequences in liver magnetic resonance imaging (MRI) and is used for precontrast, dynamic postcontrast, and delayed postcontrast imaging. The purpose of this study is to compare image quality and liver lesion detection (LLD) on a shorter-duration T1W VIBE sequence using the controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) technique with the conventional T1W GRAPPA-VIBE sequence during a single liver MRI session on a 1.5-T Seimens scanner. METHODS: Twenty consecutive patients (9 women and 11 men; age range, 36-85 years) were included in this prospective study. All patients underwent a complete liver MRI on a 1.5-T magnet (Aera; Siemens Medical Systems, Erlangen, Germany) that consisted of a T1W (in/out-of-phase), T2W, DWI, and precontrast and postcontrast multiphasic images (late arterial, 50 seconds, 120 seconds, and 300 seconds) with GRAPPA-VIBE. The CAIPI-VIBE images were acquired for precontrast and at 300 seconds (5 minutes) postcontrast phases (6.9 seconds per phase) in addition to GRAPPA-VIBE (21 seconds per phase). The shorter time for the CAIPI-VIBE was selected to allow postprocessing of image acquisition in the setting of multi-late arterial phase (single breath hold) postcontrast images. Five radiologists independently analyzed image quality with predefined scores for liver edge sharpness, artifacts, fat saturation deficiency, visualization of the portal veins and hepatic veins, and LLD (size, <0.5-3.8 cm). Score 0 was suboptimal (inadequate), 1 was acceptable for diagnosis, and 2 was optimal (excellent). Kappa statistics were used to assess agreement among readers. Generalized linear mixed model with generalized estimation equation method was used to estimate and compare the LLD failure rates. RESULTS: No statistically significant difference was seen in the degree of reader variability between CAIPI-VIBE and GRAPPA-VIBE for all evaluated categories using multirater κ statistics. For the precontrast and 5-minutepostcontrast phase sequences, greater than 95% of images were considered to be of acceptable quality in all image quality categories for both sequences. Forty-one lesions were evaluated in 17 patients with total of 204 observations (n = 204) by 5 readers. For 5-minute postcontrast images, the LLD rate of CAIPI-VIBE (80%) was lower than GRAPPA-VIBE (84%) (P = 0.03) for small lesions (0.5-1.7 cm). There was no significant difference in lesion detection on precontrast images. CONCLUSIONS: At 1.5 T, the CAIPI-VIBE may be helpful in reducing scan time and demonstrates similar image quality compared with the traditional GRAPPA-VIBE. The CAIPI-VIBE has shorter breath-hold time requirement and thus can be an acceptable alternative for the precontrast and 5-minute postcontrast GRAPPA-VIBE in patients with breath-hold difficulties.

Multidetector CT detection of peritoneal metastases: evaluation of sensitivity between standard 2.5 mm axial imaging and maximum-intensity-projection (MIP) reconstructions.

OBJECTIVE: Our purpose was to evaluate the sensitivity of multidetector CT for the detection of peritoneal metastases between standard 2.5 mm axial imaging and maximum-intensity-projection (MIP) reconstructions. MATERIALS AND METHODS: The Institutional Review Board approved this retrospective study and waived the need to obtain patient consent. We retrospectively identified 36 patients with pancreatic adenocarcinoma and peritoneal metastatic disease who underwent a pancreatic protocol CT examination of the abdomen and pelvis between January 2012 and January 2014. Three independent radiologists reviewed a randomized combination of standard axial (2.5 mm reconstructed thickness, 2.5 mm interval) and axial MIP reconstructions (6, 3 mm interval) over two sessions. Each reader recorded metastasis location in PACS. Subsequent consensus review by two radiologists determined the final number and size of metastases. RESULTS: The reviewers found 328 peritoneal implants in 36 patients. After accounting for the size, location, and number of lesions as well as multiple readers, a generalized estimating equations model showed that the statistical combination of MIP with standard technique significantly increased the odds of correctly identifying a lesion (OR 2.16; 95% CI 1.86-2.51; p value < 0.0001) compared to standard technique alone. MIP reconstruction as a standalone technique was less sensitive compared to standard technique alone (OR 0.81; 95% CI 0.65-0.99; p value = 0.0468). When compared to standard axial imaging, evaluation via MIP reconstructions resulted in the identification of an additional 50 (15%), 45 (14%), and 55 (17%) lesions by Readers 1-3, respectively. CONCLUSION: The axial 6 mm MIP series is complimentary in the CT evaluation of peritoneal metastases. MIP reconstruction evaluation identified a significant number of additional lesions, but is not adequate as a standalone technique for peritoneal cavity assessment.

Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer.

There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

Imaging cholangiocarcinoma: CT and MRI techniques.

Cross-sectional imaging plays a crucial role in the detection, diagnosis, staging, and resectability assessment of intra- and extrahepatic cholangiocarcinoma. Despite this vital function, there is a lack of standardized CT and MRI protocol recommendations for imaging cholangiocarcinoma, with substantial differences in image acquisition across institutions and vendor platforms. In this review, we present standardized strategies for the optimal imaging assessment of cholangiocarcinoma including contrast media considerations, patient preparation recommendations, optimal contrast timing, and representative CT and MRI protocols with individual sequence optimization recommendations. Our recommendations are supported by expert opinion from members of the Society of Abdominal Radiology's Disease-Focused Panel (DFP) on Cholangiocarcinoma, encompassing a broad array of institutions and practice patterns.

Pancreatic Cyst Size Measurement on Magnetic Resonance Imaging Compared to Pathology.

BACKGROUND: While multiple cyst features are evaluated for stratifying pancreatic intraductal papillary mucinous neoplasms (IPMN), cyst size is an important factor that can influence treatment strategies. When magnetic resonance imaging (MRI) is used to evaluate IPMNs, no universally accepted sequence provides optimal size measurements. T2-weighted coronal/axial have been suggested as primary measurement sequences; however, it remains unknown how well these and maximum all-sequence diameter measurements correlate with pathology size. This study aims to compare agreement and bias between IPMN long-axis measurements on seven commonly obtained MRI sequences with pathologic size measurements. METHODS: This retrospective cohort included surgically resected IPMN cases with preoperative MRI exams. Long-axis diameter tumor measurements and the presence of worrisome features and/orhigh-risk stigmata were noted on all seven MRI sequences. MRI size and pathology agreement and MRI inter-observer agreement involved concordance correlation coefficient (CCC) and intraclass correlation coefficient (ICC), respectively. The presence of worrisome features and high-risk stigmata were compared to the tumor grade using kappa analysis. The Bland-Altman analysis assessed the systematic bias between MRI-size and pathology. RESULTS: In 52 patients (age 68 ± 13 years, 22 males), MRI sequences produced mean long-axis tumor measurements from 2.45-2.65 cm. The maximum MRI lesion size had a strong agreement with pathology (CCC = 0.82 (95% CI: 0.71-0.89)). The maximum IPMN size was typically observed on the axial T1 arterial post-contrast and MRCP coronal series and overestimated size versus pathology with bias +0.34 cm. The radiologist interobserver agreement reached ICCs 0.74 to 0.91 on the MRI sequences. CONCLUSION: The maximum MRI IPMN size strongly correlated with but tended to overestimate the length compared to the pathology, potentially related to formalin tissue shrinkage during tissue processing.

Gadolinium accumulation and fibrosis in the liver after administration of gadoxetate disodium in a rat model of active hepatic fibrosis.

PURPOSE: To evaluate the effect of gadoxetate disodium on fibrosis in a rat model of active hepatic fibrosis. MATERIALS AND METHODS: The local committee for animal research approved this study. Hepatic fibrosis was induced during 12 weeks of intraperitoneal injection of carbon tetrachloride (CCl(4)). Gadoxetate disodium was administered at 10 mmol/kg for 5 consecutive days starting after the final dose of CCl(4) (clinical dose of gadoxetate disodium is 0.25 mmol/kg). Three groups of Sprague-Dawley rats were studied. Group 1 consisted of six rats treated only with gadoxetate disodium, group 2 consisted of nine rats treated only with CCl(4), and group 3 consisted of nine rats treated with both gadoxetate disodium and CCl(4). Seven days after the final injection of gadoxetate disodium, the rats were sacrificed, and histologic findings and gadolinium deposition in the liver were examined. Fibrosis stage and gadolinium deposition were compared by using the Mann-Whitney test and Student t test. RESULTS: Fibrosis grading in groups 2 and 3 did not differ significantly (mean Batts-Ludwig fibrosis stage in group 2 was 2.67 and in group 3 was 2.78, P = .70; mean Ishak fibrosis stage in group 2 was 3.89 and in group 3 was 4.11, P = .71). Gadolinium deposition in the liver was slightly increased in group 3 in comparison to group 1 (3.2 ppm versus 4.0 ppm, P = .01), although this reversed when corrected as a percentage of total injected dose (0.022% versus 0.017%, P = .003). CONCLUSION: The high-dose administration of gadoxetate disodium in the setting of active hepatic fibrosis was not associated with increased fibrosis, suggesting that gadoxetate disodium does not incite a nephrogenic systemic fibrosis-like fibrotic change in the setting of active hepatic inflammation.

Liver steatosis: concordance of MR imaging and MR spectroscopic data with histologic grade.

PURPOSE: To determine if the concordance of magnetic resonance (MR) imaging and MR spectroscopic data with histologic measures of steatosis is affected by histologic magnification level, tissue heterogeneity, or assessment of tissue area versus that of hepatocytes. MATERIALS AND METHODS: This study was institutional review board approved and HIPAA compliant. Written informed consent was obtained. In- and out-of-phase MR imaging and MR spectroscopic measures of steatosis were compared in 33 patients with nonalcoholic fatty liver disease and in 15 healthy volunteers. Concordance of MR imaging and MR spectroscopic data with histologic findings was assessed for (a) histologic examination at standard (×40 and ×100) versus high magnification (×200 and ×400), (b) heterogeneity and homogeneity of livers, and (c) percentage of tissue and hepatocytes that contained lipids. Evaluations included linear regression and Fisher exact tests. RESULTS: In- and out-of-phase MR imaging and MR spectroscopic data were well correlated (R2=0.93) and generally concordant with histologic measures. Patients in whom MR fat fractions were higher than expected compared with steatosis grades at standard magnification histologic examination were upgraded significantly more often when high magnification was used than were the remaining patients (100% [10 of 10] vs 47% [7 of 15], P<.01). MR imaging and MR spectroscopic data of homogeneous livers were significantly more likely than those of heterogeneous livers to be concordant with steatosis grades when high magnification was used (81% [13 of 16] vs 47% [8 of 17], P<.05). For all patients, percentage of fat in tissue was lower than that in hepatocytes, which affected individual patients, but not the overall correlation. CONCLUSION: MR imaging and MR spectroscopic data were generally concordant with histologic measures of steatosis. Discordance between them may reflect differences in magnification at histologic examination and in liver heterogeneity.

Liver diffusivity in healthy volunteers and patients with chronic liver disease: comparison of breathhold and free-breathing techniques.

PURPOSE: To compare liver ADC obtained with breathhold and free-breathing diffusion weighted imaging (DWI) in healthy volunteers and patients with liver disease. MATERIALS AND METHODS: Twenty-eight subjects, 12 healthy volunteers and 16 patients (9 NAFLD, 7 chronic active HCV), underwent breathhold (BH) and free-breathing (FB) DWI MRI at 1.5 Tesla. Pearson's correlation coefficient was used to determine correlation while paired t-tests assessed differences between BH and FB ADC. Estimated bias was calculated using the Bland-Altman method. RESULTS: Liver ADC (×10(-3) mm(2) /s) was lower on BH for all groups (mean difference 0.36 ± 0.20; P < 0.01). ADC was higher in healthy volunteers (BH 1.80 ± 0.18; FB 2.24 ± 0.20) compared with NAFLD patients (BH 1.43 ± 0.27; FB 1.78 ± 0.28) (P < 0.001) and HCV patients (BH 1.63 ± 0.191; FB 1.88 ± 0.12). Overall correlation between BH and FB ADC was (r = 0.75), greatest in NAFLD (r = 0.90) compared with the correlation in HCV (r = 0.24) and healthy subjects (r = 0.34). Bland-Altman plots did not show agreement in mean absolute difference and estimated bias between subjects. CONCLUSION: Correlation between BH and FB liver ADC is moderate indicating that BH and FB should not be used interchangeably. Additionally, the lower ADC values in BH versus FB should be accounted for when comparing different liver DWI studies.

MRI steatosis grading: development and initial validation of a color mapping system.

OBJECTIVE: The purpose of this article is to develop and validate a chemical-shift imaging-derived color mapping system for evaluation of liver steatosis. MATERIALS AND METHODS: Opposed phase MRI was evaluated for 85 subjects (51 with presumed nonalcoholic fatty liver disease and 34 healthy volunteers). Liver signal intensity loss was compared with histologic analysis for 52 subjects, assuming grade 0 steatosis for healthy volunteers, to determine signal-intensity-loss threshold points differentiating steatosis grades and subsequent Spearman correlation. Color scale grading was then applied for 78 subjects. Interpretation of color maps for steatosis severity and heterogeneity was performed by three readers. Analyses of agreement among readers and of color map steatosis grade with biopsy were performed using weighted kappa values. RESULTS: The numbers of subjects with steatosis grades 0, 1, 2, and 3 were 41, 12, 13, and 19, respectively. A correlation of 0.90 was obtained using selected threshold values of 5.9% or less, 6-26.1%, 26.2-36.8%, and greater than 36.8% for steatosis grades 0, 1, 2, and 3, respectively. Interobserver agreement for color map grading of steatosis was excellent (κ = 0.93-0.94). Color map interpretation for all readers also showed excellent agreement with histologic findings for whole liver (κ = 0.82-0.86) and estimated biopsy site location (κ = 0.81-0.86; anterior region of right lobe). Heterogeneous steatosis on color maps was identified in 56-60% of subjects with nonalcoholic fatty liver disease and in 7% of healthy volunteers and was associated with greater disagreement between color map and histology grading (61-74%) compared with the whole group (37-40%). CONCLUSION: MRI-derived color map estimation of liver steatosis grade appears to be reproducible and accurate.

Reducing the rate of repeat imaging: import of outside images to PACS.

OBJECTIVE: Repeat imaging at the transfer of care between institutions is a potential source of overutilization. The purpose of this study was to assess whether importing images obtained at one institution to the PACS at another institution reduces the number of repeat imaging examinations performed, sparing patients unnecessary cost and radiation. MATERIALS AND METHODS: Informed consent was waived for this retrospective study, which included 267 patients who had undergone CT or MRI of the abdomen at our or another institution within 4 months before transarterial chemoembolization. Patients were divided into the following four groups based on the availability of their images from institutions other than ours (outside images): outside imaging performed but images not available; outside images available on CD or film but not imported; outside images imported to PACS; and no outside imaging, that is, all imaging performed at our institution. The rates of repeat imaging in the four groups were compared. RESULTS: When outside images were not available, 72% (13/18) of patients underwent repeat imaging; when outside images were available but not imported, 52% (14/27); when outside images were imported to PACS, 11% (9/79); and when imaging was performed only at our institution, 13% (18/143). Patients whose outside images were imported were significantly less likely to undergo repeat imaging than were both groups whose outside images were not imported (p < 0.001), and their rate of repeat imaging was similar to that of patients who did not undergo outside imaging (p = 0.79). After adjustment for potential confounders, including age, sex, referring institution, and size and number of lesions, the odds that a patient whose images were imported would undergo repeat imaging were significantly lower than those of a patient whose outside images were not imported (odds ratios, 31 for images not available and 9.0 for images available but not imported; both p < 0.001) and were similar to those of a patient who underwent all imaging at our institution (odds ratio, 0.71; p = 0.51). CONCLUSION: Importing outside images to PACS reduces the rate of repeat imaging.

Pancreatic imaging mimics: part 1, imaging mimics of pancreatic adenocarcinoma.

OBJECTIVE: The purpose of this article is to describe the imaging features of diseases that may closely simulate pancreatic adenocarcinoma, either radiologically or pathologically. CONCLUSION: Neoplastic and inflammatory diseases that can closely simulate pancreatic adenocarcinoma include neuroendocrine tumor, metastasis to the pancreas, lymphoma, groove pancreatitis, autoimmune pancreatitis, and focal chronic pancreatitis. Atypical imaging findings that should suggest diagnoses other than adenocarcinoma include the absence of significant duct dilatation, incidental detection, hypervascularity, large size (> 5 cm), IV tumor thrombus, and intralesional ducts or cysts.

Imaging of müllerian duct anomalies.

The müllerian ducts are paired embryologic structures that undergo fusion and resorption in utero to give rise to the uterus, fallopian tubes, cervix, and upper two-thirds of the vagina. Interruption of normal development of the müllerian ducts can result in formation of müllerian duct anomalies (MDAs). MDAs are a broad and complex spectrum of abnormalities that are often associated with primary amenorrhea, infertility, obstetric complications, and endometriosis. MDAs are commonly associated with renal and other anomalies; thus, identification of both kidneys is important. However, MDAs are not associated with ovarian anomalies. Hysterosalpingography (HSG) is routinely used in evaluation of infertility. Because a key component of MDA characterization is the external uterine fundal contour, HSG is limited for this purpose. Patients suspected of having an MDA are often initially referred for pelvic ultrasonography (US). Magnetic resonance (MR) imaging is typically reserved for complex or indeterminate cases. MR imaging is the imaging standard of reference because it is noninvasive, does not involve ionizing radiation, has multiplanar capability, allows excellent soft-tissue characterization, and permits a greater field of interrogation than does US. Use of MR imaging for evaluation of MDAs reduces the number of invasive procedures and related costs by guiding management decisions.

CD14 expression and Kupffer cell dysfunction in non-alcoholic steatohepatitis: superparamagnetic iron oxide-magnetic resonance image and pathologic correlation.

BACKGROUND AND AIM: Kupffer cell (KC) function and CD14 expression contributes to pathogenesis of non-alcoholic steatohepatitis (NASH). However, these relationships remain unclear. We investigated the relationship of KC function with superparamagnetic iron oxide-enhanced magnetic resonance imaging (SPIO-MRI), histopathological severity of NASH, and number of CD14-positive KCs in NASH. METHODS: This retrospective study included 32 patients (24 with NASH and eight with simple steatosis) who had previously undergone SPIO-MRI with T2-weighted gradient-recalled echo sequence. All subjects were diagnosed pathologically and were evaluated for necroinflammation grade, fibrosis stage, and number of CD14-positive KCs. Patients with NASH and simple steatosis were compared by using the Mann-Whitney test to determine differences in percent reduction of liver-to-muscle signal intensity ratio (reduction-%LMR), as a surrogate parameter of KC function, and number of CD14-positive KCs. Kruskal-Wallis test and Pearson's correlation coefficient were used to analyze relation among reduction-%LMR, histopathological severity and number of CD14-positive KCs. RESULTS: There were statistically significant differences in reduction-%LMR and number of CD14-positive KCs between NASH and simple steatosis patients (Mann-Whitney test, P < 0.001 for all comparisons). Reduction-%LMR decreased with an increase in necroinflammation grade or fibrosis stage. The number of CD14-positive KCs increased with an increase in necroinflammation grade and fibrosis stage (Kruskal-Wallis test, both, P < 0.001). A high correlation was seen between number of CD14-positive KCs and reduction-%LMR (Pearson r = 0.81; P < 0.001). CONCLUSIONS: KC phagocytic function evaluated with SPIO-MRI correlated with histopathological severity and number of CD14-positive KCs. These results support the concept that KC phagocytic dysfunction contributes to the pathogenesis of NASH.

Plasma growth hormone is a potential biomarker of response to atezolizumab and bevacizumab in advanced hepatocellular carcinoma patients.

INTRODUCTION: Hepatocellular carcinoma (HCC) has limited systemic therapy options when discovered at an advanced stage. Thus, there is a need for accessible and minimally invasive biomarkers of response to guide the selection of patients for treatment. This study investigated the biomarker value of plasma growth hormone (GH) level as a potential biomarker to predict outcome in unresectable HCC patients treated with current standard therapy, atezolizumab plus bevacizumab (Atezo/Bev). MATERIALS AND METHODS: Study included unresectable HCC patients scheduled to receive Atezo/Bev. Patients were followed to determine progression-free survival (PFS) and overall survival (OS). Plasma GH levels were measured by ELISA and used to stratify the HCC patients into GH-high and GH-low groups (the cutoff normal GH levels in women and men are ≤3.7 µg/L and ≤0.9 µg/L, respectively). Kaplan-Meier method was used to calculate median OS and PFS and Log rank test was used to compare survival outcomes between GH-high and -low groups. RESULTS: Thirty-seven patients were included in this analysis, of whom 31 were males and 6 females, with a median age of 67 years (range: 37-80). At the time of the analysis, the one-year survival rate was 70% (95% CI: 0.51, 0.96) among GH low patients and 33% (95% CI: 0.16, 0.67) among GH high patients. OS was significantly superior in GH-low compared to GH-high patients (median OS: 18.9 vs. 9.3 months; p = 0.014). PFS showed a non-significant trend in favor of GH-low patients compared to the GH-high group (median PFS: 6.6 vs. 2.9 months; p = 0.053). DISCUSSION AND CONCLUSIONS: Plasma GH is a biomarker candidate for predicting treatment outcomes in advanced HCC patients treated with Atezo/Bev. This finding should be further validated in larger randomized clinical trials in advanced HCC patients.

Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.

BACKGROUND: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. METHODS: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. FINDINGS: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. INTERPRETATION: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. FUNDING: Bristol Myers Squibb and the US National Institutes of Health.