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Locoregional treatments (LRT) continue to advance for hepatocellular carcinoma (HCC). Selective internal radiation therapy (SIRT) or transarterial radioembolization (TARE) with radioactive 90 Yttrium (Y90) microspheres is currently widely accepted, and external beam and stereotactic body radiation (EBRT/SBRT) are increasingly used as LRT 1-5 . Assessment of treatment response after these radiation-based therapies can be challenging, given that the adjacent liver also undergoes treatment related changes, inflammatory changes occur, and there is a variable time for response to develop. In 2017, the liver imaging reporting and data system (LI-RADS) workgroup initially developed a single algorithm for the imaging assessment of treatment response encompassing all types of locoregional therapies, the LI-RADS treatment response (LR-TR) algorithm. Recognizing that response and imaging patterns differ between radiation and non-radiation based therapies, the LR-TR working group recently updated the algorithm to reflect the unique characteristics of tumor response for therapies involving radiation. This article aims to elucidate the changes in the new version of the LI-RADS TR, with a guide for algorithm utilization and illustration of expected and unexpected findings post liver directed therapies for HCC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Liver congestion is increasingly encountered in clinical practice and presents diagnostic pitfalls of which radiologists must be aware. The complex altered hemodynamics associated with liver congestion leads to diffuse parenchymal changes and the development of benign and malignant nodules. Distinguishing commonly encountered benign hypervascular lesions, such as focal nodular hyperplasia (FNH)-like nodules, from hepatocellular carcinoma (HCC) can be challenging due to overlapping imaging features. FNH-like lesions enhance during the hepatic arterial phase and remain isoenhancing relative to the background liver parenchyma but infrequently appear to wash out at delayed phase imaging, similar to what might be seen with HCC. Heterogeneity, presence of an enhancing capsule, washout during the portal venous phase, intermediate signal intensity at T2-weighted imaging, restricted diffusion, and lack of uptake at hepatobiliary phase imaging point toward the diagnosis of HCC, although these features are not sensitive individually. It is important to emphasize that the Liver Imaging Reporting and Data System (LI-RADS) algorithm cannot be applied in congested livers since major LI-RADS features lack specificity in distinguishing HCC from benign hypervascular lesions in this population. Also, the morphologic changes and increased liver stiffness caused by congestion make the imaging diagnosis of cirrhosis difficult. The authors discuss the complex liver macro- and microhemodynamics underlying liver congestion; propose a more inclusive approach to and conceptualization of liver congestion; describe the pathophysiology of liver congestion, hepatocellular injury, and the development of benign and malignant nodules; review the imaging findings and mimics of liver congestion and hypervascular lesions; and present a diagnostic algorithm for approaching hypervascular liver lesions. © RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Purpose: Compare reader performance when adding the Hybrid Multidimensional-MRI (HM-MRI) map to multiparametric MRI (mpMRI+HM-MRI) versus mpMRI alone and inter-reader agreement in diagnosing clinically significant prostate cancers (CSPCa)., Methods: All 61 patients who underwent mpMRI (T2-, diffusion-weighted (DWI), and contrast-enhanced scans) and HM-MRI (with multiple TE/b-value combinations) before prostatectomy or MRI-fused-transrectal ultrasound-guided biopsy between August, 2012 and February, 2020, were retrospectively analyzed. Two experienced readers (R1, R2) and two less-experienced readers (less than 6-year MRI prostate experience) (R3, R4) interpreted mpMRI without/with HM-MRI in the same sitting. Readers recorded the PI-RADS 3-5 score, lesion location, and change in score after adding HM-MRI. Each radiologist's mpMRI+HM-MRI and mpMRI performance measures (AUC, sensitivity, specificity, PPV, NPV, and accuracy) based on pathology, and Fleiss' kappa inter-reader agreement was calculated and compared., Results: Per-sextant R3 and R4 mpMRI+HM-MRI accuracy (82% 81% vs. 77%, 71%; p=.006, <.001) and specificity (89%, 88% vs. 84%, 75%; p=.009, <.001) were higher than with mpMRI. Per-patient R4 mpMRI+HM-MRI specificity improved (48% from 7%; p<.001). R1 and R2 mpMRI+HM-MRI specificity per-sextant (80%, 93% vs. 81%, 93%; p=.51,>.99) and per-patient (37%, 41% vs. 48%, 37%; p=.16, .57) remained similar to mpMRI. R1 and R2 per-patient AUC with mpMRI+HM-MRI (0.63, 0.64 vs. 0.67, 0.61; p=.33, .36) remained similar to mpMRI, but R3 and R4 mpMRI+HM-MRI AUC (0.73, 0.62) approached R1 and R2 AUC. Per-patient inter-reader agreement, mpMRI+HM-MRI Fleiss Kappa, was higher than mpMRI (0.36 [95% CI 0.26, 0.46] vs. 0.17 [95% CI 0.07, 0.27]); p=.009)., Conclusion: Adding HM-MRI to mpMRI (mpMRI+HM-MRI) improved specificity and accuracy for less-experienced readers, improving overall inter-reader agreement., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale and Objectives: The purpose of this study was to develop and evaluate a patient thickness-based protocol specifically for the confirmation of enteric tube placements in bedside abdominal radiographs. Protocol techniques were set to maintain image quality while minimizing patient dose., Materials and Methods: A total of 226 pre-intervention radiographs were obtained to serve as a baseline cohort for comparison. After the implementation of a thickness-based protocol, a total of 229 radiographs were obtained as part of an intervention cohort. Radiographs were randomized and graded for diagnostic quality by seven expert radiologists based on a standardized conspicuity scale (grades: 0 non-diagnostic to 3+). Basic patient demographics, body mass index, ventilatory status, and enteric tube type were recorded and subgroup analyses were performed. Effective dose was estimated for both cohorts., Results: The dedicated thickness-based protocol resulted in a significant reduction in effective dose of 80% (p-value < 0.01). There was no significant difference in diagnostic quality between the two cohorts with 209 (92.5%) diagnostic radiographs in the baseline and 221 (96.5%) diagnostic radiographs in the thickness-based protocol (p-value 0.06)., Conclusion: A protocol optimized for the confirmation of enteric tube placements was developed. This protocol results in lower patient effective dose, without sacrificing diagnostic accuracy. The technique chart is provided for reference. The protocol development process outlined in this work could be readily generalized to other imaging clinical tasks., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a dismal survival rate. Screening the general population for early detection of PDAC is not recommended, but because early detection improves survival, high-risk individuals, defined as those meeting criteria based on a family history of PDAC and/or the presence of known pathogenic germline variant genes with PDAC risk, are recommended to undergo screening with MRI and/or endoscopic ultrasound at regular intervals. The Pancreatic Cancer Early Detection (PRECEDE) Consortium was formed in 2018 and is composed of gastroenterologists, geneticists, pancreatic surgeons, radiologists, statisticians, and researchers from 40 sites in North America, Europe, and Asia. The overarching goal of the PRECEDE Consortium is to facilitate earlier diagnosis of PDAC for high-risk individuals to increase survival of the disease. A standardized MRI protocol and reporting template are needed to enhance the quality of screening examinations, improve consistency of clinical management, and facilitate multiinstitutional research. We present a consensus statement to standardize MRI screening and reporting for individuals with elevated risk of pancreatic cancer.

Purpose: Imaging of the peritoneum and related pathology is a challenge. Among peritoneal diseases, malignant peritoneal mesothelioma (MPeM) is an uncommon tumor with poor prognosis. To date, there are no specific guidelines or imaging protocols dedicated for the peritoneum and MPeM. The objective of this study was to analyze the literature describing imaging modalities used for MPeM to determine their relative clinical efficacy and review commonly reported imaging features of MPeM to promote standardized reporting., Methods: We performed a systematic review of original research articles discussing imaging modalities in MPeM from 1999 to 2020. Effectiveness measures and common findings were compared across imaging modalities., Results: Among 582 studies analyzed, the most-used imaging modality was CT (54.3%). In the differentiation of MPeM from peritoneal carcinomatosis, one study found CT had a diagnostic sensitivity of 53%, specificity of 100%, and accuracy of 68%. Two studies found fluorodeoxyglucose positron emission tomography (FDG-PET) had sensitivity of 86-92%, specificity of 83-89%, and accuracy of 87-89%. Another study found magnetic resonance imaging (MRI) was the best predictor of the peritoneal carcinomatosis index. Characteristics shown to best differentiate MPeM from other diseases included ascites, peritoneal thickening, mesenteric thickening, pleural plaques, maximum tumor dimension, and number of masses., Conclusion: Most published MPeM imaging studies utilized CT. PET/CT or MRI appear promising, and future studies should compare effectiveness of these modalities. MPeM imaging reports should highlight ascites, number of and maximum tumor dimension, peritoneal/mesenteric thickening, and associated pleural plaques, allowing for better aggregation of MPeM imaging data across studies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The need for liver transplants is increasing because the prevalence of liver diseases and the indications for transplants are growing. In response to the shortage of grafts from deceased donors, more transplants are being performed worldwide with grafts from living donors. Radiologic evaluation is an integral component in the assessment of donor candidates to ensure their eligibility and to choose the most appropriate surgical approach. MRI is the preferred modality for evaluation of the liver parenchyma and biliary tree. In most centers, a combination of MRI and CT is used to take advantage of the higher spatial resolution of CT for evaluation of arteries. However, MRI-only assessment is feasible. In addition to assessment of the liver parenchyma for abnormalities such as steatosis, a detailed evaluation of the hepatic vascular and biliary system for pertinent anatomic variants is crucial, because these variants can affect surgical techniques and outcomes in both recipients and donors. In this pictorial article, after a brief review of the most common surgical techniques and postsurgical liver anatomy, the biliary and vascular anatomy are discussed, with specific attention paid to the variants that are pertinent to this surgical procedure. The roles of liver segmentation and volumetric assessment and current imaging techniques and protocols are also discussed. Online supplemental material is available for this article. © RSNA, 2021.

Purpose: High spectral and spatial resolution (HiSS) MRI is a spectroscopic imaging method focusing on water and fat resonances that has good diagnostic utility in breast imaging. The purpose of this work was to assess the feasibility and potential utility of HiSS MRI for the diagnosis of prostate cancer., Methods: HiSS MRI was acquired at 3 T from six patients who underwent prostatectomy, yielding a train of 127 phase-coherent gradient echo (GRE) images. In the temporal domain, changes in voxel intensity were analyzed and linear (R) and quadratic (R1, R2) quantifiers of signal logarithm decay were calculated. In the spectral domain, three signal scaling-independent parameters were calculated: water resonance peak width (PW), relative peak asymmetry (PRA), and relative peak distortion from ideal Lorentzian shape (PRD). Seven cancer and five normal tissue regions of interest were identified in correlation with pathology and compared., Results: HiSS-derived quantifiers, except R2, showed high reproducibility (coefficients of variation, 5%-14%). Spectral domain quantifiers performed better than temporal domain quantifiers, with receiver operator characteristic areas under the curve ranging from of 0.83 to 0.91. For temporal domain parameters, the range was 0.74 to 0.91. Low absolute values of the coefficients of correlation between monoexponential decay markers (R, PW) and resonance shape markers (PRA, PRD) were observed (range, 0.23-0.38)., Conclusion: The feasibility and potential diagnostic utility of HiSS MRI in the prostate at 3 T without an endorectal coil was confirmed. Weak correlation between well-performing markers indicates that complementary information could be leveraged to further improve diagnostic accuracy., (© 2021 International Society for Magnetic Resonance in Medicine.)

Liver cancer is the fastest-growing cause of cancer deaths in the United States and is a complex disease. The response of hepatocellular carcinoma (HCC) to treatment can be variable. Predicting response to determine the most effective therapy is an active area of research. Our understanding of underlying factors which drive response to therapy is continually increasing. As more therapies for the treatment of this disease evolve, it is crucial to identify and match the ideal therapy for a particular tumor and patient. The potential predicative imaging features of tumor behavior, while of research interest, have not been validated for clinical use and do not currently inform treatment planning. If further validated though, prognostic features may be used in the future to personalize treatment plans according to individual patients and tumors. Unexpected post-treatment responses such as potential tumor biology changes and abscopal effect which are important to be aware of. This review is intended for radiologists who routinely interpret post treatment HCC imaging and is designed to increase their cognizance about how HCC tumor biology drives response to therapy and explore rare responses to therapy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although a small portion of patients with hepatocellular carcinoma (HCC) have radiologically evident extrahepatic disease at the initial presentation, a larger number of them develop metastatic disease later during the course of treatment or after definitive treatment. Furthermore, early metastatic disease could be overlooked by imaging due to small size and non-specificity of findings. Extrahepatic spread of HCC occurs via different pathways and is directly fueled by tumor biology and its molecular characteristics. Early and accurate detection of extrahepatic disease in patients with HCC has significant impact on management and selection of treatment options. Additionally, precise staging of disease will allow for better prediction of survival and outcome. Different pathways of regional and systemic spread of HCC with their proposed mechanisms and relevant underlying molecular derangement will be discussed in this article. Potential roles in management of patients with HCC will be discussed and reviewed in this article., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Prostate MRI has seen increasing interest in recent years and has led to the development of new MRI techniques and sequences to improve prostate cancer (PCa) diagnosis which are reviewed in this article. Numerous studies have focused on improving image quality (segmented DWI) and faster acquisition (compressed sensing, k-t-SENSE, PROPELLER). An increasing number of studies have developed new quantitative and computer-aided diagnosis methods including artificial intelligence (PROSTATEx challenge) that mitigate the subjective nature of mpMRI interpretation. MR fingerprinting allows rapid, simultaneous generation of quantitative maps of multiple physical properties (T1, T2), where PCa are characterized by lower T1 and T2 values. New techniques like luminal water imaging (LWI), restriction spectrum imaging (RSI), VERDICT and hybrid multi-dimensional MRI (HM-MRI) have been developed for microstructure imaging, which provide information similar to histology. The distinct MR properties of tissue components and their change with the presence of cancer is used to diagnose prostate cancer. LWI is a T2-based imaging technique where long T2-component corresponding to luminal water is reduced in PCa. RSI and VERDICT are diffusion-based techniques where PCa is characterized by increased signal from intra-cellular restricted water and increased intracellular volume fraction, respectively, due to increased cellularity. VERDICT also reveal loss of extracellular-extravascular space in PCa due to loss of glandular structure. HM-MRI measures volumes of prostate tissue components, where PCa has reduced lumen and stromal and increased epithelium volume similar to results shown in histology. Similarly, molecular imaging using hyperpolarized 13 C imaging has been utilized.

Objective: Meckel diverticulum may become symptomatic if it is complicated by hemorrhage, intestinal obstruction, diverticulitis, or tumor. Although classically described in children, it is often missed in adults because of lack of suspicion and difficulty in detection. The purpose of this article is to review the imaging findings and management of Meckel diverticulum and its complications., Conclusion: Although it is infrequently encountered incidentally, Meckel diverticulum should be considered especially when interpreting examinations for abdominal pain, small-bowel obstruction, and gastrointestinal bleeding.

Phenotypic heterogeneity in microbial communities enables genetically identical organisms to behave differently even under the same environmental conditions. Photorhabdus luminescens, a bioluminescent Gram-negative bacterium, contains a complex life cycle, which involves a symbiotic interaction with nematodes as well as a pathogenic association with insect larvae. P. luminescens exists in two distinct phenotypic cell types, designated as the primary (1°) and secondary (2°) cells. The 1° cells are bioluminescent, pigmented and can support nematode growth and development. Individual 1° cells undergo phenotypic switching after prolonged cultivation and convert to 2° cells, which lack the 1° specific phenotypes. The LysR-type regulator HexA has been described as major regulator of this switching process. Here we show that HexA controls phenotypic heterogeneity in a versatile way, directly and indirectly. Expression of hexA is enhanced in 2° cells, and the corresponding regulator inhibits 1° specific traits in 2° cells. HexA does not directly affect bioluminescence, a predominant 1° specific phenotype. Since the respective luxCDABE operon is repressed at the post-transcriptional level and transcriptional levels of the RNA chaperone gene hfq are also enhanced in 2° cells, small regulatory RNAs are presumably involved that are under control of HexA. Another phenotypic trait that is specific for 1° cells is quorum sensing mediated cell clumping. The corresponding pcfABCDEF operon could be identified as the first direct target of HexA, since the regulator binds to the pcfA promoter region and thereby blocks expression of the target operon. In summary, our data show that HexA fulfills the task as repressor of 1° specific features in 2° cells in a versatile way and gives first insights into the complexity of regulating phenotypic heterogeneity in Photorhabdus bacteria.

Natural orifice transluminal endoscopic surgery (NOTES) is a surgical technique that has been evolving rapidly. Endoscopic submucosal dissection was initiated in 1999, in Japan, for en-bloc resection of large lesions of the stomach (Zhou et al., World J Gastroenterol 19:6962-6968, 2013, ; Kobara et al., Clin Exp Gastroenterol 7:67-74, 2014). Since then, many additional therapies utilizing natural transluminal endoscopic approach have evolved. Peroral endoscopic myotomy (POEM) is a minimally invasive type of transluminal endoscopic surgery that was recently developed for the treatment of achalasia and esophageal motility disorders. The peroral endoscopic myotomy is a less invasive surgical treatment that is suitable for all types of achalasia and used as an alternate to the Heller myotomy. The radiographic findings of achalasia and surgical changes after Heller myotomy have been described, however, very little is available on the post-POEM esophagram appearance. The purpose of this article is to illustrate the anatomy, surgical procedure, and normal and abnormal findings seen on esophagrams in patients who have undergone a POEM.

The radiological findings of child abuse have been a focus of radiological education. Intimate partner violence (IPV) is a significant health burden; however, this is not frequently illustrated in the radiology literature. Health care providers play a crucial role in screening, treating, and preventing future acts of domestic violence. Radiologists in particular are in a unique position in cases of domestic violence, unbiased by interaction with the victim and potentially the abuser. Head and neck injuries are the most common; however, any part of the body is at risk for injury in cases of domestic violence. Fostering awareness of domestic violence and familiarizing radiologists with the most common imaging findings of IPV can help these specialists make the proper diagnosis and improve patient care.

Purpose: To compare the diagnostic accuracy of magnetic resonance imaging elastography (MRE) and anatomic MRI features in the diagnosis of severe hepatic fibrosis and cirrhosis., Materials and Methods: Three readers independently assessed presence of morphological changes associated with hepatic fibrosis in 72 patients with liver biopsy including: caudate to right lobe ratios, nodularity, portal venous hypertension (PVH) stigmata, posterior hepatic notch, expanded gallbladder fossa, and right hepatic vein caliber. Three readers measured shear stiffness values using quantitative shear stiffness maps (elastograms). Sensitivity, specificity, and diagnostic accuracy of stiffness values and each morphological feature were calculated. Interreader agreement was summarized using weighted kappa statistics. Intraclass correlation coefficient was used to assess interreader reproducibility of stiffness measurements. Binary logistic regression was used to assess interreader variability for dichotomized stiffness values and each morphological feature., Results: Using 5.9 kPa as a cutoff for differentiating F3-F4 from F0-2 stages, overall sensitivity, specificity, and diagnostic accuracy for MRE were 85.4%, 88.4%, and 87%, respectively. Overall interreader agreement for stiffness values was substantial, with an insignificant difference (P = 0.74) in the frequency of differentiating F3-4 from F0-2 fibrosis. Only hepatic nodularity and PVH stigmata showed moderately high overall accuracy of 69.4% and 72.2%. Interreader agreement was substantial only for PVH stigmata, moderate for C/R m, deep notch, and expanded gallbladder fossa. Only posterior hepatic notch (P = 0.82) showed no significant difference in reader rating., Conclusion: MRE is a noninvasive, accurate, and reproducible technique compared with conventional features of detecting severe hepatic fibrosis., (Copyright © 2012 Wiley Periodicals, Inc.)

Ultrasound-guided fine needle aspiration (USG-FNA) is a safe, effective, and dependable test used to assess thyroid nodules. However, the size of the lesion can adversely affect the outcome of the procedure. The aim of this study was to assess specimen adequacy and diagnostic specificity in USG-FNA of thyroid nodules measuring < or = 1.5 cm. A total of 219 thyroid FNAs were performed in a one year; 26 were obtained by pathologists, 139 by clinicians, and 54 by radiologists under ultrasound guidance. Of the 54 ultrasound-guided aspirates, 19 cases (35%) were performed on nodules < or = 1.5 cm (range 0.8-1.5 cm, mean 1.3 cm). Cytologic material from these 19 cases was reviewed along with corresponding available follow-up surgical material. Standard criteria for specimen adequacy and established morphologic criteria for diagnostic specificity were assessed in each case. All 19 cases met criteria for specimen adequacy, and in 17 cases (89%) specific cytologic diagnoses were made (cellular/adenomatous nodule--2 cases, colloid nodule--10 cases, Hashimoto's thyroiditis--4 cases, and papillary cystic carcinoma--1 case). The diagnoses were confirmed by surgical follow-up in six cases including the case of papillary carcinoma. One case diagnosed as suspicious for a papillary carcinoma subsequently was found to be a follicular adenoma by histology. In one case, a diagnosis of lymphocytic thyroiditis versus intrathyroidal lymphoid tissue was made (See Table I). In majority of cases of USG-FNA of nonpalpable thyroid nodules, adequate material may be obtained for a specific cytopathologic diagnosis., (2006 Wiley-Liss, Inc.)

Melanocytomas are very rare benign melanocytic tumors of the central nervous system (CNS). We present a case of a cervical melanocytoma diagnosed after trauma as a result of persistent neck pain and abnormal neurological examination. Early recognition of benign melanocytic lesions of the CNS is important, as a complete resection can often lead to cure with no need for further treatment.

Purpose: To determine whether the evolution of the core apparent diffusion coefficient (ADC) of water in ischemic stroke varies with patient age or infarct etiology., Materials and Methods: One hundred forty-seven patients with stroke underwent 236 diffusion-weighted magnetic resonance imaging examinations. Etiologies of lesions were classified according to predefined criteria; in 224 images, the diagnosis of lacune could be firmly established or excluded. ADC was measured in the center of each lesion and in contralateral normal-appearing brain. A model was used to describe the time course of relative ADC (rADC), which is calculated by dividing the lesion ADC by the contralateral ADC, and to test for age- or etiology-related differences in this time course., Results: Transition from decreasing to increasing rADC was estimated at 18.5 hours after stroke onset. In subgroup analysis, transition was earlier in nonlacunes than in lacunes (P =.02). There was a trend toward earlier transition in patients older than the median age of 66.0 years, compared with younger patients (P =.06). Pseudonormalization was estimated at 216 hours. Among nonlacunes, the rate of subsequent rADC increase was more rapid in younger patients than in older patients (P =.001). Within the smaller sample of lacunes, however, no significant age-related difference in this rate was found., Conclusion: Differences in ADC depending on the patient's age and infarct etiology suggest differing rates of ADC progression.

Purpose: Lesion volume is often used as an end point in clinical trials of oncology therapy. We sought to compare the common method of using orthogonal diameters to estimate lesion volume (the diameter method) with a computer-assisted planimetric technique (the perimeter method)., Methods: Radiologists reviewed 825 magnetic resonance imaging studies from 219 patients with glioblastoma multiforme. Each study had lesion volume independently estimated via the diameter and perimeter methods. Cystic areas were subtracted out or excluded from the outlined lesion. Inter- and intrareader variability was measured by using multiple readings on 48 cases. Where serial studies were available in noncystic cases, a mock response analysis was used., Results: The perimeter method had a reduced interreader and intrareader variability compared with the diameter method (using SD of differences): intrareader, 1.76 mL v 7.38 mL (P < .001); interreader, 2.51 mL v 9.07 mL (P < .001) for perimeter and diameter results, respectively. Of the 121 noncystic cases, 23 had serial data. In six (26.1%) of those 23, a classification difference occurred when the perimeter method was used versus the diameter method., Conclusion: Variability of measurements was reduced with the computer-assisted perimeter method compared with the diameter method, which suggests that changes in volume can be detected more accurately with the perimeter method. The differences between these techniques seem large enough to have an impact on grading the response to therapy.