Nicolaus Wagner-Bartak

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial

BACKGROUND The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. METHODS Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of each 28-day cycle. 375 mg/m(2) intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00294632. FINDINGS 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3-4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached [NR]). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response. INTERPRETATION Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL. FUNDING Celgene.

Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial

BACKGROUND Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity. METHODS Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT01880567, and is still ongoing, but no longer accruing patients. FINDINGS Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45-86), and the median number of previous regimens was three (range 1-9). At a median follow-up of 16·5 months (IQR 12·09-19·28), 44 (88%, 95% CI 75·7-95·5) patients achieved an objective response, with 22 (44%, 30·0-58·7) patients achieving a complete response, and 22 (44%, 30·0-58·7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment. INTERPRETATION Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data. FUNDING Pharmacyclics LLC, an AbbVie Company.

Subcutaneous Abdominal Wall Masses: Radiological Reasoning

OBJECTIVE A 36-year-old woman presented to her primary care physician with right lower abdominal pain. Her physician subsequently requested a CT to rule out appendicitis. Contrast-enhanced CT was performed and revealed no evidence of appendicitis but showed two subcutaneous ovoid soft-tissue masses anterior to the rectus sheath in the upper pelvis. Pelvic MRI confirmed the two masses, which showed mild enhancement. The objective of this article is to discuss a diagnostic approach to subcutaneous soft-tissue masses in the abdominal wall. Diagnosis was endometriosis of the abdominal wall. CONCLUSION Integrating salient imaging findings with clinical history is crucial when approaching the diagnosis of subcutaneous soft-tissue masses. The diagnosis of endometriosis should be entertained when soft-tissue masses are seen in the distribution of a cesarean section scar in a woman of reproductive age. Pain, particularly with a cyclic pattern, is highly suggestive of endometriosis. If endometriosis is suspected on CT or ultrasound, MRI can be performed for further evaluation. Definitive diagnosis is made with biopsy. Because subcutaneous nodules are so amenable percutaneous biopsy, imaging features, although of interest, are somewhat ancillary to the diagnostic workup.

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.

Cushing Syndrome: Diagnostic Workup and Imaging Features, With Clinical and Pathologic Correlation

OBJECTIVE Cushing syndrome (CS) is a constellation of clinical signs and symptoms resulting from chronic exposure to excess cortisol, either exogenous or endogenous. Exogenous CS is most commonly caused by administration of glucocorticoids. Endogenous CS is subdivided into two types: adrenocorticotropic hormone (ACTH) dependent and ACTH independent. CONCLUSION Cushing disease, which is caused by a pituitary adenoma, is the most common cause of ACTH-dependent CS for which pituitary MRI can be diagnostic, with bilateral inferior petrosal sinus sampling useful in equivocal cases. In ectopic ACTH production, which is usually caused by a tumor in the thorax (e.g., small cell lung carcinoma, bronchial and thymic carcinoids, or medullary thyroid carcinoma) or abdomen (e.g., gastroenteropancreatic neuroendocrine tumors or pheochromocytoma), CT, MRI, and nuclear medicine tests are used for localizing the source of ACTH. In ACTH-independent CS, which is caused by various adrenal abnormalities, adrenal protocol CT or MRI is usually diagnostic.

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.

Computed Tomography Image Quality Evaluation of a New Iterative Reconstruction Algorithm in the Abdomen (Adaptive Statistical Iterative Reconstruction-V) a Comparison with Model-Based Iterative Reconstruction, Adaptive Statistical Iterative Reconstruction, and Filtered Back Projection Reconstructions

Objective The purpose of this study was to compare abdominopelvic computed tomography images reconstructed with adaptive statistical iterative reconstruction–V (ASIR-V) with model-based iterative reconstruction (Veo 3.0), ASIR, and filtered back projection (FBP). Methods and Materials Abdominopelvic computed tomography scans for 36 patients (26 males and 10 females) were reconstructed using FBP, ASIR (80%), Veo 3.0, and ASIR-V (30%, 60%, 90%). Mean ± SD patient age was 32 ± 10 years with mean ± SD body mass index of 26.9 ± 4.4 kg/m2. Images were reviewed by 2 independent readers in a blinded, randomized fashion. Hounsfield unit, noise, and contrast-to-noise ratio (CNR) values were calculated for each reconstruction algorithm for further comparison. Phantom evaluation of low-contrast detectability (LCD) and high-contrast resolution was performed. Results Adaptive statistical iterative reconstruction–V 30%, ASIR-V 60%, and ASIR 80% were generally superior qualitatively compared with ASIR-V 90%, Veo 3.0, and FBP (P < 0.05). Adaptive statistical iterative reconstruction–V 90% showed superior LCD and had the highest CNR in the liver, aorta, and, pancreas, measuring 7.32 ± 3.22, 11.60 ± 4.25, and 4.60 ± 2.31, respectively, compared with the next best series of ASIR-V 60% with respective CNR values of 5.54 ± 2.39, 8.78 ± 3.15, and 3.49 ± 1.77 (P <0.0001). Veo 3.0 and ASIR 80% had the best and worst spatial resolution, respectively. Conclusions Adaptive statistical iterative reconstruction–V 30% and ASIR-V 60% provided the best combination of qualitative and quantitative performance. Adaptive statistical iterative reconstruction 80% was equivalent qualitatively, but demonstrated inferior spatial resolution and LCD.

Adrenal Cortical Hyperplasia: Diagnostic Workup, Subtypes, Imaging Features and Mimics

Adrenal cortical hyperplasia manifests radiologically as a non-malignant growth, or enlargement, of the adrenal glands, specifically the cortex, although the cortex cannot be definitively identified by conventional imaging. Controlled by the pituitary gland, the adrenal cortex drives critical processes, such as the production of cortisol, mineralocorticoid and sex hormones. Any disruption in the multiple enzymes and hormones involved in these pathways may cause serious or life-threatening symptoms, often associated with anatomical changes in the adrenal glands. Diagnosis and treatment of adrenal cortical hyperplasia requires a thorough clinical evaluation. As imaging has become more robust so has its role in the diagnosis and treatment of adrenal conditions. CT has been the primary modality for adrenal imaging owing to reproducibility, temporal and spatial resolution and broad access. MRI serves a complimentary role in adrenal imaging and can be used to further evaluate indeterminate CT findings or serve as an adjunct tool without the use of ionizing radiation. Ultrasound and fluoroscopy (genitography) are most commonly used in children and foetuses to evaluate congenital adrenal hyperplasia. This article will discuss the clinical presentation, laboratory workup and imaging features of adrenal cortical hyperplasia, both congenital and acquired.

Free-breathing radial volumetric interpolated breath-hold examination vs breath-hold cartesian volumetric interpolated breath-hold examination magnetic resonance imaging of the liver at 1.5T.

AIM To compare breath-hold cartesian volumetric interpolated breath-hold examination (cVIBE) and free-breathing radial VIBE (rVIBE) and determine whether rVIBE could replace cVIBE in routine liver magnetic resonance imaging (MRI). METHODS In this prospective study, 15 consecutive patients scheduled for routine MRI of the abdomen underwent pre- and post-contrast breath-hold cVIBE imaging (19 s acquisition time) and free-breathing rVIBE imaging (111 s acquisition time) on a 1.5T Siemens scanner. Three radiologists with 2, 4, and 8 years post-fellowship experience in abdominal imaging evaluated all images. The radiologists were blinded to the sequence types, which were presented in a random order for each patient. For each sequence, the radiologists scored the cVIBE and rVIBE images for liver edge sharpness, hepatic vessel clarity, presence of artifacts, lesion conspicuity, fat saturation, and overall image quality using a five-point scale. RESULTS Compared to rVIBE, cVIBE yielded significantly (P < 0.001) higher scores for liver edge sharpness (mean score, 3.87 vs 3.37), hepatic-vessel clarity (3.71 vs 3.18), artifacts (3.74 vs 3.06), lesion conspicuity (3.81 vs 3.2), and overall image quality (3.91 vs 3.24). cVIBE and rVIBE did not significantly differ in quality of fat saturation (4.12 vs 4.03, P = 0.17). The inter-observer variability with respect to differences between rVIBE and cVIBE scores was close to zero compared to random error and inter-patient variation. Quality of rVIBE images was rated as acceptable for all parameters. CONCLUSION rVIBE cannot replace cVIBE in routine liver MRI. At 1.5T, free-breathing rVIBE yields acceptable, although slightly inferior image quality compared to breath-hold cVIBE.

Qualitative Slow Blood Flow in Lower Extremity Deep Veins on Doppler Sonography: Quantitative Assessment and Preliminary Evaluation of Correlation With Subsequent Deep Venous Thrombosis Development in a Tertiary Care Oncology Center

To determine whether the qualitative sonographic appearance of slow deep venous flow in the lower extremities correlates with quantitative slow flow and an increased risk of deep venous thrombosis (DVT) in oncology patients.