Liza Lindenberg

Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.

IMPORTANCE Carfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combinations tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival. OBJECTIVE To assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM). DESIGN, SETTING, AND PARTICIPANTS Clinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM). INTERVENTIONS Eight 28-day cycles were composed of carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing. MAIN OUTCOMES AND MEASURES Primary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed. RESULTS Of 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively. CONCLUSIONS AND RELEVANCE Carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.

Prospective Study Evaluating Na18F PET/CT in Predicting Clinical Outcomes and Survival in Advanced Prostate Cancer

This prospective pilot study evaluated the ability of Na18F PET/CT to detect and monitor bone metastases over time and its correlation with clinical outcomes and survival in advanced prostate cancer. Methods: Sixty prostate cancer patients, including 30 with and 30 without known bone metastases by conventional imaging, underwent Na18F PET/CT at baseline, 6 mo, and 12 mo. Positive lesions were verified on follow-up scans. Changes in SUVs and lesion number were correlated with prostate-specific antigen change, clinical impression, and overall survival. Results: Significant associations included the following: SUV and prostate-specific antigen percentage change at 6 mo (P = 0.014) and 12 mo (P = 0.0005); SUV maximal percentage change from baseline and clinical impression at 6 mo (P = 0.0147) and 6–12 mo (P = 0.0053); SUV change at 6 mo and overall survival (P = 0.018); number of lesions on Na18F PET/CT and clinical impression at baseline (P < 0.0001), 6 mo (P = 0.0078), and 12 mo (P = 0.0029); and number of lesions on Na18F PET/CT per patient at baseline and overall survival (P = 0.017). In an exploratory analysis, paired 99mTc-methylene diphosphonate bone scans (99mTc-BS) were available for 35 patients at baseline, 19 at 6 mo, and 14 at 12 mo (68 scans). Malignant lesions on Na18F PET/CT (n = 57) were classified on 99mTc-BS as malignant 65% of the time, indeterminate 25% of the time, and negative 10% of the time. Additionally, 69% of paired scans showed more lesions on Na18F PET/CT than on 99mTc-BS. Conclusion: The baseline number of malignant lesions and changes in SUV on follow-up Na18F PET/CT significantly correlate with clinical impression and overall survival. Na18F PET/CT detects more bone metastases earlier than 99mTc-BS and enhances detection of new bone disease in high-risk patients.

Prostate Cancer Imaging with Novel PET Tracers.

Molecular imaging of prostate cancer is in a dynamic phase of development. Currently approved techniques are limited and researchers have been working on novel agents to improve accuracy in targeting and detecting prostate tumors. In addition, the complexity of various prostate cancer states also contributes to the challenges in evaluating suitable radiotracer candidates. We have highlighted nuclear medicine tracers that focus on mechanisms involved in bone metastasis, prostate cancer cell membrane synthesis, amino acid analogs, androgen analogs, and the prostate specific membrane antigen. Encouraging results with many of these innovative radiotracer compounds will not only advance diagnostic capabilities for prostate cancer but open opportunities for theranostic applications to treat this worldwide malignancy.

Evaluation of Prostate Cancer with PET/MRI

In the ongoing effort to understand and cure prostate cancer, imaging modalities are constantly evolving to assist in clinical decisions. Multiparametric MRI can be used to direct prostate biopsies, improve diagnostic yield, and help clinicians make more accurate decisions. PET is superior in providing biologic information about the cancer and is sensitive and highly specific. Integrated PET/MRI is a welcome technical advance with great potential to influence the diagnosis and management of prostate cancer in clinical practice.

Advancement of MR and PET/MR in Prostate Cancer

Multiparametric magnetic resonance (mpMRI) imaging has assumed a larger role in the diagnosis and management of prostate cancer. The current method of detecting prostate cancer relies on blind systematic biopsy, guided only by transrectal ultrasound that generally directs the needle biopsy to sextants of the prostate rather than specific lesions. MpMRI is playing an increasing role in the detection of primary cancer as it can visualize cancers and direct biopsies. However, even mpMRI is inherently nonspecific and numerous biopsies performed under MR guidance prove to be negative. Positron emission tomography (PET) has the potential to improve the sensitivity and specificity for prostate cancer in combination with mpMRI. Prostate-specific membrane antigen is a widely expressed tumor antigen in prostate cancer for which multiple PET ligands, labeled with 68Ga and 18F, are being developed. However, the low spatial resolution of PET mandates that it be combined with a higher resolution imaging modality, which typically has been computed tomography (CT). However, MRI is not only better at localizing lesions in the prostate and prostatic bed, but it is also more sensitive than CT for early bone marrow changes in bone metastases caused by prostate cancer. Prostate-specific membrane antigen-based PET agents show promise in the early detection of recurrent and metastatic disease. Recent developments in hybrid imaging now allow PET/MRI to be performed simultaneously on a single scanner allowing one-to-one correspondence between the PET activity and MRI findings. This offers the opportunity for both high sensitivity and specificity with excellent anatomic location and could allow for more targeted biopsies and treatments. Here, we review the current status of PET/MRI for prostate cancer.

Advances in medical imaging for the diagnosis and management of common genitourinary cancers

Medical imaging of the 3 most common genitourinary (GU) cancers-prostate adenocarcinoma, renal cell carcinoma, and urothelial carcinoma of the bladder-has evolved significantly during the last decades. The most commonly used imaging modalities for the diagnosis, staging, and follow-up of GU cancers are computed tomography, magnetic resonance imaging (MRI), and positron emission tomography (PET). Multiplanar multidetector computed tomography and multiparametric MRI with diffusion-weighted imaging are the main imaging modalities for renal cell carcinoma and urothelial carcinoma, and although multiparametric MRI is rapidly becoming the main imaging tool in the evaluation of prostate adenocarcinoma, biopsy is still required for diagnosis. Functional and molecular imaging using 18-fluorodeoxyglucose-PET and sodium fluoride-PET are essential for the diagnosis, and especially follow-up, of metastatic GU tumors. This review provides an overview of the latest advances in the imaging of these 3 major GU cancers.

Bone marrow abnormalities and early bone lesions in multiple myeloma and its precursor disease: a prospective study using functional and morphologic imaging

Abstract The incidence and importance of bone marrow involvement and/or early bone lesions in multiple myeloma (MM) precursor diseases is largely unknown. This study prospectively compared the sensitivity of several imaging modalities in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM. Thirty patients (10 each with MGUS, SMM and MM) were evaluated with skeletal survey, [18F]FDG-PET/CT, [18F]NaF-PET/CT and morphologic dynamic contrast enhanced (DCE)-MRI. An additional 16 SMM patients had skeletal surveys and FDG-PET/CT. Among MGUS patients, DCE-MRI found only one focal marrow abnormality; other evaluations were negative. Among 26 SMM patients, five (19%) were re-classified as MM based on lytic bone lesions on CT and six had unifocal or diffuse marrow abnormality. Among MM, marrow abnormalities were observed on FDG-PET/CT in 8/10 patients and on DCE-MRI in nine evaluable patients. Abnormal NaF uptake was observed only in MM patients with lytic lesions on CT, providing no additional clinical information.

Screening of cancer tissue arrays identifies CXCR4 on adrenocortical carcinoma: correlates with expression and quantification on metastases using 64 Cu-plerixafor PET

Expression of the chemokine receptor CXCR4 by many cancers correlates with aggressive clinical behavior. As part of the initial studies in a project whose goal was to quantify CXCR4 expression on cancers non-invasively, we examined CXCR4 expression in cancer samples by immunohistochemistry using a validated anti-CXCR4 antibody. Among solid tumors, we found expression of CXCR4 on significant percentages of major types of kidney, lung, and pancreatic adenocarcinomas, and, notably, on metastases of clear cell renal cell carcinoma and squamous cell carcinoma of the lung. We found particularly high expression of CXCR4 on adrenocortical cancer (ACC) metastases. Microarrays of ACC metastases revealed correlations between expression of CXCR4 and other chemokine system genes, particularly CXCR7/ACKR3, which encodes an atypical chemokine receptor that shares a ligand, CXCL12, with CXCR4. A first-in-human study using 64Cu-plerixafor for PET in an ACC patient prior to resection of metastases showed heterogeneity among metastatic nodules and good correlations among PET SUVs, CXCR4 staining, and CXCR4 mRNA. Additionally, we were able to show that CXCR4 expression correlated with the rates of growth of the pulmonary lesions in this patient. Further studies are needed to understand better the role of CXCR4 in ACC and whether targeting it may be beneficial. In this regard, non-invasive methods for assessing CXCR4 expression, such as PET using 64Cu-plerixafor, should be important investigative tools.

Imaging of subclinical haemopoiesis after stem-cell transplantation in patients with haematological malignancies: A prospective pilot study

BACKGROUND Haemopoietic stem-cell transplantation (HSCT) eradicates host haemopoiesis before venous infusion of haemopoietic stem cells (HSCs). The pathway to cellular recovery has been difficult to study in human beings because of risks associated with interventions during aplasia. We investigated whether 18F-fluorothymidine (18F-FLT) imaging was safe during allogenic HSCT and allowed visualisation of early cellular proliferation and detection of patterns of cellular engraftment after HSCT. METHODS Eligible patients were aged 18-55 years, had high-risk haematological malignancies. All patients underwent myeloablation followed by HSCT. The imaging primary endpoint was detection of early subclinical engraftment after HSCT with 18F-FLT PET or CT. Imaging was done 1 day before and 5 or 9, and 28 days, and 1 year after HSCT. This study is registered with ClinicalTrials.gov, number NCT01338987. FINDINGS Between April 1, 2014, and Dec 31, 2015, 23 patients were enrolled and assessable for toxic effects after completing accrual. 18F-FLT was not associated with any adverse events or delayed engraftment. 18F-FLT imaging objectively identified subclinical bone-marrow recovery within 5 days of HSC infusion, which was up to 20 days before engraftment became clinically evident. Quantitatively, 18F-FLT intensity differed significantly between myeloablative infusion before HSCT and subclinical HSC recovery (p=0·00031). 18F-FLT biodistribution over time revealed a previously unknown path of cellular recovery of haemopoiesis in vivo that mirrored fetal ontogeny. INTERPRETATION 18F-FLT allowed quantification and tracking of subclinical bone-marrow repopulation in human beings and revealed new insights into the biology of HSC recovery after HSCT. FUNDING National Institutes of Health, Bens Run/Bens Gift, Albert and Elizabeth Tucker Foundation, Mex Frates Leukemia Fund, Jones Family fund, and Oklahoma Center for Adult Stem Cell Research.

An automatic 3D CT/PET segmentation framework for bone marrow proliferation assessment

Clinical assessment of bone marrow is limited by an inability to evaluate the marrow space comprehensively and dynamically and there is no current method for automatically assessing hematopoietic activity within the medullary space. Evaluating the hematopoietic space in its entirety could be applicable in blood disorders, malignancies, infections, and medication toxicity. In this paper, we introduce a CT/PET 3D automatic framework for measurement of the hematopoietic compartment proliferation within osseous sites. We first perform a full-body bone structure segmentation using 3D graph-cut on the CT volume. The vertebrae are segmented by detecting the discs between adjacent vertebrae. Finally, we register the bone marrow CT volume with its corresponding PET volume and capture the spinal bone marrow volume. The proposed framework was tested on 17 patients, achieving an average accuracy of 86.37% and a worst case accuracy of 82.3% in automatically extracting the aggregate volume of the spinal marrow cavities.