[Show abstract][Hide abstract] ABSTRACT: Carney triad is a rare syndrome involving gastrointestinal stromal tumor, pulmonary chondroma, and extra-adrenal paraganglioma. We present a 21-year-old woman with the complete triad who was evaluated with MRI, F-FDOPA, F-FDA, and F-FDG. F-FDOPA best demonstrated the paraganglioma, whereas hepatic metastases noted by MRI demonstrated increased uptake only by F-FDG.
Clinical Nuclear Medicine 11/2014; 40(1). DOI:10.1097/RLU.0000000000000616 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19+ B-cell malignancies. Patients and Methods: We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Results: Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL. Conclusion: This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.
[Show abstract][Hide abstract] ABSTRACT: Multiple Endocrine Neoplasia Type 2 (MEN2) is a rare autosomal dominant syndrome caused by mutations in the RET protooncogene and is characterized by a strong penetrance of medullary thyroid carcinoma (all subtypes) and is often accompanied by pheochromocytoma (MEN2A/2B) and primary hyperparathyroidism (MEN2A). The evaluation and management of MEN2-related tumors is often different from that of sporadic counterparts. This review article provides an overview of clinical manifestations, diagnosis and surgical management of MEN2 patients. This review also presents applications of the most up-to-date imaging modalities to MEN2 patients that are tightly linked to the clinical management and aims to guide physicians towards a rationale for the use of imaging prior to prophylactic thyroidectomy, initial surgery, and reoperations for persistent/recurrent disease. This review also concludes that, in the near future, it is expected that these patients will indeed benefit from newly developed PET approaches which will target peptide receptors and protein kinases. Identification of MEN2-specific radiopharmaceuticals will also soon arise from molecular profiling studies. Furthermore, subtotal (cortical-sparing) adrenalectomy, which is a valid option in MEN2 for avoiding long-term steroid replacement, will benefit from an accurate estimation through imaging of differential adrenocortical function. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Hereditary head and neck paragangliomas (HNPGLs) account for at least 35% of all HNPGLs, most commonly due to germline mutations in SDHx susceptibility genes. Several studies about sympathetic paragangliomas have shown that (18) F-FDG PET/CT was not only able to detect and localize tumors, but also to characterize tumors ((18) F-FDG uptake being linked to SDHx mutations). However, the data concerning (18) F-FDG uptake specifically in HNPGLs have not been addressed. The aim of this study was to evaluate the relationship between (18) F-FDG uptake and the SDHx mutation status in HNPGL patients.
(18) F-FDG PET/CT from sixty HNPGL patients were evaluated. For all lesions, we measured the maximum standardized uptake values (SUVmax), and the uptake ratio defined as HNPGL SUVmax over pulmonary artery trunk SUVmean (SUVratio). Tumor sizes were assessed on radiological studies.
Sixty patients (53.3% with SDHx mutations) were evaluated for a total of 106 HNPGLs. HNPGLs SUVmax and SUVratio were highly dispersed (1.2-30.5 and 1.0-17.0 respectively). The HNPGL (18) F-FDG uptake was significantly higher in SDHx versus sporadic tumors on both univariate and multivariate analysis (p=0.002). We developed two models for calculating the probability of a germline SDHx mutation. The first one, based on a per-lesion analysis, had an accuracy of 75.5%. The second model, based on a per-patient analysis, had an accuracy of 80.0%.
(18) F-FDG uptake in HNPGL is strongly dependent on patient genotype. Thus, the degree of (18) F-FDG uptake in these tumors can be used clinically to help identify patients in whom SDHx mutations should be suspected. This article is protected by copyright. All rights reserved.
European Journal of Clinical Investigation 01/2014; 44(3). DOI:10.1111/eci.12239 · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Following cancer radiotherapy, reconstruction of doses to organs, other than the target organ, is of interest for retrospective health risk studies. Reliable estimation of doses to organs that may be partially within or fully outside the treatment field requires reliable knowledge of the location and size of the organs, e.g., the stomach, which is at risk from abdominal irradiation. The stomach location and size are known to be highly variable between individuals, but have been little studied. Moreover, for treatments conducted years ago, medical images of patients are usually not available in medical records to locate the stomach. In light of the poor information available to locate the stomach in historical dose reconstructions, the purpose of this work was to investigate the variability of stomach location and size among adult male patients and to develop prediction models for the stomach location and size using predictor variables generally available in medical records of radiotherapy patients treated in the past. To collect data on stomach size and position, we segmented the contours of the stomach and of the skeleton on contemporary computed tomography (CT) images for 30 male patients in supine position. The location and size of the stomach was found to depend on body mass index (BMI), ponderal index (PI), and age. For example, the anteroposterior dimension of the stomach was found to increase with increasing BMI (≈0.25 cm kg(-1) m(2)) whereas its craniocaudal dimension decreased with increasing PI (≈-3.3 cm kg(-1) m(3)) and its transverse dimension increased with increasing PI (≈2.5 cm kg(-1) m(3)). Using the prediction models, we generated three-dimensional computational stomach models from a deformable hybrid phantom for three patients of different BMI. Based on a typical radiotherapy treatment, we simulated radiotherapy treatments on the predicted stomach models and on the CT images of the corresponding patients. Those dose calculations demonstrated good agreement between predicted and actual stomachs compared with doses derived from a reference model of the body that might be used in the absence of individual CT scan data.
Physics in Medicine and Biology 12/2013; 58(24):8739-8753. DOI:10.1088/0031-9155/58/24/8739 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Head and neck paragangliomas (HNPGLs) account for approximately 3% of all paragangliomas (PGLs). Most often, HNPGLs are benign, nonsecreting, and slowly progressing. The initial physical examination and biochemical diagnosis usually adds very little to the proper diagnosis of these tumors, and, therefore, radiologists and nuclear medicine physicians play a pivotal role in providing the initial diagnosis, the locoregional staging, and the plan for detecting potential multicentric or metastatic lesions. Based on several current studies, the most accurate use of HNPGL-specific initial and subsequent imaging modalities must be guided by the knowledge of genetics and the specifically measured biochemical profile of these tumors for the proper management of these patients. Thus, this short review article presents the application of the most up-to-date anatomical and functional imaging approaches to HNPGLs tightly linked to the clinical management of these patients. Based on the most recent studies, 18F-FDOPA PET/CT has been shown to be a useful addition to anatomical imaging in the preoperative localization and molecular assessment of HNPGLs. It is estimated that the frequency of metabolically active PGLs on 18F-FDOPA PET/CT in this region is higher than 90%. For patients with hereditary PGL syndromes, (18)F-FDG-PET/CT should be reserved. Imaging of somatostatin receptors using Octreoscan or 68Ga-labeled somatostatin analogues plays an important role for selecting patients for targeted radiation therapy. This review also concludes that it is expected that in the near future, these patients will indeed benefit from new diagnostic approaches based on the identification of new targets by molecular profiling studies that will result in the development of novel PGL-specific radiopharamceuticals.
Seminars in nuclear medicine 11/2013; 43(6):462-473. DOI:10.1053/j.semnuclmed.2013.06.005 · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Erdheim-Chester disease is an uncommon non-Langerhans-cell histiocytosis, due to excessive production of histiocytes deposited in various organs and tissues in the human body. FDG PET was performed in a 68-year-old man with documented active Erdheim-Chester disease to evaluate the extent of the disease. The patient was previously treated with high-dose subcutaneous Interferon α2b, 1,000,000 units 3 times a week, but treatment was interrupted approximately 5 weeks before evaluation at the National Institutes of Health because of adverse effects of the medication. FDG PET/CT showed lesions were imaged in brain, heart, mediastinum, abdomen, and skeleton.
Clinical nuclear medicine 05/2013; DOI:10.1097/RLU.0b013e31828da5e6 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.
We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes.
The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.
Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).
New England Journal of Medicine 04/2013; 368(15):1408-16. DOI:10.1056/NEJMoa1214561 · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Predictive biomarkers are needed to triage patients to best therapy. We prospectively planned examination of sequential blood, biopsy, and functional imaging with which to confirm mechanism and identify potential predictive biomarkers in a phase Ib clinical trial expansion cohort of solid tumor patients receiving sorafenib/bevacizumab. The maximally-tolerated doses of sorafenib 200mg twice daily with bevacizumab 5mg/kg every other week were given to biopsiable patients. Patients were randomized to receive either sorafenib or bevacizumab monotherapy for the first 28 day cycle with the second drug added with cycle 2. Biopsies, dynamic contrast-enhanced MRI, and FDG-PET were done pre-therapy, and at 2, and 6 weeks (2 weeks into combination therapy). Tumor and serum proteomics, Ras/Raf mutational analysis, and functional imaging results were examined individually and across the dataset to identify potential changes predictive of response to therapy and those which confirm biochemical drug mechanism(s). Therapy with sorafenib/bevacizumab resulted in clinical benefit in 45% of this mixed solid tumor group. ERK activation and microvessel density were decreased with monotherapy treatment with sorafenib or bevacizumab, respectively; whereas, decreased signal over the group of total AKT, phospho(p)-VEGF receptor2, p-endothelial nitric oxide synthase, BRAF and cleaved PARP was associated with earlier progression of disease. Tumor metabolic activity decreased in those patients with clinical benefit lasting longer than 4 months, and increased with progressive disease. Cleavage of caspase 3 and PARP were increased, and Ki67 expression decreased in patients with prolonged clinical benefit, consistent with decreased proliferation and increased apoptosis. The conglomerate analysis, incorporating pharmacodynamic and tumor biochemistry, demonstrated sorafenib/bevacizumab targeted vascular activity in the tumor. Results suggest potential biomarkers for which changes, as a group, during early therapeutic exposure may predict clinical benefit.
[Show abstract][Hide abstract] ABSTRACT: Metaiodobenzylguanidine (MIBG) is an analog of guanethidine which has been used for imaging a variety of neuroendocrine tumors (NETs). While 131I-MIBG is approved by the FDA for imaging, no reagents are yet approved for therapy. Thus, 131I-MIBG used for therapy trials is either made in accordance with USP regulations or used under an investigational new drug application (IND). Procedure guidelines for the use of 131I-MIBG in therapy have been published. 131I-MIBG is used mostly to treat neuroblastoma, pheochromocytoma/paraganglioma (PHEO/PGL), and carcinoid tumors. Preparation of patients prior to treatment with 131I-MIBG includes discontinuing therapy with drugs known to interfere with uptake of MIBG by tumor cells. Blocking the thyroid is necessary. Because patients may have nausea and vomiting after administration of MIBG, antiemetics are often administered prior to therapy and in the first 3 days post-administration. To minimize the bladder dose, hydration is encouraged. Candidates for 131I-MIBG therapy should have a reasonable performance status and a life expectancy of at least 3 months. Acceptable hematopoietic parameters are required prior to MIBG therapy. There are no uniform guidelines for selecting or excluding patients from consideration for 131I-MIBG therapy. Most investigators require tumor localization on a diagnostic MIBG scan. Other selection criteria often include evidence of disease progression or symptoms. 131I-MIBG is administered i.v. by pump through a plastic indwelling catheter or central line. Slow administration is a precaution to minimize pharmacologic effects from the unlabeled MIBG. There is no standard activity for therapy. Most studies use fixed activities based on empirical evidence of limited toxicity. Others have used fixed activities adjusted to body weight based on dose escalation studies. Some studies use estimates of dose to radiosensitive organs to define a safe upper limit. Response assessment may be performed as early as 2 months, but more frequently at 3–6-month intervals unless the patient is known to have fast-growing disease. Follow-up typically involves anatomic and functional imaging with 123I-MIBG or [18F]FDG. The frequency of retreatment is variable, ranging from every 4 weeks to every 6 months. PHEO/PGL are tumors that originate in chromaffin tissue of the adrenal medulla or sympathetic nervous system and often secrete catecholamines. Some PHEO/PGL are related to genetic defects which are associated with an increased incidence of malignant and/or extra-adrenal disease. Lymph nodes, bone, liver, and lung are the most common sites of metastases. The optimal therapy for PHEO/PGL consists of surgical resection when feasible. Given the often suboptimal response to chemotherapy, newer therapeutic modalities such as 131I-MIBG are now being applied. Although many patients can benefit from 131I-MIBG treatment, complete response rates are low. There is a suggestion that the response of soft tissue disease to MIBG therapy is superior to that of bone. It also appears that patients with smaller volume disease following surgical resection are more likely to respond. Biochemical catecholamine response has been often reported after treatment. The duration of responses is variable, with 5-year survivals between 45% and 85%. There has not been a systematic comparison of regimens using low, mid, or high activities of 131I-MIBG in PHEO/PGL. However, there is some evidence that higher activities >500 mCi or myeloablative regimens may be associated with higher response rates. The use of high-specific activity 131I-MIBG for therapy seems to reduce side effects. Few data have been published regarding combined chemotherapy with 131I-MIBG therapy in patients with PHEO/PGL. Carcinoids are slow-growing NETs that often secrete substances leading to hormonal syndromes. The most frequent sites for carcinoids are the gastrointestinal tract (73.7%) and the bronchopulmonary system (25.1%). Initial staging and follow-up relies on CT and MRI, to evaluate for nodal and metastatic liver disease. Imaging with 111In-pentetreotide or, more recently, with 68Ga-somatostatin analogs is performed. Scintigraphy with 123I/131I-MIBG is often performed and a published review reported a sensitivity of 70%. At presentation, the best management is surgical removal, or in cases with metastatic disease, debulking for palliation. Unfortunately, metastatic disease at presentation is frequent, and no consistently effective therapeutic strategies are available. Symptomatic tumor response is often seen following therapy with octreotide analogs, whereas objective tumor regression is rare. Interferon may also result in symptomatic improvement. Multiple chemotherapy regimens have been utilized with none showing objective tumor response greater than 15%. The uptake with consequent accumulation of 131I-MIBG in carcinoid raised the possibility of using the radiopharmaceutical therapeutically. Recently, radiolabeled octreotide analogs have been utilized showing a higher overall accumulation in carcinoids than MIBG. Although carcinoid patients rarely have a complete response to 131I-MIBG therapy, objective response rates of 11–27.5% have been reported. Symptomatic response rates range from 38 to 92%. Biochemical responses are seen less commonly. Median 5-year survivals of 42–78% have been reported after 131I-MIBG therapy in carcinoid. Initial single activities of >14.8 GBq (400 mCi) have been recommended to improve survival and symptomatic improvement. Studies combining 131I-MIBG with chemotherapy or biologic therapy are rare. Neuroblastoma is a tumor that arises from primordial neural crest cells and is almost exclusively found in infants and young children. It is the most common tumor of childhood. Therapy relies on induction chemotherapy, surgery, and radiotherapy (given that this is a radiosensitive tumor) followed by consolidation of remission with autologous stem cell transplant (ASCT) or cis-retinoic acid with or without antibody immunotherapy. High-risk patients often relapse and are resistant to conventional therapy. 131I-MIBG therapy has been utilized as palliative therapy for patients with multiple relapses, first-line therapy, and combined therapy with chemotherapy or biologic therapy for consolidation. Several 131I-MIBG dosing strategies have been pursued. Most 131I-MIBG trials have selected patients with advanced disease that have failed first-line therapy, while others have incorporated 131I-MIBG into multiprong dosing strategies. Several trials demonstrated that repeated activities of 131I-MIBG could be administered safely. Partial objective responses were reported in up to 40% of patients but complete responses were usually lower (seldom over 10%). Because many trials were not prospective, reporting criteria in terms of outcome were variable and the parameters measured in terms of duration of response are inconsistent and include survival, overall response, and event free survival (EFS). The most significant toxicity associated with 131I-MIBG therapy in both children and adults is hematologic. The nadir in children has been reported to occur at approximately 28 days after a single 131I-MIBG administration (range 9–42). When chemotherapy is combined with 131I-MIBG therapy, this nadir may occur earlier and is felt to be predominantly driven by the chemotherapy. Patients treated with high activities of 131I-MIBG (≥444–666 MBq/kg (12–18 mCi/kg)) may require bone marrow transplant because of significant and prolonged marrow toxicity, particularly in heavily pretreated subjects. Because higher doses induce considerable neutropenia, significant infections are occasionally encountered. Myelodysplasia (MDS)/acute myelocytic leukemia have been reported in patients who have received both chemotherapy and large amounts of 131I-MIBG. Second malignancies have been also reported. This occurrence of second malignancy and bone marrow disorders indicates that these patients require close follow-up, especially in those with prolonged survival. Hypothyroidism can also occur. Common systemic/constitutional toxicity associated with large doses of 131I-MIBG are often observed, including asthenia, nausea, and vomiting. Although 131I-MIBG localizes in normal organs such as the heart, lung, kidney, liver, and adrenals, there have been very limited complications related to cardiac, renal, liver or adrenal insufficiency. Pulmonary toxicity is most frequently related to infectious disorders.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the clinical value of 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET in relation to tumour localization and the patient's genetic status in a large series of pheochromocytoma/paraganglioma (PHEO/PGL) patients and to discuss in detail false-negative results.
A retrospective study of PGL patients who were investigated with 18F-FDOPA PET or PET/CT imaging in two academic endocrine tumour centres was conducted (La Timone University Hospital, Marseilles, France and National Institutes of Health (NIH), Bethesda, MD, USA).
One hundred sixteen patients (39·7% harbouring germline mutations in known disease susceptibility genes) were evaluated for a total of 195 PHEO/PGL foci. 18F-FDOPA PET correctly detected 179 lesions (91·8%) in 107 patients (92·2%).
Lesion-based sensitivities for parasympathetic PGLs (head, neck, or anterior/middle thoracic ones), PHEOs, and extra-adrenal sympathetic (abdominal or posterior thoracic) PGLs were 98·2% [96·5% for Timone and 100% for NIH], 93·9% [93·8 and 93·9%] and 70·3% [47·1 and 90%] respectively (P < 0·001).
Sympathetic (adrenal and extra-adrenal) SDHx-related PGLs were at a higher risk for negative 18F-FDOPA PET than non-SDHx-related PGLs (14/24 vs 0/62, respectively, P < 0·001). In contrast, the risk of negative 18F-FDOPA PET was lower for parasympathetic PGLs regardless of the genetic background (1/90 in SDHx vs 1/19 in non-SDHx tumours, P = 0·32).
18F-FDOPA PET failed to detect two head and neck PGLs (HNPGL), likely due to their small size, whereas most missed sympathetic PGL were larger and may have exhibited a specific 18F-FDOPA-negative imaging phenotype. 18F-FDG PET detected all the missed sympathetic lesions.
18F-FDOPA PET appears to be a very sensitive functional imaging tool for HNPGL regardless of the genetic status of the tumours. Patients with false-negative tumours on 18F-FDOPA PET should be tested for SDHx mutations.
[Show abstract][Hide abstract] ABSTRACT: No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2-3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 10(7) to 5.8 × 10(9) vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5.8 × 10(9) vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.
Proceedings of the National Academy of Sciences 11/2012; 109(47). DOI:10.1073/pnas.1210662109 · 9.81 Impact Factor