Ronald Walker

Magnetic Resonance Imaging in Multiple Myeloma: Diagnostic and Clinical Implications

PURPOSE Magnetic resonance imaging (MRI) permits the detection of diffuse and focal bone marrow infiltration in the absence of osteopenia or focal osteolysis on standard metastatic bone surveys (MBSs). PATIENTS AND METHODS Both baseline MBS and MRI were available in 611 of 668 myeloma patients who were treated uniformly with a tandem autologous transplantation-based protocol and were evaluated to determine their respective merits for disease staging, response assessment, and outcome prediction. RESULTS MRI detected focal lesions (FLs) in 74% and MBS in 56% of imaged anatomic sites; 52% of 267 patients with normal MBS results and 20% of 160 with normal MRI results had FL on MRI and MBS, respectively. MRI- but not MBS-defined FL independently affected survival. Cytogenetic abnormalities (CAs) and more than seven FLs on MRI (MRI-FLs) distinguished three risk groups: 5-year survival was 76% in the absence of both more than seven MRI-FLs and CA (n = 276), 61% in the presence of one MRI-FL (n = 262), and 37% in the presence of both unfavorable parameters (n = 67). MRI-FL correlated with low albumin and elevated levels of C-reactive protein, lactate dehydrogenase, and creatinine, but did not correlate with age, beta-2-microglobulin, and CA. Resolution of MRI-FL, occurring in 60% of cases and not seen with MBS-defined FL, conferred superior survival. CONCLUSION MRI is a more powerful tool for detection of FLs than is MBS. MRI-FL number had independent prognostic implications; additionally, MRI-FL resolution identified a subgroup with superior survival. We therefore recommend that, in addition to MBS, MRI be used routinely for staging, prognosis, and response assessment in myeloma.

F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma

F18-fluorodeoxyglucose positron emission tomography (FDG-PET) is a powerful tool to investigate the role of tumor metabolic activity and its suppression by therapy for cancer survival. As part of Total Therapy 3 for newly diagnosed multiple myeloma, metastatic bone survey, magnetic resonance imaging, and FDG-PET scanning were evaluated in 239 untreated patients. All 3 imaging techniques showed correlations with prognostically relevant baseline parameters: the number of focal lesions (FLs), especially when FDG-avid by PET-computed tomography, was positively linked to high levels of beta-2-microglobulin, C-reactive protein, and lactate dehydrogenase; among gene expression profiling parameters, high-risk and proliferation-related parameters were positively and low-bone-disease molecular subtype inversely correlated with FL. The presence of more than 3 FDG-avid FLs, related to fundamental features of myeloma biology and genomics, was the leading independent parameter associated with inferior overall and event-free survival. Complete FDG suppression in FL before first transplantation conferred significantly better outcomes and was only opposed by gene expression profiling-defined high-risk status, which together accounted for approximately 50% of survival variability (R(2) test). Our results provide a rationale for testing the hypothesis that myeloma survival can be improved by altering treatment in patients in whom FDG suppression cannot be achieved after induction therapy.

Long-term outcome results of the first tandem autotransplant trial for multiple myeloma.

Total Therapy 1, the first tandem autotransplant trial for newly diagnosed patients with multiple myeloma, was designed to increase the frequency of complete response (CR) and thereby extend survival. With a median follow‐up of 12 years, 62 of 231 initially enrolled patients are alive (17% at 15 years); 31 remain event free (7% at 15 years) including 16 of 94 (41%) that initially achieved CR. Currently alive patients less frequently had cytogenetic abnormalities (CAs) at baseline (P = 0·002), postenrolment (P < 0·001) and at relapse (P = 0·004); elevations of serum C‐reactive protein (CRP) (P = 0·003) and lactate dehydrogenase (P = 0·029), anaemia (P = 0·029) and they more often completed two transplants within 12 months (P = 0·019). Postenrolment overall survival (OS) and event‐free survival (EFS) were superior in the absence of CA of the hypodiploidy or deletion 13 variety (P < 0·001 and 0·037 respectively) and in the presence of low CRP at baseline (P = 0·001 and 0·017 respectively). Postrelapse survival was longer in the absence of CA at relapse (P < 0·001), IgA isotype (P = 0·002), International Staging System stage 3 (P = 0·014), and when patients had two protocol transplants prior to relapse (P = 0·038). Ten‐year EFS and OS could be accomplished in 15% and 33% of patients, respectively, when all agents available in 1989, especially high‐dose melphalan, were applied together upfront for the management of myeloma.

18F-Fluorodeoxyglucose Positron Emission Tomography Contributes to the Diagnosis and Management of Infections in Patients With Multiple Myeloma: A Study of 165 Infectious Episodes

PURPOSE Correctly identifying infection in cancer patients can be challenging. Limited data suggest that positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may be useful for diagnosing infection. To determine the role of FDG-PET in the diagnosis of infection in patients with multiple myeloma (MM). PATIENTS AND METHODS The medical records of 248 patients who had FDG-PET performed for MM staging or infection work-up revealing increased uptake at extramedullary sites and/or bones and joints that would be atypical for MM between October 2001 and May 2004 were reviewed to identify infections and evaluate FDG-PET contribution to patient outcome. RESULTS One hundred sixty-five infections were identified in 143 adults with MM. Infections involved the respiratory tract [99; pneumonia (93), sinusitis (six)], bone, joint and soft tissues [26; discitis (10), osteomyelitis (nine), septic arthritis (one), cellulitis (six)], vascular system [18; septic thrombophlebitis (nine), infection of implantable catheter (eight), septic emboli (one)], gastrointestinal tract [12; colitis (seven), abdominal abscess (three), and diverticulitis and esophagitis (one each)], and dentition [periodontal abscess (10)]. Infections were caused by bacteria, mycobacteria, fungi, and viruses. FDG-PET detected infection even in patients with severe neutropenia and lymphopenia (30 episodes). The FDG-PET findings identified infections not detectable by other methods (46 episodes), determined extent of infection (32 episodes), and led to modification of work-up and therapy (55 episodes). Twenty silent, but clinically relevant, infections were detected among patients undergoing staging FDG-PET. CONCLUSION In patients with MM, FDG-PET is a useful tool for diagnosing and managing infections even in the setting of severe immunosuppression.

Expression of Heparanase by Primary Breast Tumors Promotes Bone Resorption in the Absence of Detectable Bone Metastases

Heparanase is an enzyme that cleaves heparan sulfate and through this activity promotes tumor growth, angiogenesis, invasion, and metastasis in several tumor types. In human breast cancer patients, heparanase expression is associated with sentinel lymph node metastases. However, the precise role of heparanase in the malignant progression of breast cancer is unknown. To examine this, a variant of MDA-MB-231 cells was transfected with the cDNA for human heparanase (HPSE cells) or with vector alone as a control (NEO cells). Transfection produced a 6-fold increase in heparanase activity in HPSE cells relative to NEO cells. When injected into the mammary fat pads of severe combined immunodeficient mice, the tumors formed by HPSE cells initially grow significantly faster than the tumors formed by NEO cells. The rapid growth is due in part to increased angiogenesis, as microvessel densities are substantially elevated in primary HPSE tumors compared with NEO tumors. Although metastases to bones are not detected, surprisingly vigorous bone resorption is stimulated in animals bearing tumors formed by the HPSE cells. These animals have high serum levels of the C-telopeptide derived from type I collagen as well as significant elevation of the active form of tartrate-resistant acid phosphatase (TRAP)-5b. In contrast, in animals having a high tumor burden of Neo cells, the serum levels of C-telopeptide and TRAP-5b never increase above the levels found before tumor injection. Consistent with these findings, histologic analysis for TRAP-expressing cells reveals extensive osteoclastogenesis in animals harboring HPSE tumors. In vitro osteoclastogenesis assays show that the osteoclastogenic activity of HPSE cell conditioned medium is significantly enhanced beyond that of NEO conditioned medium. This confirms that a soluble factor or factors that stimulate osteoclastogenesis are specifically produced when heparanase expression is elevated. These factors exert a distal effect resulting in resorption of bone and the accompanying enrichment of the bone microenvironment with growth-promoting factors that may nurture the growth of metastatic tumor cells. This novel role for heparanase as a promoter of osteolysis before tumor metastasis suggests that therapies designed to block heparanase function may disrupt the early progression of bone-homing tumors.

Diagnosis of Deep Septic Thrombophlebitis in Cancer Patients by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Scanning: A Preliminary Report

PURPOSE To determine the role of the fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan in the diagnosis and management of deep septic thrombophlebitis (STP). PATIENTS AND METHODS We conducted a prospective observational evaluation of FDG-PET in patients with cancer and suspected STP. Retrospective evaluation of patients with cancer and deep venous thrombosis (DVT) who underwent FDG-PET and extremity duplex scan (DS) was also performed. RESULTS Strong venous uptake was observed in FDG-PET of nine STP episodes versus 0 of 27 DVT episodes (P <.001). FDG-PET identified central vein STP in five patients, whereas DS and venography were negative in five and two of these patients, respectively. FDG-PET diagnosis of STP resulted in therapeutic changes in all patients. In four patients, follow-up FDG-PET confirmed resolution. CONCLUSION In cancer patients, FDG-PET identifies STP even in areas not optimally visualized by DS or venography, distinguishes STP from DVT, and leads to significant therapeutic changes.

Complete response in myeloma extends survival without, but not with history of prior monoclonal gammopathy of undetermined significance or smouldering disease

Complete response (CR) is still considered an important surrogate marker for outcome in multiple myeloma (MM). Long‐term survival after transplantation, however, has been observed in a substantial proportion of patients who never achieved CR. The tandem transplant trial, Total Therapy 2, enrolled 668 patients, who were randomised up‐front to thalidomide (THAL) or no THAL; 56 patients were identified as having had, for at least 6 months prior to initiation of therapy, monoclonal gammopathy of undetermined significance (MGUS, n = 21), smouldering MM (SMM, n = 22) or solitary plasmacytoma of bone (SPC, n = 13). The clinical characteristics and outcomes of patients with such ‘evolved’ MM (E‐MM) and of those with ‘unknown’ prior history (U‐MM) were compared. Fewer patients with MGUS/SMM‐E‐MM had anaemia or renal failure; CR was lower (22% vs. 48%) but 4‐year estimates of event‐free survival (54% vs. 56% with U‐MM) and overall survival (65% vs. 70% with U‐MM) were similar to those with SPC‐E‐MM or U‐MM. In the latter group, achieving CR was associated with prolonged survival. In comparison with U‐MM, E‐MM evolved from MGUS/SMM was associated with lower CR rate without adversely affecting survival. In contrast, CR was an independent favourable feature for survival in U‐MM.

Imaging of Multiple Myeloma and Related Plasma Cell Dyscrasias

Multiple myeloma (MM) is an incurable plasma cell malignancy of the bone marrow. MM has 3 components: diffuse marrow infiltration, focal bone lesions, and soft-tissue (extramedullary) disease. The hallmark biomarker in blood or urine is a monoclonal immunoglobulin, the monoclonal protein. Waldenstrom macroglobulinemia is a similar disease with secretion of IgM. Staging is classically performed with the 1975 Durie–Salmon system, which includes conventional radiographs. Recently updated, the Durie–Salmon Plus staging system includes CT, MRI, and 18F-FDG PET/CT. The hallmark radiographic lesion of symptomatic MM is a well-demarcated, focal osteolytic bone lesion. The number of focal bone lesions correlates inversely with outcome. Extramedullary disease is typically an aggressive, poorly differentiated form of MM that confers inferior outcome, with median survival of less than 1 y if present at diagnosis. Achievement of a complete response on 18F-FDG PET before stem-cell transplantation correlates with a superior outcome.

Accuracy of FDG-PET to diagnose lung cancer in areas with infectious lung disease: A meta-analysis

IMPORTANCE Positron emission tomography (PET) combined with fludeoxyglucose F 18 (FDG) is recommended for the noninvasive diagnosis of pulmonary nodules suspicious for lung cancer. In populations with endemic infectious lung disease, FDG-PET may not accurately identify malignant lesions. OBJECTIVES To estimate the diagnostic accuracy of FDG-PET for pulmonary nodules suspicious for lung cancer in regions where infectious lung disease is endemic and compare the test accuracy in regions where infectious lung disease is rare. DATA SOURCES AND STUDY SELECTION Databases of MEDLINE, EMBASE, and the Web of Science were searched from October 1, 2000, through April 28, 2014. Articles reporting information sufficient to calculate sensitivity and specificity of FDG-PET to diagnose lung cancer were included. Only studies that enrolled more than 10 participants with benign and malignant lesions were included. Database searches yielded 1923 articles, of which 257 were assessed for eligibility. Seventy studies were included in the analysis. Studies reported on a total of 8511 nodules; 5105 (60%) were malignant. DATA EXTRACTION AND SYNTHESIS Abstracts meeting eligibility criteria were collected by a research librarian and reviewed by 2 independent reviewers. Hierarchical summary receiver operating characteristic curves were constructed. A random-effects logistic regression model was used to summarize and assess the effect of endemic infectious lung disease on test performance. MAIN OUTCOME AND MEASURES The sensitivity and specificity for FDG-PET test performance. RESULTS Heterogeneity for sensitivity (I2 = 87%) and specificity (I2 = 82%) was observed across studies. The pooled (unadjusted) sensitivity was 89% (95% CI, 86%-91%) and specificity was 75% (95% CI, 71%-79%). There was a 16% lower average adjusted specificity in regions with endemic infectious lung disease (61% [95% CI, 49%-72%]) compared with nonendemic regions (77% [95% CI, 73%-80%]). Lower specificity was observed when the analysis was limited to rigorously conducted and well-controlled studies. In general, sensitivity did not change appreciably by endemic infection status, even after adjusting for relevant factors. CONCLUSIONS AND RELEVANCE The accuracy of FDG-PET for diagnosing lung nodules was extremely heterogeneous. Use of FDG-PET combined with computed tomography was less specific in diagnosing malignancy in populations with endemic infectious lung disease compared with nonendemic regions. These data do not support the use of FDG-PET to diagnose lung cancer in endemic regions unless an institution achieves test performance accuracy similar to that found in nonendemic regions.

Incidence of thyroid carcinoma in fluorodeoxyglucose positron emission tomography-positive thyroid incidentalomas

OBJECTIVE: Fluorodeoxyglucose (FDG) whole body positron emission tomography (PET) scan may show clinically occult second lesions. Such lesions in the thyroid are increasingly common. There are several recent reports of a high probability of malignancy in these lesions ranging from 14% to 63%. STUDY DESIGN AND SETTING: This is a retrospective review of 15,711 PET scans at a multi-disciplinary thyroid clinic at a tertiary care university medical center. Twenty-two patients were referred with thyroid PET “incidentalomas.” The review included 18 FDG-PET scans, ultrasound guided fine needle aspiration biopsies, and thyroid surgery pathology. Aspiration cytology or pathology were the main outcome measures. RESULTS: Three patients had malignancy of the PET-positive thyroid lesions. Papillary thyroid micro carcinomas were detected in four of the specimens that showed a benign pathology of the dominant nodule. CONCLUSION: Our experience shows a 14% malignancy rate for the dominant (imaged) nodule and a total malignancy rate of 32% when the incidental micro carcinomas are included. Both of these rates are significantly lower than results published previously.