Iliac Crest Bone Marrow Biopsy Research Articles

Expression of Tie2 (angiopoietin receptor) on the monocyte subpopulations from ischemic stroke patients: Histological and flowcytometric studies.

Different subpopulations of monocytes play roles in phagocytosis, inflammation, and angiogenic processes e.g., Tie2-expressing monocytes (TEMs). The brain is flooded with macrophages that are derived from monocytes within 3-7 days after a stroke. This study aimed to determine the expression level of Tie2 (an angiopoietin receptor) on monocytes and their subpopulations in ischemic stroke patients using the histological and immunohistological study of bone marrow biopsies and blood flow cytometry examination. Ischemic stroke patients within two days were selected. Participants in the control group were healthy volunteers of matched age and gender. Sample collection was performed within 24 to 48 hours after medical consultants confirmed the stroke diagnosis. An iliac crest bone marrow biopsy was obtained and fixed for histological and immunohistological staining with antiCD14 and antiCD68. Flow cytometry was used to determine the total monocyte population, monocyte subpopulations, and TEMs after staining with monoclonal antibodies to CD45, CD14, CD16, and Tie2. Post-stroke patients' bone marrow cells were hypercellular. There was an apparent increase in CD68 and CD14-positive cells. Ischemic stroke patients exhibited low percentages of nonclassical monocytes CD14lowCD16++, with an increase in intermediate monocytes CD14highCD16+. Moreover, ischemic stroke patients had significantly higher levels of TEMs than control group. The results of this study demonstrate dysregulation of angiogenesis in monocyte subsets in ischemic stroke patients, which could be used as an early diagnostic marker of neurovascular damage and may need angiogenic therapy or improved medications to prevent further damage of blood vessels.

Bone Marrow Biopsy, Does CT Guidance Add Value?

Background: Bone marrow aspirate and biopsies (BMAB) remain a corner stone in the diagnosis and management of various hematologic disorders. Specialized testing, such as cytogenetics, immunophenotypic and molecular analysis performed on these specimens, plays a crucial role in diagnosis and staging of Leukemias/Lymphomas, as well as in finding out molecular targets for potential therapeutic benefits. Thus, inadequate, and poor-quality specimens can limit making a precise diagnosis and providing optimal treatment. At our institution, we recognized that a substantial number of non-CT guided BMAB were being reported as suboptimal, although diagnosis was being made. Also, recently more CT guided (CTG) BMAB are being implemented. A drawback with CTG BMAB is scheduling delays, that can potentially result in treatment delays, and fatal outcomes especially in conditions like Acute Leukemias. Additionally, there is concern of higher cost associated with CT guided BMAB. Therefore, we performed a retrospective analysis on BMAB procedures performed at our institution between January 2019 and April 2022. Purpose:Evaluate and compare the quality of BMAB procedures performed with and without CT guidance (blind procedure) at our institution, and their respective waiting times.Identify potential areas for improvement.Provide data to help guide in choosing the most appropriate procedure. Methods: We retrospectively reviewed all adult BMAB procedures performed at our institution between January 2019 and April 2022, including patient demographics. Pathology reports were reviewed for adequacy of aspirate smears and core biopsies. Samples were deemed inadequate even if one of bone marrow aspirate or core or clot specimens were described by the pathologist as "suboptimal", "inadequate", "fragmented", "crushed", "hemodiluted", "no spicules", or "scant". Waiting period for the procedure was defined as the duration of time (in days) from the date of placing an order for biopsy (CTG or blind) to the date of procedure. CTG BMAB are typically performed by intervention radiologists (IR) while bind BMAB are usually performed by Oncologists (Fellows or attendings) at our institutions. Results: A total of 469 posterior iliac crest bone marrow aspirate and biopsy procedures were performed. More patients underwent BMAB procedure under CT guidance (61% vs 39% for non-CTG). More CTG BMAB samples were categorized as adequate (69%), compared to the non CTG (55%), (p=0.02). No statistical difference was noted in patient's age (p=0.639) or gender (p=.22) or Body mass index (BMI) (p=2.05) of CTG and non CTG groups (see table). The mean waiting period was longer for CTG procedure (27 days +/- 20 (0-135), compared to non CTG (15 days +/- 17 (0-105) (p=0.031). Although our pathologist described a sample as "suboptimal", a definitive diagnosis was still able to be made in all cases using the available bone marrow clot, aspirate and core specimens. Conclusion/Interventions: CTG BMAB procedures were more likely to result in adequate samples when compared to non-CTG procedures, however with longer waiting period and higher costs. So, we propose that obtaining non-CTG BMAB will improve cost effectiveness and reduce the wait times. To improve the adequacy of non CTG BMAB, we propose some interventions: 1. Provide an organized training during fellowship that includes theory followed by simulation, and practice-based training under supervision. 2. Discuss ICSH (International Council for Standardization in Hematology) guidelines for bone marrow adequacy criteria with the providers. For example, the length of a core biopsy from an adult should be at least 2cm. As our study suggests significant scheduling delays with CTG BMAB, such orders when requested, may be considered as urgent procedures to avoid potential treatment delays and poor outcomes. Alternately, when an aggressive hematologic disorder like acute leukemia is suspected, blind approach may be undertaken for prompt diagnosis. Interestingly, BMI was not significantly different in the two groups. However, if locating physical landmarks is impaired by body habitus, then CT guided BMAB should be strongly considered. We would like to highlight the importance of having adequate personnel including nurse navigators, technicians who play a vital role in obtaining timely insurance clearance, and procedure scheduling. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Utility and prognostic value of PET/CT, bone marrow biopsy and aspirate for detection of bone marrow involvement in diffuse large B-cell lymphoma

Objective: This study aimed to determine the value of bone marrow biopsy (BMB) , bone marrow aspiration (BMA) , and positron emission tomography combined with computed tomography (PET/CT) in bone marrow (BM) involvement and prognosis evaluation in diffuse large B-cell lymphoma (DLBCL) . Methods: The clinical data of patients with DLBCL who underwent PET/CT, BMB, and BMA of the iliac crest were retrospectively analyzed in Peking Union Medical College Hospital from January 2015 to November 2017. The BM involvement on PET/CT was defined as the ratio of maximal standardized uptake values of iliac crest BM to liver parenchyma intensity ≥1. Results: A total of 76 patients without liver involvement were enrolled, there were 32 males, and the median age was 53 (17-79) . Moreover, 16 patients (21.1%) had BM involvement on PET/CT, 12 (15.8%) had positive BMB, and 13 (17.1%) had positive BMA. Excellent correlation between BMA and BMB (κ=0.943) was found, including good correlation between PET/CT and BMB/BMA (κ=0.763 and 0.776, respectively) . After a median follow-up of 52 (0-82) months, BM involvement by BMB (P=0.037) and BMA (P=0.007) were poor prognostic factors for overall survival, positive PET/CT had no significant effect on prognosis (P>0.05) . Conclusion: PET/CT, BMB, and BMA are effective methods to detect BM involvement with great concordance. However, iliac crest BMB and BMA showed superior performance in prognosis evaluation.

PET/CT and bone marrow biopsy (BMB) in evaluating bone marrow in lymphoma

BackgroundBone marrow assessment is an important part in the Ann Arbor staging system in lymphoma. It is done routinely through posterior iliac crest bone marrow biopsy (BMB) which is an invasive technique with limited examination of one site. 18F-FDG PET/CT is now used for staging of lymphoma. The purpose of this study was to compare the sensitivity of PET/CT and BMB in detecting bone marrow infiltration (BMI) in lymphoma and determine agreement between both in assessing bone marrow and whether we can evaluate the bone marrow by PET/CT without the need of the routine BMB.ResultsPET/CT detected 24 (16.5%) cases with positive BMI that were missed by BMB. BMB detected only 2 (1.4%) cases that were missed by PET/CT. The PET/CT showed a higher sensitivity of 95.6% than BMB 46.7% in detecting BMI in lymphoma. We found a moderate agreement between PET/CT and BMB results in the whole cohort using Cohen’s k computation. It was found that 0.47 with p value less than 0.0001.ConclusionsPET/CT can detect more bone marrow involvement in lymphoma compared with BMB. It can replace the routine invasive BMB in many cases, especially those showing multifocal uptake in both Hodgkin and non-Hodgkin lymphoma. PET/CT can also help to guide the site of the biopsy in some cases. Iliac crest BMB is still needed in cases showing diffuse FDG uptake to differentiate malignant uptake from reactive hyperplasia, and in those with limited FDG avidity and in some cases with negative uptake to exclude early infiltration if management will differ.

Fluorodeoxyglucose-Positron Emission Tomography Predicts Bone Marrow Involvement in the Staging of Follicular Lymphoma.

Standard bone marrow biopsy (BMB) and bone involvement with follicular lymphoma (FL) on positron emission tomography (PET)/computed tomography (CT) both predict early clinical failure in FL. The key clinical question is whether PET/CT findings can obviate the need for BMB. The goal of this study was to determine the value of PET/CT in determining bone involvement in FL, using posterior iliac crest BMB as the gold standard. A total of 548 patients with newly diagnosed grade 1-3A FL were included. The presence, pattern, and location of bone involvement, spleen involvement, and standardized uptake values (SUVs) in the L3 vertebral body were recorded for all patients and compared with the BMB report. Excluding patients with focal bone lesions on PET/CT, the sensitivity and specificity of PET/CT in detecting bone or marrow involvement, compared with BMB, were 53% and 88%, respectively. The sensitivity and specificity of spleen involvement on PET/CT in predicting a positive BMB were 55% and 86%, respectively. An L3 SUVmax of less than 2.0 resulted in a negative predictive value (NPV) of 96% for marrow involvement on BMB; an L3 SUVmean below 1.4 resulted in an NPV of 100%. In newly diagnosed FL, PET/CT-detected bone and splenic involvement is highly specific for a positive BMB, and very low SUV values (<2.0 SUVmax and < 1.4 SUVmean ) in the lumbar spine have a high NPV for a negative BMB. Routine BMB may be obviated in these patients. BMB remains necessary to definitively exclude bone marrow involvement in a large majority of patients with a negative PET. Predicting early clinical failure in follicular lymphoma (FL) is important but difficult. Bone marrow involvement by FL is associated with early clinical failure, and determining this involvement is a key component of the initial staging. This study highlights that in certain patients, positron emission tomography/computed tomography is sufficient in determining bone or marrow involvement, without the need for a confirmatory bone marrow biopsy (BMB). An algorithm is provided based on these findings to help clinicians determine which patients would benefit from BMB and when it can be avoided.

Diagnostic performance of 18F-2-fluoro-2-deoxy-D-glucose PET/computerized tomography in identifying bone marrow infiltration in new patients with diffuse large B-cell lymphoma and Hodgkin lymphoma.

To compare between F-2-fluoro-2-deoxy-D-glucose PET/computerized tomography (F-FDG PET/CT) and routine iliac bone marrow biopsy (BMB) in assessment of bone marrow infiltration (BMI) in Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) patients at initial presentation. A retrospective analysis of 138 patients (50 Hodgkin lymphomas, 88 DLBCLs). The study included 70 males and 68 females with median age of 43 years. All patients underwent F-FDG PET/CT and iliac crest BMB before treatment. Any focal or patchy FDG uptake in the bone marrow, superior-to hepatic uptake was interpreted as abnormal with or without corresponding CT changes. Treatment response was evaluated clinically with each cycle of chemotherapy, radiologically after three cycles and at the end of treatment. The overall diagnostic performance showed significant higher sensitivity of F-FDG PET/CT than that of BMB (73.9 versus 62.5%, P = 0.046), while the specificity was higher in BMB than in F-FDG PET/CT (100% in BMB versus 93.5% in F-FDG PET/CT). In Hodgkin lymphoma, sensitivity, negative predictive value (NPV) and accuracy were significantly higher in F-FDG PET/CT compared with BMB, being 87.5, 94.4 and 96% versus 50, 81 and 84% (P = 0.02, 0.03, 0.04, respectively). However, for DLBCL patients, almost comparable results were found between both tests in terms of sensitivity, NPV and accuracy (66.7, 83.9 and 81.8% versus 68.8, 84.9 and 88.6%, respectively). After PET/CT scan, 12 patients (8.6%) were upstaged to stage IV, eight of them were negative by BMB. F-FDG PET/CT seemed to be an excellent diagnostic test in assessment of BMI at initial assessment and staging of Hodgkin lymphoma and DLBCL patients.

Maximizing FDG-PET/CT Utility in Staging of Follicular Lymphoma (FL): The Role of Spleen Involvement and Bone Standardized Uptake Values

Background: FDG PET/CT and bone marrow biopsy (BMB) are considered standard procedures for the staging of patients with new, untreated FL. A key issue in FL is the early identification of patients who will fail early. We recently reported (Am J Hematology 2019) that the presence of ≥2 EN sites, spleen, bone or soft tissue involvement as detected by PET all predicted failure to achieve EFS24. In Hodgkin lymphoma and diffuse large B-cell NHL, PET has replaced the routine need for a staging BMB. However, there is no such evidence in FL. The goal of this study was to determine the value of FDG PET/CT in determining bone involvement in FL using BMB as the gold standard. Methods: Patients were identified using the Mayo Clinic Lymphoma Database. 548 patients with newly diagnosed FL grades 1-3A between years 2003-2016, available BMB results, and PET/CT imaging at diagnosis, were included in the analysis. The presence of bone and spleen involvement on PET/CT, SUVmax and SUVmean of the axial skeleton at L3, and BMB results were recorded and compared. Results: In all, 36% (197/548) of patients had a positive BMB, and 34% (189/548) had bone involvement detected on PET/CT. Compared to BMB, the sensitivity and specificity of PET/CT in detecting bone involvement as determined by BMB were 60% and 80%, respectively. We noted that 59 patients had focal bone involvement on PET/CT rather than a diffuse component, and found that 47% (28/59) of these patients had a negative BMB obtained in the posterior iliac crest. Excluding these patients, the sensitivity and specificity of PET/CT in detecting bone involvement were 53% and 88%, respectively (Table 1). With respect to the spleen, 29% (157/548) of patients had evidence of splenic FL involvement on PET/CT, and of these, 69% (109/157) also had a positive BMB. The sensitivity and specificity of spleen involvement on PET/CT in predicting bone involvement on BMB were 55% and 86%, respectively (Table 2). We recorded SUV data at L3 in the 439 patients who had either a diffuse pattern of bone involvement on PET/CT, or a PET/CT read as negative. We analyzed the positive and negative predictive values (PPV and NPV) of SUVmax and SUVmean at several cut-off points to determine whether axial bone SUV is reliable at determining patients with a positive or negative BMB. The NPV for an SUVmax of less than 2.0 was 96% (n=25 patients classified as negative). For SUVmean, the best cut-off point was at less than 1.4, where NPV was 100% (n=15 patients classified as negative). There was no logical cut-off point for a significant PPV &gt; 95%. Conclusion: In newly diagnosed FL, the sensitivity and specificity of bone involvement on PET/CT are insufficient for PET/CT to routinely replace BMB. However, in patients where the need for BMB at staging is being debated, certain factors on PET/CT can help facilitate this decision. The detection of focal bone lesions, especially those that may be missed on posterior iliac crest BMB, can make BMB unnecessary. If both the spleen and bone appear involved on PET/CT, this confers a relatively high chance that BMB will be positive. If SUVmax at L3 is less than 2.0, or if SUVmean is less than 1.4, the BMB will likely be negative, with a NPV &gt; 95%. This decision-making algorithm is outlined in Figure 1 and may serve as a useful guideline for clinical trials and routine practice. Disclosures No relevant conflicts of interest to declare.

18F-Fluorodeoxyglucose Positron Emission Tomography Versus Bone Marrow Biopsy for the Evaluation of Bone Marrow Infiltration in Newly Diagnosed Lymphoma Patients: Real-World Clinical Management of Patients at the National Cancer Institute, México

Background: Defining the extent of disease is essential for determining the prognosis and management of patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL) as the presence of advanced disease, including involvement of an extralymphatic site, is associated with inferior outcomes (Cheson et al, 2014). 18F-fluorodeoxyglucose positron emission tomography (FDG PET-CT) has an excellent diagnostic performance for evaluation of bone marrow infiltration (BMI) in patients with lymphoma but it is expensive and not always available at low and middle-income health care facilities. Unilateral bone marrow biopsy (BMB) is a more accessible test and has been the standard to identify lymphomatous BMI. Unfortunately, it is an unpleasant procedure for the patient and can be limited by technical constraints. The aim of this single-center retrospective cohort study was to evaluate the diagnostic performance of FDG PET-CT for BMI in lymphoma patients, comparing it with BMB as the gold standard. Also, we evaluated for discordant results between both studies along with its effect on patient treatment. Methods: Newly diagnosed lymphoma patients evaluated at the National Cancer Institute between July 2017 and December 2018 were identified from our institutional lymphoma data base. Five hundred patient files were reviewed for bone marrow evaluation at diagnosis by BMB and FDG PET-CT as well as for other clinical characteristics. Only 355 patients had both FDG PET-CT and BMB performed and adequately reported, so the rest were excluded from the analysis. Fisher's exact and Pearson Chi-square tests were used to compare categorical variables. Comparisons of continuous variables were performed using Mann-Whitney U test. Setting BMB as the gold standard, diagnostic performance of FDG PET-CT for detecting BMI was evaluated. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratios (LR) and accuracy were calculated for the most common histological subtypes. Logistic regression model was used for univariate and multivariate analysis of predictors for positive BMB and positive FDG PET-CT for BMI. Results: The most common histologic type was diffuse large B-cell lymphoma (DLBCL) in 42.4% of cases, followed by HL in 20.4%, and follicular lymphoma (FL) in 11.2%. Median age was 53 years. B symptoms were present in 59.6% of cases and 71.4% debuted with advanced stage of disease (Ann Arbor III and IV). BMB was positive in 17% of all patients and 28% had a positive FDG PET-CT for BMI (Table 1). BMB was positive in 17.2% of HL, 12.3% of DLBCL, 29.8% of FL and 15.6% of other types of lymphoma patients. Overall, sensitivity of FDG PET-CT was 74.1%, specificity 80.1%, PPV 42.2%, NPV 94.1%, +LR 3.73, -LR 0.32 and accuracy 79.2%. The diagnostic performance of FDG PET-CT in patients with HL, DLBCL, FL and other types of lymphoma is shown in Table 2. As for predictors for BMB positivity, the presence of B symptoms, neutropenia and thrombocytopenia were independent factors for BMI with adjusted OR of 2.44, 95% CI (1.19, 4.99), 5.64, 95% CI (1.32, 24.08) and 4.12, 95% CI (1.66, 10.26), respectively. For positive FDG PET-CT, the presence of B symptoms, thrombocytopenia and advance stage remained significant with adjusted OR of 2.96, CI 95% (1.73, 5.05), 2.75, 95% CI (1.17, 6.48) and 19.22, 95% CI (5.90, 62.66), respectively. Seventy-four patients had discordant results between BMB and FDG PET-CT. The discrepancy in BMB and FDG PET-CT results did not have an effect on treatment. Conclusions: In addition to international clinical practice guidelines recommendations, in our center we recommend performing a BMB to those patients with HL and FDG PET-CT negative for BMI who present with cytopenias and B symptoms at the time of diagnosis. For patients with DLBCL our FDG PET-CT sensitivity was lower than expected, so we recommend a complementary BMB to all DLBCL patients with a positive FDG PET-CT for BMI (stage IV) that otherwise would be early stages (I and II) and would benefit from less aggressive therapy. In all other NHL including FL, we recommend performing a unilateral BMB with immunohistochemical analyses and flow cytometry, if available, for initial evaluation of BMI. Still in the absence of FDG PET-CT, a whole-body contrast-enhanced CT along with a unilateral posterior iliac crest BMB could adequately stage most types of lymphoma at low and middle-income health care facilities. Disclosures No relevant conflicts of interest to declare.

Contrast Enhanced Ultrasound of Splenic Lymphoma Involvement Case presentation

The study present a case of splenic lymphoma in a middle-aged male, showing up with abdominal pain, weight loss and recurrent oral candidosis. Blood test revealed remarkable leukocytosis, anemia and thrombocytopenia. Abdominal ultrasound showed marked splenomegaly with multiple hyperechogenic lesions. Contrast enhanced ultrasound (CEUS), performed on the lower pole of the spleen, showed a lesion lightly hypoenhanced in the arterial time, with progressive washout and marked hypoenhancement in the late phase, raising the suspicion of a malignant pathology. MRI results were consistent with a high suspicion of splenic malignancy, a possible lymphoid infiltration. The peripheral blood smear revealed lymphocytosis with villous lymphocytes, a variant form of hairy cell leukaemia. Iliac crest bone marrow biopsy confirmed the diagnosis. Our aim behind highlighting the topic is to underline the role of CEUS in identifying a malignant lesion, promptly leading us to further hematological investigation.

Fluorodeoxyglucose-positron emission tomography staging can replace bone marrow biopsy in Hodgkin's lymphoma. Results from Brazilian Hodgkin's Lymphoma Study Group

ObjectiveTo investigate, in a large prospective multicenter study, whether 2-[18F]-fluoro-2-deoxy-d-glucose-positron emission tomography is sufficiently accurate to identify clinically important bone marrow involvement by Hodgkin's lymphoma to replace routine bone marrow biopsy in a developing tropical country. MethodsPatients newly diagnosed with Hodgkin's lymphoma were recruited from six cancer centers in Brazil. All were staged by the results of positron emission tomography/computed tomography that were centrally reviewed and by iliac crest bone marrow biopsy. Patients were classified as having marrow disease if they had lymphoma identified by marrow biopsy histology or had focal 2-[18F]-fluoro-2-deoxy-d-glucose marrow uptake that resolved following chemotherapy. ResultsA total of 246 participants were recruited from six different centers and 62 (25.2%) were judged to have Hodgkin's lymphoma in the bone marrow. Positron emission tomography and biopsies were concordant in 206 patients (83%). Positron emission tomography correctly identified marrow disease in 59/62 patients (95.1%) and marrow biopsy in 25/62 patients (40.3%). In 22/62 (35.4%) patients, the two techniques were concordant in the diagnosis of marrow involvement. Of the forty discordant results, positron emission tomography found bone marrow involvement in 37 patients, upstaging 22 to stage IV and having an impact on therapeutic decision in nine cases given their reallocation from early to advanced stage. Three false negative positron emission tomography results were obtained with bone marrow biopsy giving positive findings. All three cases were classified as stage IV regardless of bone marrow findings implying no modification in the clinical management. The sensitivity, specificity and accuracy of positron emission tomography for detecting bone marrow disease were 95%, 100% and 98% and for bone marrow biopsy they were 40%, 100% and 84%, respectively. ConclusionWe conclude that positron emission tomography can replace marrow biopsy in Brazilian patients with Hodgkin's lymphoma without compromising clinical management.

POEMS syndrome: 2017 Update on diagnosis, risk stratification, and management.

POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. The diagnosis of POEMS syndrome is made with 3 of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy RISK-ADAPTED THERAPY: For those patients with a dominant sclerotic plasmacytoma, first-line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3-6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low-dose conventional therapy or high dose with stem cell transplantation. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. The benefit of anti-VEGF antibodies is conflicting. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

Repair of Torn Avascular Meniscal Cartilage Using Undifferentiated Autologous Mesenchymal Stem Cells: From In Vitro Optimization to a First-in-Human Study

Meniscal cartilage tears are common and predispose to osteoarthritis (OA). Most occur in the avascular portion of the meniscus where current repair techniques usually fail. We described previously the use of undifferentiated autologous mesenchymal stem cells (MSCs) seeded onto a collagen scaffold (MSC/collagen‐scaffold) to integrate meniscal tissues in vitro. Our objective was to translate this method into a cell therapy for patients with torn meniscus, with the long‐term goal of delaying or preventing the onset of OA. After in vitro optimization, we tested an ovine‐MSC/collagen‐scaffold in a sheep meniscal cartilage tear model with promising results after 13 weeks, although repair was not sustained over 6 months. We then conducted a single center, prospective, open‐label first‐in‐human safety study of patients with an avascular meniscal tear. Autologous MSCs were isolated from an iliac crest bone marrow biopsy, expanded and seeded into the collagen scaffold. The resulting human‐MSC/collagen‐scaffold implant was placed into the meniscal tear prior to repair with vertical mattress sutures and the patients were followed for 2 years. Five patients were treated and there was significant clinical improvement on repeated measures analysis. Three were asymptomatic at 24 months with no magnetic resonance imaging evidence of recurrent tear and clinical improvement in knee function scores. Two required subsequent meniscectomy due to retear or nonhealing of the meniscal tear at approximately 15 months after implantation. No other adverse events occurred. We conclude that undifferentiated MSCs could provide a safe way to augment avascular meniscal repair in some patients. Registration: EU Clinical Trials Register, 2010‐024162‐22. Stem Cells Translational Medicine 2017;6:1237–1248

POEMS syndrome: update on diagnosis, risk-stratification, and management.

POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3-6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. The benefit of anti-VEGF antibodies is conflicting. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

Role of Bone Marrow Biopsy in the Staging of Diffuse Large B-Cell Lymphoma in the PET/CT Era

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL) and bone marrow involvement by lymphoma is seen in up to one third of cases, as assessed by iliac crest bone marrow biopsy (BMB) at the time of diagnosis. Traditionally, BMB has been the gold standard test to detect bone marrow infiltration by lymphoma. 18-Fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT), has become standard in the initial staging of DLBCL. Prior studies have suggested that PET/CT staging may obviate the need for staging BMB in patients with Hodgkin lymphoma. However, because of limited evidence, this approach has not been adopted in patients with DLBCL. We investigated whether BMB adds useful information to PET/CT staging in patients with an initial diagnosis of DLBCL.Patients and MethodsPatients with a new diagnosis of DLBCL who underwent both staging PET/CT and BMB were retrospectively identified across three institutions: British Columbia Cancer Agency (n=149, 2011-2013), Aalborg University Hospital (n=179, 2007-2013), and Copenhagen University Hospital (n=202, 2009-2012). We reviewed the reports of PET/CT scans and BMBs from each academic institution performed at the time of diagnosis prior to treatment of DLBCL. Ann Arbor stage was determined including PET/CT with and without the contribution of BMB, and the proportion of stage IV cases by each method was calculated.Results530 patients were identified: median age 65 years (range 16-90), 294 (56%) male, 137 (26%) largest mass >10cm, 263 (50%) elevated LDH, 105 (20%) performance status >2, and 149 (28%) with more than one extranodal site. International Prognostic Index score was 0-1 in 159 (30%), 2 in 145 (27%), 3 in 119 (23%), and 4-5 in 107 (20%) patients. 520 (98%) received rituximab-containing chemotherapy, 130 (25%) radiotherapy, and 3 (<1%) consolidative autologous stem cell transplantation.A total of 181 (34%) patients had bone marrow involvement established by either PET/CT (n=146, 28%), BMB (n=87, 16%), or both (n=52, 10%). Focal skeletal lesions on PET/CT were unifocal (n=42), bifocal (n=15), multifocal/diffuse (n=89). 52 of the 146 patients (36%) with positive PET/CT had a positive BMB (39 DLBCL, 13 iNHL), while 35 of the 384 patients (9%) with negative PET/CT had a positive BMB (12 DLBCL, 23 iNHL). Table 1 shows the distribution of Ann Arbor staging as defined by PET/CT alone and with inclusion of BMB results. BMB upstaged 12/209 (6%) stage I/II patients to stage IV, including 3 patients with DLBCL and 9 patients with iNHL in the bone marrow.Focal skeletal lesions on PET/CT identified bone marrow involvement by lymphoma (DLBCL or iNHL) with sensitivity 60%, specificity 79%, positive predictive value 36%, and negative predictive value 91%. In a subgroup analysis excluding the 36 patients with iNHL in the bone marrow, focal skeletal lesions on PET/CT identified bone marrow involvement by DLBCL with sensitivity 78%, specificity 79%, positive predictive value 29%, and negative predictive value 97%.ConclusionsIn patients with DLBCL, staging PET/CT does not identify all cases with bone marrow involvement. BMB upstaged 6% of patients with stage I/II who had a PET/CT negative for any skeletal involvement. However, the majority had indolent histologies in the bone marrow, and only 1% were upstaged due to involvement of the bone marrow with DLBCL. Although PET/CT has a high negative predictive value for ruling out bone marrow involvement by high grade lymphoma, BMB remains a necessary component in the evaluation of patients with a new diagnosis of DLBCL mainly because of its ability to detect iNHL that was missed by PET/CT which may have implications in the post-treatment surveillance setting.Table 1Clinical staging by PET/CT alone and with inclusion of bone marrow biopsy results.Clinical StageStaging ModalityPatients upstaged to stage IV by bone marrow biopsyPET/CT alonePET/CT and bone marrow biopsyN (%)N (%)NI121 (23)114 (21)7 (2 DLBCL, 5 iNHL)II88 (17)83 (16)5 (1 DLBCL, 4 iNHL)III92 (17)77 (15)15 (5 DLBCL, 10 iNHL)IV229 (43)256 (48)Not applicable DisclosuresNo relevant conflicts of interest to declare.

The Clinical Utility of FDG PET-CT in Evaluation of Bone Marrow Involvement by Lymphoma.

PurposeBone marrow biopsy is a standard method for the evaluation of bone marrow infiltration by lymphoma; however, it is an invasive and painful procedure. Fluorodeoxyglucose positron emission tomography–computed tomography (FDG PET-CT) is a noninvasive imaging technique with the potential to detect bone marrow involvement by lymphoma.Materials and MethodsWe retrospectively reviewed medical records of lymphoma patients. All patients were examined by FDG PET-CT and iliac crest bone marrow biopsy for initial staging work-up.ResultsThe study population comprised 94 patients (median age, 60 years; 56 males) with Hodgkin’s lymphoma (n=8) or non-Hodgkin’s lymphoma (n=86). Maximum standardized uptake values on the iliac crest of patients with lymphoma infiltrated bone marrow were significantly higher than those of patients with intact bone marrow (2.2±1.2 g/mL vs. 1.3±0.4 g/mL; p=0.001). The calculated values for FDG PET-CT during evaluation of bone marrow involvement were as follows: sensitivity 50%, specificity 96%, positive predictive value 80%, negative predictive value 85%, and positive likelihood ratio (LR+) 11.7. The value of LR+ was 16.0 in patients with aggressive subtypes of non-Hodgkin’s lymphoma (NHL).ConclusionFDG PET-CT could not replace bone marrow biopsy due to the low sensitivity of FDG PET-CT for detection of bone marrow infiltration in lymphoma patients. Conversely, FDG PET-CT had high specificity and LR+; therefore, it could be a useful tool for image-guided biopsy for lymphoma staging, especially for aggressive subtypes of NHL. In addition, unilateral bone marrow biopsy could be substituted for bilateral bone marrow biopsy in lymphoma patients with increased FDG uptake on any iliac crest.

POEMS syndrome: 2014 Update on diagnosis, risk‐stratification, and management

POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal PCD, and at least one of the minor criteria. Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the PCD is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3-6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti-VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

POEMS syndrome: Update on diagnosis, risk‐stratification, and management

POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. The diagnosis of POEMS syndrome is made with 3 of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti-VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

Routine Bone Marrow Biopsy Adds Little Diagnostic Information in Patients with Newly Diagnosed Hodgkin Lymphoma Undergoing PET/CT Staging

Abstract 2627Accurate staging is essential for the optimal choice of first-line treatment in Hodgkin lymphoma (HL). Bone marrow biopsy (BMB) is still widely recommended as part of the routine staging workup. However, this procedure may not be necessary for patients staged with [18]F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). The aims of this study were; 1) to determine if bone marrow infiltration can be excluded based on staging PET/CT result, and 2) to investigate whether BMB still adds useful information in the PET/CT era.Patients with newly diagnosed HL undergoing pre-therapeutic staging at three Danish university centers were eligible for inclusion in this retrospective study, provided both PET/CT and BMB were performed at staging. Patients were identified in the Danish Lymphoma Registry (LYFO). BMB results were first obtained from LYFO and validated by a review of local pathology records. PET/CT records were retrieved and reviewed. The patterns of skeletal FDG uptake were categorized as follows: 1) uni-focal, 2) bi-focal, 3) multi-focal or 4) diffuse homogeneous FDG uptake. Clinical stage and risk assessment were performed with and without the account of BMB results, according to the Ann Arbor classification, the International Prognostic Score (IPS), and the German Hodgkin Study Group risk criteria for limited disease.A total of 392 HL patients (Aalborg = 59, Aarhus = 67, Rigshospitalet = 266) were included, of whom 372 patients had classical HL and 20 had nodular lymphocyte predominant HL. According to staging PET/CT, 203 patients had limited stage disease and 189 patients had advanced stage disease. The median age at diagnosis was 39 years (range 15–87) and the female:male ratio was 3/4. BMB was positive for HL in 24 patients (6%), all of whom had been independently assessed by PET/CT as stage III (n=5) or IV (n=19) disease. Thus, no patients with PET/CT stage I-II disease, irrespective of the presence of B-symptoms, had HL infiltration in the BMB (p<0.0001, Fisher’s exact test).Skeletal FDG accumulation was seen in 90 patients and characterized as uni-focal (n=15), bi-focal (n=8), multi-focal (n=45) or diffuse (n=22). Among the 68 patients with focal skeletal FDG accumulation, 20 patients had positive BMB as compared to none of the patients with diffuse FDG uptake. Sixty out of 68 patients with focal skeletal FDG uptake had PET/CT response assessment during therapy. All patients who responded to therapy showed resolution of the pathological skeletal FDG uptake. The presence of focal skeletal FDG accumulation identified HL infiltration in the BMB with a sensitivity and specificity of 83% and 87%, respectively. The positive and negative predictive values of focal skeletal FDG accumulation for HL infiltration in the BMB were 29% and 99%, respectively. With both positive BMB and focal skeletal FDG accumulation considered to reflect true bone/bone marrow involvement, the sensitivity for bone/bone marrow disease was 94% for PET/CT and 33% for BMB. In terms of prognostic information, BMB upstaged 1% of the patients (n=5) from stage III to stage IV, with a one-point change of the IPS as an additional consequence. However, none of the 392 patients were allocated to another risk group or treatment group on the basis of BMB results.At present there is no optimal gold standard for diagnosing bone/bone marrow disease in HL. Unilateral iliac crest BMB examines a very limited part of the total bone marrow volume, while PET/CT visualizes abnormal FDG accumulation throughout large parts of the skeletal system. Whether abnormal skeletal FDG uptake represents HL in all cases remains to be clarified. The most consistent finding of the present study was the absence of positive BMBs in PET/CT assessed stage I-II disease, where routine BMB seems to have no relevance. Furthermore, the omission of staging BMB would have had no impact on the treatment strategy in this cohort of 392 newly diagnosed HL patients. Disclosures:No relevant conflicts of interest to declare.

F-18 FDG PET for Evaluation of Bone Marrow Involvement in Non-Hodgkin Lymphoma

In recent years, the use of F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has become widespread for the staging of lymphoma. In non-Hodgkin lymphoma (NHL), the bone marrow (BM) involvement is a sign of extensive disease, and the iliac crest BM biopsy (BMB) is the established method for the detection of BM infiltration. However, iliac crest BMB is associated with a high rate of false-negative results. We assess the ability of FDG PET or PET/CT scan to ascertain the presence of BM involvement in aggressive and indolent NHL. The authors conducted a systematic MEDLINE search of articles published (last update, May 2010). Two reviewers independently assessed the methodological quality of each study. A meta-analysis of the reported sensitivity and specificity of each study was performed. Eight studies met the inclusion criteria. The studies had several design deficiencies. Pooled sensitivity and specificity for the detection of non-Hodgkin aggressive lymphoma were 0.74 (95% CI, 0.65-0.83) and 0.84 (95% CI, 0.80-0.89), respectively. Pooled sensitivity and specificity for the detection of non-Hodgkin indolent lymphoma were 0.46 (95% CI, 0.33-0.59) and 0.93 (95% CI, 0.88-0.98), respectively. The diagnostic accuracy of FDG PET or PET/CT scans was slightly higher but without significant statistical difference (P = 0.1507) in patients with non-Hodgkin aggressive lymphoma as compared with those with non-Hodgkin indolent lymphoma. The sensitivity to detect indolent lymphoma BM infiltration was low for FDG PET or PET/CT.

POEMS syndrome: 2011 update on diagnosis, risk‐stratification, and management

POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti-VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.