Need For Bone Marrow Biopsy Research Articles

Nuclear medicine techniques in paediatric body oncology: Present and future

Modern nuclear medicine techniques combining anatomical and functional imaging have transformed our ability to diagnose, stage and prognosticate in paediatric oncology. Progress in the use of positron emission tomography (PET) in children with cancer has been relatively restrained compared to adults due to radiation concerns, limited research, availability, and the practical challenges associated with imaging young children. However, there have been several developments in the last decade and the role of molecular imaging in paediatric oncology will only broaden with forthcoming novel tracers and molecular radiotherapy. This review article summarises the practical aspects of nuclear imaging in paediatric oncology, discusses the main imaging methods including PET and single photon emission computed tomography (SPECT), appraises the available established and novel tracers, and summarises the evidence behind molecular imaging in paediatric lymphoma, neuroblastoma, sarcomas, thyroid cancer and other tumours. 18F-FDG PET/CT is the established method for staging and response assessment after induction chemotherapy in paediatric Hodgkin lymphoma and has high sensitivity for the detection of bone marrow disease, reducing the need for bone marrow biopsy in some cases. 123I-mIBG planar with SPECT imaging remains the mainstay for neuroblastoma imaging, however there is a well-established role for 18F-FDG PET/CT in mIBG non-avid disease, and 18F-DOPA and 68Ga-DOTA PET tracers have shown promising results as upcoming alternatives. 18F-FDG PET/CT is advocated in the staging assessment of rhabdomyosarcoma and has been shown to have excellent sensitivity in the detection of bone metastases in osteosarcoma and Ewing sarcoma, although standard chest CT is still recommended for the detection of lung metastases. The role of PET in germ cell tumours, hepatoblastoma, Wilms tumour and Langerhans cell histiocytosis is complementary to standard techniques.

Reliability of Cell-Free DNA and Targeted NGS in Predicting Chromosomal Abnormalities of Patients With Myeloid Neoplasms

IntroductionCytogenetic analysis is important for stratifying patients with various neoplasms. We explored the use of targeted next generation sequencing (NGS) in detecting chromosomal structural abnormalities or copy number variations (CNVs) in patients with myeloid neoplasms.MethodsPlasma cell-free DNA (cfDNA) from 2821 myeloid or lymphoid neoplasm patients were collected. cfDNA was sequenced using a 275 gene panel. CNVkit software was used for analyzing and visualizing CNVs. Cytogenetic data from corresponding bone marrow (BM) samples was available on 89 myeloid samples.ResultsOf the 2821 samples, 1539 (54.5%) showed evidence of mutations consistent with the presence of neoplastic clones in circulation. Of these 1539 samples, 906 (59%) showed abnormalities associated with myeloid neoplasms and 633 (41%) with lymphoid neoplasms. Chromosomal structural abnormalities in cfDNA were detected in 146 (16%) myeloid samples and 76 (12%) lymphoid samples. Upon comparison of the myeloid samples with 89 BM patients, NGS testing was able to reliably detect chromosomal gain or loss, except for fusion abnormalities. When cytogenetic abnormalities were classified according to prognostic classes, there was a complete (100%) concordance between cfDNA NGS data and cytogenetic data.ConclusionsThis data shows that liquid biopsy using targeted NGS is reliable in detecting chromosomal structural abnormalities in myeloid neoplasms. In specific circumstances, targeted NGS may be reliable and efficient to provide adequate information without the need for BM biopsy considering broad mutation profiling can be obtained through adequate sequencing within the same test. Overall, this study supports the use of liquid biopsy for early diagnosis and monitoring of patients with myeloid neoplasms.

The Efficacy of PET-CT in Detecting Bone Marrow Involvement in Patients with Newly Diagnosed Lymphoma: A Retrospective Study

Background: Patients diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) undergo various investigations to determine disease stage. This includes Positron Emission Tomography with Computed Tomography (PET-CT) scan and bone marrow biopsy (BMB), which has historically been considered the gold standard for detecting involvement of the bone marrow (BM) by lymphoma. Recent studies have suggested that PET-CT scans can detect BM involvement in most patients with lymphoma. As such, there is growing interest into whether or not PET-CT scans may replace the need for BMB in staging patients with lymphoma.Objective: We conducted a retrospective chart review of patients newly diagnosed with lymphoma at our local cancer centre to evaluate the diagnostic performance of PET-CT scans in detecting BM involvement.Methods: Patients were eligible for inclusion if they were age 18 or older, had previously untreated HL or NHL diagnosed from January 2012 to August 2016, and underwent both BMB and PET-CT scan at time of staging. We collected the results of BM aspirate, flow cytometry, cytogenetics and biopsy. Patients were considered to have BM involvement if they had a positive BMB. PET-CT scans were retrospectively re-analyzed by two readers from the Division of Nuclear Medicine. Both were blinded to the patients' clinical information, including lymphoma diagnosis and BMB results. BM positivity by PET-CT scan was characterized as being either diffuse (relatively uniform increase in tracer uptake in the BM) or focal (localized increase in tracer uptake to one or more demarcated regions of BM). We performed sensitivity and specificity analyses of PET-CT scans.Results: The study included 110 patients: 102 patients with NHL and 8 with HL. The most common NHL subtype was diffuse large B-cell lymphoma (DLBCL) (n=40). For the entire cohort of patients with NHL, the sensitivity and specificity of PET-CT scan for diagnosing BM involvement were 78% (95% CI: 52-93%) and 86% (95% CI: 76-92%), respectively (Table 1). For patients with DLBCL, the sensitivity and specificity of PET-CT scan were 100% (95% CI: 52-100%) and 79% (95% CI: 63-91%), respectively. In this group, none of the patients with a negative PET-CT scan had a positive BMB. Five of the 7 patients with positive PET-CT scans but negative BMB had focal BM involvement on PET-CT scan.Conclusions: Although limited by small sample size, our data suggests that PET-CT scan is particularly adept at detecting BM involvement in patients with DLBCL and may detect focal BM involvement missed by BMB. The high sensitivity of PET-CT scan may lend support to clinicians foregoing BMB in patients with newly diagnosed lymphoma if imaging with PET-CT scan does not show involvement of the BM by lymphoma. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Liquid Biopsy As a Diagnostic Test for Myelodysplastic Syndrome and Other Acute and Chronic Myeloid Neoplasms

Cytopenia is common in cause for considering the diagnosis of myelodysplastic syndrome (MDS), especially in the elderly population. To diagnose the presence or absence of MDS, bone marrow biopsy is performed on most patients with cytopenia. Performing bone marrow biopsy is a painful procedure and can be associated with bleeding and other complications. Moreover, bone marrow morphology is unreliable for the diagnosis of MDS. Cytogenetics and molecular studies can provide conclusive evidence for the diagnosis of MDS. Liquid biopsy and testing for molecular abnormalities in cfDNA in peripheral blood plasma is significantly less invasive than traditional bone marrow testing. We evaluated the diagnostic value of liquid biopsy in determining the presence of MDS in 640 patients presented in community setting practice with cytopenia.Methodology: A total of 640 peripheral blood samples from patients with cytopenia were submitted for cfDNA testing. We used the TruSight Myeloid panel (Illumina, San Diego, CA) for detecting missense mutations and fragment length analysis (FLA) for detecting ITD in FLT3 and large indels in CALR . DNA was extracted from samples using the QIAamp DNA Mini Kit. This next generation sequencing (NGS) testing covers mutations in 54 myeloid-related genes. The average depth of sequencing was 10,000x.Results: Of the 640 tested patients, 310 (48.4%) showed mutations in one or more genes: 38% of these had mutations in one gene, 25.5% had mutations in two genes, and 36.5% had mutations in more than two genes. However, 14% of cases with mutation in one gene had two or more mutant subclones. The median age of all patients was 69 (range: 15-99) and 55% were males. Patients with mutations were significantly older (75 vs. 66 years old, P<0.0001) and more likely to be males (60% vs. 46% males, P=0.004). The most commonly mutated genes were TET2, DNMT3A, ASXL1, SRSF2, SF3B1, and RUNX1 detected in 31%, 28%, 25%, 17%, 15%, and 10% of the patients with mutations, respectively. Interestingly, 32 patients (10% of patients with any mutation) had mutations in TP53, 3% had mutations in FLT3, and 4% had mutations in NPM1 genes, indicating aggressive or acute disease. The average variant allele frequency (VAF) was <10% in 22% of cases with any mutation, between 10-20% in 19% of cases, between 20-30% in 16% of cases, and >40% in 43% of the cases. There was a significantly higher number of mutated genes in patients with average VAF >20% (P<0.0001). The combination of VAF, type of mutated gene, and number of mutated genes were considered in determining the significance of abnormal neoplastic clone and recommendation for management. The presence of mutations in NPM1, FLT3, TP53 as well as SF3B1 were considered diagnostic irrespective of the VAF. For patients with VAF at <20% in genes such as TET2, DNMT3A, and ASXL1 were not considered diagnostic for clinically significant myeloid neoplasm.Conclusions: Liquid biopsy for evaluating patients with pancytopenia can be used to evaluate the presence of abnormal hematopoietic neoplasm clones and the severity of the disease. Liquid biopsy can reduce the need for bone marrow biopsy in more than 50% of patients presenting with cytopenia. VAF, mutated gene types, and the combination of mutated genes should be considered for making management decisions based on liquid biopsy. [Display omitted] DisclosuresMa:NeoGenomics: Employment. De Dios:NeoGenomics: Employment. Funari:NeoGenomics: Employment. Jiang:NeoGenomics: Employment. Agersborg:NeoGenomics: Employment. Hummel:NeoGenomics: Employment. Blocker:NeoGenomics: Employment. Albitar:NeoGenomics: Employment.

M105 COMPLETION OF ULTRARUSH VENOM IMMUNOTHERAPY IN A PATIENT WITH ELEVATED BASELINE TRYPTASE

Baseline serum tryptase should be drawn in all patients with severe insect sting anaphylaxis, especially in those with hypotension and without urticaria. Elevated levels help identify patients with mastocytosis, using REMA scores to guide the need for bone marrow biopsy. Even without mastocytosis, elevated baseline serum tryptase is a risk factor for anaphylaxis to field stings and for reactions during desensitization itself.

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.

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.

Highlights of Abstracts on Lymphoma in the Annual Conference ISHBT Kochi 2018.

Lymphomas constitute a vast and heterogenous group of predominantly solid haematopoietic malignancies. Immunohistochemistry has always played a pivotal role in the diagnosis of lymphomas. Many new prognostic immunohistochemical markers have also come up and are being increasingly employed. The unraveling of molecular pathways in the study of lymphomas has opened the possibility of various new prognostic markers. Staging of lymphomas relies a lot on imaging. With the increasing use of positron emission tomography/computerized tomography scan for staging, many studies have shown that it has a high sensitivity for detecting bone marrow (BM) involvement especially in Hodgkin lymphoma thereby obviating the need for BM biopsy. Treatment option though heavily chemotherapy-regimen based, relapsed/refractory lymphomas pose a therapeutic challenge despite the advent of salvage chemotherapy, monoclonal antibodies and stem cell transplantation. Response rates to therapy also show a great deal of variation. The 59th Annual Conference of ISHBT "Haematocon" 2018 held at Kochi, Kerala had 27 abstracts which included 17 case series and 10 case reports presented under the lymphoma track. This brief review summarizes the salient findings as a reflection of on-going studies on lymphoma from various parts of our country.

PET/CT predicts bone marrow involvement in paediatric non-Hodgkin lymphoma and may preclude the need for bone marrow biopsy in selected patients.

To investigate the role of 18F-FDG PET/CT to detect bone marrow (BM) involvement in paediatric non-Hodgkin lymphoma (NHL). Pretreatment PET/CT scans from 93 consecutive paediatric patients with NHL were retrospectively reviewed. Patterns of BM FDG uptake and standardized uptake value of the fifth lumbar vertebra (SUVBM) were compared with bone marrow biopsy (BMB) for diagnosis of BM involvement. Of 93 patients, 41 were judged to have BM involvement. Thirty-nine were identified by PET/CT, versus 23 by BMB. Sensitivity and specificity were 95 % and 98 % for PET/CT and 56 % and 100 % for BMB, respectively. None of the patients with BM FDG uptake lower than liver had positive BMB. In 45 patients presenting homogeneously increased BM uptake, positive BMB was achieved in 93 % (14/15) of patientswith FDG uptake expanding to the distal portion of extremities, compared to 7 % (2/30) of those without. A multifocal pattern was observed in 25 patients and 18 had negative BMB. SUVBM differentiated BM involvement from benign BM activation with an area under the curve of 0.885 (p < 0.001). PET/CT had a high level of accuracy for detecting BM involvement in paediatric NHL. BMB might be omitted in selected patients. • PET/CT allows for accurate detection of bone marrow involvement. • Patterns of bone marrow FDG uptake are highly correlated with marrow disease. • Bone marrow biopsy could be omitted in selected paediatric patients.

Diagnostic Effectiveness of whole Body Diffusion- Weighted Magnetic Resonance Imaging in Focal and Diffuse Bone Marrow Involvement in Patients with Lymphoma

Objective:to compare diagnostic effectiveness of whole body diffusion-weighted imaging (DWI), other magnetic resonance imaging (MRI) pulse sequences and iliac wing trephine biopsy in the diagnosis of focal and diffuse bone marrow (BM) involvement in patients with lymphoma.Materials and methods.Prospective study included 130 patients with lymphoma who underwent whole-body MRI-DWI and iliac wing trephine biopsy before treatment (64 (49,2%) men, 66 (50,8%) women, middle age 43,3 ± 16,3 years, interval of 18–79 years). Hodgkin's lymphoma (HL) was at 57 (44%) patients, non-Hodgkin lymphomas (NHL) – at 73 (56%). Diagnostic effectiveness of T1- weighted images (T1-WI), STIR, DWI and FIESTA was analyzed. BM apparent diffusion coefficient (ADC) values were measured.Results.BM involvement was found in 42 patients, including 9 with HL and 33 with NHL. In HL, BM involvement was only focal. Diffuse involvement occurred more often (64%) in the NHL as compared to focal one. In focal involvement, all pulse sequences showed high diagnostic sensitivity (90–100%), BM biopsy sensitivity was 33% only. The proposed new criterion for the diagnosis of diffuse BM involvement in NHL – diffuse signal increase of the spine on DWI above renal parenchyma – has the highest sensitivity (90%) compared to T1-WI and STIR (67%) and FIESTA (71%) (p &lt; 0.05). In NHL, the ADC value ≤0.575 • 10−3 mm2/s discrimi nates cases of diffuse involvement and absence of BM involvement with a sensitivity of 86% and a specificity of 68% (p &lt; 0.0001). In HL, the diffuse BM signal increase on DWI is not indicative of involvement.Conclusion.All pulse sequences showed high effectiveness in the diagnosis of focal BM involvement in patients with lymphoma, iliac wing biopsy effectiveness was low. The proposed new DWI criterion for diagnosing diffuse BM involvement in NHL is the most sensitive one. A new algorithm based on whole body MRI-DWI for the diagnosis of BM involvement allows to reduce the need for BM biopsy without reducing the diagnostic effectiveness.

How We Treat Patients With Polycythemia Vera

How We Treat Patients With Polycythemia Vera

Using Next Generation Sequencing of Peripheral Blood cfDNA As a Clinical Test in Screening for Hematologic Neoplasms

Background: The recent advances in molecular techniques and the adaptation of next generation sequencing (NGS) in routine clinical testing increased our ability to use molecular approaches in the diagnosis and classification of most hematologic diseases. Bone marrow aspiration and biopsy remains necessary for initial confirmation of diagnosis of neoplastic processes in bone marrow, but significant literature suggests that screening or monitoring patients by testing peripheral bloodcfDNAmight be a reliable alternative to marrow biopsy and might reduce the need for a painful bone marrow procedure. Here we report the results of routine clinical testing ofcfDNAthat is ordered by practicing hematologist in the context of the presence or the suspicion of the presence of hematologic neoplasm.Methods: A total of 227 peripheral blood samples were submitted for screeningcfDNAfor mutations in a 54 gene focusedMyeloidpanel using NGS sequencing. DNA was extracted from plasma usingNucliSenSEasyMAGautomated platform and then assayed using theTruSightMyeloid Sequencing Panel (Illumina; San Diego, CA) with an average sequencing depth of 10,000X. The average age patients was 71 (18-96) years. The reason for submitting samples wasruling out MDS in 199 and ruling out AML or other hematologic neoplasms in 28 samples. Of these samples, 12 patients had a follow up testing of bone marrow aspiration sample.Results: Of the 227 tested samples (Figure 1), 126 (55%) showed no evidence of mutation in any of the tested genes. Based on our previous data (see ASH abstract by Albitar et al, 2016), this suggested that MDS can be ruled out in these patients and bone marrow biopsy could be avoided and not recommended. In contrast, 101 (45%) had mutations in one or more genes. Twenty-nine (~12.8%) contained a mutation in a single gene with variant allele frequency (VAF) <20% in one gene and were considered not diagnostic for the presence of clinically significant hematologic neoplasm, but follow up was recommended. Of these patients, one had a mutation in JAK2 at VAF of 6% and a second had a mutation in CALR gene at VAF of 7%, which most likely suggest the presence of early evolvingmyeloproliferativeneoplasms. Seventy-four patients (33%) had mutations in two or more genes or in one gene but with VAF≥20% and considered diagnostic for the presence of hematologic neoplasm and bone marrow morphologic evaluation was recommended. The most commonly mutated gene in these patents was TET2, detected in 30 samples, of which 8 also showed a second mutation in TET2, followed by ASXL1, and DNMT3A mutated in 24 and 26 samples, respectively. Samples containing a TET2 mutation were more likely to have a second mutation in TET2 or another gene, in contrast other genes that were frequently mutated did not show this trend (see Figure). TP53 gene was mutated in 16 samples, 7 of which as a single abnormality with VAF <20% therefore was reported as of unknown significance and recommended ruling out neoplasms in hematologic (lymphoid and myeloid) as well as solid tumors. SF3B1 gene mutations were detected in 19 samples and recommended ruling out refractory anemia with ringsideroblasts(RARS). Despite the small sampling (12 samples), follow up usingcfDNAtesting reliably recapitulated original bone marrow Biopsy’s findings. In one patient, additionalsubcloneswere detected incfDNAthat were not detected in the bone marrow aspirate.Conclusions:cfDNAtesting is reliable approach to screen for the presence of Hematologic neoplasm and potentially could avoid the need for bone marrow biopsy in almost half the patients expected to have MDS or otherhematopoeticneoplasms. Positive diagnosis can be confirmed in additional 45% of patients and only 12.8% of patients will be reported with questionable results. Except for those with TP53 mutations, the rest of the 12.8% cases can be classified as Clonal Hematopoiesis of Indeterminate Potential (CHIP). While bone marrow is still the gold standard, our real world experience shows liquid biopsies can be sensitive and non-invasive approach to rule out MDS or other hematological diseases. [Display omitted] DisclosuresFunari:NeoGenomics Laboratories: Employment. Ma:Neogenomics Laboratories: Employment. Thangavelu:Neogenomics Laboratories: Employment. De Dios:Neogenomics Laboratories: Employment. Albitar:Neogenomics Laboratories: Employment, Equity Ownership.

Staging Bone Marrow Biopsy Does Not Alter Management in Patients with Hodgkin Lymphoma and May Not be Necessary:a 10yr Single Institutional Retrospective Review of Patients with Hodgkin Lymphoma with Bone Marrow Involvement 2004-2013

Introduction: The incidence of bone marrow involvement (BMI) in patients diagnosed with Hodgkin Lymphoma (HL) is relatively low varying from 4-14% in different series occurring mainly in patients with advanced disease (stage III-IV). Ann Arbor staging system with Cotswolds modification in 1989 recommend staging bone marrow in patients with clinical stage III-IV and stage II patients with adverse risk features. It’s utility is now questionable and no longer recommended by many authors as it does not alter the way patients are managed. The advent of 18F-fluoro-2 –deoxy-D-glucose positive emission tomography (FDG-PET) scan use in the staging of patients has improved the prediction of possible bone marrow involvement obviating further the need for bone marrow biopsy. While BMI is said to be an independent prognostic factor in the survival of patient with HL, more studies have shown that BMI alone in patients with Stage IV disease does not influence survival or freedom from disease progression. Because staging bone marrow biopsy (BMB) use in HL varies from one institution to another, we performed a retrospective review in our institution in order to determine its incidence, risk factors and effect in the management of patients.Methods: We performed a retrospective search in John H Stroger, Jr. Hospital database of patients with HL seen from 2004 to 2013. 237 adult (18yr and above) patients were screened. 185 patients had BMB done as part of work up.Results: BMI was detected in 21%(38 of 185) of patients who had BMB as part of work up. M:F ratio was 2.5:1. Mean age was 39.8 +/- 11.5yrs. 51%(95 of 185) of patients who had BMB had advanced disease. 94%(33 out of 35) of patients with BMI had advanced disease prior to BMB. 3 patients with BMI were incompletely staged. Advanced disease was significantly more likely to be associated with BMI than early stage disease (OR 20.2 95% CI 4.6-87.6 p=0.0001). Less than 1%(2 out of 78) of patients with early stage disease were upstaged .The 2 patients that were upstaged had Stage IIB disease prior to BMB.38%(14 of 37) of patients with BMI were HIV positive which was higher compared to 12%(16 of 129) of patients without BMI that were HIV positive (OR 5.8 95% CI 2.4-14.0 p=0.0001). 5 of 38 patients with BMI had staging FDG-PET and all showed positivity in the skeletal system. Patients with BMI in our review were managed with 6-8cycles of chemotherapy (CT)-Adriamycin, Bleomycin, Vinblastine and Dacarbazine regimen (ABVD). 5 cases were relapsed disease. 4 of these patients with relapsed disease received Platinum/Gemcitabine regimen and one patient received Mechlorethamine, Vincristine, Procarbazine and Prednisone regimen (MOPP). Radiation Therapy (RT) was part of the management in 4 patients done for cord compression (2), bulky mediastinal disease (1) and for residual disease after chemotherapy (1).Conclusions: The incidence of BMI was high in our retrospective review compared to other series, however majority of involvement were in patients with advanced disease as in most series. Patients were rarely upstaged from early stage to advanced stage with bone marrow biopsy. This occurred in less than 1% in our retrospective review. Staging FDG-PET although done in few of our patients with BMI was predictive. Management of these patients was not significantly altered based on BMI. They were managed mainly with CT. RT needed in some of these patients was justified (cord compression, and bulky mediastinal disease). RT for residual disease is not a standard of care. Risks factors identified for BMI includes advanced disease and associated HIV infection. BMB does not alter patient management and its sole prognostic significance in patients with stage IV disease is controversial. It is therefore not necessary in the staging of newly diagnosed patients with HL. DisclosuresNo relevant conflicts of interest to declare.

Diminished reliability of tryptase as risk indicator of mastocytosis in older overweight subjects

Currently, measurement of serum tryptase level is the most commonly used test to estimate the need for bone marrow biopsy in patients suspected to have indolent systemic mastocytosis (ISM). Yet tryptase levels do not solely reflect the mast cell load and can be elevated by overweight, older age, and impaired renal function. The influence of these factors on urinary methylhistamine (MH) and methylimidazole acetic acid (MIMA) is still unknown. We investigated the impact of age, body mass index (BMI), and kidney function on the diagnostic accuracy of tryptase, MH, and MIMA to select the most optimal test indicating the necessity of a bone marrow biopsy in ISM-suspected patients. Retrospective data analysis of all adults in whom bone marrow investigations were performed because of high clinical suspicion and/or elevated tryptase, MH, or MIMA. 194 subjects were included. ISM was present in 112 and absent in 82 subjects (non-ISM). Tryptase was elevated by age and body weight in non-ISM subjects and by BMI in ISM subjects; however, these factors did not influence MH or MIMA. In the total study population, the diagnostic accuracy of tryptase, MH, and MIMA were comparable (area under the curve 0.80, 0.80, and 0.83). In subjects >50 years with a BMI >25 kg/m(2), the diagnostic accuracy of MIMA was higher compared with that of tryptase (area under the curve 0.93 vs 0.74; P = .011). In ISM-suspected patients >50 years with a BMI of >25 kg/m(2), MIMA has a greater value compared with tryptase in estimating the need for bone marrow biopsy.

FDG PET/CT for the detection of bone marrow involvement in diffuse large B-cell lymphoma: systematic review and meta-analysis

To systematically review and meta-analyse published data on the diagnostic performance of (18)F-FDG PET/CT in detecting bone marrow involvement in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). PubMed/MEDLINE and Embase were systematically searched for relevant studies. The methodological quality of each study was assessed. Sensitivities and specificities of FDG PET/CT in individual studies were calculated and meta-analysed with a random effects model. A summary receiver operating characteristic curve (sROC) was constructed with the Moses-Shapiro-Littenberg method. Weighted summary proportions of discrepancies between the FDG PET/CT and (blind) bone marrow biopsy (BMB) results among all patients were calculated. Seven studies, with a total of 654 patients with newly diagnosed DLBCL, were included. Overall, the quality of the included studies was moderate. The sensitivity and specificity of FDG PET/CT for detecting bone marrow involvement ranged from 70.8% to 95.8% and from 99.0% to 100%, with pooled estimates of 88.7% (95% confidence interval, CI, 82.5-93.3%) and 99.8% (95% CI 98.8-100%), respectively. The area under the sROC curve was 0.9983. The weighted summary proportion of FDG PET/CT-negative patients with positive BMB findings among all patients was 3.1% (95% CI 1.8-5.0%) and the weighted summary proportion of FDG PET/CT-positive patients with negative BMB findings among all patients was 12.5% (95% CI 8.4-17.3%). FDG PET/CT is accurate and complementary to BMB for detecting bone marrow involvement in patients with newly diagnosed DLBCL. A negative FDG PET/CT scan cannot rule out the presence of bone marrow involvement, but positive FDG PET/CT findings obviate the need for BMB for the detection of bone marrow involvement in these patients.

The diagnostic value of FDG–PET cannot be judged by iliac bone marrow biopsy: Author response

The Editor, We read with interest the letter entitled “The diagnostic value of FDG–PET cannot be judged by iliac bone marrow biopsy” by Cheng [1], which was written in response to our paper “Clinical utility of 18F FDG-PET/CT in the detection of bone marrow disease in Hodgkin's lymphoma” [2]. Prior to the introduction of 18-fludeoxyglucose–positron emission tomography (FDG–PET)/CT, bone marrow biopsy (BMB)—with all its limitations, which were mentioned in our paper and also highlighted by Cheng—was the gold standard for assigning bone marrow involvement (BMI) status to a lymphoma patient. Against this background, our study presented the first comparison between FDG uptake and BMB findings in Pakistani patients with Hodgkin’s lymphoma (HL). Our study highlighted, in conclusion, the complementary role of FDG–PET/CT with BMB in detecting BMI in HL, with BMB as the reference standard. We agree that BMB has a high false-negative rate and cannot accurately reflect the status of lymphoma in bone marrow. In our study, we found that of 122 patients who had negative BMBs, PET/CT was negative for BMI in 85, with no false-negatives noted; this indicates that routine BMB might be unnecessary when FDG–PET/CT is negative. The remaining 37 patients showed abnormal FDG uptake (diffuse, unifocal and multifocal). PET/CT was performed as a baseline scan followed by a mid-treatment or end-of-therapy scan to evaluate response to therapy, and the resolution of PET-positive foci during chemotherapy was considered as an additional indication of malignancy. Diffuse uptake was seen in 11 of the 37 patients; interestingly, 2 of these patients also had positive BMBs and were treated as having stage IV disease by oncologists. We agree that a diffuse homogeneous axial and appendicular skeleton often reflects benign enhancement owing to inflammation or cytokine release, and that would have accounted for resolved uptake in 9 of the 11 patients and remains non-specific in nature. However, considering the long-standing role of BMB in lymphoma staging, a lack of universal availability of FDG–PET/CT for all HL patients and occurrences such as when 2 of our 11 patients showed diffuse uptake with positive BMB, it is still too early to ignore BMB findings in lymphoma patients entirely. In ideal circumstances, PET/CT showing unifocal or multifocal sites of FDG uptake with negative BMBs should be subjected to biopsy and characterised histologically; however, this was beyond the scope of our study. We correlated unifocal and multifocal sites of uptake with corresponding CT images and were able to identify bony lesions in 17 of 37 (46%) patients with abnormal FDG uptake. However, routine CT has a low yield in detecting bone/bone marrow disease. Our study indicated a high negative predictive value (76.57%) of PET/CT in the evaluation of bone/bone marrow disease and further supported the emerging evidence that normal bone/bone marrow FDG uptake may eventually obviate the need for BMB [3-6]. The spectrum of abnormal FDG uptake from diffuse to unifocal to multifocal represents an increasing likelihood of disease involvement; however, further characterisation of patterns is needed with studies involving FDG-directed biopsies or correlative MRI [7]. We agree that the positive predictive value (PPV) of 29.72% in our study is low compared with other studies. The reason for this was that, given the retrospective nature of the disease, not all the focal lesions noted on PET/CT were biopsied; however, all patients underwent a follow-up PET/CT scan to check their response, and clinical follow-up ranging from 3 to 12 months was also taken into account. It was noted that on follow-up PET/CT, 34 of the 37 patients showed complete metabolic response with the resolution of both nodal and bony disease. These patients remained in complete remission on clinical follow-up, suggesting the true-positive nature of the lesions. 3 of the 37 patients showed progressive disease on follow-up PET/CT, of whom 1 died and the 2 others were switched to second-line chemotherapy. Because we used conventional BMB as the reference standard, this led to a low PPV. However, the follow-up PET/CT scan did show the true-positive nature of the bone lesions identified on PET/CT which were missed on BMB. We agree that BMB has long been regarded as the gold standard in diagnosing BMI, and its role needs to be re-evaluated with a biopsy of the affected sites seen on PET/CT to increase the diagnostic yield [4]. This raises the need to take PET/CT as the initial imaging tool in diagnosing bone marrow disease; however, further prospective studies are required to validate this.

Monitoring Residual Myeloma

Numerous methods exist for monitoring residual disease in multiple myeloma using peripheral blood, urine, and bone marrow (BM) techniques. This study was conducted in a cohort of 83 patients to compare residual disease detection using serum protein electrophoresis (SPE) and urine protein electrophoresis (UPE) with immunofixation with immunoperoxidase staining of BM tissue sections. Of the 83 patients, 49 had a positive SPE and/or UPE result and all had BM involvement shown by immunohistochemical analysis. The results for SPE and UPE were negative in 17 patients, and all 17 had a negative immunohistochemical BM result for a negative predictive value for SPE/UPE of 100%. In addition, SPE and UPE detected residual disease in 17 patients with negative BM biopsy studies. SPE and UPE can be used to screen patients for residual disease, and negative results for both can obviate the need for BM biopsy for the detection of residual disease by immunohistochemical analysis.

Modified International Prognostic Score (IPS) for Predicting the Need for Bone Marrow Biopsy (BMB) in Hodgkin's Lymphoma (HL).

Abstract 3661Poster Board III-597 IntroductionBMB is frequently performed during the staging process of patients (pts) with HL. Previous data suggested routine use of this procedure may be unnecessary. The Ann Arbor classification is currently used to detect pts requiring BMB, despite sensitivity (sen) of 100%, specificity (spec) is only 40%. We sought to determine whether a modified IPS [Hasenclever and Diehl (1998)] would yield greater spec while maintaining good sen. MethodsWe retrospectively reviewed charts of 1215 histologically proven HL pts from Jan 2000-Dec 2008 at Cleveland Clinic Taussig and Moll Cancer Centers. Of 1215 pts, 1089 had BMB (90%). 876 pts were included in our study. 213 were excluded due tor un-interpretable BMB or missing data. Each component of IPS was equally weighted such that one point is assigned to each positive variable [male sex, age ≥45, albumin (alb) <4 g/dL, hemoglobin (hem) <10.5 g/dL, stage IV, white blood cell (WBC) ≥15,000/mm3, lymphocyte (lymph) <600/mm3 and/or <8% of total WBC], Multivariable logistic regression was initially used to assess the association between bone marrow involvement (BMI) and each factor in the IPS. All 7 factors were significant (p<.001 for sex, age, albu, hem, stage and lymph; .07 for WBC); and therefore recursive partioning algorithm was used to identify a cutoff for determining BMI. Result88 pts (10%) had BMI, we used a modified IPS formally by calculating a score that uses “weights” based on the results of a multivariable model including all 7 factors and the relative magnitude of the associated regression coefficients (RC), [modified IPS= WBC+2x(sex+age+hem)+3x(stage+alb)+4xlymph].This model suggests lymphopenia has a stronger impact on the presence of BMI, while leukocytosis has the least impact. The percentage of BMI was 0.1,17,48, and 87 % for pts with a score of 0-8, 9-10, 11-12, and >12 respectively. Using a score of >8 as a rule for BMI, sensitivity was 99% and specificity was 87%. The prevalence of BMI by histology was 4% lymphocyte-rich, 5% nodular sclerosis, 20% mixed-cellularity and 21% lymphocyte-depleted, further analysis showed using modified IPS, sensitivity and specificity were similar across all types of histologies. ConclusionsUsing a modified IPS of > 8 for predicting BMI in HL doubled the spec associated with Ann Arbor classification. The implementation of modified IPS is a practical and reliable tool that will allow physicians to predict BMI in HL pts. Therefore eliminate unnecessary painful procedure in many pts.factorRCP valeSimplified “weight”WBC0.89.071Sex1.69<.0012Hem1.72<.0012Age1.76<.0012Stage2.66<.0013Alb2.67<.0013Lymph3.74<.0014 Disclosures:No relevant conflicts of interest to declare.

Value of International Prognostic Score (IPS) in predicting need for bone marrow biopsy (BMB) in Hodgkin's lymphoma (HL)

e19531 Background: BMB is frequently performed during the staging of patients (pts) with HL. Previous data suggested routine use of this procedure may be unnecessary. The Ann Arbor classification is currently used to detect pts requiring BMB. Despite sensitivity (sen) of 100%, specificity (spec) is only 40%. We sought to determine whether IPS [as developed by Hasenclever and Diehl (1998)] would yield greater spec while maintaining good sen. Methods: We retrospectively reviewed charts of 1215 histologically proven HL pts from Jan 2000-Dec 2008 at Cleveland Clinic Taussig and Fairview Moll Cancer Centers. Of 1215 pts, 1089 had BMB (90%). 876 pts were included in our study. 213 were excluded due to un-interpretable BMB or missing data. The IPS is calculated as the number of poor risk features present based on male sex, age ≥45, albumin (alb) &lt;4 g/dL, hemoglobin (hem) &lt;10.5 g/dL, stage IV, white blood cell (WBC) ≥15,000/mm3, lymphocyte (lymph) &lt;600/mm3 and/or &lt;8% of total WBC. Multivariable logistic regression was initially used to assess the association between BMI and each factor in the IPS. All 7 factors were significant (p&lt;.001 for sex, age, albu, hem, stage and lymph; .07 for WBC); and therefore recursive partioning algorithm was used to identify a cutoff for determining bone marrow involvement (BMI). Results: 88 pts (10%) had BMI. Using an IPS of &gt;3 to predict BMI, sen was 97% and spec 87%. BMI by histology was 4% lymphocyte-rich, 5% nodular sclerosis, 20% mixed-cellularity and 21% lymphocyte-depleted. Using the IPS&gt;3 cutoff sen and spec were similar across all types of histologies; ranging from 94–100% and 86–89% respectively. Conclusions: using an IPS of &gt;3 for predicting BMI in HL doubled the spec associated with Ann Arbor classification with little loss of sen. The implementation of IPS is a practical and reliable tool that will allow physicians to predict BMI in HL pts. It may, therefore eliminate painful BMB in many Pts. No significant financial relationships to disclose.

Plasma-based testing as a new paradigm for clinical testing in hematologic diseases

Recent advances in molecular biology have paved the way for the detection of minute quantities of cellular components with robust assays that are amenable for use in clinical laboratories. This review discusses the recently developed series of plasma-based assays that are changing the testing paradigm for hematologic diseases. These tests are based on the concept that a high turnover of neoplastic hematologic cells, relative to normal cells, enriches plasma with tumor-specific DNA, RNA and protein. Plasma-based testing promises to reduce the need for bone marrow biopsy, allow for more frequent and accurate monitoring of changes in bone marrow, allow the detection of more aggressive subclones of the malignant cells and provide a more quantitative means to measure the load of the malignant clone. We present data demonstrating that plasma, in some situations, allows even more sensitive detection than bone marrow cells. Moreover, the lessened impact of dilution by normal cells in plasma permits a distinction between homozygous and hemizygous abnormalities. Unlike solid tumors, currently available data suggest that in hematologic diseases, plasma is superior to cells in detecting molecular abnormalities.