NCCN Guidelines Insights: Chronic Myeloid Leukemia, Version 1.2017.

The NCCN Guidelines for Chronic Myeloid Leukemia (CML) provide recommendations for the management of chronic-phase and advanced-phase CML in adult patients. The median age of disease onset is 67 years. However, because CML occurs in all age groups, clinical care teams should be prepared to address issues relating to fertility and pregnancy with patients who are of reproductive age at the time of diagnosis. CML is relatively rare in children and there are no evidence-based recommendations for the management of CML in pediatric population. These NCCN Guidelines Insights discuss special considerations for the management of CML during pregnancy and for the management of CML in the pediatric population.

Fat Embolism Syndrome Secondary to Bone Marrow Necrosis in Patients with Hemoglobinopathies.

Bone marrow necrosis with subsequent embolization of the fat and necrotic tissues into the systemic circulation causing fat embolism syndrome and multiorgan failure is a rare complication of patients with hemoglobinopathies. The exact etiology of this condition is not known. Because it occurs more often in patients with compound heterozygous conditions than in sickle cell disease, some patients are unaware of their predisposition. The initial symptoms are nonspecific, such as back and/or abdominal pain, fever, and fatigue, which may rapidly progress to respiratory failure and severe neurologic compromise. Common laboratory tests reveal anemia without reticulocytosis, thrombocytopenia, leukoerythroblastic picture with immature white cells and nucleated red blood cells, increased lactate dehydrogenase, high ferritin, and, sometimes increased creatinine. The diagnosis can be delayed because of an apparent lack of awareness about bone marrow necrosis with fat embolism syndrome, its rarity, and its similarities with other conditions such as thrombotic thrombocytopenic purpura. Although a bone marrow biopsy is diagnostic, waiting for it delays definitive treatment, which appears to be essential for the recovery of end-organ damage, such as neurologic and pulmonary damage. In our experience, either multiple units of red blood cell transfusion or, preferably, red cell exchange initiated promptly, is lifesaving.

Out with the bad and in with the good; red cell exchange, white cell reduction, and platelet reduction.

Automated techniques for red cell [red blood cell (RBC)] exchange or depletion of malignant cells from the peripheral blood have allowed patients with life-threatening conditions to survive long enough to receive definitive treatment. Examples of such conditions include acute chest syndrome in sickle cell disease (SCD) or acute respiratory insufficiency due to leukostasis in acute leukemia. Conversely, other patients with SCD undergo RBC exchanges on a chronic basis to maintain a reasonable quality of life and prevent another stroke. In this review, we will discuss the techniques as well as indications for RBC exchange, leukocytapheresis, and thrombocytapheresis. To illustrate the uses of these therapeutic apheresis procedures, the authors included a summary of the most common diagnoses that comprise their use.

Best Practices in CD30 Immunohistochemistry Testing, Interpretation, and Reporting: An Expert Panel Consensus.

CONTEXT.­: Although CD30 testing is an established tool in the diagnostic workup of lymphomas, it is also emerging as a predictive biomarker that informs treatment. The current definition of CD30 positivity by immunohistochemistry is descriptive and based on reactivity in lymphomas that are defined by their universal strong expression of CD30, rather than any established threshold. Challenges include inconsistencies with preanalytic variables, tissue processing, pathologist readout, and with the pathologist and oncologist interpretation of reported results. OBJECTIVE.­: To develop and propose general best practice recommendations for reporting CD30 expression by immunohistochemistry in lymphoma biopsies to harmonize practices across institutions and facilitate assessment of its significance in clinical decision-making. DESIGN.­: Following literature review and group discussion, the panel of 14 academic hematopathologists and 2 clinical/academic hematologists/oncologists divided into 3 working groups. Each working group was tasked with assessing CD30 testing by immunohistochemistry, CD30 expression readout, or CD30 expression interpretation. RESULTS.­: Panel recommendations were reviewed and discussed. An online survey was conducted to confirm the consensus recommendations. CONCLUSIONS.­: CD30 immunohistochemistry is required for all patients in whom classic Hodgkin lymphoma and any lymphoma within the spectrum of peripheral T-cell lymphoma are differential diagnostic considerations. The panel reinforced and summarized that immunohistochemistry is the preferred methodology and any degree of CD30 expression should be reported. For diagnostic purposes, the interpretation of CD30 expression should follow published guidelines. To inform therapeutic decisions, report estimated percent positive expression in tumor cells (or total cells where applicable) and record descriptively if nontumor cells are positive.

Endoscopic ultrasound and endobronchial ultrasound-guided fine-needle aspiration of deep-seated lymphadenopathy: Analysis of 1338 cases.

BACKGROUND: We retrospectively studied 1338 samples of lymph nodes obtained by endoscopic and endobronchial ultrasound-guided fine needle aspiration biopsy (EUS and EBUS-FNAB) with an objective of characterizing the utility of this diagnostic modality in the assessment of deep-seated lymphadenopathy. The secondary aims were to establish the utility in the diagnosis of lymphoma and to determine the number of passes required to obtain adequate cellularity for flow cytometric analysis. MATERIALS AND METHODS: On-site assessment was performed by a cytopathologist using Diff-Quik (American Scientific Products, McGraw Park, IL) stain. In addition, Papanicolaou and immunohistochemical stains were performed and additional samples were sent for flow cytometric analyses (n = 145). The final cytologic diagnosis was correlated with surgical pathology diagnosis and/or clinical follow-up. In select cases, fluorescence in situ hybridization analysis with specific probes was performed on Diff-Quik smears. RESULTS: Both morphology as well as ancillary studies (flow cytometry or immunohistochemical stain and/or fluorescence in situ hybridization) show that EUS and EBUS-FNA are effective techniques to detect and stage intrathoracic and intra-abdominal tumors. Operating characteristics show that these are highly sensitive (89%) and specific (100%) techniques for the diagnosis of lymphoma. At least two passes provided an average of 5.66 million cells (range, 0.12-62.32 million) for lymphoma cases. CONCLUSIONS: EUS and EBUS-FNA are powerful modalities to stage malignancies and at least two passes can provide adequate cells for flow cytometric analysis. We also demonstrate that fluorescence in situ hybridization analysis can be performed on Diff-Quik-stained and mounted smears.

Solitary plaque on the scalp as a primary manifestation of Hodgkin lymphoma: a case report and review of the literature.

Cutaneous Hodgkin lymphoma is infrequent and typically occurs after extensive involvement of the lymph nodes. The condition decreased significantly in incidence in the past two decades, likely owing to the new treatment protocols composed of chemotherapy, radiotherapy and stem cell transplantation. Nevertheless, recognition of this uncommon but significant disease manifestation is important from a prognostic and therapeutic perspective. We are sharing a recent case of Hodgkin lymphoma where the primary presentation appeared as a solitary plaque on the left side of the occipital scalp, clinically suspected to represent a ruptured follicular cyst. The patient underwent excisional biopsy. Histological assessment revealed Hodgkin lymphoma affecting the skin. Radiological studies showed no regional lymphadenopathy. However, two enlarged lymph nodes were identified in the mediastinum and were positron emission tomography avid. The patient underwent systemic treatment without further histopathological examination of these two lymph nodes. Not being clear if these enlarged two lymph nodes were related to his cutaneous disease or not, we cannot be sure if the patient was afflicted either by primary cutaneous Hodgkin lymphoma or by secondary cutaneous involvement because of hematogenous spread. In either case, primary or secondary cutaneous Hodgkin disease is an extreme rarity. The literature is critically reviewed.

Systemic osteoprotegerin gene therapy restores tumor-induced bone loss in a therapeutic model of breast cancer bone metastasis.

Enhanced production of receptor activator of nuclear factor-kappaB ligand (RANKL) and its binding to RANK on the osteoclasts have been associated with osteolysis in breast cancer bone metastasis. Osteoprotegerin (OPG) is a decoy receptor that prevents RANKL-RANK interaction. This study determined the effects of sustained expression of OPG using a recombinant adeno-associated viral (rAAV) vector in mouse model of osteolytic breast cancer. Bone metastasis was established by intracardiac injection of the human breast cancer cell line MDA-MB-435. Following this, mice were administered a one-time intramuscular injection of rAAV encoding either OPG.Fc (OPG) or green fluorescent protein (GFP). Mice were killed 1 month later and the effects of therapy on tumor growth and bone remodeling were evaluated. Bioluminescence imaging showed significant reduction of tumor growth in bone of OPG.Fc-treated mice. Micro-computed tomography (microCT) analysis and histomorphometry of the tibia indicated significant protection of trabecular and cortical bones after OPG.Fc therapy. Despite the prevention of bone loss and tumor growth in bone, OPG.Fc therapy failed to provide long-term survival. OPG.Fc-treated mice developed more bone than age-matched normal mice, indicating a requirement for regulated transgene expression. Results of this study indicate the potential of rAAV-OPG therapy for reducing morbidity and mortality in breast cancer patients with osteolytic bone damage.

Three neglected numbers in the CBC: The RDW, MPV, and NRBC count.

The complete blood cell count (CBC) is one of the most frequently ordered laboratory tests, but some values included in the test may be overlooked. This brief review discusses 3 potentially underutilized components of the CBC: the red blood cell distribution width (RDW), the mean platelet volume (MPV), and the nucleated red blood cell (NRBC) count. These results have unique diagnostic applications and prognostic implications that can be incorporated into clinical practice. By understanding all components of the CBC, providers can learn more about the patient's condition.

Optimization of Laboratory Ordering Practices for Complete Blood Count With Differential.

Objectives: To investigate the utilization of CBC and CBC with differential (CBC w/diff) tests at University of Alabama at Birmingham Hospital, and to determine if a reduction in CBC w/diff tests could be achieved without negatively impacting patient care. Methods: The quantity of testing and distribution of repeated tests before, during, and after an educational intervention were compared. Results: CBC w/diff tests were ordered 10-fold more frequently than CBC tests. The trauma burn intensive care unit ordered the most CBC w/diff tests, with repeat tests done every 4 or 12 hours. The educational intervention reduced the number of CBC w/diff tests ordered and tests repeated every 12 hours. Conclusions: The educational intervention changed the ordering practices of CBC w/diff and CBC tests. This was sustained after the intervention and no negative effects on patient care were noted. Similar interventions may lead to optimization of ordering practices of other laboratory tests.

Transfusion-related acute lung injury: past, present, and future.

Noncardiogenic pulmonary edema caused by transfusion has been observed for almost 60 years. Today, we know this entity as transfusion-related acute lung injury (TRALI). TRALI is an uncommon but potentially fatal adverse reaction to transfusion of plasma-containing blood components. It is typified by dyspnea, cough, hypoxemia, and pulmonary edema within 6 hours of transfusion. Most commonly, it is caused by donor HLA antibodies that react with recipient antigens. It may also be caused by biologically active compounds accumulated during storage of blood products, which are capable of priming neutrophils. Without a "gold standard," the diagnosis of TRALI relies on a high index of suspicion and on excluding other types of transfusion reactions. Although current definitions of TRALI depend on symptoms, laboratory parameters can aid in the diagnosis and frequently identify the causative donor unit. As our understanding of TRALI deepens, risk reduction or prevention may become possible.

Pilot phase II study of metronomic chemotherapy in combination with bevacizumab in patients with advanced non-squamous non-small cell lung cancer.

INTRODUCTION: The goal of this study was to explore the efficacy and tolerability of metronomic chemotherapy, a novel anti-angiogenic treatment strategy, in combination with bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Subjects with newly diagnosed stage IV NSCLC were treated with 4-week cycles of paclitaxel 80mg/m2 and gemcitabine 300mg/m2 weekly for three weeks, plus bevacizumab 10mg/kg every two weeks. Radiologic assessments were performed every 8 weeks. The primary endpoint was progression free survival (PFS). An exploratory objective was to correlate plasma levels of angiogenic biomarkers with treatment response. RESULTS: Thirty-nine subjects were included in the intent to treat (ITT) analysis. The objective response rate (ORR) was 56%, the median PFS was 8.5 months, and median overall survival (OS) was 25.5 months. The PFS rate at 6, 12, and 24 months was 61%, 21%, and 11% respectively. The OS rate at 12 and 24 months was 74% and 53% respectively. Treatment was well tolerated, without significant myelosuppressive, gastrointestinal, or neurologic events. Subjects with less than median baseline values of angiopoietin-2 and IL-8 experienced significantly longer PFS. Longer OS was associated with subjects with less than the median baseline values for PLGF and angiopoietin-2. There were statistically significant differences in median values of several biomarkers between cycles 1 and 3 in subjects with objective responses. CONCLUSIONS: The combination of paclitaxel and gemcitabine, delivered in a metronomic schedule, in combination with bevacizumab, appears to be an effective and tolerable treatment strategy in patients with advanced NSCLC.

Severe hemolytic disease of the newborn in a group B African-American infant delivered by a group O mother.

Maternal-fetal ABO incompatibility is a common hematological problem affecting the newborn. In general, hemolysis is minimal and the clinical course is relatively benign, rarely causing the escalating levels of hyperbilirubinemia and significant anemia commonly associated with Rh hemolytic disease of the newborn (HDN). The incidence of HDN ranges from one in 150 births to 1:3000 births, depending on the degree of anemia and level of serum bilirubin. The etiology of ABO hemolytic disease of the newborn (ABO-HDN) is complex because anti-A and anti-B antibodies are composed mainly of IgM. Since only IgG antibodies cross the placenta, those pregnant women with high levels of IgG anti-A,B, anti-A, or anti-B with an ABO incompatible fetus will be the ones to give birth to an infant with ABO-HDN. We describe a case of a B/Rh positive term newborn born to an O/Rh negative African-American mother demonstrating aggressive hemolysis and a robust response of the bone marrow. This case was successfully managed with phototherapy and simple RBC transfusion without the need for exchange transfusion.

Is Low Positive JAK2 V617F Mutation Test Result Clinically Significant?: Multi-Institutional Study.

OBJECTIVES: Acquired somatic mutation Janus kinase 2 (JAK2) V617F is associated with various myeloproliferative neoplasms (MPN). Allele-specific real-time polymerase chain reaction has been widely adopted to detect mutation; however, the utility of low positive results is not well understood. The aim of this study is to investigate the clinical significance of low positivity of JAK2 V617F. MATERIALS AND METHODS: Retrospective analysis was performed for JAK2 V617F mutation tests performed using JAK2 MutaQuant kit (Ipsogen) in molecular laboratories at 2 major academic medical centers between 2010 and 2012. Cases with low positive JAK2 V617F, defined as 0.2% to 5% mutant allele, were documented. Chart review was performed for the clinical correlation. RESULTS: A total of 1697 JAK2 V617F tests was performed. Forty-five cases (2.65%) yielded a low JAK2 V617F positivity (average 1.45%), the majority of which (n=26, 62%) had <1%. Eight cases had a history of MPN. The remaining cases were related to reactive conditions without a clonal disease. Our data indicate that a low positivity of JAK2 V617F can be seen in MPN as well as reactive conditions. CONCLUSIONS: An interpretation of JAK2 V617F status should not be performed simply following some arbitrary cutoff. Any low positivity of JAK2 V617F should be reported and a correlation with clinical information is warranted for proper interpretation.

Trisomy 21-associated transient abnormal myelopoiesis involving the maternal space of the placenta: a case report and literature review.

We report a case of a male newborn with trisomy 21 and transient abnormal myelopoiesis at birth whose placenta showed extravasated fetal blasts in the perivillous (maternal) space. Concern for possible maternal spread of fetal malignancy prompted a Kleihauer-Betke test and flow cytometric analysis of the maternal peripheral blood on postpartum day 2. Notably, no evidence of the persistence of fetal cells in the maternal blood was identified, a finding that likely reflected successful maternal immunologic clearance of the fetal blasts and erythrocytes, and/or blast cellular fragility and limited viability. Ours is the first report, to our knowledge, documenting maternal peripheral-blood follow-up evaluation of this disorder in the English literature. We discuss our case in the context of a comprehensive review of fetoneonatal solid tumor and leukemic proliferative disorders with placental involvement and evidence of maternal metastasis.

CD138 (syndecan-1) expression in bone-forming tumors.

CD138 (syndecan-1), a cell surface proteoglycan, is sensitive and specific for plasmacytic differentiation in hematologic disorders. Expression of CD138 has been observed in a majority of epithelial neoplasms and, rarely, soft tissue tumors. However, its expression in bone tumors has not been evaluated. We studied CD138 expression in 27 osteosarcomas, 12 benign bone-forming tumors (osteoid osteoma and osteoblastoma), and 17 reactive bone cases. CD138 expression was also evaluated in a tissue microarray (TMA) constructed from 24 osteosarcomas, 24 chondrosarcomas, 12 giant cell tumors of bone, and 9 normal bone samples. Membranous expression of CD138 was found in an average of 31% of osteosarcoma cases (16/51; 14/27 [52%] in in-house cases; 2/24 [8%] in TMA cases) and in 83% of osteoid osteoma/osteoblastoma cases (10/12). Subsequent immunoglobulin κ and λ stains were negative in the CD138+ cases. All cases of chondrosarcoma, giant cell tumor of bone, and normal/reactive bone tested were nonreactive with anti-CD138. Our results show that CD138 reactivity for neoplastic cells in bone is not a definitive marker for plasmacytic origin, and caution is required to interpret CD138+ cells from a bony lesion for which a hematologic etiology has not been established.