Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinaemia: A Task Force from the 8th International Workshop on Waldenström Macroglobulinaemia.

The diagnosis of Waldenström macroglobulinaemia (WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi-institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations that took place to address these issues. We provide recommendations for history-taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations, such as anaemia, hyperviscosity, neuropathy, Bing-Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM.

Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop.

This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia (WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M (IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials.

Heating up cold agglutinins.

In this issue of Blood, Berentsen and coworkers describe a high response rate which is durable in some patients who receive combination fludarabine and rituximab for chronic cold agglutinin disease (CAD). If confirmed, this is a significant advance in therapy for a frequently difficult clinical problem.

Antitumor activity of an oncolytic adenoviral-CD40 ligand (CD154) transgene construct in human breast cancer cells.

PURPOSE: CD40 ligand (CD40L, CD154) plays a central role in immunoregulation and also directly modulates epithelial cell growth and differentiation. We previously showed that the CD40 receptor is commonly expressed in primary breast cancer tissues. In this proof-of-principle study, we examined the breast cancer growth-regulatory activities of an oncolytic adenoviral construct carrying the CD40L transgene (AdEHCD40L). EXPERIMENTAL DESIGN: In vitro and in vivo evaluations were carried out on AdEHCD40L to validate selective viral replication and CD40L transgene activity in hypoxia inducing factor-1alpha and estrogen receptor-expressing human breast cancer cells. RESULTS: AdEHCD40L inhibited the in vitro growth of CD40+ human breast cancer lines (T-47D, MDA-MB-231, and BT-20) by up to 80% at a low multiplicity of infection of 1. Incorporation of the CD40L transgene reduced the effective dose needed to achieve 50% growth inhibition (ED50) by approximately 10-fold. In contrast, viral and transgene expression of AdEHCD40L, as well its cytotoxicity, was markedly attenuated in nonmalignant cells. Intratumoral injections with AdEHCD40L reduced preexisting MDA-MB-231 xenograft growth in severe combined immunodeficient mice by >99% and was significantly more effective (P<0.003) than parental virus AdEH (69%) or the recombinant CD40L protein (49%). This enhanced antitumor activity correlated with cell cycle blockade and increased apoptosis in AdEHCD40L-infected tumor cells. CONCLUSIONS: These novel findings, together with the previously known immune-activating features of CD40L, support the potential applicability of AdEHCD40L for experimental treatment of human breast cancer.

Diabetes mellitus and pernicious anemia: interrelated therapeutic triumphs discovered shortly after William Osler's death.

William Osler died on December 29, 1919, at the age of 70. Less than 1 year later, Frederick Grant Banting began a research project at the University of Toronto to find a treatment for diabetes mellitus. John James Rickard Macleod, director of physiology, gave him space, funding, and supplies. Charles Herbert Best, an undergraduate medical student, joined Banting. In 1921, Banting and Best isolated and purified insulin from pancreatic extracts of dogs. James Bertram Collip, a biochemist, helped in the purification process. The first American patient was treated with Toronto insulin in May 1922. Banting and Macleod were awarded the Nobel Prize in 1923 "for the discovery of insulin." George Richards Minot, a young hematologist in Boston, had an obsessive interest in the effect of diet on anemia. In October 1921, Minot developed weight loss and was diagnosed with severe diabetes mellitus. By January 1923, the pioneering diabetologist, Elliott Proctor Joslin, began to treat Minot with insulin. Minot's condition improved and he returned to work. In 1926, Minot and William Parry Murphy amazed the medical world when they eradicated anemia in 45 pernicious anemia patients by feeding them a half-pound of beef liver daily. Minot shared the 1934 Nobel Prize with Murphy and George Hoyt Whipple "for their discoveries concerning liver therapy in cases of anemia." Minot remained on insulin the rest of his life. Osler described the clinical findings and blood picture of pernicious anemia nearly a half century before Minot but his observations were largely ignored. Osler had an intriguing connection to Banting. Had he lived, Osler would have been ecstatic over these two monumental therapeutic breakthroughs.

Early stage IgD multiple myeloma in a 50-year-old man.

We present the case of a 50-year-old Hispanic man who presented to the emergency department with an acute right femur fracture after 3 months of intermittent discomfort in the right leg. He was eventually diagnosed with immunoglobulin D (IgD) multiple myeloma, a rare class of myeloma that is often of advanced stage at diagnosis. Fortunately, our patient was stage I at diagnosis and did not have hypercalcemia, anemia, or renal insufficiency, as is common with myeloma. This report describes a rare case of an uncommon condition and highlights the fortunate aspects of this patient's unfortunate diagnosis.

Waldenström's macroglobulinemia: hyperviscosity syndrome and cryoglobulinemia.

Hyperviscosity syndrome (HVS) is a common manifestation of Waldenström's macroglobulinemia (WM). Patients with HVS have skin and mucosal bleeding, retinopathy with visual disturbances, and a variety of neurologic disorders. HVS can be diagnosed from physical examination by identifying the characteristic retinal venous engorgement ("sausaging") on funduscopic inspection. HVS can be accurately monitored with an Ostwald tube and reversed by plasmapheresis. Cryoglobulins precipitate or gel at temperatures < 37 degrees C and dissolve on re-warming. They may be composed of single or multiple components. Most cryoglobulins are mixed monoclonal IgMpolyclonal IgG immune complexes and many are associated with hepatitis C viral infection. Monoclonal macroglobulin autoreactive antibodies are included among the "IgM-related" disorders that influence the clinical presentation and natural history of WM.

The reserves of life: William Osler versus Almroth Wright.

William Osler's address, The Reserves of Life, was given to students at St Mary's Hospital Medical School in London in 1907. In the talk Osler likened a medical career to a race through London, pointing out that to be successful one had to have sufficient 'reserves' or staying powers. He also commented on several of his favourite topics and included some of his most memorable aphorisms. Almroth Wright was the colourful and controversial physician at St Mary's Hospital who described opsonins and was a strong advocate of vaccine therapy for bacterial infections. Wright was often critical of clinicians and scoffed at their crude methods. During the address to the St Mary's students, Osler abruptly departed from his theme to criticize Wright ('that Celtic Siren') and defend clinicians, emphasizing that the art and science of medicine were inseparable. Despite their differences, Osler and Wright maintained a cordial relationship.

John M. T. Finney: distinguished surgeon and Oslerphile.

John Finney (1863-1942) was born near Natchez, Mississippi. After receiving his medical degree from Harvard, he interned at Massachusetts General Hospital and then went to Baltimore to become one of the first interns at the new Johns Hopkins Hospital. He met William Osler the day the hospital opened and became a lifelong admirer of "the Chief." Finney specialized in gastrointestinal surgery and was recognized for his expertise in the field. Osler recommended Finney to a physician colleague, writing, "You could not be in better hands…. Finney has been most successful and his judgment is so good." Finney served for 33 years under William Halsted at Hopkins. After Halsted's death, Finney was offered the chair of surgery at Johns Hopkins but declined. He was a founder and first president of the American College of Surgeons. He also served as president of the American Surgical Association and the Society of Clinical Surgery. Finney became chief surgical consultant for the Allied Expeditionary Forces in World War I. He was decorated by the United States, France, and Belgium. Finney was a master surgeon and a role model for generations of students and physicians.

Autoantibody activity in Waldenstrom's macroglobulinemia.

Some monoclonal proteins from patients with Waldenstrom's macroglobulinemia (WM) or immunoglobulin (Ig) M monoclonal gammopathy of undetermined significance possess antigen-binding activity directed to autogenous or foreign antigens. These monoclonal IgM autoantibodies include cold agglutinins, mixed cryoglobulins, and antineural components. Because of the antigenantibody interaction, patients with these autoimmune syndromes often present with hemolytic anemia, mixed cryoglobulinemia, or peripheral neuropathy, respectively, at an earlier stage than patients with typical WM who do not have evident antibody activity. The presence of monoclonal macroglobulin autoreactive antibodies thus influences clinical presentation and natural history. Monoclonal IgM antibodies display polyreactivity to antigens of microbial origin in addition to autogenous antigens and may arise through T-independent as well as T-dependent pathways. Waldenstrom proteins with antibody activity appear to provide a link between autoimmunity, infection, and lymphoproliferative disease. Study of the antigens reacting with monoclonal IgMs may provide further insight into the pathogenesis of WM.

Immunoglobulin M myeloma: evaluation of molecular features and cytokine expression.

Immunoglobulin (Ig) M myeloma is a distinct entity with features of multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM). The malignant cells in IgM myeloma have a distinctive chromosomal translocation that differentiates them from WM. These cells are postgerminal-center in origin with isotype-switch transcripts. They appear to be arrested at a point of maturation between that of WM and MM. Preliminary data indicate that a pattern of osteoclast-activating factor and osteoprotegerin expression similar to that observed in classic MM is present in IgM myeloma. Additional studies on patients with this rare tumor may provide further insight into the pathogenesis of bone disease in plasma cell dyscrasias.

Prospects for CD40-directed experimental therapy of human cancer.

CD40, a member of the tumor necrosis factor receptor (TNF-R) family, is a surface receptor best known for its capacity to initiate multifaceted activation signals in normal B cells and dendritic cells (DCs). CD40-related treatment approaches have been considered for the experimental therapy of human leukemias, lymphomas, and multiple myeloma, based on findings that CD40 binding by its natural ligand (CD40L), CD154, led to growth modulation of malignant B cells. Recent studies also exploited the selective expression of the CD40 receptor on human epithelial and mesenchymal tumors but not on most normal, nonproliferating epithelial tissues. Ligation of CD40 on human breast, ovarian, cervical, bladder, non small cell lung, and squamous epithelial carcinoma cells was found to produce a direct growth-inhibitory effect through cell cycle blockage and/or apoptotic induction with no overt side effects on their normal counterparts. CD154 treatment also heightened tumor rejection immune responses through DC activation, and by increasing tumor immunogenicity through up-regulation of costimulatory molecule expression and cytokine production of epithelial cancer cells. These immunopotentiating features can produce a "bystander effect" through which the CD40-negative tumor subset is eliminated by activated tumor-reactive cytotoxic T cells. However, the potential risk of systemic inflammation and autoimmune consequences remains a concern for systemic CD154-based experimental therapy. The promise of CD154 as a tumor therapeutic agent to directly modulate tumor cell growth, and indirectly activate antitumor immune response, may depend on selective and/or restricted CD154 expression within the tumor microenvironment. This may be achieved by inoculating cancer vaccines of autologous cancer cells that have been transduced ex vivo with CD154, as documented by recently clinical trials. This review summarizes recent findings on CD154 recombinant protein- and gene therapy-based tumor treatment approaches, and examines our understanding of the multifaceted molecular mechanisms of CD154-CD40 interactions.

Human monoclonal macroglobulins with antibody activity.

Assays for specific antigen-binding activity were performed on sera from 172 patients with monoclonal macroglobulinemia defined by immunofixation electrophoresis. The sera were collected between 1970 and 2002. Mean IgM level was 1,409 mg/dL with a range from 70 to 6,800. Cryoglobulins were identified in 15.3% (26/170 sera: 12 trace, five single component, and nine mixed IgM-IgG). Rheumatoid factor (RF) was detected in 19 of 151 (12.6%) samples with titers ranging from 1:80 to 1:327,680. Among the nine mixed IgM-IgG cryos, eight were RF-positive and six of six displayed positivity for hepatitis C virus. Cold agglutinins (CA) were present in 8.5% (10/117) of sera with anti-I titers between 1:512 and 1:65,536. IgM binding to a series of glycosaminoglycan oligosaccharides, glycolipids, and glycoprotein antigens was found in 75 samples (43%). IgM binding to antigens having known associations to polyneuropathies occurred in 20 patients (12%). Antinuclear antibody (ANA) was documented in 10.7% (18/169) of sera. Anti-DNA activity was absent in all samples tested. Sera from 71% of patients with monoclonal macroglobulinemia in this series exhibited binding to autoantigens. Some of these immune complexes resulted in clinically significant manifestations. Our results suggest that many monoclonal immunoglobulins may be functional antibodies rather than "paraproteins." Characterization of antigen-binding activities may provide insight into the pathogenesis of monoclonal gammopathies.

Hematologic aspects of liver transplantation for Budd-Chiari syndrome with special reference to myeloproliferative disorders.

BACKGROUND: Patients who undergo orthotopic liver transplantation (OLT) for Budd-Chiari syndrome (BCS) traditionally have been anticoagulated with warfarin postoperatively. Because a significant proportion of BCS patients are found to have an underlying myeloproliferative disorder (MPD), antiplatelet therapy may be a more rational treatment strategy for this subgroup. METHODS: All patients who underwent OLT for the diagnosis of BCS at our institution through March 2000 were included in this analysis. Posttransplant therapy consisted of hydroxyurea and aspirin for those with MPDs. Standard anticoagulation or no antithrombotic treatment was given to BCS patients with other causes. Major posttransplantation complications (thrombosis and bleeding) and mortality were determined. RESULTS: Seventeen patients underwent OLT for BCS at our institution. The mean follow-up was 68.4 months. Two of seventeen patients died; one patient died of recurrent thrombosis (124 months after OLT) and the other patient died of acute hepatitis B (7 months after OLT). Twelve patients (71%) had evidence of a MPD. Two of the MPD patients were treated with warfarin before the initiation of hydroxyurea and aspirin therapy. The remaining 10 MPD patients were placed on only hydroxyurea and aspirin after OLT. Anagrelide was used in place of hydroxyurea in two patients because of cytopenias caused by the latter agent. The mean follow-up of this group of 10 patients was 59.9 months. Only one patient experienced recurrent thrombosis, which occurred more than 10 years after the original transplant. There were no major bleeding complications and posttransplant liver biopsies were well tolerated. CONCLUSIONS: Antiplatelet therapy that consists of hydroxyurea and aspirin is a safe and effective alternative to anticoagulation to prevent recurrent thrombosis in MPD patients with BCS after liver transplantation. For patients with a hypercoagulable state corrected by OLT, antithrombotic therapy probably is not required. For those patients with conditions not corrected by OLT or with idiopathic BCS, anticoagulation or other therapy to control the hypercoagulable state should be given.

Myeloma and macroglobulinemia: what are the criteria for diagnosis?

Monoclonal gammopathy of undetermined significance (MGUS) is much more common than either multiple myeloma or Waldenström's macroglobulinemia. Since individuals with MGUS do not need treatment but only monitoring, it is important to distinguish this group from those with progressive plasma cell disorders. Criteria for diagnosis of myeloma and macroglobulinemia and laboratory pitfalls related to meeting these criteria are discussed. The importance of using the serum protein electrophoretic pattern in determining the magnitude of the monoclonal immunoglobulin component and the need for accurate quantification and characterization of urine protein are emphasized. Uniform definitions and consensus on diagnostic standards are becoming increasingly necessary if more effective and less toxic therapeutic approaches for patients with myeloma and macroglobulinemia are to be applied in an optimal manner.

Role of plasmapheresis in Waldenström's macroglobulinemia.

Despite the absence of randomized trials, plasmapheresis has consistently demonstrated efficacy in treatment of Waldenström's macroglobulinemia (WM) patients with hyperviscosity syndrome (HVS). This procedure can promptly reverse most clinical manifestations of serum HVS. Early diagnosis is crucial and usually can be made from the funduscopic exam. Serial viscosity measurements can be monitored by the Ostwald tube method which is simple, reproducible, and for which there is substantial clinical correlation. The concept of a symptomatic threshold, whereby each WM patient has a distinct viscosity threshold for the development of HVS, seems valid. Maintaining serum viscosity below each patient's symptomatic threshold effectively prevents recurrent HVS. Plasmapheresis is sometimes necessary as an emergency procedure and is useful maintenance therapy in selected patients. Prophylactic plasmapheresis should be considered in patients at risk for HVS after rituximab therapy. Vigorous plasmapheresis in WM patients with syndromes because of autoreactive immunoglobulin M antibodies requires further study.

Results of an educational program to promote the use of pooled instead of single-donor platelet transfusions.

Transfusion of platelets is commonly indicated in the inpatient oncology setting. These platelets are obtained either through apheresis from a single donor or pooled from the whole blood of several donors. The amount of transfused platelets, infection risk, incidence of alloimmunization, and increases in posttransfusion platelet count are similar for these two platelet products. Although single-donor platelets are preferred over pooled platelets in some instances, single-donor platelets are often given regularly, despite a higher cost and more limited donor supply. Oncology fellows at Baylor University Medical Center at Dallas initiated an education campaign regarding the indications for pooled and single-donor platelet transfusions. The quality improvement campaign included seminars led by oncology fellows for nursing personnel and resident housestaff on the two oncology floors, as well as electronic correspondence to attending physicians. The number of pooled and single-donor platelet transfusions on the two floors was recorded for the 3 months after the education campaign (July-September 2011) and compared with the corresponding data from the previous year. Over the 3-month study period after the education campaign, the average percentage of pooled platelets transfused increased to 34.1% from 13.1% for the prior year. Given this increase, the estimated cost benefit over the 3-month study period was $45,000.