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.

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.

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.

Advance care planning knowledge and documentation in a hospitalized cancer population.

To have a better understanding of our patients' knowledge of advance directive planning and execution, as well as communication with their oncologists regarding their wishes, we conducted a survey on our inpatient hematology-oncology services. A total of 68 unique hospitalized patients with a diagnosis of cancer completed surveys. Surveys were given to all oncology patients regardless of their reason for admission. Overall, 29% of the patients reported having had a discussion with their oncologist regarding their wishes if they became seriously ill or near death. Of those who did have this conversation, the majority said that they, rather than their physician, initiated it. Although the vast majority of patients (97%) knew what a living will was, only 54% had one in place. Twenty patients had a discussion with their oncologist, and 14 of them (70%) had a living will. This percentage was higher than in the group that did not have a conversation with their physician (48%; 23 of 48 patients), but the difference was not statistically significant. Most cancer patients admitted to an inpatient oncology unit either did not have or did not recall having a discussion with their oncologist regarding end-of-life issues. This study gives us a baseline of information in evaluating future interventions directed to improve the quality of patient-physician communication regarding end-of-life planning.

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.

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.

Long-term follow-up of liver transplantation for Budd-Chiari syndrome with antithrombotic therapy based on the etiology.

BACKGROUND: Because myeloproliferative disorders (MPDs) are a frequent cause of Budd-Chiari syndrome (BCS), treatment directed toward altering platelet production and function may be more rational and effective than anticoagulation after liver transplantation. METHODS: We reviewed data on 25 patients who received liver transplantation for BCS at our institution from 1987 to 2007. Posttransplant antithrombotic treatment was based on the cause of BCS: 17 patients with MPDs received hydroxyurea/aspirin; 5 received warfarin; and 3 (2 whose hypercoagulable disorder was corrected and 1 with sarcoidosis) received no therapy. RESULTS: Both graft survival (88% at 5 years) and patient survival (92% at 5 years) were superior in the BCS group compared with the 2609 patients who received liver transplants for other indications. Vascular complications included three instances of hepatic artery stenosis (NS compared with non-BCS liver recipients), one of portal vein thrombosis (nonsignificant [NS]), and one of portal vein stenosis (NS). All 25 patients underwent multiple liver biopsies with no bleeding complications. CONCLUSIONS: Using hydroxyurea and aspirin to treat patients with BCS caused by an MPD seems to be safe and effective and avoids the risks of anticoagulation with warfarin.

Pathogenesis and morbidity of autoantibody syndromes in Waldenstrom's macroglobulinemia.

A number of autoantibody syndromes have been identified that are mediated by monoclonal macroglobulins. Chronic cold agglutinin disease (CAD), mixed cryoglobulinemia (MC), and various polyneuropathies produce symptoms and signs such as cold sensitivity and sensorimotor neuropathies that bring the patients to attention ("the patients tell you"). Many of these patients would be classified as having monoclonal gammopathy of undetermined significance (MGUS) were it not for the consequences of antigen-antibody interaction. Other patients with autoantibody syndromes have overt Waldenström's macroglobulinemia (WM). These individuals present at an earlier stage than WM patients who do not have evident antibody activity. Thus the presence of autoreactive antibodies influences clinical presentation and natural history of the disorder. The frequency of monoclonal IgMs with functional antibody activity is unknown. The principal problem is detection. New methods have been described which may more precisely identify the antigens reacting with M-proteins. Some "autoimmune" disorders may represent cross-reactions to exogenous antigens. Elucidation of antigens reacting with monoclonal IgM proteins may provide important insights into the pathogenesis of WM.

Biopsy-proven mantle cell lymphoma in brain parenchyma.

Brain parenchymal involvement by mantle cell lymphoma is rare and confers a grim prognosis. More commonly, patients with central nervous system manifestations of mantle cell lymphoma have leptomeningeal involvement on radiographic studies with malignant cells found in the cerebrospinal fluid. Risk factors for central nervous system involvement include a high proliferation index, bone marrow involvement, and blastoid morphology. We present an unusual case of a biopsy-proven mantle cell lymphoma mass lesion in the brain parenchyma as the presentation of relapse 6 months after diagnosis.

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.

Comparison of serum immunofixation electrophoresis and free light chain assays in the detection of monoclonal gammopathies.

BACKGROUND: Diagnosis of monoclonal gammopathies (MGs) is determined by demonstration of a monoclonal immunoglobulin molecule or chain in serum and/or urine. Previous results on immunofixation electrophoresis (IFE) and quantitative free light chain (FLC) measurements have been conflicting. PATIENTS AND METHODS: The purpose of this study was to compare IFE with serum FLC assays in the detection of MG. Between November 2006 and November 2007, results on routinely ordered serum IFE specimens were compared with independently conducted FLC assays. RESULTS: Monoclonal gammopathies were identified in 144 specimens by IFE; 73 patients (50.7%) had a normal kappa/lambda ratio in the FLC assay. Also, 44.6% of samples with IgG and IgA M-proteins had a normal kappa/lambda ratio. Of 357 sera that showed no M-protein by IFE, 95.8% exhibited a normal kappa/lambda ratio. Out of 11 patients with light chain disease, 9 had abnormal kappa/lambda ratios. It is unclear why half of the patients with MG by IFE had normal kappa/lambda ratios. Lower M-components in these patients suggested that some had monoclonal gammopathy of undetermined significance. CONCLUSION: For screening purposes, serum IFE should be carried out in patients with suspected MG.

Subcutaneous beta2-microglobulin amyloid shoulder nodulesin a long-term hemodialysis patient.

beta2-Microglobulin accumulation with resultant tumor formation is a known albeit rare complication of long-term hemodialysis. Although these tumors may occur in various locations, subcutaneous shoulder nodules are very infrequent. We report a patient with end-stage kidney failure who had been on hemodialysis for 16 years and noted left shoulder nodules after initiation of hemodialysis; these nodules had slowly grown larger. Biopsy of one of these nodules revealed beta2-microglobulin amyloidosis by histopathology, Congo red stain, electron microscopy, and immunohistochemistry.

Growth inhibition of human multiple myeloma cells by an oncolytic adenovirus carrying the CD40 ligand transgene.

PURPOSE: The growth-inhibitory activity of recombinant CD40 ligand (CD40L) is well documented in human multiple myeloma (MM). We examined MM-targeted delivery of CD40L by a conditional replicative oncolytic adenovirus, AdEHCD40L. EXPERIMENTAL DESIGN: The growth-regulatory activity of AdEHCD40L was determined in vitro and in vivo. Differential analysis with AdEHCD40L and parental virus (AdEHNull)-infected cultures allowed the identification of cellular and molecular pathways modulated by the CD40L transgene. RESULTS: Conditional expression of viral E1A and CD40L transgene was shown in human MM lines RPMI 8226 [interleukin (IL)-6 independent] and Kas-6/1 (IL-6 dependent) under hypoxic conditions commonly found in MM in situ. AdEHCD40L inhibited MM cell growth more effectively than AdEHNull. This enhanced growth-inhibitory activity was abrogated by cotreatment with a CD40L antibody. Chemoresistant MM lines (MR20 and LR5) were similarly susceptible to AdEHCD40L treatment. AdEHCD40L induced apoptosis and S-phase cell cycle blockade while uniquely up-regulating the previously described proapoptotic elements tumor necrosis factor-related apoptosis-inducing ligand, Fas, and IL-8. Intratumoral injections of AdEHCD40L reduced the growth of severe combined immunodeficient/hu RPMI 8226 xenografts by >50% compared with 28% reduction by AdEHNull. Adenoviral hexon and CD40L were detected in AdEHCD40L-treated tumors at day 35 after infection primarily in necrotic areas, suggesting viral replicative activity. CONCLUSIONS: These findings show that CD40L acts in concert with viral oncolysis to produce MM growth inhibition through activation of cellular apoptosis. The direct growth-inhibitory activity of AdEHCD40L, together with the well-known immune-potentiating features of CD40L, may be clinically applicable for the experimental treatment of MM or plasma cell leukemia.