Harold Ballard

KAPOSI'S SARCOMA IN HOMOSEXUAL MEN—A REPORT OF EIGHT CASES

The clinical findings in eight young homosexual men in New York with Kaposis sarcoma showed some unusual features. Unlike the form usually seen in North America and Europe, it affected younger men (4th decade rather than 7th decade); the skin lesions wee generalised rather than being predominantly in the lower limbs, and the disease was more aggressive (survival of less than 20 months rather 8-13 years). All eight had had a variety of sexually transmitted diseases. All those tested for cytomegalovirus antibodies and hepatitis B surface antigen of anti-hepatitis B antibody gave positive results. This unusual occurrence of Kaposis sarcoma in a population much exposed to sexually transmissible diseases suggests that such exposure may play a role in its pathogenesis.

Intravenous Iron Optimizes the Response to Recombinant Human Erythropoietin in Cancer Patients With Chemotherapy-Related Anemia: A Multicenter, Open-Label, Randomized Trial

PURPOSE Recombinant human erythropoietin (rHuEPO) is the standard of care for patients with chemotherapy-related anemia. Intravenous (IV) iron improves hemoglobin (Hb) response and decreases dosage requirements in patients with anemia of kidney disease, but its effect has not been studied in randomized trials in cancer patients. METHODS This prospective, multicenter, open-label, randomized trial enrolled 157 patients with chemotherapy-related anemia (Hb <or= 105 g/L, serum ferritin <or= 450 pmol/L or <or= 675 pmol/L with transferrin saturation <or= 19%) receiving subcutaneously rHuEPO 40000 U once weekly to: (1). no-iron; (2). oral iron 325 mg twice daily; (3) iron dextran repeated 100mg IV bolus; or (4) iron dextran total dose infusion (TDI). Hb and quality of life (QOL) were measured at baseline and throughout. RESULTS All groups showed Hb (P <.0001) increases from baseline. Mean Hb increases for both IV iron groups were greater (P <.02) than for no-iron and oral iron groups. The percentage of patients with hematopoietic responses was higher (P <.01) in both IV iron groups (each case 68%) compared with no-iron (25%) and oral iron (36%) groups. IV iron groups showed increases in energy, activity, and overall QOL from baseline, compared with a decrease in energy and activity for no-iron group and no change in activity or overall QOL for oral iron group. CONCLUSION rHuEPO increases Hb levels and improves QOL in patients with chemotherapy-related anemia. Magnitude of Hb increase and QOL improvement is significantly greater if IV iron is added.

Clinical Use of Intravenous Iron: Administration, Efficacy, and Safety

This section reviews the history, pharmacology, administration, efficacy, and toxicity of intravenous iron. Intravenous iron offers advantages over oral iron for the treatment of iron deficiency anemia across a wide range of disease states associated with absolute and functional iron deficiency. However, there remain concerns about the acute safety profiles of the available preparations and the potential for long-term toxicity with their repeated administration. Seven intravenous iron formulations are available. Confusion concerning the relative toxicities of the different formulations abounds. The similarities and differences are discussed. Iron repletion has been associated with adverse outcomes in infections. The relationship, if any, between intravenous iron administration and infections is reviewed. The potential advantages of total dose infusion (TDI), complete repletion in a single setting, are highlighted. A new paradigm for iron replacement therapy in iron deficiency anemia is presented.

Clinical update: intravenous iron for anaemia

For nearly half a century, parenteral iron has been considered dangerous and for use only in extreme situations and when oral iron was not tolerated. This proscription was based largely on poorly characterised and infrequent anaphylactoid reactions to the high-molecular-weight dextran preparation (Imferon) that for most of this time was the only product available. Moreover, when parenteral iron was necessary, the recommended approach was small intramuscular doses (≤100 mg), even after intravenous administration of the total iron defi cit as a single dose or as repetitive boluses was shown to be as safe and eff ective as the intramuscular route. This mindset persists despite the subsequent introduction of low-molecular-weight iron dextran and two iron salt preparations, ferric gluconate and iron saccharate (the latter is also known as iron sucrose), all of which are associated with fewer serious adverse events than the high-molecular-weight dextran. The introduction of recombinant erythropoietin for dialysis patients was associated with the development, in some individuals, of functional iron defi ciency that limited effi cacy. Intravenous iron, unlike oral iron, improves erythropoietic response in dialysis patients, and is now routinely used. The discovery of the iron regulatory peptide, hepcidin, has improved our understanding of the anaemia of chronic infl ammatory states, including cancer. Hepcidin is upregulated in these conditions, resulting in increased synthesis by the liver. Hepcidin inhibits iron transport across cell membranes, which decreases the accessibility of storage iron and gastrointestinal absorption of dietary iron, leading to an increased frequency of iron-restricted erythropoiesis, especially during therapy with recombinant erythropoietin. The most frequent laboratory fi ndings during the anaemia of chronic infl ammation are hypoferraemia and a low percent transferrin saturation, although these fi ndings are not always present. The increasing use of recombinant erythropoietin to treat anaemia in patients with chronic diseases has expanded the population of patients with functional iron defi ciency and increased interest in safe rational approaches to parenteral iron therapy. There is mounting evidence that anaemic patients with cancer undergoing chemotherapy and receiving recombinant erythropoietin respond better when parenteral iron is administered. This benefi t is independent of baseline iron variables, such as ferritin, low percentage transferrin saturation, and stainable marrow haemosiderin, leaving the clinician in need of laboratory variables to reliably detect iron-restricted erythropoiesis in patients with infl ammatory illnesses and to predict improvement of erythropoietic response to parenteral iron in the setting of infl ammatory illness. Two new laboratory measures look promising: percent hypochromic red blood cells and reticulocyte haemoglobin content. These tests are reliable and accurate correlates of functional iron defi ciency. Although these investigations are not yet widely available, their use will probably expand and guide identifi cation of functional iron defi ciency and rational intervention with parenteral iron. Currently, four parenteral iron preparations are available (table). No randomised trials have compared the safety and effi cacy of any of these agents. The largest retrospective review of dialysis experience suggests that most serious adverse events have been associated with the high-molecular-weight iron dextrans (Imferon, which is no longer available and the current preparation, Dexferrum) and are rare (<1:200 000) with the low-molecular-weight iron dextran or the two iron salts (fi gure). Adverse event rates might be somewhat higher in patients with infl ammatory diseases in which immune-mediated drug reactions may be observed more commonly than in dialysis patients. Some of the adverse clinical experience with parenteral iron is due to inappropriate supportive care. Myalgias, when they include chest and back discomfort, are mistakenly described as anaphylaxis, prompting Low–molecular–weight iron dextran Iron saccharate Ferric gluconate High–molecular–weight iron dextran

Intravenous iron : From anathema to standard of care

A growing body of literature supports the use of intravenous iron as a compliment to erythropoiesis stimulatory therapy and in a significant number of disease states where iron is necessary and oral iron is ineffective or not tolerated. The differences in efficacy, safety, and clinical nature of serious adverse events that occur with the various iron preparations are poorly understood. Misinterpretation of adverse events leads to underutilization of this important treatment modality. Understanding the history of the development and use of intravenous iron is crucial to appreciate its importance in the management of anemias of dialysis, cancer, and cancer chemotherapy and properly assess side effects and toxicity. The benefits seen with intravenous iron therapy are independent of the pretreatment levels of serum ferritin, iron, total iron binding capacity, and percent transferrin saturation. Intravenous iron has been shown to overcome hepcidin induced iron restricted erythropoiesis in iron‐replete patients. Available clinical and experimental data suggest that increased utilization of intravenous iron should be considered. Am. J. Hematol., 2008.

Villin, cytokeratin 7, and cytokeratin 20 expression in pulmonary adenocarcinoma with ultrastructural evidence of microvilli with rootlets.

Villin (V) is a glycoprotein of microvilli associated with rootlet formation. Most colonic adenocarcinomas have a V positive (+), cytokeratin (CK) 20 (+), CK7-negative (-) immunophenotype; most lung adenocarcinomas have a CK20(-), CK7(+) immunophenotype. The reports of villin immunoreactivity in lung adenocarcinoma range from 6% to 68% in studies using various fixations and varied anti-villin antibodies. Some lung adenocarcinomas have microvilli with rootlets leading to possible diagnostic confusion with metastatic colonic adenocarcinoma to lung. Nine primary lung adenocarcinomas with rootlets on ultrastructure (including four bronchioloalveolar carcinomas [BAC]), four metastatic lung adenocarcinomas with rootlets, nine metastatic colon adenocarcinomas to lung, and 10 randomly selected lung adenocarcinomas without rootlets (including five BAC), were immunostained with monoclonal antibodies to villin (1D2C3), CK7 (OV-TL12/30), and CK20 (Ks20.8) using a streptavidin peroxidase technique with heat-induced epitope retrieval. All primary lung adenocarcinomas with rootlets were CK7(+) CK20(-), and six of nine (67%) were V(+). Cytoplasmic villin positivity occurred in a diffuse--five of nine (56%), focal--two of nine (22%), or brush border pattern--two of nine (22%). Two of four metastatic lung adenocarcinomas with rootlets were V(+). One metastatic lung adenocarcinoma had a CK7(+), CK20(+), V(-) phenotype. All metastatic colonic adenocarcinomas were V(+), CK20(+), CK7(-), and 1 of 10 (10%) lung adenocarcinomas without rootlets was V(+), and all 10 were CK20(-), and CK7(+). In summary, villin positivity is more common in lung adenocarcinoma with rootlets (67%) than those without rootlets (10%). AU primary lung adenocarcinomas were CK7(+), CK20(-). The combination of villin, CK 7, and CK 20 is helpful in differentiating metastatic colon adenocarcinoma from lung adenocarcinoma with rootlets.

CD39 expression on T lymphocytes correlates with severity of disease in patients with chronic lymphocytic leukemia.

INTRODUCTION Chronic lymphocytic leukemia (CLL) is a B-cell disorder, but it is also associated with abnormalities in T-lymphocyte function. In this study we examine changes in T-lymphocyte CD39 and CD73 expression in patients with CLL. METHODS Blood samples were drawn from 34 patients with CLL and 31 controls. The cells were stained for CD3, CD4, CD8, CD19, CD39, and CD73 and analyzed by flow cytometry. RESULTS Overall, patients with CLL had a higher percentage of CD39(+) T lymphocytes than did controls. The percentage of cells expressing CD39 was higher in both CD4(+) cells and CD8(+) cells. Higher CD3/CD39 expression was associated with a later disease stage. No correlations between T-lymphocyte CD39 levels and CD38 or Zap-70 expression were observed. In contrast, the percentage of T lymphocytes and B lymphocytes that expressed CD73 was decreased in patients with CLL. Average B-lymphocyte CD73 expression was decreased in CLL because the majority of CLL clones were CD73. However a minority of CLL clones were CD73(+), and patients with CD73(+) clones tended to have earlier stage disease. CONCLUSION T-lymphocyte CD39 and CD73 expression may be useful prognostic markers in patients with CLL. Expression of CD73 on the malignant cell population in CLL may be a marker of better prognosis.

Approach to acute renal failure in biopsy proven myeloma cast nephropathy: is there still a role for plasmapheresis?

A 75-year-old Caucasian man with hypertension and severe, emphysema, presented to the Veterans Administration New York Harbor Health Care System Hospital outpatient clinic, for his bi-yearly physical in March 2003. The patient had a macrocytic anemia and a serum creatinine (Scr) level of 3.3mg per 100 ml (baseline Scr, 0.9 mg per 100 ml 1 month earlier). An outpatient nephrology consultation was initiated after a comprehensive negative gastrointestinal workup. Detailed history and physical examination were performed. He denied the following symptoms: headache, visual changes, hesitancy, frequency, oliguria, dysuria, nausea, vomiting, fever, chills, bone pain, and change in weight, appetite or bowel habits. He also denied the following: hematochezia, melena, fatigue, dyspnea, dizziness, or chest pain. His medications on presentation included lisinopril 20 mg day -1 and combination albuterol and atrovent inhaler. He denied occupational or chemical exposure, and use of herbal or over-the-counter medications. The patient quit smoking and drinking over 20 years ago. He had no history of diabetes mellitus, macroscopic hematuria, or tuberculosis. His family history was non-contributory. Physical examination revealed an alert, healthy-appearing older male with a blood pressure of 134/83 mm Hg (without orthostasis), pulse rate of 78 beats min -1 , weight of 89kg, and body mass index of 29 kg m -2 . There was no lymphadenopathy. Heart examination showed regular rate and rhythm, without murmurs, rubs, or gallops. Lungs were clear to percussion and auscultation. Abdomen had normal bowel sounds, was soft, non-tender, with no masses or hepatomegaly. There was dullness in Traubes space on deep inspiration. Extremities revealed no clubbing, cyanosis, rash, or edema. Neurological examination was essentially normal. Diagnostic studies were performed. Renal ultrasound showed 11.7 and 12.4 cm right and left kidney, respectively. Both kidneys demonstrated mildly increased, diffuse parenchymal echogenicity, consistent with mild medical renal disease, with no scarring or masses. There was no hydronephrosis. Renal veins were patent bilaterally. The bladder was not distended. Spleen was enlarged, measuring 12.6 cm. Results of the laboratory studies are detailed in Table 1. Urinary dipstick showed trace protein but sulfosalicyclic acid testing was not performed. Twenty-four-hour urine protein level was 3.1 g day -1 . Urine protein electrophoresis was unremarkable, but urine and serum immunofixation electrophoresis and serum protein electrophoresis showed a monoclonal band (IgAκ). His quantitative serum immunoglobulin A (IgA) level was 2330 mg per 100ml. Bone marrow biopsy revealed 90% plasma cells (Figure 1). Skeletal survey was negative. A diagnosis of multiple myeloma (MM) Durie-Salmon stage III was made.

CD39 activity correlates with stage and inhibits platelet reactivity in chronic lymphocytic leukemia

BackgroundChronic lymphocytic leukemia (CLL) is characterized by accumulation of mature appearing lymphocytes and is rarely complicated by thrombosis. One possible explanation for the paucity of thrombotic events in these patients may be the presence of the ecto-nucleotidase CD39/NTDPase-1 on the surface of the malignant cells in CLL. CD39 is the major promoter of platelet inhibition in vivo via its metabolism of ADP to AMP. We hypothesize that if CD39 is observed on CLL cells, then patients with CLL may be relatively protected against platelet aggregation and recruitment and that CD39 may have other effects on CLL, including modulation of the disease, via its metabolism of ATP.MethodsNormal and malignant lymphocytes were isolated from whole blood from patients with CLL and healthy volunteers. Enzyme activity was measured via radio-TLC assay and expression via FACS. Semi-quantititative RT-PCR for CD39 splice variants and platelet function tests were performed on several samples.ResultsFunctional assays demonstrated that ADPase and ATPase activities were much higher in CLL cells than in total lymphocytes from the normal population on a per cell basis (p-value < 0.00001). CD39 activity was elevated in stage 0–2 CLL compared to stage 3–4 (p < 0.01). FACS of lymphocytes demonstrated CD39 expression on > 90% of normal and malignant B-lymphocytes and ~8% of normal T-lymphocytes. RT-PCR showed increased full length CD39 and splice variant 1.5, but decreased variant 1.3 in CLL cells. Platelet function tests showed inhibition of platelet activation and recruitment to ADP by CLL cells.ConclusionCD39 is expressed and active on CLL cells. Enzyme activity is higher in earlier stages of CLL and decreased enzyme activity may be associated with worsening disease. These results suggest that CD39 may play a role in the pathogenesis of malignancy and protect CLL patients from thrombotic events.

The Renal ConsultApproach to acute renal failure in biopsy proven myeloma cast nephropathy: Is there still a role for plasmapheresis?

A 75-year-old Caucasian man with hypertension and severe, emphysema, presented to the Veterans Administration New York Harbor Health Care System Hospital outpatient clinic, for his bi-yearly physical in March 2003. The patient had a macrocytic anemia and a serum creatinine (Scr) level of 3.3mg per 100 ml (baseline Scr, 0.9 mg per 100 ml 1 month earlier). An outpatient nephrology consultation was initiated after a comprehensive negative gastrointestinal workup. Detailed history and physical examination were performed. He denied the following symptoms: headache, visual changes, hesitancy, frequency, oliguria, dysuria, nausea, vomiting, fever, chills, bone pain, and change in weight, appetite or bowel habits. He also denied the following: hematochezia, melena, fatigue, dyspnea, dizziness, or chest pain. His medications on presentation included lisinopril 20 mg day -1 and combination albuterol and atrovent inhaler. He denied occupational or chemical exposure, and use of herbal or over-the-counter medications. The patient quit smoking and drinking over 20 years ago. He had no history of diabetes mellitus, macroscopic hematuria, or tuberculosis. His family history was non-contributory. Physical examination revealed an alert, healthy-appearing older male with a blood pressure of 134/83 mm Hg (without orthostasis), pulse rate of 78 beats min -1 , weight of 89kg, and body mass index of 29 kg m -2 . There was no lymphadenopathy. Heart examination showed regular rate and rhythm, without murmurs, rubs, or gallops. Lungs were clear to percussion and auscultation. Abdomen had normal bowel sounds, was soft, non-tender, with no masses or hepatomegaly. There was dullness in Traubes space on deep inspiration. Extremities revealed no clubbing, cyanosis, rash, or edema. Neurological examination was essentially normal. Diagnostic studies were performed. Renal ultrasound showed 11.7 and 12.4 cm right and left kidney, respectively. Both kidneys demonstrated mildly increased, diffuse parenchymal echogenicity, consistent with mild medical renal disease, with no scarring or masses. There was no hydronephrosis. Renal veins were patent bilaterally. The bladder was not distended. Spleen was enlarged, measuring 12.6 cm. Results of the laboratory studies are detailed in Table 1. Urinary dipstick showed trace protein but sulfosalicyclic acid testing was not performed. Twenty-four-hour urine protein level was 3.1 g day -1 . Urine protein electrophoresis was unremarkable, but urine and serum immunofixation electrophoresis and serum protein electrophoresis showed a monoclonal band (IgAκ). His quantitative serum immunoglobulin A (IgA) level was 2330 mg per 100ml. Bone marrow biopsy revealed 90% plasma cells (Figure 1). Skeletal survey was negative. A diagnosis of multiple myeloma (MM) Durie-Salmon stage III was made.