Fatal EBV-related post-transplant lymphoproliferative disorder (LPD) after matched related donor nonmyeloablative peripheral blood progenitor cell transplant.

A 39-year-old male underwent a nonmyeloablative stem cell transplant (NMAPBPCT) from his HLA-matched sister for recurrent anaplastic large cell lymphoma in CR-2, receiving fludarabine, cyclophosphamide, and rabbit antithymocyte globulin for the preparative therapy. The patient was readmitted on day+33 for persistent culture-negative fevers. He rapidly developed marked elevations of alkaline phosphatase and bilirubin. Liver biopsy showed a periportal infiltrate of large immunoblastic appearing cells. The tumor cells did not stain for CD3/CD20/CD30 and alk protein, but did stain for CD79a/LCA and CD43. In situ hybridization for Epstein-Barr virus (EBV) RNA (EBER 1) was strongly positive in the periportal infiltrating lymphocytes. Fluorescence in situ hybridization (FISH) studies revealed female (XX) cells in the tumor cells and male (XY) in the surrounding hepatic parenchymal cells. The patient developed severe lactic acidosis, oliguric renal failure and expired on day+44. Both donor and patient had positive IgG serologies for EBV VCA and EBNA pretransplant. The donor also had a positive IgM titer for EBV VCA in the pretransplant specimen. The LPD may have been related to the intense immunosuppression of the preparative therapy and the presence of recent EBV infection in the donor.

Bone marrow cytogenetic abnormalities of aplastic anemia.

Cytogenetic abnormalities in association with aplastic anemia have been reported fairly infrequently. Clonal cytogenetic abnormalities at initial diagnosis are uncommon. A retrospective study was performed of the cytogenetic findings in patients with typical morphological and clinical features of severe aplastic anemia from a single institution for the years 1988 through 1998. A total of 30 cases of aplastic anemia, 16 men and 14 women, were identified. The median age was 60 with females being significantly older (67.5 years) in comparison to males (44 years). Bone marrow specimens failed to yield metaphases in 16 cases and normal karyotypes were detected in 11 cases. Cytogenetic abnormalities were detected in 3 cases. Clonal abnormalities, as defined, occurred in only 2 cases (6.7%). A review of the literature identified a total of 24 cases of aplastic anemia with abnormal cytogenetic findings. Overall, the most common chromosome abnormalities are trisomies of 6 and 8 and loss of chromosome 7. Trisomy 6 is more common at diagnosis while loss of chromosome 7 is more common after therapy.

Diagnosis and subclassification of primary and recurrent lymphoma. The usefulness and limitations of combined fine-needle aspiration cytomorphology and flow cytometry.

The primary diagnosis of non-Hodgkin lymphoma/leukemia by fine-needle aspiration (FNA) is still controversial and relatively underused. We evaluated our FNA experience with lymphomas using the revised European-American classification of lymphoid neoplasms to determine the reliability of FNA when combined with flow cytometry in the diagnosis of lymphoma, the types of diagnoses made, and the limitations of this technique. Slides and reports from all lymph node and extranodal FNAs performed during the period January 1, 1993, to December 31, 1998, with a diagnosis of lymphoma or benign lymphoid process were reviewed. There were 290 aspirates from 275 patients. These included 158 cases of lymphoma, of which 86 (54.4%) were primary and 72 (45.6%) were recurrent. There were 44 aspirates suggestive of lymphoma and 81 benign/reactive diagnoses. With diagnoses suggestive of lymphoma considered as positive for lymphoma, levels of diagnostic sensitivity and specificity were 95% and 85%, respectively. Specificity was 100% when only definitive diagnoses of lymphoma were considered. Clearly, FNA and immunophenotyping by flow cytometry are complementary and obviate a more invasive open biopsy for many patients with lymphadenopathy.

The cytomorphologic features of sclerosing mucoepidermoid carcinoma of the thyroid gland with eosinophilia.

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a recently described carcinoma of the thyroid gland associated with Hashimoto's thyroiditis and considered to have a relatively indolent clinical course. We describe two patients with SMECE and its aspiration and exfoliative cytologic features. Patient 1 was a 39-year-old woman with a goiter for many years. Examination of the lobectomy specimen revealed SMECE associated with Hashimoto's disease; 4 months later a total thyroidectomy was performed, metastases were found in nine lymph nodes in the neck. Two years later, fine-needle aspiration biopsy (FNAB) of a paritracheal mass revealed recurrent tumor. After 2 more years, two pleural fluid samples contained metastatic carcinoma with eosinophils. Patient 2 was a 61-year-old man with thyromegaly and vocal cord paralysis. The FNAB revealed a poorly differentiated carcinoma. The subsequent thyroidectomy demonstrated SMECE. Two years later, an FNAB of a vertebral mass demonstrated metastatic mucoepidermoid carcinoma. In all specimens, malignant cells with definite glandular and squamoid differentiation were present in small cohesive aggregates; eosinophils associated with the tumor cells were present in all specimens.

Iodine in British foods and diets.

Levels of I were determined in selected foods and dietary supplements, and in samples of the British 'Total Diet'. The average concentration of I in British milk collected in thirteen areas on four occasions during 1990 and 1991 was 150 micrograms/kg (range 40-310 micrograms/kg), compared with 230 micrograms/kg in 1977-79. No difference was found between skimmed and whole milk. Winter milk contained 210 micrograms/kg while summer milk contained 90 micrograms/kg. Regional differences were less pronounced than seasonal differences. Levels in fish and fish products were between 110 and 3280 micrograms/kg. Edible seaweed contained I levels of between 4300 and 2,660,000 micrograms/kg. Kelp-based dietary supplements contained I at levels that would result in a median intake of 1000 micrograms if the manufacturers' recommended maximum daily dose of the supplement was taken, while other I-containing supplements contained a median level of 104 micrograms in the manufacturers' maximum recommended daily dose. Intake of I, as estimated from the Total Diet Study, was 173 micrograms/d in 1985 (277 micrograms if samples with very high I contents were included) and 166 micrograms/d in 1991. These levels are above the UK reference nutrient intake of 140 micrograms/d for adults but well below the Joint Expert Committee on Food Additives provisional maximum tolerable intake of 1000 micrograms/d.

Occurrence, etiology, and clinical significance of extreme thrombocytosis: a study of 280 cases.

PURPOSE: To determine the etiology and to evaluate the clinical consequences of an extremely elevated platelet count. PATIENTS AND METHODS: A review of the medical records was performed on all patients encountered during a 5 1/2-year period who had at least one platelet count of 1,000 x 10(9)/L or greater. RESULTS: Of the total of 280 patients with extreme thrombocytosis (EXT), 231 (82%) had reactive thrombocytosis (RT), 38 (14%) had a myeloproliferative disorder (MPD), and 11 (4%) had cases of uncertain etiology. RT was more common than MPD in all age groups except those in the eighth decade and older. Symptoms of bleeding and/or vaso-occlusive phenomena were noted in association with EXT in 21 (56%) of the MPD patients but in only 10 (4%) of the RT patients. Treatment to lower the platelet count and/or inhibit platelet function was employed in 36 MPD patients and 23 RT patients. Eight patients with MPD and 34 with RT are known to have died, but no patient in either group is known to have died of a thrombotic or bleeding event when the platelet count was greater than or equal to 1,000 x 10(9)/L. CONCLUSIONS: Platelet counts greater than or equal to 1,000 x 10(9)/L should not be considered rare events in the general, acute-care hospital population, and usually represent a reactive phenomenon.

An incidental finding of extreme self-limited thrombocytosis of unknown cause.

This report describes an 11-year-old male who presented to his pediatrician at the Bowman Gray School of Medicine in Winston-Salem, N.C., because of long standing enuresis. During evaluation and the following two-week period, this patient was found to have extreme thrombocytosis ranging from 2,175 x 10(9)/L to 3,700 x 10(9)/L. In the absence of any apparent reactive cause, a presumptive diagnosis of essential thrombocythemia was made. Although chemotherapy was considered, the patient was temporarily lost to follow-up before there was a final decision about therapy. One year later, this patient's platelet count had spontaneously decreased to normal (273 x 10(9)/L), and has remained normal during a follow-up period of seven years, although only sporadic platelet counts have been obtained. His most recent physical examination revealed no abnormalities. The case is presented as further evidence that extremely high platelet counts are not necessarily dangerous and do not all require therapy.

The frequency and significance of megakaryocytic emperipolesis in myeloproliferative and reactive states.

Sixty-three bone marrow (BM) biopsy paraffin sections from patients with platelet counts of 1000 x 10(9)/1 or greater were examined to determine the incidence of megakaryocytic emperipolesis for the various myeloproliferative disorders (MPDs) and for reactive thrombocytosis. Of those cases classified as specific MPDs, 77% of primary thrombocythemia (PT) specimens, 100% of the polycythemia vera (PV) specimens, a single idiopathic myelofibrosis (IMF) specimen, and 17% of the chronic granulocytic leukemia (CGL) specimens demonstrated emperipolesis within megakaryocytes. Two of three cases grouped as MPDs but not further classified also demonstrated emperipolesis. Of the cases of reactive thrombocytosis (RT), 75% showed the presence of emperipolesis. Our results indicate that, with the exception of CGL, emperipolesis can be found in the BM megakaryocytes of the great majority of patients who have extreme thrombocytosis. The underlying cause, whether myeloproliferative or reactive, does not apparently influence the incidence of the phenomenon.

Heparin content of washed red blood cells from the cardiopulmonary bypass circuit.

Reinfusion of red blood cells (RBC) from the extracorporeal circuit following cardiopulmonary bypass (CPB) reduces patient exposure to homologous blood. Because infusing unneutralized heparin might exacerbate postoperative bleeding, this study examines the heparin content of the washed packed RBC produced by a commonly used autotransfusion device. This RBC product was derived from the residual whole blood in the oxygenator circuit after CPB. A wash volume of 750 mL of normal saline produced heparin concentrations below 0.04 USP U/mL. A 500 mL wash volume yielded heparin concentrations ranging from 0.08 to 0.22 USP U/mL, and could be used if time did not permit an additional wash. RBCs produced by the usual complete wash cycle do not contain clinically significant amounts of heparin; thus, they would not require a supplemental protamine dose.

Immunoglobulin D benign monoclonal gammopathy. A case report.

The authors report a case, perhaps the first, of immunoglobulin D (IgD) benign monoclonal gammopathy. The patient, a 48-year-old black woman, initially had a 500 mg/dl IgD-lambda M-spike, hypercalcemia, and anemia. There was no bone pain, lytic bone lesions, or evidence of renal failure. The bone marrow showed 2.8% plasma cells with a diffuse (not nodular) IgD plasmacytosis and strong lambda predominance. Only trace amounts of free lambda light chains could be demonstrated by immunoelectrophoresis in serum and concentrated urine. The anemia responded quickly to iron therapy. Chemotherapy was not initiated. Over the 6+ years of follow-up, the patient has had no progression of clinical disease attributable to her IgD monoclonal gammopathy. The IgD M-spike has steadily decreased.

Bone marrow and peripheral blood findings in patients with extreme thrombocytosis. A report of 63 cases.

Sixty-three bone marrow (BM) and peripheral blood specimens from patients with platelet counts of 1000 x 10(9)/L or greater were examined in an attempt to determine if any BM or peripheral blood findings could be used reliably to distinguish primary thrombocythemia from other myeloproliferative disorders and extreme examples of reactive thrombocytosis. Our results indicated that the BM findings in primary thrombocythemia were quite similar to those in polycythemia vera and chronic granulocytic leukemia with associated extreme thrombocytosis. However, statistically significant differences between the BM findings in myeloproliferative disorders and extreme reactive thrombocytosis were found in the numbers of megakaryocytes, presence or absence of megakaryocyte clusters, stainable iron, cellularity, and reticulin content. We concluded that BM examination is a useful procedure as an aid in determining the cause of extreme thrombocytosis.

Food patterns in the British isles.

Food supply statistics can show the general dietary pattern in European countries. However, their energy content is 50% or more above physiological needs, and because the wastage of each food will be different within a country as well as between countries, comparisons between their nutrient content and a country's mortality may be unreliable. The types and amounts of food brought into the home are closer to what people eat, and this paper describes the main dietary changes which have occurred in Britain at this level since 1970. During a time when life expectancy increased and mortality from coronary heart disease fell, the main characteristics of the diet remained British, but it became more pre-packaged. Many recent changes were in the direction advocated by nutritionists, but, because of a decline in sugars and starches as well as in fat, the proportion of energy derived from fat remained at about 42%. Intakes of several other nutrients also declined, but the ratio of polyunsaturated to saturated fatty acids doubled to 0.37.

Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation.

Subclinical plasma coagulation during cardiopulmonary bypass has been associated with marked platelet and clotting factor consumption in monkeys. To better define subclinical coagulation in man, we measured plasma fibrinopeptide A concentrations before, during, and after cardiopulmonary bypass. Patients were assigned to one of three groups of heparin management: group 1 (n = 10)--initial heparin dose 300 IU/kg, with supplemental heparin if the activated coagulation time fell below 400 seconds; group 2 (n = 6)--initial heparin dose 250 IU/kg, with supplemental heparin if activated coagulation time was less than 400 seconds; and group 3 (n = 5)--initial heparin dose 350 to 400 IU/kg, with supplemental heparin if whole blood heparin concentration was less than or equal to 4.1 IU/ml. Activated coagulation time and heparin concentration were measured every 30 minutes during cardiopulmonary bypass, and fibrinopeptide A was measured at hypothermia, normothermia, and whenever activated coagulation time was less than 400 seconds. Quantitative and qualitative blood clotting competence was assessed after cardiopulmonary bypass, including mediastinal drainage for the first 24 hours. Fibrinopeptide A values were markedly elevated during cardiopulmonary bypass but were well below the levels present before and after cardiopulmonary bypass. Fibrinopeptide A correlated inversely with heparin concentration during cardiopulmonary bypass (r = -0.46, p = 0.03), but higher fibrinopeptide A levels during cardiopulmonary bypass did not correlate with post-cardiopulmonary bypass coagulopathy. Group 3 patients received the highest heparin doses (p less than 0.05) and had the greatest postoperative blood loss (p less than 0.05). Protamine dose and heparin concentration during cardiopulmonary bypass correlated best with postoperative mediastinal drainage. Our findings support the following conclusions: (1) compensated subclinical plasma coagulation activity occurs during cardiopulmonary bypass despite activated coagulation time greater than 400 seconds or heparin concentration greater than or equal to 4.1 IU/ml; (2) post-cardiopulmonary bypass mediastinal drainage correlates strongly with increased heparin concentration during cardiopulmonary bypass (p less than 0.05) and protamine dose (p less than 0.05); and (3) during cardiopulmonary bypass at both normothermia and hypothermia, activated coagulation times greater than 350 seconds result in acceptable fibrinopeptide A levels and post-cardiopulmonary bypass blood clotting.

DNA content and proliferative index in cutaneous squamous cell carcinoma and keratoacanthoma.

The histologic separation of keratoacanthomas (KA) and well-differentiated squamous cell carcinoma (WDSCC) using established criteria may present a diagnostic dilemma in the individual case. The authors questioned whether the DNA index (DI) and/or the proliferative index (PI), as shown by flow cytometry (FCM) might assist in this differential diagnosis. Thirty-six well-differentiated squamous cell lesions of skin were independently classified as either WDSCC or KA by a panel of three pathologists. Six poorly differentiated squamous cell carcinomas (PDSCC) also were included in this study. Sections from paraffin blocks were prepared by standard techniques and analyzed by FCM. Mean DI values were: KA 0.96%, WDSCC 0.99%, and PDSCC 0.88%. The differences in the mean DIs were not statistically significant. Mean PI values were as follows: KA 16.7%, WDSCC 14.8%, and PDSCC 20.2%. Differences were not statistically significant. The authors conclude that the FCM measurements of DI and PI do not help in separating KA and WDSCC of skin.

Plasma cell dyscrasias.

In this article we have discussed the usefulness and limitations of the bone marrow examination in the differential diagnosis of the plasma cell dyscrasias. Because of the overlapping clinical and morphologic features encountered with these disorders and problems due to random marrow sampling, the difficulties in making a correct bone marrow interpretation may be quite formidable. The applicability of immunohistochemistry has been discussed and the need for clinical correlation emphasized.

Trace nutrients. 5. Minerals and vitamins in the British household food supply.

1. The amounts of magnesium, copper, zinc, phosphorus, manganese, potassium, vitamin B6, vitamin B12, folate, pantothenic acid, biotin, vitamin E and dietary fibre in the British household diet were calculated by applying appropriate values from recent analytical studies to the amounts of foods recorded in the National Food Survey during 1986. 2. National average intakes were (mg/person per d): Mg 247, Cu 1.25, Zn 9.0, P 1249, Mn 3.43, K 2694, vitamin B6 1.73, vitamin B12 6.33 micrograms, folate 230 micrograms, pantothenic acid 6.07, biotin 35 micrograms, vitamin E 8.4. Regional and income-group differences were estimated, and found to be small. Additional contributions from alcoholic drinks and confectionery were also determined. 3. Dietary fibre was estimated both as unavailable carbohydrate and as non-starch polysaccharide. The national average intakes were 21.8 and 12.9 g/d respectively. 4. Intakes were compared with Canadian (Department of National Health and Welfare, 1983) and American (National Research Council, 1980) recommended dietary allowances (RDAs). With the exception of biotin, the Canadian RDAs were met by the household diet but the much higher American RDAs were only met for vitamin B12 and pantothenic acid.