Osteosarcomatosis

A review of the 690 cases of osteosarcoma in the radiographic file of the Armed Forces Institute of Pathology revealed 29 cases of "osteosarcomatosis" (multiple skeletal sites of osteosarcoma). Fifteen of these patients were 18 years old and under and manifested rapidly appearing, usually symmetric, sclerotic metaphyseal lesions. The remaining 14 patients were more than 18 years old and had fewer, asymmetric sclerotic lesions. In most patients (28 of 29), a radiographically dominant skeletal tumor was seen. Pulmonary metastases occurred in the majority of patients and were detected at the same time as the bone lesions. These 29 patients were studied with regard to demographic data and skeletal distribution and radiographic appearance of their lesions. As a result of the findings, a metastatic origin from a primary dominant osteosarcoma is favored over a multifocal origin as the basis for osteosarcomatosis. Osteosarcomatosis is more commonly encountered in the mature skeleton than has been previously recognized.     

CLINICO-EPIDEMIOLOGICAL ALGORITHM FOR PREDICTING SYSTEMIC ARTERIAL HYPERTENSION AT HIGH ALTITUDE THROUGH MATHEMATICAL MODELLING

A population based hybrid design combining element of cohort and cross-sectional approach was used to develop a simple clinical algorithm to predict individual probability of developing hypertension (systolic BP > 140 mm Hg and/or diastolic BP > 90 mmHg). 3615 soldiers initially normotensive at the time of induction into high altitude, were studied by systematic random sampling. Multiple logistic regression analysis showed a high significant association between hypertension and age, body mass index (BMI), tobacco smoking and alcohol consumption. Using the constant/coefficient values obtained from the logistic model and the receiver operating characteristics (ROC) curve analysis, the following predictive rule was developed – To the age in years, add (BMIx 3.86); also add 5.53 if he is a smoker; and add 19.81 if he consumes alcohol. If the total exceeds 142, the individual is at high risk of developing hypertension. This algorithm carries a sensitivity of 68.2% and specificity of 78.5%.KEY WORDS: Hypertension, High altitude     

Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura

High-dose intravenous gammaglobulin (IVIgG) was given to 12 children and adults with chronic idiopathic thrombocytopenic purpura (ITP) to avoid splenectomy or because they either failed to respond to or required maintenance with high doses of steroids and/or immunosuppressives. The average platelet count increase to initial therapy was 239,500/microliters (range 23,000-790,000). A concomitant IgG Fc receptor blockade, measured by IgG-sensitized 51Cr-labeled autologous erythrocytes, was seen in 11 of 11 patients tested, both splenectomized and not splenectomized, lasting 3-4 wk. Six or more months after treatment, 2 children are in remission, 2 children and 2 adults are stable requiring no therapy with platelet counts of approximately 50,000 and 30,000, respectively, 3 children require maintenance IVIgG therapy at 2-10-wk intervals, and 1 child and 2 adults have become refractory to further IVIgG. Splenectomy was not performed in 4 children. Two adults were able to discontinue daily prednisone. The 3 patients who became unresponsive to Swiss Red Cross gamma-globulin (IgSRK) therapy did so in conjunction with a markedly elevated platelet-associated IgG and IgM. Serum IgM increased an average of 103 mg/dl after the IVIgG infusions. No significant side effects were seen.     

T-cell death by apoptosis in vertically human immunodeficiency virus- infected children coincides with expansion of CD8+/interleukin-2 receptor-/HLA-DR+ T cells: sign of a possible role for herpes viruses as cofactors?

One mechanism proposed to play a role in T-cell depletion in human immunodeficiency virus (HIV) infection is apoptosis (activation-induced cell death). We assessed whether apoptosis is related to activation of T cells in vivo and its possible triggers. DNA was extracted from peripheral blood mononuclear cells (PBMC) taken from 16 vertically HIV- infected children and 9 HIV-negative children born to HIV-positive mothers (controls) and tested by agarose gel electrophoresis for the presence of DNA fragments specific for apoptosis. Signs of apoptosis were found on in vitro culture of PBMC from 12 of 16 HIV-infected children, but not in PBMC from the nine controls. Eleven of the 12 HIV- infected children with apoptosis showed an elevated (> 15%) proportion of CD3+/HLA-DR+ cells. This was due to an increased proportion of CD8+/HLA-DR+ cells, as shown in 7 of 7 further tested patients. In none of the probands an increased (> 5%) proportion of IL-2 receptor expressing CD3+ cells was found. T cells undergoing apoptosis were preferentially of the CD8+ phenotype. Expansion of circulating CD8+/interleukin-2 receptor (IL-2R)-/HLA-DR+ T cells is known to occur during active infection with herpes viruses. To investigate the possible role of herpes viral coinfections for apoptosis in HIV infection, we focused on Epstein-Barr virus (EBV) as an example for a herpes virus usually acquired during childhood. In 10 of 12 patients with apoptosis, we found increased levels of EBV genome in PBMC and/or tissues, indicating active EBV replication. By contrast, no increased burden of EBV was found in the four HIV-infected patients without apoptosis or in the controls. Our data indicate that in children the occurrence of apoptosis in HIV infection is closely related to activation of CD8+ T cells. Furthermore, primoinfection with or reactivation of herpes viruses, such as EBV, may substantially contribute to such T-cell activation and the ensuing apoptosis. Additional studies are warranted to evaluate the contribution of herpes virus-triggered apoptosis to the T-cell loss leading to the acquired immunodeficiency syndrome.     

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).     

Denaturing interaction between sickle hemoglobin and phosphatidylserine liposomes

It is hypothesized that abnormal interaction between sickle hemoglobin (HbS) and erythrocyte membrane lipid might promote deposition of denatured hemoglobin (hemichrome) on the membrane. We compared the interaction of HbS and normal HbA with large unilamellar phosphatidylserine (PS) liposomes under low salt/pH conditions. Admixture of oxyHb and dioleoyl-PS resulted in loss of absorbance at 412 nm, the apparent first order rate constant for which was .25 +/- 0.02 hour-1 for HbA and .85 +/- 0.18 hour-1 for HbS. This was ascribable largely to formation of metHb and hemichromes and was accompanied by some actual transfer of heme from hemoglobin to lipid phase. By comparison, admixture of oxyHb with liposomes made from bovine brain PS having unsaturated acyl chains promoted even faster absorbance loss if the starting liposomal material contained detectable peroxidation by-product. In such cases, actual heme destruction developed with accompanying liberation of free iron and promotion of lipidperoxidation. Fluorescence quenching experiments indicate that hemoglobin/lipid interaction is characterized by very rapid initial electrostatic interaction, followed by development of irreversible changes. Similar changes still occur under conditions of physiologic salt/pH, but they develop much more slowly. The 3.4-fold faster oxidation of HbS versus HbA on lipid observed here represents an additional augmentation of the disparity in oxidation rates for hemoglobins in solution (1.7-fold faster for HbS than for HbA) observed previously. The accelerated promotion of Hb denaturation resulting from lipid contact may help explain deposits of hemichrome on sickle red blood cell membranes, particularly because these cells are in double jeopardy by virtue of having both the mutant HbS and abnormal amounts of peroxidized membrane lipid.     

Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss

Mohebbi N, Vargas‐Poussou R, Hegemann SCA, Schuknecht B, Kistler AD, Wüthrich RP, Wagner CA. Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near‐normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non‐consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.     

Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl- GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.     

Immunohistochemical localization of membrane and alpha-granule proteins in human megakaryocytes: application to plastic-embedded bone marrow biopsy specimens

Using a new technique for antigen localization, we have demonstrated platelet proteins in megakaryocytes in plastic-embedded biopsy specimens of normal human bone marrow. In a series of 25 specimens, megakaryocytes showed labeling with antibodies to the integral membrane glycoproteins IIIa, IIb, and the IIb-IIIa complex; granule membrane protein 140; and five alpha-granule matrix proteins: thrombospondin, factor VIII-related antigen, beta-thromboglobulin, platelet factor 4, and fibrinogen. The antibodies to the membrane glycoproteins IIIa, IIb, and IIb-IIIa produced diffuse cytoplasmic staining and heavier staining on the plasma membrane, whereas the antibodies to the alpha-granule matrix proteins produced a distinct granular staining within the cytoplasm. Staining for granule membrane protein 140 was also granular in distribution. Rare mononuclear cells consistent with megakaryocyte precursors were labeled with these markers. Other enzyme histochemical and lectin-binding studies showed that the enzyme alpha-naphthyl acetate esterase, the lectin Ulex europaeus I, and the periodic-acid Schiff reaction were consistent, but not specific, markers of megakaryocytes. This immunohistochemical technique should facilitate the examination of qualitative and quantitative changes in megakaryocytes in a variety of physiologic and pathologic processes.