Bone Marrow Necrosis Research Articles

Knochenmarksnekrose bei einer Patientin mit metastasierendem Mammakarzinom unter Chemotherapie mit Chlorambucil, Methotrexat und Prednison

In this case report the clinical course of a female patient with metastatic breast cancer receiving a mild cytostatic regimen with chlorambucil, methotrexate and prednisone is described. She developed an unusual clinico-pathological syndrome with pancytopenia, fever and bone pain resulting from a bone marrow necrosis. The clinical course illustrates the great diagnostic difficulties and the potential benefit from rapid identification of this prognostically very poor event. Leading symptoms such as fever, bone pain, pancytopenia, an increase in the sedimentation rate, in lactate dehydrogenase and alkaline phosphatase in serum are often misinterpretated as tumor progression with bone or hepatic metastases and bone marrow carcinomatosis. An iliac crest aspirate and biopsy detects the diagnosis of a marrow necrosis. These symptoms should be kept in mind in order to avoid a diagnostic pitfall resulting from a misinterpretation of the morphological picture as necrotic metastasis in bone marrow or as an artefact. It is assumed that, in addition to the underlying malignant disease, cytostatic therapy with chlorambucil, methotrexate and prednisone triggers this event.

Extensive Bone Marrow Necrosis Associated with Carcinomatosis 7 Years after Operation for Gastric Cancer

Extensive Bone Marrow Necrosis Associated with Carcinomatosis 7 Years after Operation for Gastric Cancer

Extensive bone marrow necrosis in patients with cancer and tumor necrosis factor activity in plasma

Tumor necrosis factor (TNF), a macrophage secretory protein produced by peripheral blood monocytes from patients with cancer, has been shown to possess cytotoxicity toward tumor cells in vitro. TNF in the blood of individuals with cancer is usually not detectable except with extremely sensitive radioimmunoassay or enzyme-linked immunosorbent assay (ELISA) methods. We have encountered two patients with the rare syndrome of extensive bone marrow necrosis in association with cancer. The first patient presented with marrow failure secondary to necrosis and was found to have adenocarcinoma in thoracic lymph nodes, lung, and marrow lymphatics at autopsy. Plasma tested at two dilutions (1:200 and 1:2,000) contained TNF at a concentration of 8.3 ng/ml, or 80 U/ml by a cytotoxicity assay using LM cells. The presence of TNF was confirmed with immunoblotting. The second patient had a poorly differentiated lymphoid tumor involving bone marrow, pancytopenia, and marrow necrosis. The plasma cytotoxicity assay indicated the presence of 0.7 ng/ml or 7 U/ml TNF. TNF was not detectable in plasma from six other patients with untreated cancer involving bone or bone marrow using either of our methods. The levels of TNF in the two patients with marrow necrosis were greater than those previously measured by others in patients with cancer but were comparable to those noted in patients with lethal sepsis. Since large doses of TNF have been shown to cause organ necrosis in animals, the data presented here are consistent with TNF involvement in mediating the observed marrow necrosis in our patients.

Infections with Francisella tularensis biovar palaearctica in hares (Lepus timidus, Lepus europaeus) from Sweden.

The occurrence of tularemia was studied in 1,500 hares submitted to the National Veterinary Institute, Uppsala, Sweden for postmortem examination during 1973 through 1985. A total of 109 tularemia cases was recorded based on the fluorescent antibody (FA) test for Francisella tularensis and on the gross and microscopic pathology. Tularemia was diagnosed only in the varying hare (Lepus timidus) and not in the European brown hare (Lepus europaeus). The geographical distribution of the 109 cases indicates that tularemia has not spread in Sweden during the last 45 yr, with the exception of an endemic occurrence of the disease on the island of Stora Karlsö in the Baltic sea. The disease was most frequent in the autumn and only a few cases were recorded during winter. Cases were not seen in the spring. The annual prevalence varied, with several cases in 1974 and 1981, but there were no cases in 1976 and 1980. The postmortem findings in hares dying of tularemia in the autumn were characterized by focal coagulative necrosis in liver, spleen and bone marrow, with high numbers of bacteria FA-positive for F. tularensis. In hares dying during winter months, the most characteristic findings were hemorrhagic enteritis and typhlitis, although necrotic lesions could occur in liver, spleen and bone marrow. Diseased hares on the island of Stora Karlsö were demonstrated to be infected with ticks, while hares on the mainland of Sweden generally were fed upon by mosquitoes. Twenty-six of the 109 hares with tularemia were examined bacteriologically and F. tularensis biovar palaearctica was isolated from eight. The lung extract antibody test for F. tularensis was performed in 18 of the 109 hares. All were negative. In addition to the field study, an experimental study with F. tularensis biovar palaearctica was performed. Four varying hares and three European brown hares were inoculated. None of the hares died from tularemia, and generalized infection was not demonstrated.

Acute Lymphocytic Leukemia in an Adult Presenting with Bone Marrow Necrosis

Acute Lymphocytic Leukemia in an Adult Presenting with Bone Marrow Necrosis

Viral strain dependent differences in experimental Argentine hemorrhagic fever (Junin virus) infection of guinea pigs.

Guinea pigs infected with low-passage Junin virus of human origin showed viral strain dependent differences in mortality, LD50, time to death, and in viral spread and distribution. Different Junin strains appeared to cause at least two broad patterns of Argentine hemorrhagic fever in guinea pigs. A number of strains of Junin virus caused a viscerotropic type of illness in which virus replicated predominantly in lymph nodes, spleen, and bone marrow. With the most severe visceral forms of Argentine hemorrhagic fever, the guinea pigs became viremic, developed necrosis of spleen, lymph nodes, and bone marrow, showed gastric hemorrhages, and all animals died within 13-15 days. Other Junin strains induced a neurological type of illness with transient viral replication in and lymphocyte depletion of spleen and lymph nodes, with no detectable viremia or viral replication in bone marrow. Subsequently, virus was found in the brain with varying severities of polioencephalitis, and the guinea pigs frequently showed rear leg paralysis before death occurred 28-34 days after inoculation. Not all animals infected with a neurotropic strain developed all these signs. One viral strain induced some signs characteristic of both patterns of illness. Although the disease forms in the guinea pig model did not strictly correlate with those observed in the humans from which these strains were obtained, the different strains of Junin virus consistently caused very different patterns of illness in infected guinea pigs.

Scintigraphic examination of bone and marrow infarcts in sickle cell disorders.

The bony skeleton of the patient with sickle cell disease is a frequent target of the consequences of sickling. Bone marrow necrosis, bone infarcts, osteomyelitis, and aseptic necrosis are common complications in patients with sickle cell disease. An understanding of the pathogenesis, prevalence, diagnosis, and management of these conditions is therefore important for those involved in the care of such patients.

The histopathology of enterovirus infections of new-born mice

For 32 years we have provided a routine histopathological service on animals for the Regional Virus Laboratory, Ruchill Hospital, Glasgow. This article concerns mainly experimental coxsackievirus A, coxsackievirus B and echovirus infections in new-born mice. In addition to previously reported findings, we have sometimes observed degenerative and inflammatory changes in neurons related to the Gasserian, posterior root or autonomic ganglia. Not all deposits of brown fat are simultaneously the seat of inflammatory changes; rarely, inflammation of brown fat spills over into the adjacent yellow adipose or connective tissues. Brown fat may occasionally show hyperplasia. Ballooning of the tips of small intestinal villi with interstitial oedema and/or necrosis of villous tips may indicate enanthemata associated with coxsackievirus A2,5,7,8,10,23 as well as with coxsackievirus B1 and B4 infections. Similar appearances were seldom seen with echovirus infections. Focal bone-marrow necrosis and necrosis of cartilage were associated with one coxsackievirus A10 infection, and osteitis with one coxsackievirus B3 infection. The implications of these uncommon observations for human pathology remain to be determined.

2,2,2-Trifluoroethanol-induced enteropathy in rats: chemically or bacterially mediated effects.

The lethal effects of the fluorinated ether anesthetic, fluroxene, in rats are a consequence of its metabolism, which is catalyzed by cytochrome P-450 to the toxic metabolite 2,2,2-trifluoroethanol (TFE). The anesthetic or TFE (0.21 g/kg) caused decreased white blood cell counts, necrosis of bone marrow and lymphocytes, and decreased small intestine dry weight and was associated with septicemia. To elucidate the mechanism of TFE toxicity in rats we undertook histopathologic, ultrastructural and bacteriologic studies. TFE produced severe edema of intestinal lamina propria and submucosae, dilatation of crypts, loss of surface epithelium, vacuolation and necrosis of intestinal epithelial cells, and infiltration of polymorphonuclear leukocytes into the edematous lamina propria. Intestinal epithelial villi lost their cellular tissue integrity. Coccobacillary organisms were numerous in the ulcerated intestine. Hemolytic E. coli were isolated from intestinal tissue at a two-log increase in concentration relative to controls. Hemograms from TFE-treated rats exhibited marked leukopenia and morphologic differences. The platelets lost their discoid shape, extended pseudopods, and centralizing granules. Hemoglobin precipitation as Heinz bodies and crystalloid structures was observed in TFE-treated rats. Together the data suggest that TFE-induced enteropathy was most probably due to E. coli precipitated from TFE-mediated alterations in the population of small intestinal microbes. The antibiotics erythromycin, active against gram-positive bacteria, and streptomycin, active against gram-negative bacteria, and the antiendotoxin, polymyxin B, were administered to rats prior to TFE in an effort to differentiate between these mechanisms by altering the intestinal bacteria populations. The results indicate that the TFE-induced small intestinal lesions are initiated by the direct focal necrotic effect of TFE or its metabolites on the small intestinal epithelium. The focal coagulation necrosis produced by TFE predisposes the animals to lethal enteritis and systemic bacteremia.

Myeloablation with diaziquone: in vitro assessment

The promising antineoplastic agent diaziquone is associated with prolonged aplasia and rare instances of bone marrow necrosis, but only mild extramedullary toxicity. To explore the drug's potential as a myeloablative agent prior to bone marrow transplantation, we compared its effects on hematopoietic versus marrow stromal cells. After short- term (one to six hours) or prolonged (three to seven days) exposure to the drug, marrow was assayed for hematopoietic (CFU-Mix, BFU-E, CFU-GM) and stromal (CFU-F) colony-forming cells and studied in long-term marrow culture (LTMC). One- and three-hour treatments produced little cytotoxicity, even at 5000 ng/mL. After six-hour treatments with this dose, marrow was depleted of CFU-Mix, BFU-E, and CFU-GM, but produced CFU-GM in LTMCs, indicating an ongoing input of CFU-GM from a surviving pre-CFU-Mix population. In contrast, elimination of the latter may be inferred from the absence of CFU-GM in LTMCs exposed for three to seven days to diaziquone at only 150 ng/mL. Under these conditions, CFU-F recovery was 40% and adherent stromal layers in LTMCs were similar to untreated controls regarding rate of development and cellular composition. Our in vitro pre-CFU-Mix-ablative regimen correlates with clinical data that show prolonged but reversible myelosuppression at steady-state diaziquone plasma levels of 101 +/- 10 ng/mL (mean +/- standard error of mean) during 7-day constant infusions. In conclusion: hematopoietic cells are more sensitive than marrow stromal cells to the dose- and highly time-dependent cytotoxicity of diaziquone, a direct drug-induced noxious effect on the marrow microenvironment is an unlikely cause of the isolated episodes of marrow necrosis after the use of diaziquone in vivo, and prolonged infusion of diaziquone represents an attractive means for achieving myeloablation in selected clinical situations.

Myeloablation With Diaziquone: In Vitro Assessment

The promising antineoplastic agent diaziquone is associated with prolonged aplasia and rare instances of bone marrow necrosis, but only mild extramedullary toxicity. To explore the drug's potential as a myeloablative agent prior to bone marrow transplantation, we compared its effects on hematopoietic versus marrow stromal cells. After short-term (one to six hours) or prolonged (three to seven days) exposure to the drug, marrow was assayed for hematopoietic (CFU-Mix, BFU-E, CFU-GM) and stromal (CFU-F) colony-forming cells and studied in long-term marrow culture (LTMC). One- and three-hour treatments produced little cytotoxicity, even at 5000 ng/mL. After six-hour treatments with this dose, marrow was depleted of CFU-Mix, BFU-E, and CFU-GM, but produced CFU-GM in LTMCs, indicating an ongoing input of CFU-GM from a surviving pre-CFU-Mix population. In contrast, elimination of the latter may be inferred from the absence of CFU-GM in LTMCs exposed for three to seven days to diaziquone at only 150 ng/mL. Under these conditions, CFU-F recovery was 40% and adherent stromal layers in LTMCs were similar to untreated controls regarding rate of development and cellular composition. Our in vitro pre-CFU-Mix-ablative regimen correlates with clinical data that show prolonged but reversible myelosuppression at steady-state diaziquone plasma levels of 101 +/- 10 ng/mL (mean +/- standard error of mean) during 7-day constant infusions. hematopoietic cells are more sensitive than marrow stromal cells to the dose- and highly time-dependent cytotoxicity of diaziquone, a direct drug-induced noxious effect on the marrow microenvironment is an unlikely cause of the isolated episodes of marrow necrosis after the use of diaziquone in vivo, and prolonged infusion of diaziquone represents an attractive means for achieving myeloablation in selected clinical situations.

Bone and bone marrow necrosis associated with the calf form of sporadic bovine leukosis.

The presence of neoplastic cells in the medullary cavity of bone may have various consequences including erosion of cortical bone, fat and marrow embolism, peripheral blood cytopenias, pathologic fracture, and necrosis of medullary bone and bone marrow elements.'-'O In man, infarction of bone is recognized to have many causes including intramedullary lymphoid tumors. *,2,5,6 In this report, we describe multiple bone infarcts in six calves that had sporadic bovine leukosis. Each of these animals was presented individually with one of the following complaints: unthriftiness and inactivity, posterior ataxia, superficial lymph node enlargement, lameness, and/or respiratory distress. Both sexes (three male, three female) and various breeds (Simmental(3), Hereford (l), Hol

Unusual association of bone marrow necrosis, disseminated intravascular coagulation, and a rare 8;16 chromosomal translocation in an adult patient with acute nonlymphocytic leukemia.

In a patient with acute nonlymphocytic leukemia of the classic type (FAB subtype M2), three infrequently observed phenomena occurred together; bone marrow necrosis, disseminated intravascular coagulation, and an 8;16 chromosomal translocation. All three resolved with antileukemic therapy, only to reemerge when the leukemia relapsed, suggesting a causal relationship among these phenomena. Such observations and the consistent application of cytogenetic studies to patients with leukemia may help elucidate the significance of specific chromosomal abnormalities in patients with leukemia.

Chemical of current interest--benzene.

Benzene is one of the world's major commodity chemicals. It is derived from petroleum and coal and is used both as a solvent and as a starting material in chemical syntheses. The numerous industrial uses of benzene over the last century need not be recounted here, but the most recent addition to the list of uses of benzene is as a component in a mixture of aromatic compounds added to gasoline for the purpose of replacing lead compounds as anti-knock ingredients. The best known and longest recognized toxic effect of benzene is the depression of bone marrow function seen in occupationally exposed individuals. These people have been found to display anemia, leucopenia, and/or thrombocytopenia. When pancytopenia, i.e., the simultaneous depression of all three cell types, occurs and is accompanied by bone marrow necrosis, the syndrome is called aplastic anemia. In addition to observing this decrease in humans and relating it to benzene exposure, it has been possible to establish animal models which mimic the human disease. The result has been considerable scientific investigation into the mechanism of benzene toxicity. Although the association between benzene exposure and aplastic anemia has been recognized and accepted throughout most of this century, it is only recently that leukemia, particularly of the acute myelogenous type, has been related to benzene. The acceptance of benzene as an etiological agent in aplastic anemia in large measure derives from our ability to reproduce the disease in most animals treated with sufficiently high doses of benzene over the necessary time period. Unfortunately, despite extensive efforts in several laboratories, it has not been possible to establish a reproducible, reliable model for the study of benzene-induced leukemia. The recent demonstration that several animals exposed to benzene either by inhalation or in the drinking water during studies by Drs. B. Goldstein and C. Maltoni suggests that such a model may be forthcoming. Nevertheless, at this time it is not clear whether bone marrow damage of the type that leads to aplastic anemia is required for the development of leukemia. Most studies of benzene toxicity have involved dosing animals with benzene either by inhalation or by injection, using high doses to ensure a toxic response. Very few studies have concentrated on the oral route of administration and none have concentrated on administering benzene by mouth at the low doses occasionally detected in drinking water.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone marrow necrosis in children with malignant disease.

The authors reviewed the case records of 1419 children with acute leukemia and other types of malignant disease involving the bone marrow to define the clinical and laboratory features associated with marrow necrosis as well as the prognostic significance of this complication. Only seven patients were found to have this abnormality: four with newly diagnosed acute lymphoblastic leukemia (ALL), one with relapsed ALL, and two with disseminated neuroblastoma. All patients presented with severe bone pain, bone tenderness, and fever. Levels of serum lactic dehydrogenase were uniformly increased, being especially high in patients with ALL. There was no evidence of severe infection or disseminated intravascular coagulation, complications that have been causally related to marrow necrosis. Four of the five children with ALL remain in complete remission for 10+ to 48+ months. Both patients with neuroblastoma are off therapy, in remission, for 9+ to 15+ months. In contrast to earlier reports, bone marrow necrosis does not appear to confer a poor prognosis in children with malignancy.

Fat Embolism in Sickle Cell Disease

This is a unique instance of fatal fat embolism secondary to bone marrow necrosis in a patient with sickle cell-hemoglobin C disease, systemic lupus erythematosus, and Sjögren's syndrome. An elevated level of IgG and treatment with corticosteroids appeared to be major factors in the death of this patient. This complication occurs most often in patients with sickle cell-hemoglobin C disease, especially in pregnant women near term. It should be suspected in any patient with sickle cell disease in whom unexplained fever, respiratory, and neurologic symptoms typical of fat emboli develop following the onset of bone pain. Exchange blood transfusion may be lifesaving.

Bone Marrow Necrosis Associated With Tumor Emboli and Disseminated Intravascular Coagulation

To the Editor. —Bone marrow necrosis, which has been described in sickle cell disease, infectious diseases, and cancer,1-6is a disorder rarely diagnosed during life. In the November 1982Archives(1982;142:2223-2225), Pardoll et al reported a case of bone marrow necrosis associated with sickle cell disease. Reticuloendothelial scans showed widespread abnormalities consistent with marrow infarction; widespread microvascular obstruction by masses of sickle cells seems plausible as a mechanism of marrow necrosis.5Nevertheless, the bone marrow necrosis pathogenesis is unknown in neoplasia and infectious diseases. We report a case of bone marrow necrosis diagnosed antemortem in a patient with gastric metastatic adenocarcinoma, where postmortem pathologic studies may bring further knowledge about necrosis physiopathology. Report of a Case. —A 60-year-old man was admitted to the hospital after three weeks of fever, dyspnea, and bone pain in the lower part of the back. Physical examination showed a severely ill patient, pale with petechia on the limbs, and necrosis in his right toes.

Bone marrow necrosis associated with tumor emboli and disseminated intravascular coagulation

Bone marrow necrosis associated with tumor emboli and disseminated intravascular coagulation

Fatal Disseminated Cytomegalovirus Infection in an Apparently Normal Adult

An ostensibly normal 43-year-old man had intermittent fever, erythema multiforme, and leukopenia that evolved into fulminant hepatic and bone marrow necrosis. The cause of his illness was compatible with cytomegalovirus (CMV) infection since there was a fourfold increase in immunofluorescent antibody titer. This report suggests that CMV can produce a rapidly progressive and overwhelming infection in an apparently healthy adult.

Bone Marrow Necrosis

Bone marrow necrosis (BMN) is a rare finding in specimens from living patients. It is most commonly found in patients with neoplastic disorders, severe infections and sickle cell disease. We present a patient with Hodgkin's disease who developed extensive BMN 11 months before death. A concise review of the literature is also presented.