Rosai-Dorman disease causing cervical myelopathy.

STUDY DESIGN: A case report of a rare disease entity and review of the literature. OBJECTIVES: To illustrate the occurrence of an unusual disease affecting the spine and spinal canal. SUMMARY OF BACKGROUND DATA: Rosai-Dorman disease is considered an idiopathic benign lymphoproliferative disease that typically occurs in the earlier decades of life. The usual manifestation is painless massive cervical lymphadenopathy, although involvement of many extra nodal sites is common. This case illustrates Rosai-Dorman disease occurring in an elderly man with myelopathy and mass lesions of the cervical, thoracic, and lumbar spinal canal without typical lymphadenopathy.- METHODS: Case report illustrating clinical presentation as well as radiographic and pathologic findings, including comparisons to cases previously reported. RESULTS: Surgical decompression with incomplete resection of the lesion was performed, providing diagnosis and treatment guidance. The patient experienced significant neurologic improvement of myelopathy. CONCLUSIONS: Recognizing clinical and laboratory features of this disease may permit earlier diagnosis and limit or avoid surgical intervention in some cases.

Two-generation reproductive toxicity study of plant stanol esters in rats.

Plant stanol esters are intended for use as an ingredient in food to reduce the absorption of cholesterol from the gastrointestinal tract. Consumption of plant stanol esters has a demonstrated diet-derived public health benefit, as shown by numerous clinical studies. Plant stanol esters are ring-saturated analogs of common dietary sterols that are transesterified with fatty acids from vegetable oils such as canola oil. The reproductive and developmental toxicity of plant stanol esters was investigated in male and female Wistar rats during F0 and F1 generations using dietary concentrations of 1.75, 4.38, and 8.76% stanol esters (equivalent to 1, 2.5, and 5% total stanols). No adverse treatment-related effects were noted on reproductive performance of male or female rats in any dose group. Increased food consumption was observed in high-dose F0 generation males throughout the entire premating period and in F1 males at specific time periods during the premating period. This increase in food consumption was also observed in F0 generation females (mid- and high-dose groups) and F1 generation females (low-, mid-, and high-dose groups) at specific time periods throughout the 10-week premating period. At different intervals throughout the gestation and lactation periods, increased food consumption was observed in F0 generation females of the mid- and high-dose groups, while increased food consumption was noted in F1 generation females of the mid- and high-dose groups during gestation, but not during lactation. Such increases in food consumption are expected as a result of the animals' attempt to compensate for the reduced caloric value of the test diet compared to controls. No adverse developmental effects were noted in F1 or F2 pups of the low- and mid-dose groups based on evaluation of the following parameters: litter size, pup mortality, pups weights, and sex ratio. However, a treatment-related effect on body weight and body weight change was observed in both F1 and F2 male and female pups of the high-dose group, particularly during the latter stages of lactation (postnatal days 14 and 21) in F1 pups, and during the majority of the lactation period (postnatal days 4-21). Lower body weight in the high-dose pups is attributed to a reduction in the caloric value of the test diet compared to control. The pups, unlike adult animals, are particularly sensitive to reductions in caloric value of feed since they are in a rapid growth phase of their development. It is likely that they could not increase their food consumption enough to adequately meet their caloric and nutritional needs. In conclusion, dietary concentrations of up to 4.38% plant stanol esters (equivalent to 2.5% total stanols in the diet) are not associated with adverse effects on reproduction, pup mortality, pup body weight, or pup body weight change.

13-week oral toxicity study with stanol esters in rats.

Plant sterols and their saturated derivatives, known as stanols, reduce serum cholesterol when consumed in amounts of approximately 2 g per day. Stanol fatty acid esters have been developed as a highly fat-soluble form that may lower cholesterol more effectively than stanols. Stanol esters occur naturally in human diets, but at levels far below those known to lower cholesterol. The present study was conducted to assess the safety of stanol esters upon subchronic ingestion at levels comparable to or exceeding those recommended for lowering cholesterol. Two stanol fatty acid ester preparations, wood-derived stanol esters and vegetable oil-derived stanol esters, were fed to groups of 20 male and 20 female Wistar rats for 13 weeks, at dietary concentrations of 0, 0.2, 1, and 5% total stanols (equivalent to 0, 0.34, 1.68, and 8.39% wood-derived stanol esters and 0, 0.36, 1.78, and 8.91% vegetable oil-derived stanol esters). Both preparations were well tolerated as evidenced by the absence of clinical changes or major abnormalities in growth, food and water consumption, ophthalmoscopic findings, routine hematological and clinical chemistry values, renal concentrating ability, composition of the urine, appearance of the feces, estrus cycle length, organ weights, gross necropsy findings, and histopathological findings. Plasma cholesterol and phospholipids were slightly decreased in males fed the stanol esters. In both sexes, plasma levels of plant sterols were decreased whereas those of stanols tended to increase. Fecal excretion of sterols, including cholesterol, and stanols was markedly increased in the stanol ester groups. Compared to controls, male rats fed stanol esters showed somewhat lower liver weights and more pronounced glycogen depletion. These hepatic changes were considered to reflect an altered nutritional condition and not a pathological condition. Plasma levels of vitamin E, vitamin K1, and, to a lesser extent, vitamin D were decreased in males and females fed the high-dose diets. Hepatic levels of vitamins E and D showed similar changes (vitamin K1 in the liver was not determined). For both preparations, the mid-dose level (1% total stanols in the diet) was a no-observed-adverse-effect level. This dietary level provided approximately 0.5 g total stanols/kg body wt/day.

90-Day oral toxicity study of D-tagatose in rats.

D-tagatose is a ketohexose, tastes like sugar and is useful as a low-calorie sweetener. To assess D-tagatose's safety, an oral 90-day toxicity study was conducted on male and female Crl:CDBR rats at dietary doses of 5, 10, 15, and 20% D-tagatose. One control group (dietary control) received only lab chow; a second control group received 20% cellulose/fructose in the diet. There were no treatment-related effects at 5% D-tagatose in the diet. At higher doses, treatment-related effects included transient soft stools in male and female animals from the 15 and 20% dose groups. This was anticipated as a result of the osmotic effect of a large dose of relatively undigested sugar and was not considered a toxic effect. All treatment groups gained weight over the study period; however, mean body weights were statistically significantly decreased in the 15 and 20% dose-group males and the 20% dose-group females at selected intervals compared to dietary control animals. No significant reduction in mean food consumption was noted in the treatment groups compared to the dietary control. Statistically significantly increased relative liver weights were noted in male and female animals from the 10, 15, and 20% dose groups compared to the dietary control. No gross pathological findings correlated with these increased liver weights. Minimal hepatocellular hypertrophy was observed in male and female animals from the 15 and 20% dose groups. An independent review of the liver slides concluded that histomorphologic changes associated with D-tagatose were restricted hepatocyte hypertrophy and hepatocyte glycogen accumulation. Therefore, it was concluded that increased liver weights and minimal hypertrophy were the result of adaptation to the high dietary levels (greater than 5% in the diet) of D-tagatose. No adverse effects were seen at 5% D-tagatose in the diet.

Developmental toxicity study of D-tagatose in rats.

D-tagatose is a low-calorie sweetener that tastes like sucrose. The developmental toxicity of D-tagatose was investigated in Crl:CD(SD)BR rats administered D-tagatose at three dose levels (4000, 12,000, and 20,000 mg/kg body wt/day) via gastric intubation on days 6-15 of gestation. No compound-related toxicity was seen among any of the maternal groups. No treatment-related clinical effects were seen in the maternal animals at the 4000 mg/kg/day dose level. At the mid- and high-dose levels, most maternal animals had unformed or watery stools; this effect was most prominent early in the treatment period (Gestation Days 6-8). This effect was attributed to the osmotic effect of the large amount of D-tagatose given to the animals at these doses. Since D-tagatose is not digested or absorbed to a large extent, most of the sugar passes into the colon where it absorbs water and is fermented by colonic bacteria. Mean weight gain for the low- and mid-dose animals was comparable to the control; however, the high-dose group experienced a mean weight loss over the Gestation Day 6-9 interval. Over the entire treatment interval, however, mean weight gain for the high-dose animals was comparable to control. The decreased weight gain in the high-dose animals during the Gestation Day 6-9 interval was considered to be a direct result of laxation. In addition to the effect of laxation on body weight, reduced food consumption also contributed to the decreased weight gain. In the low-dose animals, no effect on food consumption was seen; however, both mid- and high-dose animals had food consumption values that were statistically significantly lower than the control. Food consumption was lowest during the Gestation Day 6-9 interval, the period when laxation was most prominent. Food consumption rebounded and was statistically significantly higher than the control for the mid- and high-dose animals during the posttreatment interval. Maternal liver weight for the low-dose animals was comparable to the control. However, a statistically significant increase in mean maternal liver weight was noted for the mid-and high-dose animals. Based on a lack of any corresponding histopathology, the increased liver weights were not considered toxicologically significant. There were no adverse effects on reproductive performance noted in any treatment group. No adverse treatment-related fetal effects on fetal weight, sex distribution, liver weight, or external, skeletal, or visceral malformations were noted at any dose level.

Genotoxicity tests on D-tagatose.

D-tagatose is a low-calorie sweetener that tastes like sucrose. Its genotoxic potential was examined in five standard assays: the Ames Salmonella typhimurium reverse mutation assay, the Escherichia coli/mammalian microsome assay, a chromosomal aberration assay in Chinese hamster ovary cells, a mouse lymphoma forward mutation assay, and an in vivo mouse micronucleus assay. D-tagatose was not found to increase the number of revertants per plate relative to vehicle controls in either the S. typhimurium tester strains or the WP2uvrA- tester strain with or without metabolic activation at doses up to 5000 microg/plate. No significant increase in Chinese hamster ovary cells with chromosomal aberrations was observed at concentrations up to 5000 microg/ml with or without metabolic activation. D-tagatose was not found to increase the mutant frequency in mouse lymphoma L5178Y cells with or without metabolic activation up to concentrations of 5000 microg/ml. D-tagatose caused no significant increase in micronuclei in bone marrow polychromatic erythrocytes at doses up to 5000 mg/kg. D-tagatose was not found to be genotoxic under the conditions of any of the assays described above.

Cutaneous pseudolymphoma: an unusual presentation of a deep subcutaneous thigh mass.

Cutaneous pseudolymphoma is considered to be a benign (reactive) cutaneous lymphoid infiltrate; the term designates reactive diseases of the skin that histologically mimic cutaneous lymphoma. We report a case in which a 63-year-old female presented with a 5-month history of a progressive skin eruption and an enlarging subcutaneous mass following a presumed insect bite. Excisional biopsy showed this to be a pseudolymphoma extending from the dermis into the subcutaneous tissue. A number of pathological features that distinguish pseudolymphoma from cutaneous lymphoma, including histology, immunophenotype, and immunogenotype, are reviewed. The case herein challenges previous beliefs that pseudolymphoma is confined to cutaneous involvement and indicates that the process can involve deeper tissues. The final criterion for distinguishing benign from reactive processes is biological behavior. Since the depth of invasion in cutaneous pseudolymphoma has not previously been appreciated, the patient will need to be carefully examined periodically until the biological behavior of the process has been determined.

HLA-DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute leukemia: a previously unrecognized form of acute leukemia potentially misdiagnosed as French-American-British acute myeloid leukemia-M3.

We have identified and characterized a previously unrecognized form of acute leukemia that shares features of both myeloid and natural killer (NK) cells. From a consecutive series of 350 cases of adult de novo acute myeloid leukemia (AML), we identified 20 cases (6%) with a unique immunophenotype: CD33+, CD56+, CD11a+, CD13lo, CD15lo, CD34+/-, HLA-DR-, CD16-. Multicolor flow cytometric assays confirmed the coexpression of myeloid (CD33, CD13, CD15) and NK cell-associated (CD56) antigens in each case, whereas reverse transcription polymerase chain reaction (RT-PCR) assays confirmed the identity of CD56 (neural cell adhesion molecule) in leukemic blasts. Although two cases expressed CD4, no case expressed CD2, CD3, or CD8 and no case showed clonal rearrangement of genes encoding the T-cell receptor (TCR beta, gamma, delta). Leukemic blasts in the majority of cases shared unique morphologic features (deeply invaginated nuclear membranes, scant cytoplasm with fine azurophilic granularity, and finely granular Sudan black B and myeloperoxidase cytochemical reactivity) that were remarkably similar to those of acute promyelocytic leukemia (APL); particularly the microgranular variant (FAB AML-M3v). However, all 20 cases lacked the t(15;17) and 17 cases tested lacked the promyelocytic/retinoic acid receptor alpha (RAR alpha) fusion transcript in RT-PCR assays; 12 cases had 46,XX or 46,XY karyotypes, whereas 2 cases had abnormalities of chromosome 17q: 1 with del(17)(q25) and the other with t(11;17)(q23;q21) and the promyelocytic leukemia zinc finger/RAR alpha fusion transcript. All cases tested (6/20), including the case with t(11;17), failed to differentiate in vitro in response to all-trans retinoic acid (ATRA), suggesting that these cases may account for some APLs that have not shown a clinical response to ATRA. Four of 6 cases tested showed functional NK cell-mediated cytotoxicity, suggesting a relationship between these unique CD33+, CD56+, CD16- acute leukemias and normal CD56+, CD16- NK precursor cells. Using a combination of panning and multiparameter flow cytometric sorting, we identified a normal CD56+, CD33+, CD16- counterpart cell at a frequency of 1% to 2% in the peripheral blood of healthy individuals. Our studies suggest that this form of acute leukemia may arise from transformation of a precursor cell common to both the myeloid and NK cell lineages; thus we propose the designation myeloid/NK acute leukemia. Recognition of this new leukemic entity will be important in distinguishing these ATRA-nonresponsive cases from ATRA-responsive true APL.

Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300-400 kilobases on chromosome band 3q26.

Retroviral activation of Evi-1 gene expression is one of the most common transforming events in murine myeloid leukemias. To evaluate the role of the EVI1 gene in human acute myelogenous leukemia (AML), leukemic blasts or cell lines from 116 patients were examined. In eight patients the EVI1 gene was expressed and all but one had cytogenetically detectable translocations of chromosome 3q26 where the EVI1 gene has been localized. To identify breakpoints, a restriction map that spans 1700 kilobases (kb) of the EVI1 locus was developed by pulsed-field gel electrophoresis. In one case, t(3;3)(q21;q26), a rearrangement was localized to 170-330 kb 5' of the gene. In a second case, t(3;3)(q21;q26), there was a rearrangement 13 kb 5' of the gene. This rearrangement was cloned and shown to be due to the fusion of sequences from 3q21-22 with the EVI1 locus. In the third case, ins(3)-(q21q25q27), there was a rearrangement that mapped 150 kb downstream from the 5' end of the gene.

The molecular biology of acute myeloid leukemia. Proto-oncogene expression and function in normal and neoplastic myeloid cells.

Proto-oncogenes and suppressor genes fall into four functional groups: growth factors, growth factor and hormone receptors, signal transducers, and transcriptional regulatory factors. Many of these genes are selectively expressed in myeloid cells and may play a role in normal development of the myeloid lineages. Furthermore, chromosomal rearrangements, deletions, and mutations may disrupt the normal expression or function of these genes, promoting MPD and leukemogenesis. Many of the genes altered by karyotypic abnormalities in myeloid disorders are only beginning to be identified. Future studies undoubtedly will determine the molecular mechanisms whereby these genes, residing at karyotypic breakpoints in myeloid disorders, promote neoplastic transformation of myeloid cells.