Transformation of the small cell variant Ki-1+ lymphoma to anaplastic large cell lymphoma: pathologic and clinical features.

The disease spectrum of anaplastic large cell lymphoma (ALCL) includes a biologically aggressive small cell variant (SCV). The SCV may progress to ALCL, but little is known about the transformation process and its significance. The goals of this study were (1) to identify the clinical and pathologic features that characterize ALCL arising in SCV and (2) to determine whether some cases with ALCL histologic appearance at the outset arose from an SCV. Seventeen SCV were reviewed, and four cases (24%) transformed to ALCL as shown by subsequent biopsy. The ALCLs were predominantly monomorphic (3 cases) rather than pleomorphic (1 case). Residual SCV was detected at transformation in 3 of 4 cases. Twenty-one de novo T-cell ALCLs were reviewed for an SCV component; such a component was identified in two ALCLs with monomorphic features, suggesting a preceding SCV phase. There was no change in the immunophenotype between the SCV and ALCL, all marking as EMA+ T cells. Expression of p80 was detected in 3 of 4 (75%) SCV with transformation and 10 of 12 (77%) SCV without transformation. Chromosomal abnormalities involving the sex chromosomes and 6, 7, 9, and 15, in addition to the characteristic t(2;5)(p23;q35), were present in 2 cases at transformation. Times to transformation ranged from 1 to 146 months (mean: 63 months) after diagnosis. Transformation to ALCL signaled a rapid clinical course, with 75% of patients dying in less than a year; one patient remains alive at 15 months. In summary, some ALCLs, particularly those with monomorphic features, arise from an SCV. Transformation to ALCL signals a rapid course, with death occurring in less than a year in most cases. Necrosis in the SCV may be predictive of transformation. Chromosomal abnormalities in addition to the t(2;5)(p23;q35) are present at transformation, suggesting that multiple genetic alterations are involved in disease progression.

Impairment in cochlear function produced by chloramphenicol and noise.

Ototoxic interaction between chloramphenicol and noise was studied in two separate investigations. In the first study, permanent ototoxicity was demonstrated in a group of rats which were subjected to short-duration, high-intensity noise and were then given chloramphenicol orally. The anatomical damage in this group was consistent with observed changes in cochlear round window recordings of cochlear microphonics at 4 kHz and of the N1 component of the eighth nerve action potential. In the second study, a temporary depression in the function of the cochlea was observed in rats subjected to the noise-chloramphenicol regimen used in the first study. Depressions in recordings of the round window similar to those in the first study were seen only during the first five days of recordings. After the fifth day, the recordings of the round window were normal, indicating recovery from a temporary shift in threshold produced by chloramphenicol and noise. Incidence of purulent otitis media was found in 57 and 0% of the animals in the first and second studies, respectively. The combination of chloramphenicol and noise appears to be responsible for the production of temporary cochlear deficits. The addition of the third variable, otitis media, appears to result in permanent impairment of the cochlea.

Rarity of genomic instability in pathogenesis of systemic anaplastic large cell lymphoma (ALCL) in immunocompetent patients.

Microsatellite instability (MSI) is a recently described type of genetic alteration resulting from defects in the DNA mismatch repair genes that appears to play an integral role in neoplastic transformation. MSI has been described in a wide variety of malignancies; however, data regarding the role of MSI in the pathogenesis of non-Hodgkin's lymphoma (NHL) are limited. MSI appears to be important in some T-cell lymphomas, including ALCL arising in immunocompromised patients. In addition, MSI has recently been identified in CD30+ cutaneous lymphoproliferative processes and lymphoblastic lymphoma. In this study, we have analyzed five well-characterized cases of systemic T-cell ALCL arising in immunocompetent patients for the presence of MSI. Genomic DNA isolated from paired normal and tumor tissue was analyzed at seven microsatellite loci by polymerase chain reaction. We were unable to identify MSI or loss of heterozygosity (LOH) in our cases, suggesting that abnormalities in the DNA mismatch repair system do not play a major role in the pathogenesis of most systemic ALCL. Our data provide additional molecular evidence that the various subgroups of lymphoma with ALCL morphology are biologically distinct processes.

Inflammatory pseudotumor of the pelvis: case report with review of recent developments.

A case of a successfully treated inflammatory pseudotumor (IPT) of the pelvis in a 9-year-old male is presented. Review of the literature indicates that IPTs have been reported from a variety of anatomic locations. They form a spectrum of lesions ranging from benign, infection-related lesions to low-grade malignancies, capable of local recurrences and rare distant metastases. The site of involvement seems to have prognostic implication. Pulmonary IPTs are found in older patients and are almost always benign, whereas extrapulmonary IPTs tend to occur in younger patients and are, in general, more aggressive, with a recurrence rate of up to 24 per cent and mortality of up to 7 per cent. The treatment of choice is complete resection of the lesion.

Chromosome fragile sites in mentally retarded males: increased incidence with seizures and diphenylhydantoin therapy.

Chromosome fragile site or lesion data were examined in 154 institutionalized mentally retarded males with or without seizures or treated with anti-seizure medication. Blood lymphocytes were cultured using three different cell culture conditions and the incidence of specific chromosome fragile sites (10q25, 16q22, and 12q23) or lesions determined. Increased fragile sites were seen in mentally retarded males with seizures compared to those without seizures in cells grown in folate-deplete Medium 199. Those with seizures and treated with diphenylhydantoin had a higher incidence of induced fragile sites (p < 0.001) relative to similar patients treated with anti-seizure medication other than diphenylhydantoin. These results suggest that a cohort of patients with mental retardation and seizures are more likely to have induced cytogenetic changes when treated with diphenylhydantoin than mentally retarded individuals without seizures.

Cochlear morphology of the audiogenic-seizure susceptible (AGS) or genetically epilepsy prone rat (GEPR).

The organ of Corti (OC) of the genetically epilepsy prone rat (GEPR), a strain which is highly susceptible to audiogenic seizures (AGS), was examined by means of the scanning electron microscope (SEM). Ten female GEPRs (seizure intensity score of 2 or 3) and 10 female control rats (seizure intensity score of 0) were used in this study. (Seizure intensity was scored on an ascending scale of 0-9; 0 being no seizure (Jobe et al., 1973).) Each rat was perfused with buffered glutaraldehyde and the temporal bones fixed for one week in formalin. After decalcification, staining and microdissection, the entire OC was prepared for scanning electron microscopy (SEM). The GEPR organ of Corti contained several morphological differences when compared with controls. 1) In all 10 GEPRs, the headplates forming the top of the tunnel of Corti exhibited some form of structural abnormality. 2) Five animals had some form of stereocilia aberration of the inner (IHC) and/or outer (OHC) hair cells. 3) In 4 animals, significant numbers (10-15%) of IHC's were missing in large segments of all cochlear turns. 4) In 2 GEPRs, all OHC's were absent from the middle turn to the hook. In these 2 animals, IHC's were present in the upper middle turn but became less numerous and completely absent in the basal turn and hook. 5) One set of cochleas had 1000 more OHC's than had those of control rats. Since GEPRs are genetically susceptible to seizures, the preceding cochlear abnormalities are probably genetically-induced developmental defects. It is likely that the abnormally long stereocilia, mis-shaped stereocilia and deficits in hair cell populations are a consequence of the distorted headplates. The elongated stereocilia could be a compensatory attempt to contact the tectorial membrane during development. The mis-shaped stereocilia and hair cell deficits could represent a failure of compensatory mechanisms. The cochlear abnormalities may play a role in both susceptibility and intensity of audiogenic seizures.

Scanning electron microscopy of the cochlea in rats with Streptococcus pneumoniae otitis media.

This investigation was performed to determine the morphologic effects of bacterial otitis media on the organ of Corti. The middle ear cavities of rats were inoculated with Streptococcus pneumoniae or saline and the animals were killed on days 1, 4, 7, 10, 14, and 21 after inoculation. Middle ear cultures were obtained and the cochleas were examined using scanning electron microscopy. All animals killed on day 1 had positive cultures, but by day 21, all cultures were negative. Cochlear changes observed were (1) damage to supporting cells (Deiters' cells), (2) morphologic changes of hair cell stereocilia, and (3) loss of inner and outer hair cell stereocilia and cell bodies (to a lesser extent), especially in the lower middle and basal turns. These changes appeared to occur in a definite sequence; ie, damage to the supporting cells, changes in stereocilia, and, finally, hair cell loss. These data show that cochlear damage and hair loss can be associated with bacterial otitis media.

Ototoxic drugs and noise.

Drugs that produce tinnitus can be subdivided into those which produce temporary or permanent hearing loss and those which apparently do not cause any hearing loss. The tinnitus occurring with drugs of the first group is probably secondary to the hearing loss. However, most of the drugs that produce tinnitus without an accompanying hearing loss probably do so because of their effect on biogenic amines in the central nervous system and/or as an extension of their proconvulsant side-effects. A pre-existing cochlear impairment is the underlying factor in most patients who experience tinnitus. Not only can ototoxic drugs or high levels of noise produce cochlear impairment but the interaction of the two can place humans in more jeopardy than when exposed to either agent alone. Chloramphenicol has little ototoxic potential when administered systemically in humans. However, our studies show that when chloramphenicol is combined with noise exposure in rats, considerably more cochlear damage results than from the noise alone (chloramphenicol alone does no produce any cochlear damage). We are presently conducting more detailed studies of this ototoxic interaction to determine whether it occurs with other antibiotics (such as erythromycin) which are also commonly considered to have minimal ototoxicity.