The prognostic value of IDH mutations and MGMT promoter status in secondary high-grade gliomas.

Reports about the prognostic value of IDH mutations and the promoter region of the O6-Methyl-guanyl-methyl-transferase gene in secondary high-grade gliomas (sHGG) are few in number. We investigated the prognostic value of IDH mutations and methylation of the promoter region of the MGMT gene in 99 patients with sHGG and analyzed the clinical course of those tumors. Patients with sHGG were screened for IDH mutations by direct sequencing, and, for promoter status of MGMT gene, by the methylation-specific polymerase chain reaction. A total of 48 of 99 patients (48.5 %) had secondary anaplastic gliomas (Group 1), while 51 patients had secondary glioblastomas (Group 2). The median survival time after malignant progression of all patients with sHGG and with an IDH mutation was 4 years, which is significantly longer than in patients with wild-type IDH (1.2 years, p = 0.009). Patients' survival was not significantly influenced by the tumors' MGMT promoter status, both in Group 1- 9.7 years vs. 6.1 years, methylated vs. unmethylated promoter (p = 0.330)-as well as in Group 2-1.5 years vs. 1.6 years, methylated versus unmethylated promoter (p = 0.829). In our population, the IDH mutation status was not associated with increased PFS or median survival time in sGBM patients. However, patients with secondary anaplastic glioma and IDH mutation had a significantly improved outcome. In addition, IDH mutations are a more powerful prognostic marker concerning both PFS and MS than the MGMT promoter status in those patients.

Risk stratification using a new prognostic score for patients with secondary acute myeloid leukemia: results of the prospective AML96 trial.

Patients with secondary acute myeloid leukemia (sAML) are generally thought to have a poor prognosis. As there are no prognostic risk stratification models for patients with sAML available, the aim of this study was to obtain a scoring system. Prognostic factors influencing overall survival (OS) and event-free survival (EFS) were analyzed in 305 sAML patients treated in the prospective AML96 trial. The obtained prognostic scoring system was then validated in an independent patient cohort included in the AML2003 and AML60+ trials. In addition to the known risk factors for AML, age and karyotype, we identified the absolute platelet count and the Nucleophosmin 1 mutational status at diagnosis as prognostic factors of sAML patients. A pronounced distribution of sAML patients into three score groups was achieved showing a 2-year OS/EFS of 52/44% for patients in the low-risk group, 21/12% in the intermediate-risk group and 7/3% in the high-risk group (both P<0.001). Validation of this scoring system in a second independent set of sAML patients revealed similar significantly different survival results. In conclusion, for the first time, a prognostic scoring system is provided for sAML patients, allowing differential treatment strategies in the future.

The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia.

Loss of p53 -- a tumor suppressor gene located on the short arm of chromosome 17 (band 17p13.1) -- was detected in 105 out of 2272 (5%) adult acute myeloid leukemia (AML) patients who took part in the Study Alliance Leukemia AML96 and AML2003 multi center trials. There were 85 patients with 17p (p53) deletion with multiple aberrations and 20 patients with a 17p (p53) deletion as single aberration or with only one additional chromosomal abnormality. None of the p53-deleted patients displayed additional low-risk aberrations, like t(8;21) or inv(16). Significant positive association between p53 deletion and other high-risk factors was identified for del(5q) (P<0.001), -5 (P<0.001) and -7 (P<0.05). The molecular risk factors FLT3-ITD and NPM1 mutation showed an inverse correlation to the p53 deletion in complex aberrant patients (P<0.001). The multivariate analysis revealed p53 deletion without multiple aberrations as an independent negative prognostic factor for disease-free survival (P<0.001), relapse risk (P=0.028) and overall survival (P<0.001). Thus, the single p53 deletion should be considered as a high-risk aberration for future risk-adapted treatment strategies in AML.

The intravestibular source of the vestibular aqueduct: Its structure and pathology in Ménière's disease.

CONCLUSION: We describe a thin, highly vascular layer of mineralized cartilage, which surrounds most of the endolymphatic duct. In the normal ear this may act in helping to control the chemical composition of endolymph. In Ménière's disease (MD) there is a marked apoptotic change among the mineralized cartilage cells of this layer, which seems to be associated also with the deposition of a pathological substance in the walls of many blood vessels. This may lead to serious chemical change in the nearby endolymph and so provoke the symptoms of MD. OBJECTIVES: Endolymphatic hydrops is found in all cases of MD, but is not specific for that condition. We sought a cellular change in the vicinity of the saccule that might be more specific than the lesion of endolymphatic hydrops and thus lead to a more successful management of the disease. MATERIALS AND METHODS: We examined stained step sections of 33 autopsy temporal bones from 20 cases of MD, particularly in the region of the vestibule, and compared the changes with those found in a similar region of 65 temporal bones taken from randomly selected cases of non-Ménière conditions. RESULTS: In all temporal bones there was a well-demarcated region of the posterior vestibule, which formed a skeletal arch around the opening of the tunnel of the vestibular aqueduct into which the endolymphatic duct entered from the vestibule. This 'vestibular arch' was composed mainly of blood vessels and mineralized chondrocytes. The inner skeletal layer surrounding the course of most of the endolymphatic duct in the tunnel of the vestibular aqueduct was composed of the same tissue and was in fact continuous with the vestibular arch. In the non-Ménière temporal bones the mineralized chondrocytes were congregated around normal thin-walled blood vessels and small numbers of them seemed to be undergoing apoptosis in this vicinity. In all of the MD temporal bones, except five in which the vestibular arch was either absent or atrophic, we found pronounced changes of apoptosis among the mineralized cartilage cells and these were associated with proliferative changes in blood vessels in which a bluish-staining translucent deposit, possibly mineralization of the vascular wall, was prominent.

Immunophenotyping is an independent factor for risk stratification in AML.

BACKGROUND: Chromosomal abnormalities are one of the most important prognostic factors in acute myeloid leukemia (AML). However, only a limited number of patients have such informative chromosomal abnormalities. The prognostic value of immunophenotyping in this disease is still unclear. METHODS: Seven hundred and eighty-three newly diagnosed AML patients treated in the German SHG-AML trials in 1991 and 1996 were analyzed with a panel of 33 antibodies. Expression was correlated to overall survival, complete remission-rate, and complete remission duration, and tested in a multivariate analysis including other clinical and biological markers. RESULTS: With a median follow-up of 4.3 years, patients with AML blasts negative for CD9, CD11b, CD13, CD34, and CD41, or positive for CD15, CD33, CD38, CD64, and MPO had superior overall survival. This effect was associated with a significantly higher complete remission rate (CD13, CD34, CD41, and CD64) or a longer complete remission duration (CD9, CD11b, and CD64). Cox-regression analysis, including cytogenetic, morphologic, and biologic parameters showed CD9, CD13, CD34, and CD64 as independent factors for overall survival. These markers were used for a prognostic score. Patients were pooled in three groups with highly significant differences of overall survival. The prognostic relevance of this score was confirmed in patients with normal karyotype and/or in younger patients

Spleen enlargement in healthy donors during G-CSF mobilization of PBPCs.

BACKGROUND: Recombinant human G-CSF is widely used to mobilize PBPCs in healthy donors for allogeneic transplantation. There have been concerns about donor safety because of splenic ruptures during G-CSF application. To address this problem, changes in splenic size in 91 healthy donors during G-CSF mobilization of allogeneic PBPCs were investigated. STUDY DESIGN AND METHODS: For mobilization, G-CSF in a dosage of 7.5 microg per kg per day was administered for 5 days and PBPC collection started Day 5. Splenic size was determined by ultrasound before G-CSF application was started and on the day of the first apheresis. RESULTS: The mean increase in splenic length was 11 mm (range, 0-28 mm; p<0.0001), whereas a mean increase of 5 mm in width (range, 0-14 mm; p<0.0001) was measured. No major side effects could be observed. There was no significant correlation between the increase in splenic size and the hematologic values, or the age and body-mass index. In a multivariant analysis, no independent risk factor for the development of a spleen enlargement over 19 mm in length and 9 mm in thickness was found in 20 percent of investigated donors. CONCLUSION: In this prospective trial, a significant spleen enlargement was observed in healthy donors during G-CSF mobilization of allogeneic PBPCs. Further investigations are needed to define the degree of spleen enlargement with higher G-CSF dosages to improve donor safety.

Allogeneic transplantation of G-CSF mobilized peripheral blood stem cells from unrelated donors: a retrospective analysis.

BACKGROUND AND OBJECTIVES: Allogeneic peripheral blood stem cell transplantation (PBSCT) from matched siblings has lead to clinical results comparable to those of standard bone marrow transplantation (BMT). We report the outcome of 79 patients transplanted with PBSC from unrelated donors. DESIGN AND METHODS: In 61 cases PBSC were used for primary transplantation whereas 18 patients were treated for relapse or graft-failure. In 35 patients receiving primary transplants, T-cell depletion (TCD) using CD34 positive selection of PBSC with or without additional T-cell depletion had been performed to reduce the risk of graft-versus-host-disease (GvHD). RESULTS: The rate of primary graft-failure was higher (20%) in the TCD group than in that receiving unmanipulated grafts (UM) (5%, p=0.007). Patients with standard risk (n=34) receiving first transplants had a significantly better overall (60.4% vs. 24%, p=0.02) and disease-free survival (57.2% vs. 22.3%, p=0.006) compared to a high risk group of patients (n=21). There were no differences in the speed of neutrophil and platelet engraftment between TCD and UM transplants. As expected, the cumulative risk for acute GvHD grade II.-IV was significantly higher in the patients who had received UM grafts (71.8% vs. 38.1%, p=0.005). Although a trend towards a better survival rate was observed after TCD transplantation (52.2%) compared to the UM group (38.1%), this difference was not statistically significant. The probability of relapse was significantly higher in patients after UM transplants (38.8% vs. 8. 4%). This apparent paradox is explained by the higher number of high-risk patients in this group (p=0.03). Multivariable analysis of disease-free survival revealed risk category (p=0.02) and use of ATG (p=0.03) to be of significant impact. All patients (n=6) with non-malignant diseases are alive with full donor chimerism. INTERPRETATION AND CONCLUSIONS: These data show that PBSC from unrelated donors can be transplanted either unmanipulated or CD34 selected. Prospective studies comparing BMT with PBSCT from unrelated donors are needed in defined disease categories.

Family with low-grade neuroendocrine carcinoma of salivary glands, severe sensorineural hearing loss, and enamel hypoplasia.

Four sibs in a family on the Isle of Man, two brothers and two sisters ranging in age from 33 to 45 years, presented with low-grade malignant tumors of the submandibular gland in three cases and of the nasal cavities and maxillary sinuses in one. The neoplasms were all of the same histological type, apparently hitherto undescribed, showing well-differentiated neoplastic ducts, surrounded by neoplastic myoepithelial cells, together with sheets of epithelial cells expressing neuroendocrine markers by immunohistochemistry. Cervical neck node metastases have developed in all four cases. In the sib with a primary sinonasal neoplasm, widespread bloodstream metastases also became manifest and a single such metastasis in his brother. All four sibs have severe enamel hypoplasia and the same lesion is present in 5 of their 11 children. In the two male patients, severe sensorineural hearing loss has developed in adult life, unilateral in the left ear in one brother, bilateral in the other. In the brother with bilateral sensorineural hearing loss, magnetic resonance imaging revealed a vestibular schwannoma on the left side, which is currently under treatment. The inherited hearing loss is thought to be unilateral in this case also.

The ear in the acquired immunodeficiency syndrome: II. Clinical and audiologic investigation.

Patients with acquired immunodeficiency syndrome (AIDS) were investigated to determine the sites, nature, and severity of any otologic abnormalities. Tinnitus, "muffled" or "echoing" hearing, and vertigo were frequent complaints. Eight percent of the 155 patients studied showed evidence of chronic otitis media, usually with effusion. Mostly mild, but occasionally severe sensorineural hearing loss was found in many, affecting more severely the higher and lower frequencies than the middle range. Almost all patients showed diminished otoacoustic emissions, suggesting cochlear dysfunction resulting from infection or ototoxicity as the basis for the hearing loss. Impairment of the otoacoustic emissions by a subclinical otitis media with effusion cannot, however, be excluded. On the basis of this study it is suggested that the provision of otologic care to patients with AIDS may enhance their quality of life and, by the early detection and treatment of severe otitis media, may even prolong life.

The ear in the acquired immunodeficiency syndrome: I. Temporal bone histopathologic study.

A postmortem histopathologic investigation of temporal bones of patients with the acquired immunodeficiency syndrome (AIDS) was performed after microslicing, acid decalcification of the slices and paraffin embedding. Histopathologic changes in 49 temporal bones from 25 patients included severe otitis media in five patients (20%), low-grade otitis media in fifteen (60%), labyrinthine cryptococcosis in two, Kaposi's sarcoma deposit in the eighth nerve of one, and cytomegalovirus (CMV) inclusion-bearing cells in the inner and middle ear of six (24%). It was possible to identify the CMV genome by in situ hybridization in only two bones and expression of CMV antigen by immunohistochemistry in none, probably because of prolonged decalcification in acid. The ear is no less susceptible to AIDS-associated diseases than any other organ, and is particularly prone to CMV infection.

Fatal keratitis ichthyosis and deafness syndrome (KIDS). Aural, ocular, and cutaneous histopathology.

We report a case of KID (Keratitis, Ichthyosis, and Deafness) syndrome in which the patient died at the age of 2 months. Detailed histological study of the affected organs, particularly the inner ear and external auditory meatus, was performed. This case is the first in which previously described principles relating to the biology of the ear canal epithelium have been applied to a patient with skin disease affecting this area.

Keratosis of the tympanic membrane and deep external auditory canal. A defect of auditory epithelial migration.

We have previously described the pathways of movement of epithelium on the tympanic membrane, showing that there are two discrete and separate zones. Four cases of keratosis of the tympanic membrane and deep external auditory canal are here reported. All patients complained of tinnitus and other aural symptoms. Sequences of otoscopic photography of daubs of dye placed on the tympanic membrane showed an abnormal anterior movement over the whole tympanic membrane in two cases and complete paralysis of movement in the two others. These findings suggest that the disorder arises from damage to basal epidermal cells caused by inflammation, which is probably due to infection. Treatment is by suction-stripping of keratin from the eardrum. Careful examination of the eardrum under magnification is required in all cases of tinnitus so as to detect this condition.

A histologic study of nonmorphogenetic forms of hereditary hearing impairment.

It appears that many forms of syndromic and nonsyndromic hereditary hearing impairment are secondary to either neuroepithelial or cochleosaccular dysfunction. Making this distinction can be difficult in human temporal bone specimens; however, this added knowledge may ultimately provide prognostic and therapeutic information in hearing habilitation. Fundamental studies using animal models of different types of hereditary deafness may also prove useful in this respect.

Social support and outcome of alcoholism treatment: an exploratory analysis.

Social support is becoming recognized as a positive influence on health and health maintenance. Forms of support which bolster the patient's sense of personal efficacy should enhance the alcoholic's ability to cope with a specific stressor (i.e., overcoming his or her addiction). Patients reporting higher levels of social support during alcoholism treatment, especially support that enhances his or her self-esteem, should therefore demonstrate improved outcome compared to patients with lower levels. Sixty-one consecutive admissions to an inpatient alcoholism treatment program at a rural midwestern medical center completed an assessment of six forms of social support (Guidance, Reliable Alliance, Reassurance of Worth, Opportunity for Nurturance, Attachment, and Social Integration) in terms of support obtained from family and friends and from the treatment environment. For each patient, additional information concerning age, marital status, financial support, and previous alcohol-related hospitalizations was also obtained. Outcome of treatment was measured by readmission for an alcohol-related diagnosis within 1 year of discharge. Survival analysis found that reassurance of worth from family and friends and number of previous hospitalizations were independent and significant predictors of time to readmission. Higher levels of reassurance of worth or esteem support significantly lengthened time to readmission, with the reverse relationship found for number of previous hospitalizations. These results suggest that specific sources (family and friends) and forms (reassurance of worth) of social support are important to the recovering alcoholic and that the effect of social support on treatment outcome is independent of the alcoholic's history of prior treatment failure. Interventions or program modifications should be designed specifically to bolster these facets of social support rather than addressing more general forms of support.

Effects of adaptation on electrocochleography and auditory brain-stem responses in the elderly.

Changes in the amplitude and latency of the evoked potentials in electrocochleography (ECochG) and auditory brainstem responses (ABR) produced by increased stimulus rates (adaptation) were investigated using an extratympanic ECochG technique with simultaneous recording of the ABR in 12 elderly patients, and compared with those of eight normally hearing young adult subjects. Although the absolute latencies of the action potential (AP) and ABR waves were delayed in the elderly, the shift in latency of these components with increased stimulus rate was similar in both groups of subjects. Amplitudes of the AP and wave III component were reduced with increased stimulus rate to a degree which again was similar in both the elderly and young adults. On this basis we suggest that synaptic connections to nerve fibres from surviving hair cells in the elderly are functioning so that disturbance of this part of the acoustic nerve is not a feature of presbycusis.

Stratified squamous epithelium in relation to the tympanic membrane: its development and kinetics.

The pathways of auditory epithelial migration on the human tympanic membrane and their rate of movement were investigated by Hopkins rod photography of dye markings. The origin of these pathways was determined in both the human and the mouse by studying the development of the stratified squamous epithelium of the tympanic membrane and external auditory meatus from earliest embryonic life to maturity. Two pathways of migration are present. In one, epithelium moves from the region covering the tip of the handle of the malleus upwards to the lateral process and then posterior-superiorly with all dye on the pars flaccida to its posterior superior edge. In the second, dye moves centrifugally and radially outwards from the edges of the handle and pars flaccida regions to the annulus. Rate of movement can be determined approximately only and by reference to anatomical landmarks. The first pathway was traced embryologically to migration possibly commencing in the fundus of the primordial first branchial groove. The second pathway has its source in the growth of the meatal plate. A study of the development of the early meatal plate in the mouse suggests that movement of epithelium over the pars tensa region could be the result of a "pulling" effect of mitotically active cells in a generation center at the edge of the tympanic membrane resulting from negative contact inhibition.

Auditory epithelial migration. III. Development of the stratified squamous epithelium of the tympanic membrane and external canal in the mouse.

The development of the stratified squamous epithelium of the tympanic membrane and external auditory canal was studied in serial sections of 124 mouse ears aged from 11 gestational days to 100 days. A fold developed from the edge of the fundus of the primary canal. It possessed two regions: firstly the meatal plate, which produced the pars tensa-covering epithelium (zone 2) and most of the deep ear canal epithelium (zone 3), and secondly the fundal extension plate, which grew from that part of the fundus not forming the meatal plate. The fundal extension plate gave rise to the pars flaccida-covering epithelium (zone 1) and also to the adjacent deep canal epithelium (zone 3). A difference from human development was that zone 3 in the mouse, in both the meatal plate- and the fundal extension plate-derived areas, formed adnexal structures. In the early development of the meatal plate, zone 3, at its tip, was swollen and actively mitotic and extended always for a short distance on to the zone 2 side. Zone 2, first perceived two days after zone 3, became progressively attenuated, and by the fourth day after its formation was a single thin layer. It is suggested that the proximal part of zone 3, situated in the mature ear around the periphery of the tympanic membrane, is a generation center for unidirectional outward flux of epithelium which terminates in the mouse at the first adnexal structure. It may cause the whole of zone 2 to move in the same direction by negative contact inhibition.

Auditory epithelial migration on the human tympanic membrane: II. The existence of two discrete migratory pathways and their embryologic correlates.

The pathways of movement of dye-markings on the tympanic membranes of 30 ears of 15 volunteers were investigated by photography with a Hopkin's rod. Two discrete pathways were identified. Movement on the pars tensa was centrifugal in all directions from the edge of the handle of malleus surface. This supported our previous suggestion that pars tensa epithelial migration is based on growth of the meatal plate. Movement on the more central part of the handle surface itself, however, was always upwards to the pars flaccida epithelium and then, with all dye on the latter, in a posterosuperior direction only. The covering epithelium of the pars flaccida/handle of malleus arises from the fundus of the early embryonic external canal. To explore the possibility that its migration may also commence early, the fundus was examined histologically in 12 embryo ears. It was shaped like an inverted pear to conform to the primordial head of the malleus above and its handle below. There was distinct flattening of the whole fundal epithelium in contrast to the side wall of the external canal, lending support to the concept of a primordial flux of epithelium in the main fundus and its inferior extension. The meatal plate grew from the rim of the fundus producing the pars tensa and deep external canal epithelia. This process, however, was not associated with significant cytologic alterations or increased expression of the human proliferation antigen, Ki-67, at that rim. This suggests that the pars tensa epithelium grows and moves without the active involvement of the epithelium of the pars flaccida/handle of malleus.