Do centenarians die healthy? An autopsy study.

BACKGROUND: Our goal was to assess the prevalence of common causes of death and the demographic variables in a selected population of centenarians. METHODS: The autopsy reports and medical histories of all individuals > or =100 years, dying unexpectedly out of hospital, were gathered from 42,398 consecutive autopsies, performed over a period of 18 years at the Institute of Forensic Medicine, Vienna. These records were evaluated with regard to age and sex, circumstances of death, season, time and the cause of death, as well as the presence of any other comorbidity. RESULTS: Forty centenarians (11 men, 29 women) were identified with a median age of 102 +/- 2.0 (range: 100-108) years. Sixty percent were described as having been healthy before death. However, an acute organic failure causing death was found in 100%, including cardiovascular diseases in 68%, respiratory illnesses in 25%, gastrointestinal disorders in 5%, and cerebrovascular disease in 2%. Additionally, centenarians suffered from several comorbidities (cardiac antecedents, neurologic disorders, liver diseases, cholecystolithiasis), which were not judged to be the cause of death. CONCLUSIONS: Centenarians, though perceived to have been healthy just prior to death, succumbed to diseases in 100% of the cases examined. They did not die merely "of old age." The 100% post mortem diagnosis of death as a result of acute organic failure justifies autopsy as a legal requirement for this clinically difficult age group.

Foreign body asphyxia: a preventable cause of death in the elderly.

BACKGROUND: To assess the prevalence of food/foreign body asphyxia in the elderly Viennese population in order to reduce the incidence of these fatal events. METHODS: This is an autopsy-based, retrospective study in Vienna, Austria. Participants included all nonhospitalized (n =200) cases of choking in 1984 to 2001, from a total 42,745 consecutive autopsies performed at the Institute of Forensic Medicine. In addition, data from hospitalized adult cases of fatal choking (n =73) in 1984 to 2001, from the mortality registrar of Vienna, were included. RESULTS: The nonhospitalized choking victims were analyzed according to age (18 to 64 vs >/=65 years), sex, circumstances of death, and predisposing factors. Hospitalized cases were analyzed according to age, sex, and whether an autopsy was already performed by pathologists at the institution where they died. In the study period, 273 adults died of food/foreign body asphyxia, 73% of them out of the hospital and 27% in hospitals. Food/foreign body asphyxia in the elderly was characterized by a significantly higher asphyxiation of soft/slick foods (p <0.007) with agomphiasis (p <0.002), occurring most frequently during lunch (49%), and in 2.5% during feeding of neurologically impaired. In contrast, younger individuals choked significantly more often on large pieces of foreign material (p <0.002) and showed a significantly higher rate of blood alcohol concentration (p <0.001). CONCLUSIONS: This study demonstrates that semisolid foods are the cause of a large number of asphyxiations, especially among the elderly. Knowledge of the fact that semisolid foods are a high-risk factor in elderly individuals should be distributed in public and private healthcare systems, and awareness could be a first step in reducing the incidence of food/foreign body asphyxia.

Glioblastoma with spinal seeding.

BACKGROUND: Extracranial seeding of glioblastoma multiforme (GBM) is very rare and its development depends on several factors. This case report describes two patients suffering from GBM with spinal seeding. In both cases, the anatomic localization of the primary tumor close to the cerebrospinal fluid (CSF) was the main factor for spinal seeding. CASE REPORTS: Two patients with GBM and spinal seeding are presented. After diagnosis of spinal seeding, both patients were highly symptomatic from their spinal lesions. Case 1 experienced severe pain requiring opiates, and case 2 had paresis of lower limbs as well as urinary retention/incontinence. Both patients were treated with spinal radiation therapy. Nevertheless, they died 3 months after diagnosis of spinal seeding. RESULTS: In both patients the diagnosis of spinal seeding was made at the time of cranial recurrence. Both tumors showed close contact to the CSF initially. Even though the patients underwent intensive treatment, it was not possible to keep them in a symptom-free state. CONCLUSION: Because of short survival periods, patients deserve optimal pain management and dedicated palliative care.

Preliminary study on pharmacokinetics of dacarbazine and fotemustine in glioblastoma multiforme patients does not indicate gender-specific differences.

Twelve patients (six female and six male) with histologically proven glioblastoma multiforme were investigated during the administration of the first cycle of dacarbazine (D; 200 mg/m) and fotemustine (F; 100 mg/m). In total, 18 blood samples were collected for pharmacokinetic analysis (maximum plasma concentration, area under the concentration-time curve and total clearance) of D and F at 14 time points during therapy. D, its metabolite 5-aminoimidazole-4-carboxamide and F were evaluated by reversed-phase HPLC. For statistical calculations, groups were compared by the non-parametric Wilcoxon test. p<0.05 was considered statistically significant. No significant gender-dependent differences were observed in the pharmacokinetics of D and F. An additional response re-evaluation of 100 patients (50 female and 50 male) with glioblastoma multiforme, treated at our institution with D and F, gave no hint of any gender-dependent different response rates. We conclude that there is no evidence, neither from pharmacokinetic nor from our clinical data, to consider different dosages of D and F in female and male patients with glioblastoma multiforme.

Stabilization of a progressive hemangioblastoma under treatment with thalidomide.

After the second recurrence of spinal seeding in hemangioblastoma not associated to von-Hippel-Lindau disease, we treated an adult female patient with thalidomide 200 mg orally/day at night for longer than 1 year. The patient reported subjective relief of symptoms after 1 month. Magnetic resonance imaging (MRI) controls 1,6 and 11 months after begin of thalidomide treatment did not show further tumor progression. She remained wheelchair-bound, but mobility of her arms continuously improved. There was no thalidomide associated side-effect in this patient until her death from pneumonia due to legionnaire's disease. Antiangiogenic treatment with interferon (IFN) alpha-2a and IFN alpha-2b and with SU 5416 has been reported to be effective and well tolerated in several patients with previously progressive angioblastomas and hemangioblastomas. This case adds further evidence of the efficacy of an antiangiogenic treatment concept in a progressive hemangioblastoma.

Cytogenetic and comparative genomic hybridization findings in four cases of breast cancer after neoadjuvant chemotherapy.

To assess a potential common pattern of genetic alterations in chemotherapy-resistant tumors we analyzed four tumors from breast cancer patients (patients 1-4) after neoadjuvant chemotherapy, by comparative genome hybridization (CGH) and conventional chromosome banding analysis. All patients showed structural aberrations involving chromosomes 1, 5, 11, 16, and 17. In CGH analysis, the patients showed typical imbalances for ductal breast cancer: gains of 1q (3 patients), 5q (2 patients), 8q (3 patients), and X (4 patients) and losses of 1p33 approximately p36 (3 patients), 16q (3 patients), 17p (3 patients), 19 (4 patients), and 22q (4 patients). Other recurrent imbalances of atypical pattern for ductal breast cancer were gain of 4q21 approximately q32 (2 patients), 20q21 approximately q22 (2 patients), and 21 (2 patients) and loss of 20p (3 patients). Three patients showed involvement of several regions bearing genes of drug resistance (MDR1 [HUGO symbol: ABCB1], BCRP [HUGO symbol: ABCG2], MRP1 [HUGO symbol: ABCC1], RFC1); the fourth patient displayed an amplification in the region of MYC (alias c-myc), thus providing--at the level of the light microscope--an explanatory background for the ability of their tumors to survive anthracycline-, taxane- and cyclophosphamide-based chemotherapy. Conventional cytogenetic analysis and CGH displayed highly coincidental findings in the tumors of four patients after neoadjuvant chemotherapy for breast cancer.

Second-line chemotherapy with dacarbazine and fotemustine in nitrosourea-pretreated patients with recurrent glioblastoma multiforme.

The aim of this study was to assess the efficacy and toxicity of a combination of dacarbazine (D) and fotemustine (F) administered to a homogenous group of patients with recurrent or progressive glioblastoma multiforme (GBM). Thirty-one patients with computed tomography or magnetic resonance imaging scan evidence of recurrent or progressive GBM after first-line chemotherapy with nitrosoureas as well as radiation therapy were given a combination of D (200 mg/m2) and F (100 mg/m2). At 30 min after termination of D administration, F was given over 60 min. Treatment was performed in an outpatient setting every 21 days. A total of 140 cycles (range 1-12 cycles; median 4 cycles) was administered. One partial response (3%) lasting for 11 weeks was observed. Sixteen (52%) patients reached stable disease lasting between 7 and 94 weeks. Median survival from start of the D/F combination was 45 (range 10-150) weeks. Median time to progression was 17 (3-101) weeks for all patients. Major toxicity was myelosuppression resulting in exclusion from study in seven (23%) patients [due to thrombocytopenia common toxicity criteria (CTC) grade 2 persisting longer than 3 weeks in three patients, due to thrombocytopenia CTC grade >/=3 in three and due to leukopenia CTC grade 3 in one patient]. No other toxicity than alopecia occurred. We conclude that the D/F combination is a well-tolerated second-line regimen and can be administered in a complete outpatient setting. D/F shows efficacy even in nitrosourea-pretreated patients and justifies further investigation.

Survival improvement in patients with glioblastoma multiforme during the last 20 years in a single tertiary-care center.

METHODOLOGY: The survival of 357 consecutive patients with newly diagnosed glioblastoma multiforme (GBM) in three treatment groups reflecting different time-periods of diagnosis (A: 1982-1984; B: 1994/1995; C: 1996-1998) was analysed to assess the impact and the potential improvement of changing treatment strategies in our tertiary-care center. PATIENTS AND METHODS: Group A (n = 100) included all consecutive patients diagnosed from 1982 to 1984 and served as the historical control. Group B (n = 93) included all consecutive patients diagnosed in 1994/1995 and group C (n = 164) those diagnosed from 1996 to 1998. Survival in the three treatment groups (A vs. B vs. C) was analysed according to treatment given after neurosurgical intervention (i.e. no specific therapy versus radiotherapy versus combined radio-/chemotherapy), and according to first-line chemotherapy, age (< 40, 40-60, > 60), sex, and tumor location (hemispheric versus bilateral or multifocal tumors, and tumors involving eloquent brain areas). Survival was analysed using Kaplan-Meier's non-parametric method. A p-value < 0.05 was considered statistically significant. RESULTS: Patients in groups A and B received radio- and/or chemotherapy to a varying extent (radiotherapy: group A: 22%, group B: 62%; chemotherapy: group A: 6%, group B: 33%). Chemotherapy was administered after termination of radiotherapy in both groups. In group C, 96% of patients received combined radio-/chemotherapy which was administered concomitantly and started within three weeks after surgery. Median survival was 5.2 months in group A, 5.1 months in group B and 14.5 months in C (p < 0.0001). Nine patients in group A (9%), 9 in group B (10%) and 40 in group C (25%) survived more than 18 months (p < 0.05). CONCLUSIONS: Survival improvement in group C might be attributable to the early start of combined radio-/chemotherapy. Therapy was administered on a complete outpatient basis, enabled by a dedicated interdisciplinary neuro-oncologic team caring for group C. Toxicity was mild and patients' acceptance excellent.

Survival and prognostic factors of patients with unresectable glioblastoma multiforme.

The aim of this study was to assess survival and prognostic factors of 98 consecutive patients with unresectable glioblastoma multiforme (GBM) after stereotactic biopsy. Patients were diagnosed between 1993 and 1998, and the treatment modality subsequent to stereotactic biopsy was determined by the year of diagnosis. Before 1995, patients did not receive further specific therapy after stereotactic biopsy (n=36). In 1996, patients were administered radiotherapy starting within 6 weeks after stereotactic biopsy (n=24). From 1997 to 1998, patients received combined radio-/chemotherapy (RCT; CCNU orally) starting within 2 weeks after stereotactic biopsy (n=38). Patients' age ranged from 21 to 84 (median 64) years and their median Karnofsky performance score 2 weeks after stereotactic biopsy was 80 (range 60-100). Survival and prognostic factors were analyzed with respect to administered treatment modalities (without specific therapy versus radiotherapy versus combined RCT), with respect to age (>oror=or<80), tumor location (frontal, parieto-temporal, central, occipital) and tumor size (>or5 cm) by the Kaplan-Meier method, by log-rank test and multivariate Cox regression analysis. Post-biopsy treatment modality was the strongest predictor for survival. Median (range) survival was 9 (3-47) weeks in those without specific therapy, 13 (5-54) weeks in patients receiving radiotherapy and 31 (11-101) weeks in patients receiving combined RCT (p

Unexpected out-of-hospital deaths in persons aged 85 years or older: an autopsy study of 1886 patients.

PURPOSE: The aim of this study was to determine the causes of death in the very elderly. METHODS: We reviewed 24,081 consecutive autopsies performed over 10 years (1989 to 1998) at the Institute of Forensic Medicine, Vienna, Austria. We focused on autopsies of people aged 85 years or older who died unexpectedly out of hospital. RESULTS: The mean age of the 1886 patients (561 men and 1325 women) at the time of death was 88 +/- 3 years (range, 85 to 108 years). Thirty-one percent (n = 588) of those who died were described as having been previously healthy. Cardiovascular disease was the most common cause of death (n = 1465 [77%]). Thirteen percent (n = 246) died of respiratory illness, 5% (n = 94) of gastrointestinal disorders, and 3% (n = 53) of diseases of the central nervous system. Genitourinary and metabolic diseases were uncommon. CONCLUSION: Although this out-of-hospital sample is not representative of the entire elderly population, postmortem examinations emphasize the importance of cardiovascular diseases in causing unexpected deaths in older persons.

Feasibility and toxicity of CCNU therapy in elderly patients with glioblastoma multiforme.

In our institution, 103 glioblastoma multiforme (GBM) patients aged from 55 to 83 years were treated since November 1994 as follows. All patients underwent surgical intervention (gross total resection, n = 35; subtotal resection, n = 38; stereotactic biopsy, n = 30). Subsequently all patients were offered radiotherapy and chemotherapy with CCNU. Results were as follows: 101 patients started radiotherapy, 93 patients completed it (96% of the patients aged < 65 years and 85% of the patients > or =65 years). All patients received at least 1 cycle of chemotherapy (median 3 cycles). Chemotherapy-associated toxicity was generally mild, more pronounced in females and did not increase with age. Median time to progression was 10.5+/-3.2 months for the patients < 65 years and 5.1+/-1 months for patients > or =65 years. median overall survival was 17.5+/-3.8 months in patients < 65 years and 8.6+/-1 months in patients > or =65 years (p < 0.0001). In multivariate analysis, age and female sex remained independent prognostic factors. Our data indicate that a treatment concept including concomitant radio- and chemotherapy is feasible even in elderly patients with GBM.

Alterations in intestinal permeability following the intensified polydrug-chemotherapy IFADIC (ifosfamide, Adriamycin, dacarbazine).

PURPOSE: The aim of this study was to investigate the severity and time-course of alterations in gastroduodenal and intestinal permeability in relation to nausea/emesis following administration of the highly emetogenic polydrug regimen IFADIC (ifosfamide, Adriamycin, dacarbazine) using a differential lactulose/mannitol absorption (SLM) test. We also assessed the ease of administration and patients' tolerance of the SLM test. METHODS: The SLM test was performed in seven patients with soft tissue sarcomas on days 1, 3 and 14 of cycle I and cycle III of chemotherapy; seven healthy volunteers served as controls. The degree of correlation between the clinical grade of nausea/emesis according to WHO criteria and gastroduodenal permeability, expressed in terms of urinary sucrose excretion, and intestinal permeability, expressed in terms of the permeability index (urinary lactulose to mannitol permeability ratio), was also assessed. RESULTS: The permeability index values were significantly different (P < or =0.01) on days 1, 3 and 14 during both cycles of chemotherapy. The median permeability index on day 3 was higher (P < =0.01) in patients with nausea/emesis than in those without symptoms. Additionally, the permeability index when nausea was present (day 3) was higher (P < or =0.01) than when nausea/emesis was absent (days 1 and 14). In 59% of patients the increased permeability index on day 3 was accompanied by nausea/emesis of WHO grade 3. Gastroduodenal permeability did not alter consistently following chemotherapy. CONCLUSIONS: Our study confirms an acute, transient increase in intestinal permeability following the polydrug regimen IFADIC, accompanied by nausea/emesis of WHO grade 3 in the majority of patients. Normal intestinal permeability was achieved on day 14 in all patients, thus allowing intensified 2-weekly treatment administration. The SLM test may be recommended as a feasible test for the objective assessment of alterations in intestinal permeability following chemotherapy administration.