Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme.

BACKGROUND: XR5000 is a tricyclic carboxamide that intercalates DNA and inhibits both topoisomerase I and II. The aim of this study was to evaluate the efficacy and tolerability of XR5000 in patients with recurrent glioblastoma multiforme previously untreated with chemotherapy at relapse. PATIENTS AND METHODS: Patients received XR5000 at a dose of 3010 mg/m2 as a 120-h central venous infusion every 3 weeks. An independent panel assessed response every two cycles using McDonald's criteria (tumour size, steroid intake and neurological status); toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 2.0. RESULTS: Sixteen patients were enrolled (one ineligible patient was excluded from efficacy evaluation). Performance status was zero (five patients), one (nine patients) or two (one patient). They received 30 cycles of XR5000 (median 2, range 1-5). Haematological toxicity was mild, with only one patient experiencing grade 3 neutropenia. Other related grade 3/4 adverse events included chest pain (one patient), axillary vein thrombosis (one patient) and rigors/fever in the absence of neutropenia (one patient). There were no objective responses, 14 patients progressing on XR5000 and one having stable disease. CONCLUSIONS: Although XR5000 was generally well tolerated, these results do not support further evaluation in patients with glioblastoma multiforme using this dose and schedule.     

LAMA tumor in the rat as an experimental model for pre-B-cell leukemia

A late pre-B-cell leukemia model in the rat, the LAMA tumor, is described. A mouse monoclonal antibody (HIS30) was developed against LAMA cells. HIS30 reacts with a membrane antigen in tumor tissue, whereas its reactivity with normal tissues is limited to the zona glomerulosa of the adrenal cortex and to the adrenal medulla. HIS30 was used for both the immunohistological detection of tumor cells in tissue sections and the immunolocalization of tumor cells in vivo. To enable in vitro studies with the LAMA model, an in vitro growing cell line (LAMA-K1) was established from the LAMA tumor. LAMA-K1 is immunophenotypically similar to the original tumor. Two tumor transplantation models were characterized. In the first model LAMA was implanted s.c., and local tumor growth occurred at the injection site, which was then followed by lymphatogenic and subsequently hematogenic tumor spread. In the second model i.v. transplantation caused direct hematogenic tumor dissemination. In both models early dissemination was especially prominent to the bone marrow, spleen, and liver. Later in the disease most visceral organs became involved, and partial paralysis of the animal was observed in the end stage of the disease. In combination with HIS30, the LAMA pre-B-cell tumor offers a model for both the investigation of in vivo transplanted tumor cells and for the in vivo detection of tumor cells by HIS30 in LAMA tumor-bearing rats.     

Population pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide, 2-dechloroethylcyclophosphamide, and phosphoramide mustard in a high-dose combination with Thiotepa and Carboplatin

The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4-hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). The aim of this study was to develop a population pharmacokinetic model describing the complex pharmacokinetics of CP, 4OHCP, 2DCECP, and PM when CP is administered in a high-dose combination with thiotepa and carboplatin. Patients received a combination of CP (1000-1500 mg/m/d), carboplatin (265-400 mg/m/d), and thiotepa (80-120 mg/m/d) administered in short infusions over 4 days. Twenty blood samples were collected per patient per course. Concentrations of CP, 4OHCP, 2DCECP, PM, thiotepa, and tepa were determined in plasma. Using NONMEM, an integrated population pharmacokinetic model was used to describe the pharmacokinetics of CP, 4OHCP, 2DCECP, and PM, including the already described processes of autoinduction of CP and the interaction with thiotepa. Data were available on 35 patients (70 courses). The pharmacokinetics of CP were described with a 2-compartment model, and those of 4OHCP, 2DCECP, and PM with 1-compartment models. Before onset of autoinduction, it was assumed that CP is eliminated through a noninducible pathway accounting for 20% of total CP clearance, whereas 2 inducible pathways resulted in formation of 4OHCP (75%) and 2DCECP (5%). It was assumed that 4OHCP was fully converted to PM. Induction of CP metabolism was mediated by 2 hypothetical amounts of enzyme whose quantities increased in time in the presence of CP (kenz=0.0223 and 0.0198 hours). Induction resulted in an increased formation of 4OHCP (approximately 50%), PM (approximately 50%), and 2DCECP (approximately 35%) during the 4-day course, and concomitant decreased exposure to CP (approximately 50%). The formation of 2DCECP was not inhibited by thiotepa. Apparent volumes of distribution of CP, PM, and 2DCECP could be estimated being 43.7, 55.5, and 18.5 L, respectively. Exposure to metabolites varied up to 9-fold. The complex population pharmacokinetics of CP, 4OHCP, 2DCECP, and PM in combination with thiotepa and carboplatin has been established and may form the basis for further treatment optimization with this combination.     

A swelling in the knee cavity, not caused by a Baker's cyst but by a nerve sheath tumour

In a woman, aged 30 years, who presented with a right popliteal mass, a Baker's cyst (popliteal cyst) was diagnosed. Five years later she developed symptoms that were attributed to compression of the peroneal nerve by the mass. Because of the troublesome nature of these symptoms, it was decided to excise the mass. Immediately after the operation, a complete loss offunction ofthe common peroneal nerve was apparent. Histopathologic examination revealed an ancient schwannoma (nerve sheath tumour). The most important reason for not having diagnosed the schwannoma was that it was not considered in the differential diagnosis of the popliteal mass. Although Baker's cysts are the most common popliteal masses, nerve sheath tumours should also be considered in the differential diagnosis.     

Admission of elderly patients to intensive care

Elderly patients have an increased probability of dying after treatment in an intensive care unit (ICU), compared with younger patients. The risk of dying is largely determined by the admission type (patients with planned admissions have a better prognosis than those with unplanned admissions), severity of illness and functional status prior to admission. Elderly patients surviving ICU often experience a decline in functional status. No data are available on the factors that predict functional outcome. Elderly patients do not necessarily prefer life-sustaining treatment to palliative care. The willingness to undergo ICU treatment depends on the likelihood of survival and beneficial functional outcome. New prognostic models should be developed specifically to predict both survival and functional outcome in individual elderly patients after admission to ICU.     

Reviewing the effort-reward imbalance model: drawing up the balance of 45 empirical studies

The present paper provides a review of 45 studies on the Effort-Reward Imbalance (ERI) Model published from 1986 to 2003 (inclusive). In 1986, the ERI Model was introduced by Siegrist et al. (Biological and Psychological Factors in Cardiovascular Disease, Springer, Berlin, 1986, pp. 104-126; Social Science & Medicine 22 (1986) 247). The central tenet of the ERI Model is that an imbalance between (high) efforts and (low) rewards leads to (sustained) strain reactions. Besides efforts and rewards, overcommitment (i.e., a personality characteristic) is a crucial aspect of the model. Essentially, the ERI Model contains three main assumptions, which could be labeled as (1) the extrinsic ERI hypothesis: high efforts in combination with low rewards increase the risk of poor health, (2) the intrinsic overcommitment hypothesis: a high level of overcommitment may increase the risk of poor health, and (3) the interaction hypothesis: employees reporting an extrinsic ERI and a high level of overcommitment have an even higher risk of poor health. The review showed that the extrinsic ERI hypothesis has gained considerable empirical support. Results for overcommitment remain inconsistent and the moderating effect of overcommitment on the relation between ERI and employee health has been scarcely examined. Based on these review results suggestions for future research are proposed.     

Cycle length dependence of the chronotropic effects of adrenaline, acetylcholine, Ca2+ and Mg2+ in the Guinea-pig sinoatrial node

Ca (1.1-5.5 mM) has a positive chronotropic action on isolated right atria of the guinea-pig. The magnitude of the response depends on the cycle length. Magnitude and cycle length dependence of the Ca response are independent of beta-blockade by propranolol. Mg (0.6-6.0 mM) has a negative chronotropic action. At 6.0 mM it interferes with responses to adrenaline and acetylcholine by preventing pacemaker shifts. Adrenaline has a positive chronotropic action in a cycle length dependent manner. A shift of pacemaker dominance under the influence of adrenaline to an identical site in all preparations (as in the rabbit) was not observed. However, pacemaker shifts in the presence of adrenaline do occur and they are always directed towards the inferior part of the node. Acetylcholine has a negative chronotropic action, independent of cycle length. Acetylcholine also induces pacemaker shifts. Contrary to the pacemaker shifts caused by adrenaline, the new, acetylcholine-induced pacemaker center, has an identical site in all preparations. This was previously observed in the rabbit too. The acetylcholine-induced center is located about 1 mm inferior from the primary center. During exposure to acetylcholine different action potentials may be recorded at the epi- and endocardial side of the preparation, but only close to the Ach-induced center. The acetylcholine-induced center is located at the epicardial side. The response to acetylcholine predominates over the response to adrenaline. All results are discussed in comparison with our previous findings in the rabbit.     

Biological basis for human capacitation

More than 50 years ago Austin and Chang defined mammalian sperm capacitation as a period of time that sperm must reside in the female reproductive tract before they acquire the ability to fertilize oocytes. Since then numerous investigations have attempted to more clearly define the molecules and processes that are a part of capacitation. The data that have provided a more clear definition of capacitation were primarily derived from in vitro experiments. This is particularly true for studies on human sperm capacitation. While ethical constraints have limited an equal balance of in vivo studies there are those data that when coupled with some of the in vitro data allow for the formulation of a biological framework for human sperm capacitation in vivo. This review will put forth the biological basis for human capacitation.