Heaps of moles? - Mediating macroscopic and microscopic measurement of chemical substances.

In this paper I take a close look at the SI base quantity "amount of substance", and its unit, the mole. The mole was introduced as a base unit in the SI in 1971, and there is currently a proposal to change its definition. The current definition of the mole shows a certain ambiguity regarding the nature of the quantity "amount of substance". The proposed new definition removes the ambiguity, but at a cost: it becomes difficult to justify treating amount of substance as having its own dimension, and hence its own unit, the mole. I argue that the difficulties with amount of substance result from its role as a mediator between macroscopic and microscopic scales. To understand why amount of substance might have its own dimension, we need to connect amount of substance to mass, contra current proposals to separate them.

Why eliminativism?

A central thesis of Steven French's brand of ontic structural realism has always been his eliminativism about objects. Unsurprisingly, this bold and controversial thesis has seen a lot of critical discussion. In his book The Structure of the World-Metaphysics & Representation, French accordingly defends this thesis against a range of challenges. A novel feature of this defense is the use of dependence relations to articulate his eliminativism. In this paper I take a critical look at French's defense of eliminativism and argue that the dependence relations invoked do not eliminate objects.

Cerebellar location may predict an unfavourable prognosis in paediatric high-grade glioma.

BACKGROUND: High-grade glioma (HGG) of the cerebellum accounts for only 5% of paediatric HGG. Since little is known about these tumours, the present study aimed at their further characterisation. METHODS: Twenty-nine paediatric patients with centrally reviewed cerebellar HGG were identified from the HIT-GBM/HIT-HGG database. Clinical and epidemiological data were compared with those of 180 paediatric patients with cortical HGG. RESULTS: Patients with cerebellar tumours were younger (median age of 7.6 vs 11.7 years, P=0.028), but both groups did not differ significantly with regard to gender, tumour predisposing syndromes, secondary HGG, primary metastasis, tumour grading, extent of tumour resection, chemotherapy regimen, or radiotherapy. Except for an increased incidence of anaplastic pilocytic astrocytoma (APA) in the cerebellar subset (20.7% vs 3.3%; P<0.001), histological entities were similarly distributed in both groups. As expected, tumour grading had a prognostic relevance on survival. Compared with cortical HGG, overall survival in the cerebellar location was significantly worse (median overall survival: 0.92 ± 0.02 vs 2.03 ± 0.32 years; P=0.0064), and tumour location in the cerebellum had an independent poor prognostic significance as shown by Cox-regression analysis (P=0.019). CONCLUSION: High-grade glioma represents a group of tumours with an obviously site-specific heterogeneity associated with a worse survival in cerebellar location.

Low level of microsatellite instability in paediatric malignant astrocytomas.

AIM: Microsatellite instability (MSI) has been proposed as a possible mechanism in the development of cancer. The aim of the current study was to determine whether MSI is involved in the pathogenesis of paediatric malignant astrocytomas. METHODS: We screened a cohort of 126 high-grade astrocytoma samples for MSI using a sensitive and precise method of DNA analysis including a panel of five mononucleotide repeats, in combination with immunohistochemistry for DNA mismatch repair (MMR) proteins. RESULTS: We identified low level of MSI (MSI-L) in four of 126 (3.2%) paediatric malignant astrocytic tumours. To analyse the molecular profile associated with MSI-L positive tumours, we performed immunohistochemistry for protein expression of hMSH6 and p53 as well as mutational analysis of the K-ras gene. In MSI-L paediatric malignant astrocytic tumours we detected retained nuclear expression of hMSH6 protein and strong nuclear accumulation of p53 protein indicating possible mutations of TP53. There was no correlation between K-ras mutational status and frequency of MSI in this patient population. CONCLUSION: Our results suggest that the MSI-L phenotype is associated with p53 accumulation and/or mutations. However, this represents only a small subgroup of paediatric gliomas with possible distinct biological features, and the deficiencies of DNA MMR genes do not play a main role in the tumourigenesis of the majority of paediatric malignant astrocytomas.

Late response to radiochemotherapy in pediatric glioblastoma: report on two patients treated according to HIT-GBM protocols.

High-grade gliomas in children are rare and the best treatment is undetermined. The German language group study HIT-GBM compares various induction protocols for subsequent patient cohorts. Currently, cisplatinum, etoposide, ifosfamide, and vincristine are given simultaneously with extended-field radiotherapy. Imaging is done 3 weeks after to define treatment response, followed by 6-weekly controls during consolidation with lomustine, vincristine, and prednisone. The authors report on 2 patients with incompletely resected glioblastoma multiforme in which response was lacking 3 weeks after radiochemotherapy but became evident 12 weeks later. This suggests that later time points are required to assess induction protocol response.

Secondary dissemination in children with high-grade malignant gliomas and diffuse intrinsic pontine gliomas.

In children, treatment regimen for high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) are generally not stratified according to disease stage. The hypothesis was that secondary disseminating disease (SDD) in children with HGG is related to an even worse outcome. Description of SDD pattern was performed. In total, 270 children with newly diagnosed HGG or DIPG were eligible for retrospective analysis of SDD. Medical and computer records of these patients were reviewed for demographic characteristics, sites of dissemination, prognostic variables. Forty-six (17%) of the 270 patients had developed SDD. The median time to SDD was 8.2 months. The median overall survival (OS) after dissemination was 3.2 months. The SDD was located parenchymal in the supratentorial (34.8%), infratentorial (6.5%), supratentorial and infratentorial (19.6%), spinal (10.9%), spinal and cerebral (6.5%) regions of the CNS, or leptomeningeal (21.7%). For HGG patients, the median OS was shorter among patients with SDD than among patients without SDD (1.02 vs 1.41 years, P=0.0495). In the group of patients with SDD, patients with cerebrospinal fluid dissemination had a worse outcome compared with patients with parenchymal metastases. Summarising, SDD is a negative prognostic factor for patients with HGG outside the pons. Treatment stratification should be considered.

Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study.

Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden.

Impact of location on outcome in children with low-grade oligodendroglioma.

BACKGROUND: Childhood low-grade oligodendroglioma (WHO grade II) are rare. No controlled pediatric study has been published, to generate high level evidence for the best treatment. Therefore, we retrospectively analyzed data available from pediatric patients. PROCEDURE: We pooled data from two prospective German multicentre studies (HIT-DOK and HIT-LGG). Eligibility criteria were: (1) primary neoplasm, (2) histology of pure oligodendroglioma WHO grade II, (3) intracranial location, (4) age <18 years, (5) date of diagnosis: 1990-2002, (6) observation time >6 months. The outcome was analyzed by using the SPSS-software. RESULTS: Nineteen boys and 13 girls were eligible (median age 10.3 years). The tumor locations included: 26 peripheral tumors (23 cerebral hemisphere, 3 cerebellum), and 6 central tumors (4 thalamus, 1 frontal mesencephalon, 1 basal ganglia). Resections were classified as complete in 18 (14 cerebral hemispheres, 3 cerebellum, 1 thalamus) and less than complete in 14 patients (3 subtotal resections, 8 partial resections, 3 biopsy). The 5-year event-free survival (EFS) and overall survival (OS) rates of all patients were 81.3 and 84.4%, respectively (median observation time 3.8 years). All of the 26 children with peripheral tumors were alive with no tumor progression, but five of six patients with central tumors died of disease (median time to death 1.6 years). This survival difference was statistically significant for EFS (P < 0.0001) and OS (P < 0.0001). The difference between completely resected versus incompletely resected tumors was far less striking (P > 0.06). CONCLUSIONS: The outcome of children with centrally located low-grade oligodendroglioma is particularly poor, while tumors of the cerebral hemispheres and cerebellum carry an excellent prognosis, even with minor tumor resection.

High-dose chemotherapy in childhood brain tumors.

Early attempts to use high-dose chemotherapy technology in order to improve the effect of nitrosourea on high-grade gliomas resulted in minimal benefit as well as in severe toxicity. Since then, other drugs have been applied in conjunction with either autologous bone marrow or peripheral blood stem cells, including thiotepa, etoposide, melphalan, cyclophosphamide, and busulfan. The data suggest benefit in recurrent primitive neuroectodermal tumors (PNET), in newly diagnosed young children with PNET and possibly in young children with newly diagnosed ependymoma, as a strategy not only to improve tumor-free survival but also to avoid exposure of the young brain to irradiation. In other tumors such as recurrent ependymoma and newly diagnosed or recurrent brain stem glioma, high-dose chemotherapy remains ineffective. New protocols under evaluation include new agents, multiple cycles of high-dose chemotherapy and allogeneic transplantation as immunotherapeutic approach.

Valproic acid induces differentiation of a supratentorial primitive neuroectodermal tumor.

In preclinical models the antiepileptic drug valproic acid induces differentiation of neoplastic cells, representing an evolving anticancer approach that takes into account that malignant cells resemble immature progenitor cells capable of terminal differentiation. The authors report on a child suffering from a relapsing supratentorial primitive neuroectodermal tumor that received valproic acid for epilepsy treatment over 7 months before the relapse. In contrast to the initial tumor, the relapsing tumor showed glial differentiation and low proliferation index. This is the first report of a relapsed supratentorial primitive neuroectodermal tumor that shows histologically confirmed signs of tumor cell differentiation induction.

Expression of p33ING1 mRNA and chemosensitivity in brain tumor cells.

BACKGROUND: Mutations and down-regulation of tumor suppressor genes can contribute to both tumorigenesis and chemotherapy resistance. The tumor suppressor p33ING1 has growth-inhibitory and pro-apoptotic effects recruiting p53 and it plays a role in DNA repair through interaction with PCNA. We questioned whether p33ING1 mRNA expression correlates with the chemosensitivity of brain tumor cells. MATERIALS AND METHODS: Various malignant brain tumor cell lines were examined for their sensitivity to cisplatin, doxorubicin, etoposide and the antimitotic agents vincristine and paclitaxel by MTT-cytotoxicity assays. p33ING1 mRNA expression was determined by RT-PCR. RESULTS: We found that, unlike other tumor types, ING1 levels were higher in glioma cell lines than in normal control cells. Medulloblastoma cells revealed the lowest ING1 expression of the lines tested. Comparing all cell lines, p33ING1 gene expression significantly (p = 0.028) correlated with resistance to vincristine (r2 = 0.87). CONCLUSION: Our results suggest that p33ING1 mRNA levels may be used to predict the chemosensitivity of brain tumor cells to vincristine.

Treatment of paediatric pontine glioma with oral trophosphamide and etoposide.

To evaluate the overall survival of paediatric patients with pontine gliomas treated with oral trophosphamide and etoposide. Patients between 3 and 17 years of age with either typical diffuse pontine glioma on MRI or histologically proven anaplastic astrocytoma/glioblastoma multiforme located in the pons, were eligible. Treatment consisted of oral trophosphamide 100 mg x m(-2) x day(-1) combined with oral etoposide at 25 mg x m(-2) x day(-1) starting simultaneously with conventional radiation. Twenty patients were enrolled (median age 6 years, male : female=9 : 11). Surgical procedures included: no surgery: five, open biopsy: three, stereotactic biopsy: six, partial resection: three, and sub-total resection: three. Histological diagnoses included pilocytic astrocytoma: one, astrocytoma with no other specification: three, anaplastic astrocytoma: three, glioblastoma multiforme: eight, no histology: five. The most frequent side effects were haematologic and gastrointestinal. There was no toxic death. The response to combined treatment in 12 evaluable patients was: complete response: 0, partial response: three, stable disease: four, and progressive disease: five. All tumours progressed locally and all patients died. The overall median survival was 8 months. The overall survival rates at 1 and 4 years were: 0.4 and 0.05 respectively. This was not different from a control group of patients documented in the same population. Oral trophosphamide in combination with etoposide did not improve survival of pontine glioma patients. The treatment was well tolerated and should be evaluated for more chemoresponsive paediatric malignancies.

Choroid plexus tumours.

Choroid plexus tumours are rare epithelial brain tumours and limited information is available regarding their biology and the best treatment. A meta-analysis was done to determine prognostic factors and the influence of various treatment modalities. A thorough review of the medical literature (1966-1998) revealed 566 well-documented choroid plexus tumours. These were entered into a database, which was analysed to determine prognostic factors and treatment modalities. Most patients with a supratentorial tumour were children, while the most common sites in adults were the fourth ventricle and the cerebellar pontine angle. Cerebellar pontine angle tumours were more frequently benign. Histology was the most important prognostic factor, as one, five, and 10-year projected survival rates were 90, 81, and 77% in choroid plexus-papilloma (n=353) compared to only 71, 41, and 35% in choroid plexus-carcinoma respectively (P<0.0005). Surgery was prognostically relevant for both choroid plexus-papilloma (P=0.0005) and choroid plexus-carcinoma (P=0.0001). Radiotherapy was associated with significantly better survival in choroid plexus-carcinomas. Eight of 22 documented choroid plexus-carcinomas responded to chemotherapy. Relapse after primary treatment was a poor prognostic factor in choroid plexus-carcinoma patients but not in choroid plexus-papilloma patients. Treatment of choroid plexus tumours should start with radical surgical resection. This should be followed by adjuvant treatment in case of choroid plexus-carcinoma, and a "wait and see" approach in choroid plexus-papilloma.

Coronary heart disease associated with the use of human immunodeficiency virus (HIV)-1 protease inhibitors: report of four cases and review.

Four cases of human immunodeficiency virus (HIV)-infected patients who developed coronary heart disease (CHD) while under treatment with a protease inhibitor (PI) are described, and the epidemiologic and clinical features of 18 cases reported in the literature are analyzed. Cardiac manifestations mostly included myocardial infarctions. Smoking and hyperlipidemia were the most common risk factors for CHD, reported in 72 and 81% of the patients, respectively. Hypercholesterolemia was observed in 75% of the cases at the time of the cardiovascular event. Ninety percent of the patients with pretreatment normal lipid values experienced a rise in the plasma lipid levels during PI therapy. Although a definite relationship between the development of CHD and HIV PIs can not be made, this analysis suggests that PI-induced hyperlipidemia may play a role in accelerating coronary atherosclerosis in patients with concomitant risk factors. Evaluation and control of risk factors for CHD should be performed in each patient for whom treatment with a PI is indicated.

Cellular accumulation determines the activity of three novel tricyclic platinum agents.

BACKGROUND: Cisplatin (CDDP) is a very useful chemotherapeutic agent, but cellular resistance limits its efficacy in malignant glioma. In order to analyze and overcome this resistance, we synthesized three novel platinum compounds; aminoplatin, methylplatin and oxiplatin, using tricyclic DNA intercalating molecules as models. MATERIALS AND METHODS: The novel compounds differ only in one chemical group, which is positioned opposite to the DNA binding site. DNA binding, cellular penetration, and cytotoxicity were compared in three human glioma cell lines (T98G, U87-MG, and U25 IN) and a human fibroblast cell strain (HS 68). 2 RESULT: Binding to isolated DNA was most effective in aminoplatin, followed by methylplatin and oxiplatin. It differed by factors I. I, 0.35, 0.23, from the DNA binding of CDDP (factor I) for the three compounds, respectively. The cellular penetration, however, was fastest with oxiplatin (factor 10.1) followed by CDDP (1), aminoplatin (0.55), and methylplatin (0.27). The cytotoxicity of the three novel compounds followed the pattern of their cellular penetration with oxiplatin being the most active. U87-MG cells were resistant to CDDP, and in this cell line oxiplatin was more effective than CDDP in overcoming the resistance. CONCLUSION: This indicates cellular penetration to be an important feature and the ketogroup of oxiplatin to be beneficial in tricyclic platinum compounds.

The kinetics and mechanisms of the reaction of Mesna with cisplatin, oxiplatin and carboplatin.

BACKGROUND: Mesna is a sulfohydrate administered as a supportive drug in conjunction with oxazaphosphorines to prevent bladder toxicity from metabolites. When oxazaphosphorines are given simultaneously with platinum drugs, Mesna binds with platinum drugs as well. Previously we showed in cell culture, that Mesna reduces the efficacy of some platinum drugs. Here we elucidate the chemical reaction mechanism. MATERIAL AND METHODS: Cisplatin, Carboplatin and a novel platinum agent Oxiplatin were incubated with Mesna and the rate of disappearance of Mesna was measured, using an oxidation/reduction reaction between MTT and Mesna. RESULTS: All three platinum agents reacted with Mesna, but the chemical details differed largely. The molar ratios were 3:1, 2:1, and 1:1 for the reactions of Mesna with Oxiplatin, Cisplatin, and Carboplatin, respectively. The speed of the reaction followed a similar pattern, being fastest for Oxiplatin and slowest for Carboplatin. CONCLUSION: When considering the pharmacokinetics of Mesna and these platinum compounds and their reactivity, it appears unlikely that the reaction of Mesna with Carboplatin will become clinically relevant, while Cisplatin, might react with Mesna in patient serum.

Interferon-gamma inhibits growth and migration of A172 human glioblastoma cells.

Malignant gliomas are highly proliferative and invasive tumors with poor prognosis. We investigated the influence of Interferon-gamma (IFN-gamma) on the human malignant glioma cell line A172, measuring cell viability (MTT-test), proliferation (3H-thymidine-uptake), cell death (FACS) adhesion to hyaluronic acid (HA, adhesion-assay) and migration (Boyden-chamber). IFN-gamma significantly decreased cell viability and proliferation. Measured by FACS, an up-regulation of CD95 expression has been shown in combination with an increased rate of cell death, first seen after 96 hours IFN-gamma treatment. Adhesion to HA was decreased after pre-treatment with IFN-gamma. This was not mediated by down-regulation of the main HA-receptor CD44, since IFN-gamma did not change CD44 expression. IFN-gamma-treated cells showed a significantly diminished migration rate through a native or HA-coated 8-microm polycarbonate membrane. To summarise, IFN-gamma influences both the main characteristics of malignancy: it decreases cell proliferation and induces cell death, further it diminishes migration of A172 human glioblastoma cells.

Oral trofosfamide and etoposide in pediatric patients with glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme in childhood is rare, and the prognosis for patients with the disease is poor. The Pediatric Oncology Society of the Germanic language group (GPOH) enrolls patients in a series of pilot trials, the first of which is reported here (HIT-GBM-A). METHODS: Twenty-two patients with glioblastoma multiforme, World Health Organization Grade 4, between the ages of 3-15 years (45% male) were enrolled during the period 1995-1997. There were 13 supratentorial tumors, 8 brainstem tumors, and 1 cerebellar tumor. The patients underwent the following procedures: stereotactic biopsy (n = 3 patients), open biopsy (n = 1 patient), partial resection (n = 6 patients), subtotal resection (n = 4 patients), and macroscopic total resection (n = 8 patients). Adjuvant treatment consisted of oral chemotherapy with trofosfamide, 100 mg/m(2), and etoposide, 25 mg/m(2), daily or for 21-day cycles interrupted by 1-week rests. Standard fractionated radiation (54 grays) was started concurrently with the first cycle. RESULTS: The chemotherapy was well tolerated, with no treatment-related deaths and only minor side effects. The responses in 12 evaluable patients after two cycles were as follows: 1 complete response, 1 partial response, 3 patients with stable disease, and 7 patients with progressive disease. The median overall survival was 12 months. The 1-year, 2-year, and 4-year overall survival rates were 52%, 26%, and 22%, respectively, and the event free survival rates were 26%, 22%, and 4%, respectively. None of the four surviving patients (3.2 years, 3.4 years, 4.0 years, and 4.2 years after diagnosis) is event free. Two patients are alive after tumor progression: One patient was diagnosed with a medulloblastoma, and one patient was diagnosed with an osteosarcoma as second malignancies. A control group extracted from the Surveillance, Epidemiology, and End Results data had lower survival rates: the difference between the groups was not statistically significant (P = 0.26). CONCLUSIONS: This chemotherapy will not be used in a randomized trial of patients with glioblastoma; however, it may be evaluated for patients with tumors that have more chemoresponsive histologies.