The clinical pharmacology of the adenosine deaminase inhibitor 2′-deoxycoformycin

Summary 2-deoxycoformycin (2-dCF; Pentostatin), a stoichiometric inhibitor of mammalian adenosine deaminase (ado deaminase), exhibits immunosuppressive and antilymphocytic activity in animal test systems. A clinical pharmacology/phase I study of 2-dCF administered as a single agent has been completed (18 patients). Dose levels ranged from 0.1 mg/kgx1 to 0.25 mg/kg/dayx5; ado deaminase and 2-dCF were measured spectrophotometrically. Plasma decay curves were bi-exponential ( and t_1/2 values about 1 and 10 h respectively). Recovery of unchanged 2-dCF from urine (48 h) was 32%–48% of the administered drug. Major toxic manifestations were lymphocytopenia (all patients) and urate nephropathy (1 patient, with subsequent patients in the series receiving allopurinol, 300 mg/day). Three partial responses were seen in seven patients with acute lymphocytic leukaemia receiving 0.25 mg 2-dCF/kg/dayx5.     

Impact de l’accès à Internet dans la relation médecin/malade en cancérologie. Réflexions à partir d’un cas clinique.

Résumé: De plus en plus de patients atteints de cancer surfent sur Internet pour trouver des informations sur leur pathologie. Les caractéristques dInternet—facilité daccès, absence de médiation, encyclopédisme, profusion—bouleversent les modes daccès, de transmission et dutilisation du savoir médical. La relation médecin/patient en est bouleversée, plus spécialement dans le cas des maladies graves où le contenu émotif lié à la délivrance du diagnostic (et plus encore du pronostic) exacerbe les enjeux de la relation. À partir dun cas clinique particulièrement représentatif, cet article a pour objet de réfléchir à différentes problématiques:—quen est-il de linformation médicale aujourdhui?—lutilisation dInternet est-elle susceptible dentraver ladaptation psychique des patients confrontés au cancer?—quelles réflexions peut-on en tirer pour la pratique du cancérologue?     

Evaluation of response to postradiation eight in one chemotherapy in childhood brain tumors

Ten children, 3 to 15 years of age with high risk primary brain tumors were treated with postradiation eight in one chemotherapy; vincristine, lomustine, procarbazine, hydroxyurea, cisplatin, cytosine arabinoside, cyclophosphamide and methylprednisolone. The tumors comprised of three medulloblastomas, two primitive neuroectodermal tumors, one ependymoblastoma and four anaplastic ependymomas. Treatment involved surgery (two total resection, six subtotal and two biopsy only) followed by conventional radiotherapy (primary tumor: 50–54 Gy, whole brain: 30–45 Gy, and spinal axis: 25–36 Gy). Objective tumor response with radiotherapy was achieved in 7 of 9 patients (78%) (6/8 patients with residual tumor and one patient with complete resection but positive cerebrospinal fluid cytology). Complete response was attained in 4 of 9 patients (44%). Eight in one chemotherapy was initiated four weeks after radiation and repeated at 4 weekly intervals for 5–8 courses. Postradiation eight in one failed to show any additional effect on tumor responses. Median survival was 34 months (range 9–48 months) with five of ten patients alive: four in complete and one in partial remission. All the five survivors were among the patients who had achieved response to initial treatment. This result suggested that degree of response to initial treatment might determine subsequent outcome and thus the choice of modality for initial therapy might be important.     

Overexpression of the p73 gene is a novel finding in high-risk B-cell chronic lymphocytic leukemia

The p73 protein shares structural and functional similarities with thetumour-suppressor p53, but its role in neoplastic transformation is unknown.Alternative splicing leads to the expression of at least nine p73 C-terminalmRNA splice variants (, , , , , , ,1, ). In this survey, we analyse the expression of p73 byreal-time quantitative RT–PCR, its known C-terminal variants with anRT–PCR-Southern technique and by Western blot in samples of 51 patientswith B-CLL, normal B lymphocytes from eight individuals, and fivehaematopoetic cell lines. p73 protein expression positively correlatedwith higher risk B-CLL stages (P = 0.046). Total p73 mRNAexpression was higher (P = 0.01) and p73 protein morefrequently detected (P = 0.008) in B-CLL compared with normalCD19+–B-lymphocytes. p73 C-terminal mRNA variants were expressed bothin B-CLL and in normal B-lymphocytes, but their expression was biased sincethe (P = 0.041), the (P <0.001), and the variant (P = 0.033) prevailed in normalB-lymphocytes. In summary, we conclude that the accumulation of p73, theexpression pattern of particular p73 variants and its link to progression mayplay a distinct role in the molecular pathology B-CLL.     

Phase I/II tolerability/pharmacokinetic study with one-hour intravenous infusion of doxifluiridine (5′-dFUrd) 3 g/m2 VS 5 g/m2 QD x 5 per month

Summary Eighteen patients with advanced solid cancer were treated with daily 5-dFUrd infusions given over 1 h on days 1–5 of a 4-week cycle. Nine patients received 3 g/m² 5-dFUrd daily and another nine patients 5 g/m². One patient on 5 g/m² 5-dFUrd was not fully evaluable for tolerability due to early death (progressive disease) 4 weeks after the first cycle. A total of 48 cycles was given. The gastrointestinal and hematological toxicity was generally mild (grade 1–2). Central neurotoxicity (ataxia, unsteadiness, diplopia, dysarthria, sometimes confusion) was observed in 7 of 8 patients on 5 g/m² 5-dFUrd leading to premature discontinuation of treatment in 3 patients (after 2 cycles). Only 3 of the 9 patients in the 3 g/m² group had slight signs of cerebellopathy. Typically, the reversible neurological side effects started at the end of the 2nd week of a cycle. The serum elimination kinetics of 5-dEUrd and its metabolites 5-FU and 5-dFUH₂ have been investigated in the serum and showed very low intra- and interindividual variations. Peak concentrations of the 5-dFUrd at the end of the infusion approximated 500 mol/l and 1000 mol/l for the 3 g/m² and 5 g/m² group, respectively. The peak of the serum 5-FU was reached at the same time, the ratio 5-FU/5-dFUrd being around 10%. The elimination half-life time for 5-FU was protracted by a factor of 2–3 compared with the direct injection of 5-FU.Monthly infusion of 5-dFUrd 5 mg/m² per day on days 1–5 lead to an unacceptable frequency and degree of neurological toxicity. Similar infusions of 5-dFUrd 3 g/m² per day on days 1–5 were well tolerated.     

Comparative pharmacokinetics and metabolism of doxorubicin and 4-demethoxy-4′-O-methyldoxorubicin in tumor-bearing mice

Summary It has been reported that 4-demethoxy-4-O-methyldoxorubicin (4-dm-4-O-methylDX) is more potent than doxorubicin (DX), equally active in some murine leukemias and solid tumors, and almost devoid of cardiotoxicity. We used HPLC to investigate the metabolism and the disposition of this drug in comparison with DX in mice bearing colon 38 adenocarcinoma SC and treated with IV doses of the two drugs that were equiactive and equitoxic (4-dm-4-O-methylDX 1 mg/kg; DX 10 mg/kg). 4-Dm-4-O-methylDX was metabolized to a polar metabolite, presumably 4-demethoxyDX, which was eliminated more slowly than the parent drug from all the organs and accounted for 25%–50% of total fluorescence; traces of two metabolites less polar than the parent drug (2% of total fluorescence) were found only at early times in the liver. In DX-treated mice traces of doxorubicinol (1%–3% of total fluorescence) were found in tumor and organs, and two aglycones were detected only at early times in the liver. In plasma both drugs declined biexponentially and 4-dm-4-O-methylDX was eliminated slightly faster than DX. The rate of elimination of the new analogue from lung, kidney, spleen, and small intestine was faster than that of DX; in heart and liver 4-dm-4-O-methylDX was detectable for only up to 24 h, while DX was detectable for up to 7 days. In the tumor the kinetics and the elimination patterns of the two drugs were similar. The distribution of 4-dm-4-O-methylDX, as a percentage of the administered dose, was 1.3–2 times higher than that of DX in the organs and 3 times higher in the tumor, which suggests an improved selectivity of the new analogue for the tumor compared with DX.The work described in this paper was supported by grant N. 84.00855.44 of the Oncologia project of the Consiglio Nazionale delle Ricerche, Rome, Italy     

Biomarkers for local recurrence after breast‐conservation — a nested case‐control study

Purpose: A previous cohort study of 759 women with invasive T1T2 breast cancer operated on with breastconserving surgery in Stockholm between 1976 and 1986 indicated that age <50 years, no postoperative irradiation, and nodal involvement were independent risk factors for ipsilateral breast tumor recurrences (IBTR). The aim of the current study was to analyse if selected biological markers assayed in tumor specimens from these patients could add prognostic information, thereby helping to identify groups of patients at high versus low risk of IBTR.Methods: The study was designed as a casecontrol study nested within the cohort. The cohort was stratified according to nodal status and the use of postoperative irradiation. In these four strata, the cases were those 80 women who developed IBTR between 1977 and 1994. In each stratum, women without IBTR were randomly selected as controls (n=159). Median time at risk was 12 (8–18) years. The following factors were analysed: histopathological tumor grade according to Elston–Ellis, DNA ploidy, immunohistochemical staining for apoptosis, angiogenesis, Ki67 (MIB1), cerbB2, p53, waf1, and bcl2. The prognostic role of each factor was assessed using linear logistic regression methods.Results: In univariate analyses only age <50 years was identified as a significant risk factor for IBTR, whereas none of the studied biomarkers yielded statistically significant information. However, in a multivariate model, age, MIB-1-index, and tumor grade significantly influenced the risk for IBTR: the odds-ratio (OR) for age 50 years was 0.4, 95% confidence interval (CI)=0.2–0.9; for medium or high grade tumors it was 0.4 (CI=09–0.9); and for MIB-1-index >30%, 2.1 (CI=1.0–4.4). In women 50 years, MIB-1-index >30% was associated with an OR of 3.5 (CI=1.4–8.8) compared to those who were younger. Patients 50 years with MIB-1-index 30% were thus identified as a low-risk group with an OR of 0.2 (CI=0.1–0.5). A possible high-risk group was patients <50 years with tumors showing a combination of c-erbB-2 and waf-1 immunoreactivity, with an OR of 6.7 (CI=1.3–34.7).Conclusion: Women 50 years with MIB-1-index 30% constituted a subgroup with a low risk of IBTR. This observation raises the issue whether this group of patients might be spared postoperative irradiation following breast-conserving surgery. However, due to the methodology of the study, including the large number of comparisions, the presented results warrant cautious interpretation and should be regarded as tentative.     

Pharmacokinetics of carboplatin administered with lobradimil to pediatric patients with brain tumors

Purpose To determine the pharmacokinetics of adaptively dosed carboplatin when administered in combination with the bradykinin agonist, lobradimil (RMP-7, Cereport), to pediatric patients with brain tumors.Methods Carboplatin pharmacokinetic studies were performed on 21 of 25 children with primary brain tumors who received carboplatin and lobradimil on two consecutive days every 28 days in a phase I dose-escalation trial of lobradimil. Carboplatin was adaptively dosed, based on the radioisotopic glomerular filtration rate (GFR) to achieve a target plasma area under the concentration vs time curve (AUC) of 3.5 mgmin/ml per dose ×2 (2.5 mgmin/ml per dose ×2 in patients with prior craniospinal radiation or myeloablative chemotherapy). The adaptive dosing formula was: carboplatin dose (mg/m²)=target AUC (mgmin/ml) × [0.93 × GFR (ml/min/m²)+15]. Carboplatin was infused over 60 min (n=15) or 15 min (n=6). The 10-min lobradimil infusion (100–600 ng/kg ideal body weight) began 5 min before the end of the carboplatin infusion. Frequent blood samples were drawn over 24 h after the first dose of carboplatin/lobradimil. Ultrafilterable platinum was measured by atomic absorption spectroscopy, and the AUC of ultrafilterable platinum was derived using the linear trapezoidal rule and extrapolated to infinity.Results The median GFR was 65 ml/min/m² (range 38–95 ml/min/m²) and the median carboplatin doses for the 2.5 and 3.5 mg min/ml target AUCs were 154 and 276 mg/m²/day (124–235 and 179–360 mg/m²/day), respectively. The measured carboplatin AUC exceeded the target AUC in all 21 patients by a median of 35% (range 0.2–131%). The median carboplatin AUCs at the 2.5 and 3.5 mgmin/ml target AUCs were 3.4 and 4.8 mgmin/ml (2.51–5.8 and 3.9–7.7 mgmin/ml), respectively. Carboplatin clearance was lower than values previously reported in children and correlated poorly with GFR (r²=0.14).Conclusions Adaptive dosing of carboplatin based on GFR overestimated the dose required to achieve the target carboplatin AUC in pediatric patients with brain tumors treated with concurrent lobradimil. The degree to which the measured carboplatin AUC exceeded the target AUC appeared to be greater at higher doses of lobradimil, suggesting that the failure of the adaptive dosing method was related to an unexpected pharmacokinetic drug interaction.     

Conjugation of interferon alpha to a humanized monoclonal antibody (HuBrE-3vl) enhances the selective localization and antitumor effects of interferon in breast cancer xenografts

Human mammary carcinoma xenografts (MCF-7) growing in nude mice were treated with natural interferon (n-IFN-) alone or conjugated to a humanized monoclonal antibody (MoAb) anti-breast mucin (HuBrE-3vl) or to irrelevant human IgG₁. The IFN and the conjugates were administered as 20 intra-lesional (i.l.) injections to 1 of 2 xenografts in each mouse, or i.p. The growth inhibitory effects of HuBrE-3vl/nIFN- were significantly greater than those of nIFN- used as a single agent or conjugated to HuIgG₁. These effects occurred locally in the tumors receiving i.l. injections and systemically, although to a slightly lesser extent, in the noninjected tumors of mice treated i.l. and in the xenografts of mice treated i.p. Biodistribution studies showed that the uptake of ¹²⁵I-HuBrE-3vl/nIFN- by the tumors 24 hours after i.l. or s.c. injection was greater than that of ¹²⁵I-HuIgG₁/nIFN-,¹²⁵ I-nIFN- alone, or by normal tissues, documenting a tumor targeting effect and favorable tumor:normal tissues (T:NT) ratios. The targeting effects and the resulting tumor growth inhibition were favored by the IFN-mediated up-regulation of the HuBrE-3vl reactive antigen, which was more prominent after 3 weeks of treatment with HuBrE-3vl/nIFN-. These results were superior to those we obtained previously with nIFN- conjugated to another MoAb of the same group (Mc5). These studies point out the potential usefulness of HuBrE-3vl/nIFN- for the local and systemic treatment of breast cancer lesions by providing a means of delivering high doses of IFN to the tumors while minimizing the amount of IFN binding to normal tissues.     

Exploratory study of drug plasma levels during bicalutamide 150 mg therapy co-administered with tamoxifen or anastrozole for prophylaxis of gynecomastia and breast pain in men with prostate cancer

Objective:A randomized multicenter (14 centers) trial was conducted in 114 men with prostate cancer to determine whether the antiestrogen tamoxifen (Nolvadex) 20 mg or the aromatase inhibitor anastrozole (Arimidex) 1 mg prevent gynecomastia and breast pain during treatment with the non-steroidal antiandrogen bicalutamide (Casodex) 150 mg, without compromising efficacy, safety, or quality of life. Plasma samples were collected in a subgroup of these patients to investigate whether trough (pre-dose) concentrations of bicalutamide 150 mg are influenced by concomitant administration of tamoxifen 20 mg or anastrozole 1 mg; the results of this pilot study are reported in this article. Methods: A subpopulation of patients from a randomized placebo-controlled trial evaluating tamoxifen 20 mg and anastrozole 1 mg for the prevention of gynecomastia and breast pain in men receiving bicalutamide 150 mg for early or recurrent prostate cancer were selected on a voluntary basis from three of the trial centers. Plasma samples were collected on days 7, 14, 28, and 84 of therapy and analyzed to determine the plasma concentrations of (R)–bicalutamide and (S)-bicalutamide. In addition, plasma concentrations of tamoxifen, N–desmethyltamoxifen, and anastrozole were determined. Results: A total of 21 patients were selected. There was no significant difference between treatment groups with respect to the trough plasma concentrations of either bicalutamide enantiomer at any point during the study. Plasma concentrations of the enantiomers, and the relative proportion of the ®)- and (S)–enantiomers, were consistent with those reported in previous studies. Plasma concentrations of tamoxifen, N–desmethyltamoxifen, and anastrozole were also similar to those described elsewhere in the literature. Conclusions: The findings of this pilot study suggest that trough plasma concentrations of bicalutamide enantiomers following administration of bicalutamide 150 mg are not markedly influenced by concomitant administration of tamoxifen 20 mg or anastrozole 1 mg. However, an effect of tamoxifen on bicalutamide pharmacokinetics can not be completely excluded due to the size of this study. Further studies are needed to clarify the effect of tamoxifen on bicalutamide pharmacokinetics and prostate cancer control in bicalutamide-treated patients. Arimidex, Casodex, and Nolvadex are trademarks of the AstraZeneca group of companiesThis trial was sponsored by AstraZeneca (Milan, Italy)     

Pediatric Medulloblastoma: Prognostic Value of p53, bcl-2, Mib-1, and Microvessel Density

The aim of this study was to retrospectively assess the prognostic value of p53 and bcl-2 protein expression, cell proliferation index (Mib-1 index), and tumor microvessel density (factor VIII-related antigen) in pediatric medulloblastoma patients. Tumor specimens of 55 patients (age 2–18 years) with medulloblastoma treated with a curative intent between 1972 and 1991 were studied. Slides of paraffin embedded tissue were stained with monoclonal antibodies (mAb) and examined under high power light microscopy for the presence of immunoreactivity. Microvessel density was scored both in the area of most intense staining (Angio-max) and in 3 additional randomly selected areas. The sum of these 4 scores was termed Angio-total. Angio-max and Angio-total were evaluated separately by two independent investigators to assess reproducibility. None of the parameters studied, i.e. p53 or bcl-2 expression, Mib-1 index or microvessel density scores were associated with patient survival. Microvessel scores between observers were significantly but weakly correlated, with correlation coefficients (r)<0.5 for both Angio-max and Angio-total. Leptomeningeal spread at diagnosis was the only independent factor associated with a poor survival (p=0.003). There was no association of leptomeningeal metastasis with any of the biological markers tested in this study.     

Expression of LFA-1/ICAM-1 in CNS lymphomas: possible mechanism for lymphoma homing into the brain

We examined a possible role for the adhesion molecules LFA-1 and ICAM-1 in localizing central nervous system non-Hodgkin's lymphomas (CNS-NHLs) to the brain. Fresh frozen sections from 12 monoclonal CNS NHLs (11 primary, one secondary) were stained with monoclonal antibodies to LFA-1 chain (CD11a), chain (CD18) and, ICAM-1 (CD54). Additional staining made use of rat monoclonal antibodies to the human and mouse high endothelial venule antigens HECA 452 and MECA 79 and mouse ICAM-1. The expression of these same molecules was also studied in mice with severe combined immunodeficiency (SCID) mice, bearing intracranial human lymphoblastoid cells.Eleven of the CNS-NHL tumors expressed LFA-1 (one strongly, one intermediate, nine weakly). Nine of the tumors weakly expressed LFA-1.. Nine of twelve tumors weakly expressed ICAM-1. In six of seven tumors definite blood vessels stained for ICAM-l. Non-tumor brain from two patients and non-tumor cerebral blood vessels showed no staining with CD11a, CD18 or CD54 antibodies. Strong expression of LFA- and LFA- as well as ICAM-1 was noted in human lymphoblastoid cells (LCLs)/SCID mouse CNS lymphomas. Tumor blood vessels in these mice stained for mouse ICAM-1. Normal SCID mouse brains showed no staining with CDII, CD18, CD54 or mouse ICAM-1 antibodies. Human, human/mouse CNS lymphomas, normal human, and mouse brains showed no staining with either HECA 452 or MECA 79.Our data suggests that CNS lymphomas express LFA-1, LFA-1 and to a lesser degree ICAM-1 antigen, while tumor blood vessel endothelium expresses ICAM-1. LFA-1-LFA-1/ICAM-1 interaction may play a role in large cell lymphoma homing and persistence in the brain.     

Psychological distress following first recurrence of disease in patients with breast cancer: prevalence and risk factors

Purpose: To investigate the effect of understanding their own disease by patients with metastatic breast cancer on their survival potential after being informed by their physician. Patientsandmethods: Two hundred and fourteen women with metastatic breast cancer who participated in a multi-institutional, randomized phase III trial (Japan Clinical Oncology Group (JCOG) Study 8808) were asked whether they understood their own disease after being given information about the clinical trial. They were classified into two groups on the basis of whether they understood or not. We estimated their survival after the time of registration and derived relative hazard ratios from Cox's proportional hazards model. Results: There were 190 patients in the better understanding group and 24 in the poor understanding group. Median survival times after registration were 28.3 and 16.1 months, respectively. The better understanding group showed a significant difference from the poor understanding group (p=0.016). In multivariate regression analysis, patients who did not understand still showed poorer survival than those who understood (hazard ratio = 2.09; 95% confidence interval (CI) 1.16–3.78; p=0.014)     

Urinary testosterone as a marker of risk of recurrence in operable breast cancer

Summary We investigated the role of urinary testosterone levels as a marker of risk of recurrent disease in 113 operable breast cancer patients (70 premenopausal, 43 postmenopausal). Twenty-four-hour urine collections for testosterone measurement were obtained before surgical treatment, between 20–40 days thereafter, and then every 6 months for 5 years. The cutoff values to separate high testosterone (A+) from normal testosterone (A–) were 8.0µg/24h in premenopause and 4.9µg/24h in postmenopause. Urinary testosterone levels were considered high when they exceeded the cutoff value in at least 2 of the first 3 measurements (pretreatment, post-treatment, 6 months) of each patient. According to the aforementioned criterion, 33 patients (29.2%) had high testosterone levels, which were associated to axillary node involvement in 16 patients. Thirteen of the latter relapsed during the 5-year follow-up period (5/7 in premenopause, 8/9 in postmenopause). Relapse-free survival (RFS) curves were drawn only for node-positive patients owning to the small number of recurrences observed in the node-negative group. In premenopausal node-positive patients, RFS was significantly different for patients presenting high and normal urinary testosterone levels (77% vs 28%, respectively; logrank test, p< 0.006). In postmenopausal node-positive patients, RFS was also different between the two groups (54% vs 11% in high and normal excretors, respectively) but the difference was not statistically significant. The present findings suggest that urinary testosterone is a prognostic indicator of early breast cancer recurrence in node-positive patients.     

Local Recurrence of Metastatic Brain Tumor after Stereotactic Radiosurgery or Surgery Plus Radiation

In this study, we compared the recurrence of metastatic brain tumors after radiosurgery versus after surgery plus radiation, and analyzed the factors associated with the recurrence of brain metastases. Twenty-eight and 35 patients with metastatic brain tumors underwent radiosurgery (52 lesions) and surgery plus radiation (46 lesions), respectively, between 1995 and 2001. The median tumor volume was 1.55ml (range: 0.02–10.4ml) in radiosurgery patients and 17.9ml (range: 0.26–195ml) in surgery plus radiation patients. The median radiosurgical tumor central and margin doses were 28.9 and 23.8Gy (range: 20–35 and 25–15Gy), respectively. The median total dose was 46.7Gy (range: 30–63Gy) in the surgery plus radiation group.The recurrence time from surgery plus radiation group (25 months) was significantly longer than that from the radiosurgery group (7.2 months) (p=0.0199). The factors affecting the recurrence of brain metastases after radiosurgery were size, central dose of radiation and histology (colon vs. others). No factors affected the recurrence of brain metastases after surgery plus radiation. To avoid early recurrences of metastatic brain tumors, surgery plus radiation is the preferable therapeutic modality. The size and histology of brain metastases, and the dose of radiation should be considered for the effective treatment of tumors by radiosurgery.     

Brain metastasis in pediatric extracranial solid tumors: survey and literature review

Objectives: Brain is a rare site of metastasis in most extracranial pediatric solid tumors. The aim of this study is to investigate the incidence, treatment, prognosis of brain metastasis in extracranial pediatric malignant tumors in a single institution and to review the literature.Methods: From September 1989 to December 2002, 1100 children 16years of age with extracranial solid tumors including lymphomas were diagnosed and treated in the Division of Pediatric Oncology, Oncology Institute, Istanbul University. Patients with parenchymal metastases in the brain were assessed.Results: Sixteen (10 female, 6 male) of 1100 patients (1.45%) with extracranial solid tumors developed brain metastases. The median age of the patients was 10.5 (1–16)years. The diagnosis was sarcomas in 12 patients: 5 osteosarcomas, 4 Ewings sarcoma family tumors, 1 rhabdomyosarcoma, 1 clear cell sarcoma of the soft tissue, 1 alveolar soft part sarcoma. Two patients had Wilms tumor and two had germ cell tumors. Four patients (25%) had brain metastasis at diagnosis. Twelve (75%) developed brain metastasis during therapy or relapse at a median duration of 16 (1–70)months from initial diagnosis. All patients had metastases to various sites, mostly lung, at the time the brain metastases were detected. Treatment included surgery, followed by postoperative radiotherapy (RT) and chemotherapy (CT) in 1, S and RT in 1, S in 1, RT and CT in 6, RT in 1, CT in 1 and no treatment in 5. Only one patient with alveolar soft part sarcoma is alive with disease 20months from diagnosis of brain metastasis. All other patients died at a median time of 2months (2days–6months) from the time of brain metastasis.Conclusions: Children with metastatic cancer who develop headaches or any other neurologic symptom should be investigated for possible brain metastasis. Although, the outcome for these patients is dismal in this series and in the literature; reports of long term survival in a few cases with Wilms tumor, osteosarcoma and alveolar soft part sarcoma who had isolated brain metastasis, suggest that a subset of patients may benefit from therapy.This study was partially presented as a poster in the International Society of Pediatric Oncology (SIOP) meeting in Porto, 2002 and in the 10th International Symposium on Pediatric Neuro-oncology, London in June 2002.     

Alcohol consumption and risk of breast cancer: a cohort study

Objectives: To study the association between alcohol consumption and breast cancer risk. Methods: A case–cohort analysis was undertaken within the cohort of 56,837 women who were enrolled in the Canadian National Breast Screening Study (NBSS) and who completed a self-administered dietary questionnaire. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40–59 at recruitment.) The cohort was recruited between 1980 and 1985, and during follow-up to the end of 1993 a total of 1469 women in the dietary cohort were diagnosed with biopsy-confirmed incident breast cancer. For comparative purposes a subcohort consisting of a random sample of 5681 women was selected from the full dietary cohort. After exclusions for various reasons the analyses were based on 1336 cases and 5238 noncases. Results: When compared to nondrinkers the adjusted incidence rate ratios (95% confidence intervals) for those consuming>0 and 10g of alcohol/day, >10 and 20g/day, >20 and thinsp;30g/day, >30 and 40g/day, >40 and 50g/day, and >50g/day were 1.01 (0.84–1.22), 1.16 (0.91–1.47), 1.27 (0.91–1.78), 0.77 (0.51–1.16), 1.00 (0.57–1.75), and 1.70 (0.97–2.98), respectively; the associated p value for the test for trend was 0.351. Similar findings were obtained when analyses were conducted separately in the screened and control arms of the NBSS, in premenopausal and postmenopausal women, for screen-detected and interval-detected breast cancer, and by levels of other breast cancer risk factors. Conclusions: The results of this study suggest that alcohol consumption might be associated with increased risk of breast cancer at relatively high levels of intake.     

Influence of tumor size on the main drug-metabolizing enzyme systems in mouse colon adenocarcinoma Co38

Mouse colon adenocarcinoma Co38 is widely used as a screening model for human colon tumors. To understand better the influence of tumor size on the main drug-metabolizing enzyme systems, we tested 15 mouse Co38 tumors at different sizes. The average weight was 917±444 mg (range, 300–1,400 mg). Cytochromes P-450 (1A1/1A2, 2B1/B2, 2C8–10, 2E1, 3A4), epoxide hydrolase (EH), and glutathione-S-transferases (GST-,-, and-) were assayed by immunoblotting. The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: 1-chloro-2,4-dinitrobenzene-GST (CDNB-GST), selenium-independent glutathione peroxidase (GPX), 3,4-dichloronitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), total glutathione (GSH), uridine diphosphate-glucuronosyltransferase (UDP-GT), -glucuronidase (G), sulfotransferase (ST), and sulfatase (S). Our results showed the absence of all probed P-450s and EH in Co38 tumors. No relationship was found between the Co38 tumor weights and GPX, GST-, and EA-GST (regression analysis). However, a significant correlation was found between the tumor weights and all other enzymes investigated. For certain enzymes or cofactors, a linear decrease (P<0.05) was observed as a function of tumor weight (CDNB-GST, DCNB-GST, GST-, GST-, GSH, and G). Other enzymatic activities (UDP-GT, S, and ST) were found to decrease in medium-size tumors and to increase in large tumors (P<0.05; quadratic correlation). These data demonstrate that the expression of many drug-metabolizing enzyme systems is altered during tumor growth and suggest that tumoral response to chemotherapy could be altered as a function of tumor size.This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Association pour la Recherche sur le Cancer (ARC, Villejuif)     

Selective incorporation of111In-labeled PHOTOFRIN™ by glioma tissuein vivo

The use of PHOTOFRIN for photodynamic therapy of human gliomas has been studied by i.v. administration and laser photosensitization. Defining the uptake of PHOTOFRIN in the patient's tumor in comparison with the surrounding normal brain tissue is highly desirable for patient selection and study ofin vivo kinetics. We utilized a non-invasive approach to the detection of PHOTOFRIN uptake in brain tumors with¹¹¹In-oxine radiolabeled PHOTOFRIN and external imaging and quantitation using a gamma camera. Biodistribution of¹¹¹In-labeled PHOTOFRIN in 13 organs was determined in four dogs and 15 mice with gliomas.^99mTc-DTPA was used as a control for nonspecific uptake. The greatest concentration of¹¹¹In-PHOTOFRIN in the brain tumor occurred at 24 hours post i.v. administration. The brain tumor PHOTOFRIN uptake was seven times greater than that of normal brain. The decreased blood background at 72 hours made this the optimum time for imaging. Specific tumor tissue uptake of¹¹¹In-PHOTOFRIN occurred, well beyond that resulting from blood-brain-barrier (BBB) breakdown.     

Genetic polymorphisms of platelet adhesive molecules: association with breast cancer risk and clinical presentation

The main platelet adhesive receptors integrin 21, integrin IIb3 and glycoprotein (GP) Ib are also expressed in breast carcinoma cells. They play a key role in tumor cell-induced platelet aggregation and in adhesive interactions necessary for tumoral invasion and metastasis. Several polymorphisms affecting these molecules, two in integrin 2 (C807T and G1648A), one in integrin 3 (T1565C) and one in GP Ib (VNTR), influencing their levels, structure, and possibly their function, have been previously described and associated with cardiovascular diseases. In this study, we investigated the association of these polymorphisms with breast cancer risk or clinical presentation. We studied 101 patients with invasive breast cancer. The main prognostic variables were recorded, and genomic PCR analysis of these polymorphisms was performed. A group of 101 control subjects matched on age and sex was studied and compared with patients. No association was found between VNTR (GP Ib) polymorphism and breast cancer risk or presentation. Genotype and allele frequencies of C807T and G1648A polymorphisms of integrin 2 were not statistically different in breast cancer patients and controls, although we found an association between the 1648G/G genotype and higher disease stages (III and IV) (p = 0.02). Breast cancer risk was higher in carriers of 3 integrin T/T genotype (OR = 2.08, 95% CI = 1.04–4.16, p = 0.04). Furthermore, genotype 1565T/T was also associated with axillary nodal metastasis (p = 0.017) and with tumoral diameter greater than 2 cm (p = 0.02). Although confirmatory studies are needed, our results suggest that polymorphic genetic variation of integrins expressed in platelets and epithelial breast cells could modify the risk and the biological aggressiveness of breast carcinomas.