Boron Neutron Capture Therapy for Glioblastoma Multiforme: Clinical Studies in Sweden

A boron neutron capture therapy (BNCT) facility has been constructed at Studsvik, Sweden. It includes two filter/moderator configurations. One of the resulting neutron beams has been optimized for clinical irradiations with a filter/moderator system that allows easy variation of the neutron spectrum from the thermal to the epithermal energy range. The other beam has been designed to produce a large uniform field of thermal neutrons for radiobiological research. Scientific operations of the Studsvik BNCT project are overseen by the Scientific Advisory Board comprised of representatives of major universities in Sweden. Furthermore, special task groups for clinical and preclinical studies have been formed to facilitate collaboration with academia. The clinical Phase II trials for glioblastoma are sponsored by the Swedish National Neuro-Oncology Group and, presently, involve a protocol for BNCT treatment of glioblastoma patients who have not received any therapy other than surgery. In this protocol, p-boronophenylalanine (BPA), administered as a 6-h intravenous infusion, is used as the boron delivery agent. As of January 2002, 17 patients were treated. The 6-h infusion of 900mg BPA/kg body weight was shown to be safe and resulted in the average blood–boron concentration of 24g/g (range: 15–32g/g) at the time of irradiation (approximately 2–3h post-infusion). Peak and average weighted radiation doses to the brain were in the ranges of 8.0–15.5Gy(W) and 3.3–6.1Gy(W), respectively. So far, no severe BNCT-related acute toxicities have been observed. Due to the short follow-up time, it is too early to evaluate the efficacy of these studies.     

Role of Ceramide During Cisplatin-induced Apoptosis in C6 Glioma Cells

Cisplatin is commonly used for the treatment of malignant brain tumors. However, the mechanisms of cell death by cisplatin are not fully understood. Therefore, the present study was designed to elucidate the apoptotic signaling pathway(s) activated by cisplatin in a C6 rat glioma cell line. C6 cells were treated with various concentrations of cisplatin (0.2–10g/ml) for 24–72h. At 10g/ml cisplatin, over 90% of the cells became dead at 72h. Apoptotic death was confirmed by condensation and fragmentation of nuclei, and DNA laddering. Even in cells treated with 1.5g/ml cisplatin, typical apoptotic cells were observed at 72h. The intracellular level of ceramide, measured Escherichia coli diacylglycerol kinase markedly increased during 24–72h after the addition of 10g/ml cisplatin. The activity of caspase-3(-like) proteases increased and reached a peak at 48h. Inhibitors of caspases reduced the number of apoptotic cells. Pretreatment of C6 cells with glutathione or N-acetyl-cysteine, which are known to block the activation of neutral magnesium-dependent sphingomyelinase, inhibited ceramide formation, leading to suppression of both activation of caspase-3(-like) proteases and apoptosis by cisplatin. In contrast, pretreatment of the cells with N-oleoylethanolamine (OE), a ceramidase inhibitor, potentiated apoptosis induced by cisplatin. Furthermore, OE enhanced sensitivity of the cisplatin-resistant cells to cisplatin. These results suggest that ceramide is closely implicated in apoptosis of glioma cells by cisplatin through activation of caspase-3(-like) proteases.     

Neuroblastoma and parental occupation

Objectives: We evaluated parental occupation and the risk of neuroblastoma using data from a large case–control study conducted by the Children's Cancer Group and the Pediatric Oncology Group.Methods: We compared the distribution of 73 paternal and 57 maternal occupational groups among 504 newly diagnosed cases of neuroblastoma and individually matched controls obtained by telephone random digit dialing in the United States and Canada.Results: An increased risk of neuroblastoma was found for fathers employed as broadcast, telephone and dispatch operators (odds ratio [OR]=6.1; 95% confidence interval [CI]=0.7–50.9), electrical power installers and power plant operators (OR=2.7; CI=0.9–8.1), landscapers and groundskeepers (OR=2.3; CI=1.0–5.2), and painters (OR=2.1; CI=0.9–4.8). Elevated odds ratios were found for mothers employed as farmers and farm workers (OR=2.2; CI=0.6–8.8), florists and garden store workers (OR=2.4; CI=0.6–9.9), hairdressers and barbers (OR=2.8; CI=1.2–6.3), electric power installers and power plant operators, and sailors, fishers, and railroad workers. No increase in risk was found for other paternal occupations previously associated, including electricians, electrical equipment assemblers and repairers (OR=1.1; CI=0.6–2.0), or welders (OR=0.5; CI=0.1–1.6).Conclusion: The study reinforced some prior evidence of increased risks in electrical, farming and gardening, and painting occupations, but failed to confirm other previously reported associations. Further analyses of exposure to electromagnetic fields, metals, solvents, and pesticides are currently under way.     

Infertility and risk of fatal ovarian cancer in a prospective cohort of US women

Objectives: It is difficult to separate the possible role of fertility drugs from underlying infertility as risk factors for ovarian cancer. The present study examined the relationship between self-reported infertility and death from ovarian cancer among married women unlikely to have been exposured to fertility drugs.Methods: Women were selected for study from the 676,526 female participants in Cancer Prevention Study II (CPS-II). After twelve years of follow-up, 797 deaths from ovarian cancer were observed among women with no prior history of cancer or hysterectomy and 40 years of age or older in 1967 when ovulatory stimulants were approved in the United States. Cox proportional hazards modeling was used to compute rate ratios (RRs) and to adjust for other potential risk factors.Results: Overall, self-reported infertility was not significantly associated with ovarian cancer mortality (adjusted rate ratio (RR)=1.1, 95 percent confidence interval (CI)=0.9-1.3). Ovarian cancer death rates among nulligravid women with self-reported infertility, however, were 40 percent higher than for nulligravid women who never tried to become pregnant (RR=1.4, 95 percent CI=0.9-2.4). Multigravid women who reported infertility problems were not at increased risk.Conclusions: These results suggest that infertility itself, without concomitant exposure to fertility drugs, may increase risk of fatal ovarian cancer among nulligravid women.     

Progression of Premalignant MCF10AT Generates Heterogeneous Malignant Variants with Characteristic Histologic Types and Immunohistochemical Markers

The purpose of this study was to evaluate the pain experience of women during mammography for breast cancer screening. Possible associations with personal and medical history, sociodemographics and/or situational factors were studied. It was also investigated whether this pain influenced the intention to return for future breast cancer screening. In the Netherlands, women between 50–75 years are invited for screening every two years. A total of 1200 participants were asked to fill up a questionnaire. The response rate was 79.5% (n=954), and 945 questionnaires contained adequate information for analyses. A total of 689 women (72.9%) described mammography as mild to severely painful. In this group, compared to the group that reported no pain, the following factors occurred significantly more often: sensitive breasts (P=0.001), family history of breast diseases (P=0.017), expected pain based on former mammography (P=0.001), high education (P=0.008), anxiety (P=0.001), breast sensitivity in last three days (P=0.001), insufficient attention of technologist (P=0.001). Other factors like age, hormonal status, breast size and hormone use were not associated with the pain experienced. Thirty-two women (3.3%) indicated that they would not attend further screening, 25 (2.6%) reported that the pain might deter them, six women (0.6%) had other reasons, one woman (0.1%) was sure not to come because of severe pain. In conclusion, a large majority of women attending breast cancer screening describes mammography as painful (72.9%). Factors associated with pain were described. Relatively few women (2.7%) indicated that the pain might deter them from future mammography. Recommendations are given to reduce the pain experienced during screening mammography.     

Survival and tumor characteristics of German hereditary breast cancer patients

Reports from different countries have been inconclusive in attempting to relate the BRCA1 mutation status to the survival of breast cancer patients. The purpose of this study was to investigate overall and disease-free survival for German hereditary breast cancer patients. Data on clinical outcome and data on age at diagnosis of breast cancer, histology, tumor size, lymph node status, histological grade, and laterality of 36 breast cancer patients from 12 families with a BRCA1 mutation and from one family with strong evidence for linkage to BRCA1 were compared with those of 49 hereditary breast cancer patients from 23 families that did not harbor a BRCA1 mutation. Overall and disease-free survival was estimated for both groups. BRCA1 mutation carriers had a significantly earlier age of diagnosis than non-carriers (p=0.0001) and more frequently developed contralateral breast cancer (p=0.04). Also, BRCA1-associated tumors more frequently were of larger size (p=0.041) and higher grade of malignancy (p=0.005) than non-BRCA1-associated tumors. Whereas no difference in overall survival was seen, disease-free survival at 10 years differed significantly with 53.3% for BRCA1 mutation carriers and 76% for non- carriers (p=0.02). However, after stratification for age and in multivariate analysis for mutation status, age, and bilaterality, it was shown that the worse prognosis for BRCA1 mutation carriers disappeared. Our results suggest that the worse prognosis of BRCA1 mutation carriers in terms of disease-free survival may in large part be due to the age of onset of breast cancer in this population. Thus, BRCA1 mutation status does not appear to be an independent prognostic factor.     

Ultrastructural Changes of the Vascular Endothelium after Intra-arterial Administration of Tumor Necrosis Factor-alpha (TNFα) in Rat Gliomas

The ensuing ultrastructural changes in tumor vascular endothelial cells following intra-arterial administration of tumor necrosis factor- (TNF) were studied in an experimental rat glioma model. C6 glioma cells were implanted in Wistar rats and then after 14 days, 5×10³U of human natural-type TNF (1.7×10⁵U/m²) was administered through the carotid artery. The animals were sacrificed at 3 or 24h after TNF treatment. A detailed examination with transmission electron microscope revealed swelling of the tumor vascular endothelial cell nuclei and mitochondria with matrix densities at 3h. At 24h, these cells demonstrated the presence of high amplitude mitochondrial swelling or the violent blebbing characteristic of damaged mitochondria; the cytoplasm was swollen enormously and there were dissolution of cytoplasmic organelles and rupture of the plasma membrane. The observed findings were typical of cell necrosis and confirms yet another mechanism by which TNF exerts its anti-tumor effects, that is, necrotizing effects on tumor vascular endothelium. The information appears to be important in the context of clinical application of intra-arterial TNF in the treatment of malignant gliomas.     

Prevention of rat mammary carcinoma utilizing leuprolide as an equivalent to oophorectomy

A clinical trial is currently under way to examine the effectiveness of leuprolide as a breast cancer chemopreventive agent and contraceptive. This trial, as well as similar proposed studies, is based on the assumption that leuprolide is as effective as surgical castration in preventing the onset of mammary tumors; however, this has not been well documented in the DMBA animal model. We directly compared leuprolide and oophorectomy in this model and examined a combined therapy of leuprolide/bromocriptine. Twenty-seven day old female Sprague-Dawley rats were randomly allocated into one of eight groups. All rats received a 20-mg dose of DMBA at the age of 55 days. Group 1 (n=10), no treatment; Group 2 (n=9), leuprolide (100g/kg/day) for eight weeks beginning four weeks prior to DMBA; Group 3 (n=10), oophorectomy four weeks prior to DMBA with replacement estrogen beginning four weeks following DMBA. Estrogen replacement was achieved with a 0.05-mg estradiol tablet releasing 0.833g/day over a 60-day period. Group 4 (n=10), leuprolide (100g/kg/day) initiated two weeks prior to DMBA and continuing for two weeks following DMBA; Group 5 (n=9), oophorectomy two weeks prior to DMBA with 0.05mg of estradiol in depot form, releasing 0.833g/day, beginning four weeks following DMBA and continuing until week 16 of the study; Group 6 (n=10), leuprolide (100g/kg/day) beginning two weeks prior to DMBA and continuing for the duration of the experiment; Group 7 (n=10), leuprolide (100g/kg/day) for eight weeks beginning two weeks prior to DMBA; Group 8 (n=9), leuprolide (100g/kg/day) and bromocriptine (83g/day) for eight weeks beginning two weeks prior to DMBA. At nineteen weeks (15 weeks post DMBA), animals were sacrificed and autopsies performed. One hundred percent of untreated animals developed tumors. No animals undergoing oophorectomy four weeks prior to DMBA or receiving leuprolide four weeks prior to and simultaneously with DMBA developed tumors. In animals pretreated two weeks prior to DMBA with leuprolide or oophorectomy, each group had one animal with tumor development. No tumors developed in the animals receiving ongoing injections of leuprolide. However, one tumor developed in those receiving leuprolide for the first eight weeks beginning two weeks prior to DMBA administration. One animal receiving both leuprolide and bromocriptine developed one tumor. We conclude that chemical oophorectomy (with leuprolide) is as effective as surgical oophorectomy in inhibiting DMBA induced carcinogenesis.     

Tolerance of the Normal Canine Brain to Epithermal Neutron Irradiation in the Presence of p-boronophenylalanine

Twelve normal dogs underwent brain irradiation in a mixed-radiation, mainly epithermal neutron field at the Brookhaven Medical Research Reactor following intravenous infusion of 950mg of ¹⁰B-enriched BPA/kg as its fructose complex. The 5 × 10cm irradiation aperture was centered over the left hemisphere. For a subgroup of dogs reported previously, we now present more detailed analyses including dose–volume relationships, longer follow-ups, MRIs, and histopathological observations. Peak doses (delivered to 1cm³ of brain at the depth of maximum thermal neutron flux) ranged from 7.6Gy (photon-equivalent dose: 11.8Gy-Eq) to 11.6Gy (17.5Gy-Eq). The average dose to the brain ranged from 3.0Gy (4.5Gy-Eq) to 8.1Gy (11.9Gy-Eq) and to the left hemisphere, 6.6Gy (10.1Gy-Eq) to 10.0Gy (15.0Gy-Eq). Maximum tolerated threshold doses were 6.7Gy (9.8Gy-Eq) to the whole brain and 8.2Gy (12.3Gy-Eq) to one hemisphere. The threshold peak brain dose was 9.5Gy (14.3Gy-Eq). At doses below threshold, some dogs developed subclinical MRI changes. Above threshold, all dogs developed dose-dependent MRI changes, neurological deficits, and focal brain necrosis.     

High-dose chemotherapy with autologous stem cell rescue for children with high risk and recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors

Current treatment for high risk and recurrent medulloblastoma (MB) and supratentorial primitive neuroectodermal tumors (stPNET) has a very poor prognosis in children. High dose chemotherapy (HDCT) and autologous stem cell rescue have improved survival rates. We present 19 patients (thirteen classified in the high risk group and six patients with recurrent disease) that received HDCT and autologous stem cell rescue.In the high risk group [Med Pediatr Oncol 38 (2002) 83], all patients underwent neurosurgical debulking. Standard chemotherapy was prescribed in 10 patients. Radiotherapy was given to 4 patients (all older than 4years old). In the recurrence disease group [Childs Nerv Syst 15 (1999) 498], five patients underwent surgery. Radiotherapy was given to those who were not previously irradiated. The HDCT in twelve patients consisted of busulfan 4mg/kg/day, orally over 4days in 6-hourly divided doses and melphalan at a dose of 140mg/m²/day by intravenous infusion over 5min on day –1. Three patients additionally received thiotepa 250mg/m²/day intravenously over 2days and four patients additionally received topotecan 2mg/m²/day over 5days by intravenous infusion over 30min. The other seven patients received busulfan and thiotepa at the same doses.Patients stem cells were mobilized with granulocyte colony-stimulating factor at a dose of 12g/kg twice daily subcutaneously for four consecutive days. Cryopreserved peripheral blood progenitor cells were re-infused 48h after completion of chemotherapy. With a median follow-up of 34months (range 5–93) eight complete responses and one partial response were observed. Three patients died of treatment-related toxicities (15%). The 2 year event-free survival was 37.67±14% in all patients and 57±15% for the high risk group.Therefore we conclude that HDCT may improve survival rates in patients with high risk/recurrent MB and stPNET despite treatment toxicity.     

Repetitive 5-aminolevulinic acid-mediated photodynamic therapy on human glioma spheroids

The response of human glioma spheroids to repetitive 5-aminolevulinic acid-mediated photodynamic therapy (PDT) was investigated. In all cases, light fluences were kept below toxic thresholds to simulate conditions typically found at 1–2cm depths in brain adjacent to tumor. Significant inhibition of spheroid growth was observed following multiple PDT treatments at sub-threshold light fluences. The effect appears to be insensitive to the treatment intervals investigated (weekly or bi-monthly). In all cases, suppression of growth was observed for the duration of treatment. Low fluence rates (5mWcm^–2) appear to be more effective than high fluence rates (25mWcm^–2). No evidence of PDT resistance was found in this investigation.     

Granulocyte colony-stimulating factor-producing malignant pleural mesothelioma with the expression of other cytokines

We report a 65-year-old man with malignant pleural mesothelioma that produced granulocyte colony-stimulating factor (G-CSF) and other cytokines. At the first presentation, the WBC count was 8600 cells/µl and C-reactive protein (CRP) was 0.6mg/dl. Seventeen months later, the WBC count had increased to 53600 cells/µl (93% neutrophils) and CRP to 27.1mg/dl. The serum concentration of G-CSF had increased to 36.0pg/dl (normal range, <5.0pg/dl), interleukin 1 (IL-1) to 46.0pg/dl (normal range, <10pg/dl), and IL-6 to 197pg/dl (normal range, <4.0pg/dl). The patient died 19 months after the first presentation, and 6 weeks after sudden leukocytosis. At autopsy, a diagnosis of malignant pleural mesothelioma was made. The tumor cells were positive for anti-human G-CSF, granulocyte-macrophage colony-stimulating factor, IL-1, and IL-6 antibodies. Malignant mesothelioma may produce G-CSF and other cytokines. Mesothelial cells may have the potential to produce G-CSF and other cytokines in the progress of malignant formation, and this may be a factor influencing the poor prognosis.     

Distribution of Small Magnetic Particles in Brain Tumor-bearing Rats

Small (10–20nm) uncharged magnetic particles (SMP) were evaluated for their ability to target intracerebral rat glioma-2 (RG-2) tumors in vivo. In an effort to determine the influence of particle size on blood-tumor barrier uptake, the tissue distribution of the injected particles was evaluated following intraarterial injection (4mg/kg SMP) in male Fisher 344 rats bearing RG-2 tumors with a magnetic field of 0G or 6000G applied to the brain for 30min. Animals were sacrificed at 30min or 6h post-injection after which tissues were collected and analyzed for magnetite content. In the presence of a magnetic field, SMP localized in brain tumor tissue at levels of 41–48% dose/g tissue after 30min and 6h respectively, significantly greater than non-target tissues. In the absence of a magnetic field only 31–23% dose/g tissue was achieved for the same time points. Tumor targeting of the SMP for brain tumor was demonstrated by large target selectivity indexes (ts) of 2–21 for normal brain tissue, indicating a 2–21 fold increase in concentrations compared to normal brain. In comparison with larger (1µm) diameter magnetic particles, SMP concentrated in brain tumor at significantly higher levels than magnetic neutral dextran (p=0.0003) and cationic aminodextran (p=0.0496) microspheres previously studied. TEM analysis of brain tissue revealed SMP in the interstitial space of tumors, but only in the vasculature of normal brain tissue. These results suggest that changes in the vascular endothelium of tumor tissue promote the selective uptake of SMP and provide a basis for the design of new small drug-loaded particles as targeted drug delivery systems for brain tumors.     

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.     

Boron Neutron Capture Therapy of Brain Tumors: Clinical Trials at the Finnish Facility Using Boronophenylalanine

Two clinical trials are currently running at the Finnish dedicated boron neutron capture therapy (BNCT) facility. Between May 1999 and December 2001, 18 patients with supratentorial glioblastoma were treated with boronophenylalanine (BPA)-based BNCT within a context of a prospective clinical trial (protocol P-01). All patients underwent prior surgery, but none had received conventional radiotherapy or cancer chemotherapy before BNCT. BPA-fructose was given as 2-h infusion at BPA-dosages ranging from 290 to 400mg/kg prior to neutron beam irradiation, which was given as a single fraction from two fields. The average planning target volume dose ranged from 30 to 61Gy (W), and the average normal brain dose from 3 to 6Gy (W). The treatment was generally well tolerated, and none of the patients have died during the first months following BNCT. The estimated 1-year overall survival is 61%. In another trial (protocol P-03), three patients with recurring or progressing glioblastoma following surgery and conventional cranial radiotherapy to 50–60Gy, were treated with BPA-based BNCT using the BPA dosage of 290mg/kg. The average planning target dose in these patients was 25–29Gy (W), and the average whole brain dose 2–3Gy (W). All three patients tolerated brain reirradiation with BNCT, and none died during the first three months following BNCT. We conclude that BPA-based BNCT has been relatively well tolerated both in previously irradiated and unirradiated glioblastoma patients. Efficacy comparisons with conventional photon radiation are difficult due to patient selection and confounding factors such as other treatments given, but the results support continuation of clinical research on BPA-based BNCT.     

Accuracy of mammography and echography versus clinical palpation in the assessment of response to primary chemotherapy in breast cancer patients with operable disease

The response to primary chemotherapy is an important prognostic factor in patients with non metastatic breast cancer. In this study we compared the assessment of response performed by clinical palpation to that performed by echography and mammography in 141 out of 157 consecutive breast cancer patients (T2-4, N0-1, M0) submitted to primary chemotherapy. A low relationship was recorded between tumor size assessed clinically and that evaluated by either mammography: Spearman R=0.38 or echography: R=0.24, while a greater correlation was found between the tumor dimension obtained by the two imaging techniques (R=0.62). According to the WHO criteria, the grade of response of breast cancer to primary chemotherapy, showed by mammography and echography, was less marked than the grade of response seen at clinical examination. Residual tumor size assessed clinically depicted a stronger correlation with pathological findings (R=0.68) than the residual disease assessed by echography (R=0.29) and mammography (R=0.33). Post-chemotherapy histology evaluation revealed pathological complete response in three cases (2.1%). Two of these cases were judged as complete responders by clinical palpation but only one was recognized by mammography, and none by echography. Clinical response, but not the response obtained by the two imaging techniques, was a significant predictor for longer disease free survival (p=0.04). To conclude, physical examination measurements remain the method of choice in evaluating preoperatively the disease response in trials of primary chemotherapy. Prediction of pathological outcome is not improved by echography and mammography.     

Differential Effect of Cycloheximide on Neuronal and Glioma Cells Treated with Chemotherapy and Radiation

Dividing cells and non-dividing cells are distinct in their cell cycle kinetics, and react differently when facing cytotoxic stimuli. A protein synthesis inhibitor, cycloheximide (CHX), has recently been found to protect neuronal cells from oxidative stress. We investigated whether CHX exerts differential effects on dividing and non-dividing cells in the brain under cytotoxic stimuli. Mitotic C6 rat glioma cells and postmitotic neuronal cells were studied with a cytotoxic regimen combining -irradiation (RT) and 1,3-bis,2-chloroethyl-1-nitrosurea (BCNU). Cells were exposed to BCNU (1µg/ml) for 15h before -irradiation and incubated with CHX (1µg/ml) from 30min before and until 5h after irradiation. Clonogenic assay was used to assess cytotoxic effects on C6 glioma cells. LDH assay was used for the viability of H19-7 postmitotic neuronal cells. A 2.27–3.75 fold enhancement of cytotoxicity was noticed with the addition of CHX to BCNU and 2–10Gy of radiation. Our data demonstrated that CHX enhanced cytotoxocity of RT plus BCNU, while no additional toxicity was incurred to the postmitotic neuronal cells when CHX was added. We further studied whether the inhibition of DNA repair, assayed by single-cell DNA electrophoresis (comet assay), is a contributing factor for the enhanced cytotoxicity on C6 glioma cells.Interestingly, the initial DNA damage after RT plus BCNU was equivalent; whereas DNA repair was significantly less at 5h after radiation in CHX-treated C6 glioma cells. Protecting non-dividing neuronal cells to avoid excesive functional deficit is an integral part of a successful brain tumor treatment regimen. Taking advantage of the differential effect of CHX on glioma and neuronal cells may improve tumor control without excessive neural toxicity.     

Impact of videotaped information on frequency and confidence of breast self-examination

Background Videotaped education materials to teach breast self-examination (BSE) are used worldwide. However, evaluation of videotaped BSE instructions is lacking. Methods Premenopausal women (mean age 33.4±11.2 years) without history of breast cancer were approached to participate in this experimental study and randomly assigned to a video intervention group (VG; n=130; length of the video=15 min) or non-video comparison group (NVG; n=121). All participants answered a questionnaire on BSE behavior and health beliefs. No additional training was given. The total duration of the session including completion of the questionnaire was 15min for the NVG and 30min for the VG. Three months later, changes in BSE behavior were compared in the two groups. The influence of health beliefs on actual BSE behavior was investigated as well. Results Women of both the VG and NVG performed BSE significantly more frequently at follow-up than at baseline. Analysis of covariance, using the baseline BSE-frequency as co-variate and the follow-up BSE frequency as the dependent variable, revealed that women in the VG (adjusted mean=7.9 times per year, 95%CI=6.5–9.4) performed BSE more frequently than women of the NVG (adjusted mean=6.1 times per year, 95%CI=4.6–7.5) (F=4.2, df=2, p=0.02). Among motivational predictors, having an example of a role model (modeling) was shown by regression analysis to explain the greatest amount of variance (13%) in BSE frequency. Conclusion Use of an educational videotape increased the frequency of BSE among premenopausal women.     

Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer

Objective: The incidence of esophageal adenocarcinoma has risen rapidly in the past two decades, for unknown reasons. The goal of this analysis was to determine whether gastroesophageal reflux disease (GERD) or the medications used to treat it are associated with an increased risk of esophageal or gastric cancer, using data from a large population-based case–control study. Methods: Cases were aged 30–79 years, newly diagnosed with esophageal adenocarcinoma (n=293), esophageal squamous cell carcinoma (n=221), gastric cardia adenocarcinoma (n=261), or non-cardia gastric adenocarcinoma (n=368) in three areas with population-based tumor registries. Controls (n=695) were chosen by random digit dialing and from Health Care Financing Administration rosters. Data were collected using an in-person structured interview. Results: History of gastric ulcer was associated with an increased risk of non-cardia gastric adenocarcinoma (OR 2.1, 95% CI 1.4–3.2). Risk of esophageal adenocarcinoma increased with frequency of GERD symptoms; the odds ratio in those reporting daily symptoms was 5.5 (95% CI 3.2–9.3). Ever having used H₂ blockers was unassociated with esophageal adenocarcinoma risk (OR 0.9, 95% CI 0.5–1.5). The odds ratio was 1.3 (95% CI 0.6–2.8) in long-term (4 or more years) users, but increased to 2.1 (95% CI 0.8–5.6) when use in the 5 years prior to the interview was disregarded. Risk was also modestly increased among users of antacids. Neither GERD symptoms nor use of H₂ blockers or antacids was associated with risk of the other three tumor types. Conclusions: Individuals with long-standing GERD are at increased risk of esophageal adenocarcinoma, whether or not the symptoms are treated with H₂blockers or antacids.     

Flow cytometric analysis of primary tumors and their corresponding metastatic nodes in breast cancer

Human breast carcinoma is biologically heterogeneous, and its clinical course may vary from one which is indolent to one which rapidly progresses. Although it is the metastasis rather than the primary tumor that ultimately overwhelms the patients, studies concerning the DNA pattern have focused on the primary tumors. This study was undertaken to identify heterogeneities between primary tumors and metastases, and to evaluate the prognostic significance of the ploidy pattern and the S-phase fraction (SPF) of metastatic nodes in axillary node positive patients. Seventy-four frozen specimens of the primary and corresponding metastatic nodes from 37 patients have been analyzed by flow cytometry and the SPF calculated. The results of ploidy pattern analysis in primaries revealed 25 diploidy (67.6%) and 12 aneuploidy (32.4%), while those in metastasis showed 17 diploidy (46.0%) and 20 aneuploidy (54.0%). The aneuploidy group in metastatic nodes had the poorer histological grade (85.0% vs. 15.0%, p=0.02), and more mean metastatic nodes (5.75±2.10 vs. 3.05±1.56, p=0.018), and more frequent lymphatic vessel invasion (65.0% vs. 11.8%, p=0.031) than its counterpart. Decreased expression of ER (70.6% vs. 25.0% p=0.006) and increased expression of c-erbB2 (65.0% vs. 23.5%, p=0.012) were observed in the aneuploidy of metastatic nodes. The group with higher SPF in metastatic nodes had more metastatic nodes (5.47±2.31 vs. 4.00±1.78, p=0.042), and the higher incidence of lymphatic vessel invasion (57.9% vs. 22.2%, p=0.027), and poor histological grade (71.4% vs. 37.5%, p=0.039). In conclusion, the cell populations in metastatic nodes revealed DNA pattern which differed from that of primary tumors. The ploidy pattern and SPF in metastatic nodes might be considered as discriminate measure for risk factors in breast cancer patients with positive axillary node.