Boron environments in Pyrex® glass--a high resolution, Double-Rotation NMR and thermodynamic modelling study.

It is shown, using the important technological glass Pyrex® as an example, that 1D and 2D (11)B Double-Rotation (DOR) NMR experiments, in combination with thermodynamic modelling, are able to provide unique structural information about complex glasses. (11)B DOR NMR has been applied to Pyrex® glass in order to remove both dipolar and quadrupolar broadening of the NMR lines, leading to high resolution spectra that allow unambiguous, accurate peak fitting to be carried out, of particular importance in the case of the 3-coordinated [BO(3)] (B3) trigonal planar environments. The data obtained are of sufficient quality that they can be used to test the distributions of borate and borosilicate superstructural units predicted by the thermodynamics-based Model of Associated Solutions. The model predicts the dominant boron-containing chemical groupings in Pyrex® glass to be those associated with B(2)O(3) and sodium tetraborate (with smaller amounts of sodium triborate, sodium diborate, sodium pentaborate, danburite and reedmergnerite). Excellent agreement is found between model and experiment provided the (11)B peaks with isotropic chemical shifts of -1.4 ppm and 0.5 ppm are assigned to B4 species from borosilicate units ([B(OSi)(4)] and [B(OSi)(3)(OB)]) and borate superstructural units (mainly triborate rings with some pentaborate and diborate) respectively. The peaks with isotropic shifts of 14 ppm and 18.1 ppm are then assigned to B3 in borate superstructural units (mainly triborate and pentaborate along with connecting B3) and boroxol rings respectively. The assignments of the DOR NMR peaks, are supported by the presence of cross-peaks in (11)B spin-diffusion DOR NMR spectra which can be used to develop a structural model in which B(2)O(3)-like regions are linked, via borate and borosilicate superstructural units, to the majority silica network. Pyrex® is thus shown to have a heterogeneous structure, with distinct molecular groupings that are far removed from a random distribution of network polyhedra with only short-range order.

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1-45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159-0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454-0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3-4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.

Determination of NMR interaction parameters from double rotation NMR.

It is shown that the anisotropic NMR parameters for half-integer quadrupolar nuclei can be determined using double rotation (DOR) NMR at a single magnetic field with comparable accuracy to multi-field static and MAS experiments. The (17)O nuclei in isotopically enriched l-alanine and OPPh(3) are used as illustrations. The anisotropic NMR parameters are obtained from spectral simulation of the DOR spinning sideband intensities using a computer program written with the GAMMA spin-simulation libraries. Contributions due to the quadrupolar interaction, chemical shift anisotropy, dipolar coupling and J coupling are included in the simulations. In l-alanine the oxygen chemical shift span is 455 +/- 20 ppm and 350 +/- 20 ppm for the O1 and O2 sites, respectively, and the Euler angles are determined to an accuracy of +/- 5-10 degrees . For cases where effects due to heteronuclear J and dipolar coupling are observed, it is possible to determine the angle between the internuclear vector and the principal axis of the electric field gradient (EFG). Thus, the orientation of the major components of both the EFG and chemical shift tensors (i.e., V(33) and delta(33)) in the molecular frame may be obtained from the relative intensity of the split DOR peaks. For OPPh(3) the principal axis of the (17)O EFG is found to be close to the O-P bond, and the (17)O-(31)P one-bond J coupling ((1)J(OP)=161 +/- 2 Hz) is determined to a much higher accuracy than previously.

Increased expression and activity of RhoA are associated with increased DNA synthesis and reduced p27(Kip1) expression in the vasculature of hypertensive rats.

We have previously shown that the function of the small G protein Rho is required for vascular smooth muscle cell proliferation and migration. We hypothesized that changes in Rho or Rho signaling might contribute to enhanced vascular proliferative responses associated with hypertension. Western blot analysis revealed that total RhoA expression was approximately 2-fold higher in aortas, tail arteries, and aortic smooth muscle cells (ASMCs) obtained from adult male spontaneously hypertensive rats (SHR) compared with those from Wistar Kyoto rats (WKY). An increase in active GTP-bound RhoA was detected in aortic homogenates by affinity precipitation with the RhoA effector rhotekin and by examining RhoA-[(35)S]GTPgammaS binding. RhoA protein and activity were also increased in vessels from rats treated with N-nitro-L-arginine methyl ester to increase blood pressure. Thrombin-stimulated RhoA activation was also significantly greater in ASMCs from SHR. As a functional correlate of these changes in Rho signaling, thrombin-stimulated DNA synthesis was enhanced in tail arteries and ASMCs from SHR. Expression of the cyclin-dependent kinase inhibitor p27(Kip1) was decreased by two thirds in SHR, and this decrease was mimicked in ASMCs by expression of a constitutively active (GTPase-deficient) mutant of RhoA. Wortmannin (10 nmol/L) fully inhibited the decrease in p27(Kip1) induced by RhoA, and a membrane-targeted catalytic subunit of phosphatidylinositol-3 kinase (PI3K [p110(CAAX)]) decreased p27(Kip1) expression, suggesting that RhoA signals through PI3K. These data provide evidence that RhoA brings about changes in DNA synthesis through reduced expression of p27(Kip1), mediated in part via PI3K, and suggest that increases in RhoA expression and activity contribute to the enhanced vascular responsiveness observed in hypertension.

An animal model to study toxicity of central nervous system therapy for childhood acute lymphoblastic leukemia: effects on growth and craniofacial proportion.

Many long term survivors of childhood acute lymphoblastic leukemia have short stature, as well as craniofacial and dental abnormalities, as side effects of central nervous system prophylactic therapy. An animal model is presented to assess these adverse effects on growth. Cranial irradiation (1000 cGy) with and without prednisolone (18 mg/kg i.p.) and methotrexate (2 mg/kg i.p.) was administered to 17- and 18-day-old Sprague-Dawley male and female rats. Animals were weighed 3 times/week. Final body weight and body length were measured at 150 days of age. Femur length and craniofacial dimensions were measured directly from the bones, using calipers. For all exposed groups there was a permanent suppression of weight gain with no catch-up growth or normal adolescent growth spurt. Body length was reduced for all treated groups, as were the ratios of body weight to body length and cranial length to body length. Animals subjected to cranial irradiation exhibited microcephaly, whereas those who received a combination of radiation and chemotherapy demonstrated altered craniofacial proportions in addition to microcephaly. Changes in growth patterns and skeletal proportions exhibited sexually dimorphic characteristics. The results indicate that cranial irradiation is a major factor in the growth failure in exposed rats, but chemotherapeutic agents contribute significantly to the outcome of growth and craniofacial dimensions.

An animal model to study toxicity of central nervous system therapy for childhood acute lymphoblastic leukemia: effects on behavior.

Central nervous system prophylactic therapy used in the treatment of acute lymphoblastic leukemia can reduce intelligence quotient scores and impair memory and attention in children. Cranial irradiation, intrathecal methotrexate, and steroids are commonly utilized in acute lymphoblastic leukemia therapy. How they induce neurotoxicity is unknown. This study employs an animal model to explore the induction of neurotoxicity. Male and female Sprague-Dawley rats at 17 and 18 days of age were administered 18 mg/kg prednisolone, 2 mg/kg methotrexate, and 1000 cGy cranial irradiation. Another 18-day-old group was administered 1000 cGy cranial irradiation but no drugs. Matching controls received saline and/or a sham exposure to radiation. All animals at 6 weeks and 4 months of age were tested for alterations in spontaneous behavior. A computer pattern recognition system automatically recorded and classified individual behavioral acts displayed during exploration of a novel environment. Measures of behavioral initiations, total time, and time structure were used to compare treated and control animals. A permanent sex-specific change in the time structure of behavior was induced by the prednisolone, methotrexate, and radiation treatment but not by radiation alone. Unlike hyperactivity, the effect consisted of abnormal clustering and dispersion of acts in a pattern indicative of disrupted development of sexually dimorphic behavior. This study demonstrates the feasibility of an animal model delineating the agent/agents responsible for the neurotoxicity of central nervous system prophylactic therapy.

Relationship between the neurotoxicity of the hypoxic cell radiosensitizer SR 2508 and the pharmacokinetic profile.

Complete pharmacological data from 71 patients treated on the phase I trial of SR 2508 were analyzed to see if the dose-limiting toxicity of peripheral neuropathy is related to the individual patient's pharmacokinetic profile. In a retrospective analysis, the risk of toxicity was best predicted by using the bivariate model of total drug exposure and the time over which the treatment course was given. Drug exposure [area under the curve (AUC)] for a single treatment was calculated by the integral over time of the serum concentration of SR 2508. Since the AUC was constant during the course of a patient's treatment, the total drug exposure (total-AUC) was estimated by the product of the AUC times the number of drug administrations. While the clinical efficacy of hypoxic cell sensitizers remains to be proven, SR 2508 is better tolerated than its predecessors, misonidazole and desmethylmisonidazole, as three times the amount of SR 2508 can be given. If this model is confirmed in the current phase II and III trials, the probability of developing neuropathy would be predictable for an individual patient from measurements made at the time of the first drug dose, allowing for the adjustment of drug schedule to avoid all but minor toxicity.

Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy.

Forty-two evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4'-epimer of doxorubicin in cumulative doses ranging from 147 mg/m2 to 888 mg/m2. In this study of the Northern California Oncology Group, myofibrillar loss and sarcoplasmic vacuolization were identified and shown to be identical to those previously described for doxorubicin. However, when these biopsies were compared to 119 biopsies obtained from 98 patients treated with doxorubicin, milligram for milligram, epirubicin caused less endomyocardial injury than doxorubicin (P = 0.0013). Age, sex, type of primary malignancy, prior cardiac disease, and hypertension did not influence the degree of histologically demonstrated anthracycline injury induced by epirubicin.

Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy.

BACKGROUND: We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We present long-term data (median follow-up 8.5 years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors. METHODS AND RESULTS: We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3-26] for PP and 9.7 [95% confidence interval 3.2-29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3-9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥ 240 beats per minute was equivalent to the control survival rate. Ectopy (≥ 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females. CONCLUSIONS: ICD therapy is indicated for PP in postpubertal males and in females ≥ 30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death.

Postoperative radiation therapy for epithelial ovarian cancer: the curative role based on a 24-year experience.

We updated 152 cases of epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stages I through III, treated at the Stanford Medical Center (Stanford, Calif) with irradiation as the only postoperative therapy. In 133 patients, radiation was directed only to those regions of known disease, while it was delivered to the whole abdomen and pelvis by the Martinez technique in 19 patients. Mean follow-up time was 6.8 years. The results were analyzed as freedom from relapse (FFR) at 15 years; overall, FFR constituted 44% of the patients. Statistically significant differences of FFR appeared between stages II (60%) and III (16%); among the histopathologic variants endometrioid (64%), serous papillary (45%), and undifferentiated (7%); between pathologic grades 2 (68%) and 3 (20%); between amounts of postoperative residual disease less than 2 cm (48%) and greater than 2 cm (16%); and between ages less than 40 (80%) and greater than or equal to 40 (38%). Considering all stages and grades together, FFR in the 54 cases with unfavorable residuum (greater than 2 cm) was 14%. Among the 98 with favorable residuum (none, or less than 2 cm) FFR was 62%; and 14 (39%) of the 36 relapses were in the untreated upper abdomen. Results in the favorable group support effectiveness of irradiation as postoperative therapy. These patterns of relapse suggest that whole-abdominopelvic irradiation would further increase FFR. We believe that, for favorable disease as defined such radiotherapy should be the standard for comparison.

Advanced epithelial ovarian cancer: salvage whole abdominal irradiation for patients with recurrent or persistent disease after combination chemotherapy.

Between 1979 and 1984, 53 patients received whole abdominal irradiation in a curative salvage effort for residual (32 patients) or recurrent (21 patients) epithelial ovarian cancer after combination chemotherapy (cisplatin-based in 48 patients). Residual cancer less than or equal to 2 cm in diameter was confirmed at operation in all patients before irradiation consisting of 2,550 to 3,000 rad to the whole abdomen with partial liver/kidney shielding and boosting of the dose to the diaphragmatic/paraaortic nodal regions and pelvis to approximately 4,000 and 5,000 rad, respectively. Twelve patients (23%) did not complete therapy as a result of hematologic intolerance. Actuarial overall and disease-free survival at 3 years are 35% and 30%, respectively, with follow-up for disease-free patients ranging from 30 to 79 months (median, 43 months). Twenty-seven of 36 relapses (75%) occurred within the irradiated abdomen alone. At 3 years, 70% of patients with well- or moderately-differentiated tumors were disease-free v 10% of those with poorly differentiated tumors (P less than .001). Among prognostic factors evaluated, including grade, initial residual disease before chemotherapy, residual disease at time of irradiation, age, chemotherapy response v progression, and completion of irradiation, only grade and initial residual disease before chemotherapy were statistically significant in multivariate analysis (both P less than .01). Patients with the combination of high-grade tumor, initial residual disease greater than 2 cm before chemotherapy, and macroscopic disease after "second-look" laparotomy do not benefit from irradiation. Eleven patients (21%) developed an apparent treatment-related bowel obstruction after completion of irradiation. Selected subsets of patients do well; however, the role of irradiation in this setting can be confirmed only with randomized clinical study.

Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer.

Antitumor and pharmacodynamic studies were performed in MCF-7 human breast cancer cells and companion xenografts with the farnesyl protein transferase inhibitor, R115777, presently undergoing Phase II clinical trials, including in breast cancer. R115777 inhibited growth of MCF-7 cells in vitro with an IC(50) of 0.31 +/- 0.25 microM. Exposure of MCF-7 cells to increasing concentrations of R115777 for 24 h resulted in the inhibition of protein farnesylation, as indicated by the appearance of prelamin A at concentrations >1 microM. After continuous exposure to 2 microM R115777, prelamin A levels peaked at 2 h post drug exposure and remained high for up to 72 h. R115777 administered p.o. twice daily for 10 consecutive days to mice bearing established s.c. MCF-7 xenografts induced tumor inhibition at a dose of 25 mg/kg [percentage of treated versus control (% T/C) = 63% at day 21]. Greater inhibition was observed at doses of 50 mg/kg (% T/C at day 21 = 38%) or 100 mg/kg (% T/C at day 21 = 43%). The antitumor effect appeared to be mainly cytostatic with little evidence of tumor shrinkage to less than the starting volume. Tumor response correlated with an increase in the appearance of prelamin A, but no changes in the prenylation of lamin B, heat shock protein 40, or N-Ras were detectable. In addition, significant increases in apoptotic index and p21(WAF1/CIP1) expression were observed, concomitant with a decrease in proliferation as measured by Ki-67 staining. An increase in prelamin A was also observed in peripheral blood lymphocytes in a breast cancer patient who responded to R115777. These data show that R115777 possesses preclinical antitumor activity against human breast cancer and that the appearance of prelamin A may provide a sensitive and convenient pharmacodynamic marker of inhibition of prenylation and/or response.

Toxicity of open-field whole abdominal irradiation as primary postoperative treatment in gynecologic malignancy.

Between June 1979 and March 1985, 77 patients received whole abdominal radiation as the sole postoperative treatment for gynecologic malignancy. With an open-field technique of irradiation, a median of 3,000 cGy was delivered to the entire abdominal contents with partial liver and kidney shielding; the total dose to the pelvis after boosts was 5,100 cGy, and that to the sub-diaphragmatic and para-aortic nodal regions was 4,200 cGy. The primary sites of malignancy were the endometrium in 41 patients, ovary in 25, uterus in 5, fallopian tube in 4, and cervix in 2. Seven patients (9%), all older than 60 years, experienced acute gastrointestinal toxicity that interrupted treatment, only one of whom failed to complete the prescribed course as a result. Hematologic toxicity was sufficient to interrupt therapy in 21 patients (27%), 1 of whom failed to complete therapy as a result. Hematologic toxicity was not increased in elderly patients. All patients were followed up for a minimum of 30 months (median, 43 months) or until death. Six patients experienced a treatment-related bowel obstruction (two of whom had concomitant progressive intra-abdominal disease); the 3-year actuarial risk for a treatment-related bowel obstruction was 9%. This risk was significantly increased by high-dose boosting for residual disease. Only one instance of clinical radiation pneumonitis occurred, and no cases of clinical hepatitis were noted; however, subclinical evidence of pulmonary and hepatic radiation effect was frequent. Whole abdominal irradiation as described has modest toxicity for patients with gynecologic cancer who are at high risk for intra-abdominal failure.

The effect of glutathione (GSH) depletion in vivo by buthionine sulfoximine (BSO) on the radiosensitization of SR 2508.

The effect of glutathione depletion (GSH) on the efficacy of SR 2508 was evaluated in two murine tumor models with single large doses of radiation or with low doses administered in an accelerated fractionated schedule. To deplete tumor GSH, buthionine sulfoximine (BSO) was administered in the animals drinking water (10 mM) following two i.p. injections of 450 mg/kg. This treatment decreased RIF and MCA tumor GSH concentrations by 95% and 80%, respectively. Mice (C3H/Sed) received BSO for 48-72 hr before the first dose of radiation, and were maintained on BSO drinking water for the duration of the fractionated course of therapy. SR 2508 (200-1000 mg/kg) was injected 45 min prior to each fraction of radiation. Radiation was administered as a single dose of 15 Gy or 20 Gy, for RIF and MCA tumors, respectively. Alternatively, animals received a fractionated course of radiotherapy which consisted of 2.5 Gy/fraction for the RIF, and 3 Gy/fraction for the MCA tumors, b.i.d. for five days (total of 10 fractions). Tumor response with and without BSO, and with and without SR 2508, was determined by regrowth delay. BSO pretreatment increased the efficacy of SR 2508 with single dose radiation in the MCA but not RIF tumor. SR 2508 administered with fractionated radiation produced lower enhancement ratios (SER) than with a single radiation dose. However, BSO significantly enhanced the efficacy of SR 2508 with fractionated radiation. BSO increased the maximum SER for SR 2508 (3 mM/fraction) from 1.2 to 1.4 in the RIF tumor, and from 1.4 to 1.8 in the MCA tumor. BSO also increased the toxicity of SR 2508 by a factor of 2. However, the ability of BSO to increase the efficacy of low doses of sensitizer at clinically relevant doses of radiation suggests that this combined modifier treatment may be of clinical benefit.

Combination of external beam irradiation and multiple-site perineal applicator (MUPIT) for treatment of locally advanced or recurrent prostatic, anorectal, and gynecologic malignancies.

We have devised a single after-loading applicator, the Martinez Universal Perineal Interstitial Template (MUPIT), which has been used in combination with external beam irradiation to treat 104 patients with either locally advanced or recurrent malignancies of the cervix, vagina, female urethra, prostate, or anorectal region. Twenty-six patients treated for prostate cancer are excluded because of their short follow-up. Local failure developed in 13 of the 78 remaining patients (16.6%)--major complications developed in 4 patients (5.1%). Follow-up has been 1 year to 7 1/2 years; 60/78 patients have been followed for more than 2 years. All local recurrences and complications occurred before 18 months. The device consists of two acrylic cylinders, an acrylic template with an array of holes that serve as guides for trocars, and a cover plate. In use, the cylinders are placed in the vagina and/or rectum or both and then fastened to the template so that a fixed geometric relationship among the tumor volume, normal structures, and source placement is preserved throughout the course of the implantation. Appropriate computer programs have been developed to calculate the dose from these implants. The advantages of the system are (a) greater control of the placement of sources relative to the tumor volume and critical structures, as a result of the fixed geometry provided by the template and cylinders, and (b) improved dose-rate distributions obtained by means of computerized optimization of the source placement and strength during the planning phase. We conclude that the local control rate (83.4%) with low morbidity (5.1%) achieved with the combination of external beam irradiation and MUPIT applicator in these patients with locally advanced malignancies represents an improvement over previous published results with other applicators.

Initial results of a phase I trial of continuous infusion SR 2508 (etanidazole): a radiation therapy oncology group study.

To exploit both the oxygen-mimetic and "pre-incubation" or continuous exposure effects of the 2-nitroimidazole radiosensitizers, we are conducting a Phase I trial of continuous infusion SR 2508 for patients receiving brachytherapy. Following the administration of a loading dose of 2 g/m2, SR 2508 is administered by continuous infusion for 48 hr. Twenty-one patients have completed treatment. The initial total dose was 8 g/m2 with patients currently receiving 15 g/m2. No toxicity has been observed. At the higher doses the steady-state plasma concentrations have been between 50 and 70 micrograms/ml. It is not yet known whether or not hypoxic sensitizers will be of benefit clinically, and if so, when during a course of treatment is the optimal time to use them. Given the lack of toxicity and plasma concentrations achievable with continuous infusion, future studies will be conducted using SR 2508 during both the external beam and brachytherapy aspects of treatment.

Final report of the phase I trial of continuous infusion etanidazole (SR 2508): a Radiation Therapy Oncology Group study.

Seventy-eight patients have been treated on a Phase I trial using continuous infusion etanidazole while undergoing brachytherapy for locally advanced tumors. There were two sequential schemata, the first treated 63 patients with doses ranging from 8-23 g/m2 over 48 hr and the second treated 15 patients with doses ranging from 20-23 g/m2 over 96 hr. The tumor sites were: brain (n = 42), cervix (n = 22), and breast (n = 14). Patients received a loading dose of etanidazole of 2 g/m2 followed by a continuous infusion for a total of 48 or 96 hr while radioactive implants were in place. Of the 63 patients in the 48-hr study, 52 were entered at doses of less than or equal to 21 g/m2 and there were no definite neuropathies but two patients with the cramping/arthralgia syndrome. Of the 11 patients entered at 22-23 g/m2, 1 patient had symptoms of peripheral neuropathy (Grade II) and 6 had the cramping/arthralgia syndrome. This is a new syndrome, distinct from the peripheral neuropathy, characterized by transient alterations in sensations consisting of cramping, arthralgias, or tingling that resolved completely at intervals varying from a few hours to about 1 week post-treatment. The cramping/arthralgia syndrome limited dose escalation; therefore, the maximum tolerated dose over 48 hr was determined to be 20-21 g/m2. The 96-hr infusion was limited to patients with recurrent gliomas undergoing stereotactic implantation. To date, 15 patients have been treated with doses of 20-23 g/m2. No toxicity was encountered at doses less than or equal to 22 g/m2. At 23 g/m2, one patient developed Grade III neuropathy and three patients had mild cramping/arthralgia syndrome, for whom the drug was discontinued. Therefore, it appears the maximum tolerated dose at 96 hr will be approximately 23 g/m2, which is 10-15% higher than for the 48-hr infusion.

Historical vignette: The radium bomb: Harvey Cushing and the interstitial irradiation of gliomas.

Harvey Cushing performed over 2000 operations on patients with brain tumors, including 832 for gliomas. He implanted radioactive radium needles, known as a "radium bomb," in a small number of these patients. He was not impressed with the results and did not pursue this method of treatment in a serious way. The authors present here Cushing's little-known experience with brachytherapy and discuss the reasons for his lack of interest in this technique, despite his advocacy of radiotherapy for certain lesions. An interesting perspective is offered for contemporary neurosurgeons involved in the treatment of brain tumors with cranial irradiation.

Strategic use of familiarity in display-based problem solving.

The authors report 4 experiments that investigated the role of recognition memory and plausibility in a display-based problem-solving task (computer menu search). It was found that both the familiarity of options and their plausibility played a role in determining choices when the correct options could not be recollected. The use of familiarity was adaptive: Participants relied less on familiarity when it was a less valid guide to correct choices. The implications of these findings for theories of problem solving and learning are discussed.

Effect of dietary fibre on the mutagenicity and distribution of 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ).

Female BALB/c mice were fed either a fibre-free diet or one supplemented with 30% wheat-bran for 5 weeks. The ability of these mice to convert MeIQ to a bacterial mutagen in vivo was determined using intrasanguinous host-mediated bacterial mutation assays. Less mutagenic activity was detected in the livers of mice fed the bran-supplemented diet compared with those fed the fibre-free diet. Subsequent experiments demonstrated that the effect of brain was not due to modifications in hepatic metabolism, but to changes in uptake of MeIQ from the gastrointestinal tract.