Fractionated stereotactic external beam radiotherapy in the management of brain metastases.

24 patients with 28 brain metastases were treated with fractionated stereotactic radiotherapy (SRT). Doses ranged from 10 Gy in two fractions to 20 Gy in two fractions. 13 patients received SRT boost after whole brain radiotherapy (WBRT), 5 were treated with SRT alone and 6 were treated at the time of recurrence following WBRT. The median progression-free survival at the treated site was 18 months and the median survival was 18 months. All patients were treated without admission to hospital. Toxicity of fractionated SRT was minimal and patients treated without WBRT did not suffer significant alopecia. Fractionated SRT offers a non-toxic non-invasive alternative to excision surgery in patients with solitary brain metastases. The optimum fractionation schedule and the role of whole brain irradiation remain to be determined.

Short intensive primary chemotherapy and radiotherapy in sporadic primary CNS lymphoma (PCL).

PURPOSE: To assess the efficacy and toxicity of combined modality therapy with short intensive primary chemotherapy in the treatment of primary CNS lymphoma (PCL). METHODS AND MATERIALS: Prospective study of 31 nonimmunodeficient patients with PCL treated with initial chemotherapy (13 shortened MACOP-B; and 18 modified MACOP with high dose methotrexate) followed by radiotherapy (whole brain and a boost). Patients were aged 18-72 years (median 51 years). Eight patients had positive CSF cytology of which one had spinal meningeal disease; one patient had vitreous involvement. RESULTS: The overall complete response (CR) rate after chemotherapy and radiotherapy was 69% (95% Confidence Interval: 49-84%). At a median follow-up of 24 months (4 months to 10 years) median survival was 23 months and 5-year survival 34%. Age, sex, performance status, number of lesions, CSF cytology, and extent of surgery were not of prognostic significance for survival on univariate analysis. Eleven patients developed mucositis (Grade 3+) and 21 hematological toxicity (Grade 3+) with 22 septicemic episodes in 15 patients. Three patients developed dementia, one assumed to be treatment related, and two due to recurrent disease. CONCLUSION: The survival results of short intensive primary chemotherapy followed by radiotherapy are similar to the results of chemotherapy in Stage IV aggressive systemic non-Hodgkin's lymphoma, although the treatment was associated with high morbidity. The apparently favorable results when compared to radiotherapy alone may at least in part be due to selection of patients with good prognostic factors. To confirm the benefit of combined chemotherapy and radiotherapy over either of the two modalities alone requires evaluation in large prospective and ideally randomized studies.

Modifying radical radiotherapy in high grade gliomas; shortening the treatment time through acceleration.

PURPOSE: To evaluate the efficacy and toxicity of accelerated radiotherapy in patients with primary high grade glioma, where acceleration is used as a means of delivering a shortened course of radical radiotherapy. PATIENTS AND METHODS: Two-hundred and eleven patients with primary high grade glioma were treated at the Royal Marsden NHS Trust between 1987 and 1997 with accelerated radiotherapy (55 Gy in 34 fractions twice daily), to planning target volume (PTV) defined as enhancing tumour and a 3 cm margin. All had histologically confirmed high grade glioma (53 anaplastic astrocytoma, 137 glioblastoma multiforme, 4 gliosarcoma, 5 gemistocytic astrocytoma, 12 high grade astrocytoma not otherwise specified). The mean Karnofsky performance status (KPS) was 90 and median age was 54 years (range 19-77). RESULTS: Of 211 patients entered, 201 were able to complete radiotherapy; 39 patients (19%) had deterioration in KPS during radiotherapy and this was transient in 11. Median survival of 211 patients was 10 months with 1 year, 2 year, and 3 year survival probabilities of 38%, 14%, and 8% respectively. Age and extent of excision were independent prognostic factors for survival. Previous comparison to matched cohort receiving 60 Gy in 30 daily fractions did not demonstrate significant survival difference. CONCLUSION: Accelerated radiotherapy is a feasible treatment approach for patients with high grade glioma. The survival and functional outcome are comparable to conventional radiotherapy and the treatment is without serious acute toxicity. While acceleration of conventional dose irradiation could be tested in randomised studies, it is unlikely this approach would result in a clinically meaningful survival benefit. Accelerated radiotherapy therefore remains one of the ways of delivering radical irradiation in patients with high grade glioma. However, it adds complexity to what is a palliative treatment regimen and the rationale and advisability should be re-examined, particularly in terms of impact on quality of life, true patient preference, and health economic considerations.

Hypofractionated stereotactic radiotherapy in the management of recurrent glioma.

PURPOSE: This study aimed to assess the efficacy and toxicity of hypofractionated stereotactic radiotherapy (SRT) in the management of patients with recurrent glioma. METHODS AND MATERIALS: From January 1989 to July 1994, 36 patients with glioma were treated at the time of recurrence. Twenty-nine had recurrent high-grade astrocytoma, 3 high-grade oligodendroglioma, 1 high-grade ependymoma, and 3 pilocytic astrocytoma. Hypofractionated stereotactic radiotherapy was given using either three noncoplanar arcs or four to six noncoplanar fixed beams at 5 Gy/fraction, to doses ranging from 20 to 50 Gy initially on a dose escalation program. Two patients received 20 Gy, 8 received 30 Gy, 10 received 35 Gy, 10 received 40 Gy, 5 received 45 Gy, and 1 received 50 Gy, treating 5 days/week. RESULTS: The median survival of 29 patients with recurrent high-grade astrocytoma was 11 months from the time of SRT. This compared to a median survival of 7 months for a cohort matched for age, performance status, and initial histologic grade who received nitrosourea-based chemotherapy at recurrence (p < 0.05). Initial low-grade astrocytoma histology was the only favorable prognostic factor for survival on univariate analysis. Three patients with recurrent oligodendroglioma remain alive 11, 23, and 34 months after SRT. Three children treated for recurrent pilocytic astrocytoma remain alive 14, 41, and 55 months following SRT. Presumed radiation damage, defined as reversible steroid-dependent toxicity, was observed in 13 patients (36%) and required reoperation in 2 (6%). A total dose of >40 Gy was a major predictor of radiation damage (p < 0.005). CONCLUSION: Hypofractionated SRT is a noninvasive, well-tolerated, outpatient-based method of delivering palliative, high-dose, focal irradiation.

Advice on hair and scalp care during cranial radiotherapy: a prospective randomized trial.

BACKGROUND: The advice on hair washing during brain irradiation is aimed at minimizing radiation induced skin toxicity. We performed a prospective randomized trial to assess the effect of advice on scalp care on the local skin reaction in patients undergoing cranial radiotherapy. METHODS: One hundred and nine patients undergoing cranial radiotherapy were randomized into two groups. Patients in group 1 were advised not to wash hair during treatment and patients in group 2 to maintain normal pattern of hair washing. They were assessed weekly over a period of 10 weeks from the start of treatment. Symptoms of pain and itching were recorded using a modified RTOG/EORTC acute skin reaction scoring system and skin reaction was assessed clinically using erythema/desquamation score. The frequency of hair washing and the distress of changing the practice of normal hygiene were recorded on a diary card. Skin reaction scores were compared as a summary measure using area under the curve per week (AUC/week) and median scores, and the differences between groups were assessed by means of the t-test. RESULTS: One hundred and nine patients commencing cranial radiotherapy according to standard protocol were randomized into the trial (group 1, 55 patients; group 2, 54 patients). Patients asked to restrict hair washing, washed at a lower average frequency. There were no significant differences between scores of skin reaction in the two groups for each of the variables measured. CONCLUSIONS: The practice of normal hair washing is not associated with increased severity of adverse skin reaction. As a request to change the pattern of normal hygiene may cause distress, the current advice should be to maintain normal hair washing during cranial radiotherapy.

Efficacy and toxicity of fractionated stereotactic radiotherapy in the treatment of recurrent gliomas (phase I/II study).

Twenty-two patients with recurrent glioma have been treated on a dose escalation protocol with fractionated stereotactic external beam radiotherapy (SRT). All had previously received radical radiotherapy (median dose 55 Gy) as part of the initial treatment. The dose of SRT was increased from 30 Gy in six fractions to 50 Gy in ten fractions. Median survival from the date of SRT was 9.8 months. There was no significant acute morbidity but five patients who received > or = 40 Gy developed steroid responsive neurological deterioration assumed to represent late radiation damage. The survival and toxicity in patients with recurrent glioma are comparable with interstitial therapy. Fractionated SRT is a noninvasive form of localised radiation which may be a suitable alternative to interstitial therapy in this group of patients.

Hypofractionated radiotherapy for poor prognosis malignant glioma: matched pair survival analysis with MRC controls.

PURPOSE: To assess the survival benefit of palliative hypofractionated radiotherapy in patients with poor prognosis high grade glioma by a matched comparison to conventionally treated controls. METHOD: Ninety-two elderly and/or disabled patients with high grade glioma with poor prognostic features received palliative partial brain radiotherapy to a dose of 30Gy in six fractions over 2 weeks. Patients were matched for WHO histological grade, performance status and age from a cohort of patients treated with conventionally fractionated radiotherapy to a dose of 60Gy in 30 fractions in an Medical Research Council (MRC) BR05 trial. RESULTS: Patients treated with hypofractionated radiotherapy had a median survival of 5 months with a 1-year survival rate of 12% from diagnosis. The median survival of case-matched controls was estimated to be 2.5-4.5 months longer. Following hypofractionated radiotherapy, Barthel score was improved or remained stable in 68% of patients. CONCLUSION: Hypofractionated partial brain radiotherapy is a well-tolerated regimen with palliative benefit. Comparison with matched controls suggests lesser survival benefit than would be obtained with radical radiotherapy. However, this is compensated by lower intensity and duration of irradiation induced side effects. It is postulated that there may not be a significant difference in good quality survival or 'quality adjusted survival' between the two regimens and this requires testing in prospective trials.

Protein synthesis in vitro by cryopreserved Plasmodium falciparum.

Plasmodium falciparum-parasitized erythrocytes obtained from infected owl monkeys (Aotus trivirgatus) and stored in the frozen state retain both the capacity to incorporate 14C isoleucine into protein and to infect animals. The cryopreservation method involves the use of glycerol and the reconstitution of isotonicity after thawing. Animals have been infected from material held for up to 273 days and protein synthesis has been demonstrated in vitro for up to 180 days after freezing. The specificity of protein synthesis as an activity of the parasites was shown by the inactivity of control uninfected erythrocytes stored by the same method. Additional evidence for the specificity of the reaction was obtained from inhibition studies with chloroquine; a 7 X 10(-5) M concentration of the drug resulted in 50% inhibition of the initial rate of protein synthesis.

Relations among children's social goals, implicit personality theories, and responses to social failure.

Two studies examined children's thought patterns in relation to their responses to social challenge. In Study 1, 4th and 5th graders tried out for a pen pal club under either a performance goal (stressing the evaluative nature of the tryout) or a learning goal (emphasizing the potential learning opportunities). In their behavior and attributions following rejection, children who were focused on a performance goal reacted with more helplessness, whereas children given a learning goal displayed a more mastery-oriented response. Study 2 found that in response to hypothetical socially challenging situations, 4th, 5th, and 6th graders who believed personality was nonmalleable (entity theorists) vs. malleable (incremental theorists) were more likely to endorse performance goals. Together, these studies indicate that children's goals in social situations are associated with their responses to social failure and are predicted by their implicit theories about their personality.

Stereotactic radiotherapy for solitary brain metastases.

PURPOSE: Surgery is considered to be the treatment of choice for patients with solitary brain metastases. We report a single-centre experience of stereotactic radiotherapy (SRT)/radiosurgery as an alternative to surgery and define prognostic parameters that provide for a more rational selection of patients for appropriate treatment. PATIENTS AND METHODS: Between 1990 and 1997, 96 patients with 106 brain metastases received SRT to a dose of 20 Gy in two fractions (range 20-30 Gy in 24 fractions) either alone or in combination with whole brain radiotherapy. RESULTS: After SRT, 51% of patients had improvement in neurological function. The median survival of the 96 patients was 9 months. The Radiation Therapy Oncology Group prognostic grouping for patients with multiple brain metastases (prognostic factors: age, performance status, systemic metastases, status of primary tumour) was applicable to this cohort, with median survivals of 15, 8 and 2 months for favourable, intermediate and poor prognostic groups respectively. CONCLUSION: SRT is a non-invasive method of treatment of solitary brain metastases and the outcome is comparable with the results obtained after surgical excision. Prognosis is determined by factors defined for patients with multiple brain metastases, with performance status being the most important. SRT/radiosurgery should be reserved for patients with favourable prognostic factors, with a Karnofsky performance status >70, who have a reasonable chance of good quality prolonged survival. In future trials, radiosurgery should be compared in terms of survival, quality of life and health economics to whole brain radiotherapy and surgery.

Lack of initiation and promotion potential of deoxynivalenol for skin tumorigenesis in Sencar mice.

The mycotoxin deoxynivalenol (DON; vomitoxin) was tested for its potential to initiate or promote skin tumours through a two-stage treatment regimen in female Sencar mice. DON's capability for initiation was tested by applying a single topical dose (200 micrograms) followed by multiple treatments of the promoter phorbol 12-myristate 13-acetate (PMA). The test for promotion involved initiation with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) followed by multiple DON treatments (50 micrograms). Appropriate control groups were included in the study design. Mice were observed for 26 wk and skin tumours were counted. Results of the study showed that DON was not an initiator or a promoter. When DON was tested as an initiator, there were no statistically significant differences in the number of cumulative tumours or the number of tumour-bearing mice between the DON-initiated/PMA-promoted group and its control, the vehicle-initiated/PMA-promoted group. When DON was administered as a promoter, no tumours were observed. Histopathology of the skin revealed that DON induced a mild diffuse squamous hyperplasia, but there was no progression of the lesion to neoplasia.

Pathological evaluation, clinical chemistry and plasma cholecystokinin in neonatal and young miniature swine fed soy trypsin inhibitor from 1 to 39 weeks of age.

The potential toxicity of dietary soy trypsin inhibitor (TI) was evaluated in neonatal miniature swine. From 1 to 6 weeks of age, two groups of male piglets were artificially reared in an Autosow and automatically fed either TI or control liquid diet. From 6 to 39 weeks of age, these two groups were fed either TI or control chow diet. A third group, sow control (SC), suckled from birth to 6 weeks of age, were also weaned to control chow from 6 to 39 weeks of age. Clinical chemistry and plasma cholecystokinin (CCK) determined at 6, 18, 30 and 39 weeks of age, and serum amylase activity with gross and histopathological analyses of major organs at 6 and 39 weeks of age are reported. TI had no effect on plasma CCK, serum amylase activity, or numerous clinical chemistry values. TI-fed piglets had a larger relative liver weight at 6 weeks of age. Relative pancreas weight decreased with age but was not affected by TI. Gross and histopathological analyses of major organs, except the spleen, were within normal limits. Increased incidence of extramedullary hematopoiesis was noted in the spleen of the TI group at 6 but not at 39 weeks of age. There was no consistent pattern in immunohistochemical foci for secretin, gastrin releasing polypeptide or CCK, and no change in DNA, RNA, mitotic index or nuclear density of pancreatic cells. At 6 weeks of age, TI increased pancreatic protein and amylase activity but not trypsin or chymotrypsin activity. None of the effects suggested that this dose of TI was toxic to either the neonatal or sexually mature miniature male swine.

A radiographic evaluation of the response of previously avulsed teeth and partially avulsed teeth to orthodontic movement.

Orthodontic movement, as documented in this study, can be accomplished successfully in the case of completely avulsed and partially avulsed teeth which have been reimplanted. These teeth respond to normal orthodontic forces and duration of treatment time by conventional orthodontic techniques and retention. Apical root resorption does occur more readily in these teeth before, during, and after orthodontic treatment. Six of the eighty-one involved teeth were lost because of complete root dissolution. The involved teeth which were reimplanted immediately without pulpal treatment and their integrity protected as living tissue were successfully treated orthodontically with no known losses as of this writing. It will be interesting to observe the tissue response of these avulsed teeth in the years ahead. How will time and circumstances deal with these teeth?

Plasmodium falciparum: passive immunization of Aotus lemurinus griseimembra with immune serum.

Owl monkeys (Aotus lemurinus griseimembra) were immunized against Plasmodium falciparum by infection and drug cure. After challenge, 3 of 4 monkeys developed extended prepatent periods and low grade parasitemias followed by self cure. The fourth monkey did not develop a patent infection. Immune monkey serum passively transferred at the time of challenge conferred immunity to 20 naive monkeys. Immunity was characterized by extended prepatent periods in 19 monkeys, low levels of parasitemia (< or = 1%) followed by self cure in 12 animals, and lack of detectable infection in 3 recipient monkeys. Immune serum collected from monkeys undergoing repeated challenges afforded more protection than serum from singly infected monkeys. However, single doses of hyperimmune serum appeared to be as effective as multiple doses. Normal serum had no effect on the course of infection in 12 monkeys. These studies confirm that owl monkeys can be immunized by infection and cure and demonstrate that this immunity can, in large part, be transferred to nonimmune recipients with serum from immune donors.

Arsanilic acid toxicity in rabbits.

Rations from several rabbitries experiencing increased mortality, weight loss and diminished reproduction were analyzed for arsanilic acid. Levels of less than 56 ppm of arsanilic acid were found. A 30 day trial was conducted where arsanilic acid was given in doses of 1.6-16.2 mg/day in water to weanling and adult rabbits. The higher doses induced diarrhea, terminal convulsions and death. Weight loss or reduced weight gains occurred in six of seven treated groups. No significant gross or microscopic lesions were observed. Chemical analysis demonstrated the presence of increased total hepatic arsenic levels in treated compared to control rabbits.

Problems in consideration of rodent hepatocarcinogenesis for regulatory purposes.

Hepatoproliferative lesions of rodents are frequently reported in petitions containing pathology data from chronic toxicity and carcinogenicity studies submitted to the Center for Food Safety and Applied Nutrition of the Food and Drug Administration. The Pathology Branch of the Office of Scientific Analysis and Support evaluates these data, which are submitted in support of the safe use of food additives, color additives, and other regulated products. Data are reviewed for the adequacy of the information provided, the terminology used to describe the reported lesions, and the overall scientific rationale used in interpreting the biological significance of the observed lesions. When questions arise during the review process, additional data, information, or clarification are sought from the petitioner. Microslides may be requested from the petitioner so that an independent evaluation of the lesions may be conducted. Several examples of recent evaluations of hepatoproliferative lesions are presented to illustrate some of the problems encountered during the review process and to demonstrate the procedures and approaches used in the evaluation of hepatocellular lesions within the center.

Food and Drug Administration risk assessment--process and toxicologic pathology.

A general outline of the risk assessment process at the Center for Food Safety and Applied Nutrition (CFSAN) of the Food and Drug Administration based on the toxicologic evaluation of data is described. Examples of recent pathology evaluations are presented to illustrate primarily the pathology review process at the CFSAN. These examples include the review of data from rodent studies from proposed indirect food additives and data from dog studies submitted in support of an investigational new drug, a short-acting opioid, proposed as an anesthetic in humans.

Two treatment approaches for missing or peg-shaped maxillary lateral incisors: a case study on identical twins.

Patients with missing or malformed maxillary lateral incisors can be successfully treated by either replacing or restoring the lateral incisor, or by positioning and reshaping the canine to simulate the lateral incisor. Identical twins were treated, one by restoring "peg laterals" to normal contours and the other by repositioning and recontouring the canines to simulate missing lateral incisors. Results of treatment would tend to indicate that considerations other than changes in facial esthetics should determine the treatment of choice.

Modifying the Barthel Performance Index Score for use in patients with brain tumours.

Performance status scores are useful tools in the management of patients with malignant disease. No specific performance index score exist, however, for patients with glioma. The Barthel Index, has been used in our department because it has been widely used in patients following stroke and found useful. This study aims to establish whether a modification of the Barthel Index would be more appropriate for patients with glioma and, if so, what modifications should be made. The opinions of multidisciplinary health workers and carers experienced in helping patients with glioma were established by questionnaire. Difficulty with speech and the presence of seizures were statistically ranked the most significant disability in terms of overall performance status. As these are not included in the Barthel Index a modification is justified. However, to include new categories in a performance index but avoid increasing its complexity, existing categories have to be omitted. Therefore, the second aim of this study was to establish which categories within the Barthel contribute least to a change in the total score. Three-hundred-and-thirty-three prospectively recorded Barthel scores were evaluated in 81 patients over 2 years and the individual categories evaluated by multifactor analysis. The sensitivity of the categories 'bowel function' and 'independence in grooming' to a change in the total score was less than 1%. In conclusion, substituting 'speech difficulties' and the presence of seizure in place of 'bowel function' and 'independence in grooming' from the Barthel Index will improve the specificity for patients with glioma without reducing the sensitivity or acceptability for the patients and research nurses who most often complete them.(ABSTRACT TRUNCATED AT 250 WORDS)