Radiotherapy of choroidal metastases: breast cancer as primary site

Forty-two cases of metastatic breast cancer to the choroid treated by radiation therapy were reviewed. Fifteen patients (36%) had bilateral and 27 patients (64%) had unilateral choroidal involvement. In 12 patients (29%) the choroid was the first site of dissemination. The median survival period after choroidal metastases was 10 months. Most patients were treated with Co60 in doses of 2500 rads tumor dose (TD) in ten fractions, 2500 rads, (TD) in five fractions and 3000 rads (TD) in ten fractions. An early group of patients had orthovoltage therapy. Good visual responses were obtained with each of the above treatment programs. Radiation treatment in the range of 2500-3000 rads TD in a short course is recommended for palliation of metastatic breast cancer to the choroid.     

Different fractionation schemes tested by histological examination of autopsy specimens from lung cancer patients

The biological effects of different fractionation schemes have been evaluated by the histological examination of bronchial carcinomas removed at operation or autopsy following radiotherapy. Radiation was given in daily, small fractions (200 cGy (rad)), large fractions (600 cGy (rad)) every fifth day, or a single high dose followed by daily low-dose treatment. The highest proportion of tumours free of viable cells was found in patients who had received small daily fractions in both operable and inoperable tumours. A hypothesis is put forward to explain this apparent change in radio-sensitivity with different fractionation schemes.     

Effect of gamma radiation on the molecular weight and the anticoagulant activity of heparin

4 g% aqueous solutions of heparin were irradiated with the gamma radiation doses of 4.6 x 10(5) or 9.2 x 10(5) rads. The irradiated and also the non-irradiated heparin samples were fractionated using a Sephadex G-200 column. With radiation, the peak of the molecular weight distribution curves shifted toward the lower molecular weight. Also, the number average molecular weight decreased by 8.2 and 11.5% with the doses of 4.6 x 10(5) and 9.2 x 10(5) rads, respectively. The anticoagulant activity depended on the molecular weight of the heparin fractions. For the heparin fractions with molecular weights below 7,900, the anticoagulant activity decreased with radiation. Thus, for a heparin fraction with a molecular weight of 6,200, the anticoagulant activity decreased from 211 to 198 IU/mg after 4 h of irradiation.     

Study on clinical application of multiple fractions per day radiation therapy with concomitant boost technique for esophageal cancer

A continuous multiple fractions per day irradiation (MFD) using twice-a-day (BID) fractionation in the similar form of concomitant boost was devised for the treatment of advanced esophageal cancer. From Oct. 1985 to July 1991 60 patients were entered in this clinical trial and were compared with 64 patients who were treated with conventional once-a-day irradiation (CF) from July 1977 to July 1989 in survival, local control, acute and late effect. The altered fractionation schedule employed continuous concomitant boost technique with reduced field for primary site being irradiated twice-a-day. Daily fraction size were 2 Gy with large field including primary and regional lymphatics and 1.1, 1.15 and 1.2Gy with concomitant boost. Total dose of 62, 63 and 64Gy were administered in 40 fraction for 5 weeks. Acute reaction caused radiation mediastinitis, pneumonitis and esophagitis, but severe injury which interrupted treatment did not occur. Late reaction consisted of 8 radiation induced stricture [RIS] (13.3%), 2 radiation induced pericarditis(3.3%) and 1 bronchial ulcer(1.7%) in MFD. Particularly, RIS in 3.2Gy/2f/day group of MFD developed with higher frequency than in CF and another daily fraction size. Patients treated with CF and MFD experienced 5 year loco-recurrence free survival of 27.3% and 57.2% respectively (P < 0.001), which translated into 5 year cause-specific survival 13.9% and 31.5%, respectively (P < 0.05). Significant advantage in adjusted local-recurrence free survival using multivariable analysis was shown (P < 0.005). Also, a border line advantage in adjusted survival using clinical stage is now appearing in MFD as a consequence of the increased local control rate. There was no significant difference in survival and local-recurrence free survival among each daily dose groups. We concluded that our regimen of MFD using optimal daily dose of 3.15Gy/2f/day with continuous concomitant boost technique resulted in improved local control and survival rate of treatment of esophageal cancer without severe late reaction.     

Modelling the optimal radiotherapy regime for the control of T2 laryngeal carcinoma using parameters derived from several datasets

PURPOSE: A number of previous studies have used direct maximum-likelihood methods to derive the values of radiobiological parameters of the linear-quadratic model for head and neck tumors from large clinical datasets. Time factors for accelerated repopulation were included, along with a lag period before the start of this repopulation. This study was performed to attempt to utilise these results from clinical datasets to compare treatment regimes in common clinical use in the UK, along with other schedules used historically in a number of clinical series in North America and elsewhere, and to determine if an optimal treatment regime could be derived based on these clinical data. METHODS: The biologically-based linear-quadratic model, applied to local tumor control and late morbidity, has been used to derive theoretical optimum (maximising tumor control whilst not exceeding tolerance for late reactions) radiotherapy schedules based on daily fractions. The specific case of T2 laryngeal carcinoma was considered as this is treated primarily by radiotherapy in many centers. Parameter values for local control were taken from previous analyses of several large single-center and national datasets. A time factor and a lag period were included in the modelling. Values for the alpha/beta ratio for late morbidity were used in the range 1-4 Gy, which is compatible with the limited range of values reported in the literature for particular complications following radiotherapy for head and neck cancer. Early reactions and their consequential late morbidity were not modelled in this study, but assumed to be within tolerance. RESULTS: For treatments using daily fractions there was a broad optimum treatment time of between 3-6 weeks. The theoretical optimum depended to some extent on the value of the alpha/beta ratio for late morbidity, but in many cases was at or just beyond the end of the purported lag period of 3-4 weeks, although small values of alpha/beta between 1-2 Gy favour longer treatment times. Similar results were obtained using a range of parameter values derived from four independent clinical datasets. CONCLUSION: The mathematical modelling of this broad range of once-daily treatments for most of which differences in local control and late morbidity are essentially undetectable (< 5%) has shown how this clinically-recognised phenomenon is interpreted in terms of the combination of dose-response slopes, fractionation sensitivities and time factors for both tumor control and normal tissue morbidity. Although the conclusions are inevitably tempered by a number of caveats concerning confounding factors in different centers; for example, the use of different treatment volumes, the present analysis provides a framework with which to explore the potential value of modifications to conventional treatment schedules, such as the use of multiple fractions per day.     

Effect of preliminary chronic low-dose gamma-irradiation on the compensatory potentialities of the hematopoietic system

Rat experiments indicate that chronic gamma-preirradiation in a dose of 90.0 rads (dose rate 3.0 rad/day) inhibits development of adaptive reactions of hematopoietic system throughout resistance of general adaptation syndrome in emotional stress.     

Radiation therapy enhances the therapeutic effect of immunotherapy on pulmonary metastases in a murine renal adenocarcinoma model

In order to improve the efficacy of immunotherapy, we have evaluated the effects of radiation therapy combined with interleukin 2 (IL-2) treatment in a murine metastatic renal adenocarcinoma model (Renca). Pulmonary metastases were induced in Balb/c mice by intravenous injection of Renca and five days later a sublethal dose of radiation (300 rads) was administered either to the whole body or to the left lung only. One day following radiation, immunotherapy was given for 5 consecutive days of IL-2 at 5,000 Cetus units intraperitoneally, twice daily. The animals were either sacrificed on day 23 or 33 to assess tumor burden, or were followed for long term survival. We found that pretreatment with irradiation greatly enhanced the therapeutic efficacy of immunotherapy and was manifested by a significant reduction in pulmonary metastases and an increase in survival. When combined with immunotherapy, local tumor irradiation was not only as effective as whole body irradiation, but irradiation of one lung reduced the number of metastases similarly in both lungs. This suggests that local tumor irradiation may act through a systemic mechanism to increase the anti-tumor response mediated by IL-2 therapy.     

Radical irradiation with the split-course technique in carcinoma of the lung

The possible advantages of a split-course of irradiation in the treatment of patients with locally advanced and/or inoperable carcinoma of the lung were explored in over 200 cases. The patients were separated into two groups with different prognostic factors: Group A, patients with well-differentiated tumors confined to the lung and mediastinum; and Group B, cases with anaplastic tumors and/or supraclavicular metastases, bone erosion, or superior venal caval syndrome. The treatment consisted of 5500-6000 rads tumor dose in 20 to 24 fractions over a period of 7 to 8 weeks with a rest interval of 2 to 4 weeks in the middle. The 3- and 5-year survival figures, 19% and 16%, respectively, in Group A cases, along with the excellent tolerance, suggest that the split-course approach has definite advantages.     

Low- versus high-dose aspirin in prevention of ischemic stroke

Aspirin is the most extensively studied drug for the prevention of ischemic vascular disease. Meta-analyses confirm that aspirin is effective in prevention of ischemic events, including stroke. Recently, there has been considerable discussion about the best dose of aspirin to prevent stroke. Several studies tested aspirin in a daily dose of 975 mg or more alone or in combination with another drug, most commonly dipyridamole, and noted that aspirin was effective. Successively lower doses of aspirin were tested and recent studies demonstrate that low doses (< 100 mg/day) are effective. Only one study, enrolling patients with transient ischemic attack or minor stroke, has examined aspirin in a daily dose of approximately 325 mg. Side effects of aspirin are dose related; gastrointestinal bleeding and epigastric pain are less with low doses. Available data cannot confirm that low doses (< 100 mg/day) of aspirin are either more or less effective than larger (975 mg/day) doses. A direct comparison of the usefulness of low doses (< 100 mg/day) or large doses (approximately 1,000 mg/day) in patients at high risk of stroke is needed. Until the results of such a study are known, the better safety profile of low doses favors aspirin in a daily dose of 100 mg or less.     

Kinetic considerations in the choice of treatment schedules for neuraxis radiotherapy

Neuraxis radiotherapy of radiosensitive tumours such as medulloblastoma is usually carried out using conventionally sized fractions and a shrinking field technique. Plowman and Doughty (Br. J. Radiol., 64 (1991) 603-607) have proposed a partial transmission block (PTB) technique which entails the use of small daily doses over a conventional time period. Radiobiological analysis suggests that, although the PTB technique may be adequate for slowly growing tumours, therapeutic efficacy is likely to be compromised where the tumour doubling time is short. Accelerated hyperfractionation (twice daily fractions) provides a possible alternative to both conventional scheduling and the PTB technique. Direct measurement of the kinetics of tumour cells in CSF, where possible, may provide useful guidance in the choice of regimes.     

Effects of grafts of single anterior pituitary glands on the incidence and type of mammary neoplasm in neutron- or gamma-irradiated Fischer female rats

Three batches comprised of 48 young adult Fischer female rats each were subjected to total-body irradiation with 50 rads modified fission neutrons, or were given 600 rads 137Cs gamma-rays, or served as unirradiated controls. On the day following exposure, one-half of each batch was grafted with a single anterior pituitary gland beneath the left kidney capsule. The animals were observed for mammary neoplasia and all those that died during the experiment were autopsied. The experiment was terminated 538 +/- 13 days after irradiation when all neutron-irradiated, pituitary-grafted animals had one or more mammary tumors. Only 2 of the 23 untreated rats that survived until termination of the experiment developed mammary fibroadenomas, and none had mammary carcinomas. The incidence of fibroadenomas was increased, and a single carcinoma was found, in unirradiated rats with pituitary grafts. Irradiation alone caused an increase in the incidence of mammary fibroadenomas and the appearance of carcinomas. Fibroadenomas were markedly increased by the addition of pituitary grafts to irradiation. Carcinoma incidence was less markedly affected. The neutron dose of 50 rads was slightly more effective in inducing mammary neoplasms than the 600-rad dose of gamma-rays.     

Milnacipran. A review of its use in depression

Milnacipran is a cyclopropane derivative which acts by inhibiting noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at presynaptic sites; no postsynaptic receptor activity has been demonstrated. It is most commonly administered at a dosage of 50 mg twice daily for the treatment of major depressive disorder. Improvement usually occurs within 2 weeks of treatment initiation, but some patients do respond sooner. Most studies which evaluated milnacipran were of short (4 to 8 weeks) duration and results were not published in full with rigorous peer review. Nonetheless, the drug is significantly more effective than placebo for the treatment of in- or outpatients with moderate to severe major depressive disorder. Limited data suggest that it may prevent relapse and be effective for long term use, although this requires confirmation. Milnacipran 200 mg/day is generally not significantly different from amitriptyline 150 mg/day in terms of onset and efficacy. However, when doses are titrated (not a requirement for milnacipran), milnacipran 50 or 100 mg/day has a slower onset than the tricyclic antidepressant. At a dosage of 100 mg/day for 4 to 12 weeks, milnacipran generally has similar efficacy to imipramine and clomipramine 150 mg/day, although milnacipran 50 to 150 mg/day had a faster onset of activity than imipramine 50 to 150 mg/day in Japanese patients. In a 6-month trial, milnacipran was less effective than clomipramine. Milnacipran 50 or 100 mg twice daily was as effective as fluoxetine 20 mg once daily or fluvoxamine 100 mg twice daily in 4- to 12-week studies. At a dosage of 50 then 100 mg daily it was also as effective as mianserin 30 then 60 mg daily in a 4-week study. However, when administered once daily (in the evening), milnacipran 100 mg/day was not as effective as fluoxetine 20 mg/day after 6 weeks. The drug is generally well tolerated, producing no more adverse events (including anticholinergic events) than placebo, selective serotonin reuptake inhibitors or mianserin and fewer adverse events than tricyclic antidepressants in clinical trials. However, dysuria has been reported in 7% of male patients receiving milnacipran. CONCLUSIONS: Data from predominantly short term trials suggest that milnacipran generally has similar efficacy to tricyclic antidepressants and SSRIs. Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder.     

The Nicolas Andry Award-1995. Fracture healing. Radiation induced alterations

This study investigated the effects of radiation on fractures in a rat femur model. Two different radiation dosage fractionation schemes (1100 rads given in one dose and 2500 rads given in 10 divided doses over 12 days) and three different times of initiation of radiation (1 day before fracture, 3 or 10 days after fracture) were studied. Fractures exposed to these levels of radiation all appeared to heal during the course of this experiment, although with varying degrees of delay, with the exception of those exposed to a single dose of 1100 rads 3 days after fracture. These animals remained at a more immature level of repair histologically compared with the control group, throughout the entire time evaluated. The strength of the final repair remained less than the control for all the groups receiving treatment. These results may offer some explanation for the clinical observations of an increased incidence of delayed union and nonunion of fractures, an increased incidence of fracture and refracture in irradiated bone, and an increased incidence of fracture and nonunion in constructs using radiation in conjunction with allogeneic bone. Furthermore, the observed effects were generally no different in the animals treated with the two clinically relevant dose fractionation schemes chosen for this study.     

Conventionalization of germ-free rats reverses the disability of rhein anthrone to induce laxation

This study shows that rhein anthrone has no laxative potency in germ-free rats because after intracaecal administration of a dose of 50 mg/kg the large intestine transit exceeded 240 min. The time course of the laxative potency of rhein anthrone injected intracaecally was evaluated after peroral inoculation of germ-free rats with the caecal contents of conventional rats. Large intestine transit was measured at consecutive periods, on days 0, 1, 2, 3 and 5 after peroral inoculation. It appeared that 1 day after peroral inoculation the laxative potency of rhein anthrone was already established (large intestinal transit < 10 min) and laxation remained on the following days (days 2, 3 and 5). We concluded that rhein anthrone is inactive in germ-free rats and acquires laxative potency after peroral inoculation of germ-free rats with caecal contents of conventional rats.     

Estimating Evapotranspiration using Artificial Neural Network

This study investigates the utility of artificial neural networks (ANNs) for estimation of daily grass reference crop evapotranspiration (ETo) and compares the performance of ANNs with the conventional method (Penman–Monteith) used to estimate ETo. Several issues associated with the use of ANNs are examined, including different learning methods, number of processing elements in the hidden layer(s), and the number of hidden layers. Three learning methods, namely, the standard back-propagation with learning rates of 0.2 and 0.8, and backpropagation with momentum were considered. The best ANN architecture for estimation of daily ETo was obtained for two different data sets (Sets 1 and 2) for Davis, Calif. Using data of Set 1, the networks were trained with daily climatic data (solar radiation, maximum and minimum temperature, maximum and minimum relative humidity, and wind speed) as input and the Penman–Monteith (PM) estimated ETo as output. The best ANN architecture was selected on the basis of weighted standard error of estimate (WSEE) and minimal ANN architecture. The ANN architecture of 6-7-1, (six, seven, and one neuron(s) in the input, hidden, and output layers, respectively) gave the minimum WSEE (less than 0.3 mm/day) for all learning methods. This value was lower than the WSEE (0.74 mm/day) between the PM method and lysimeter measured ETo as reported by Jensen et al. in 1990. Similarly, ANNs were trained, validated, and tested using the lysimeter measured ETo and corresponding climatic data (Set 2). Again, all learning methods gave less WSEE (less than 0.60 mm/day) as compared to the PM method (0.97 mm/day). Based on these results, it can be concluded that the ANN can predict ETo better than the conventional method (PM) for Davis.     

Micellar electrokinetic chromatographic study of the interaction between enkephalin peptide analogs and charged micelles

BACKGROUND AND PURPOSE: Theoretical calculations suggest that pulsed dose-rate irradiation (PDR) should have approximately the same effectiveness as continuous low dose-rate (CLDR) when the same total dose is given in the same overall time, unless large doses per pulse (> 2 Gy) are used and/or non-exponential or very short half-times of repair (< 0.5 h) are present in the irradiated tissues. However, few animal experiments have been reported to test this theory, and some of them gave contradictory results. We have carried out experiments to determine whether PDR irradiation of 18 mm of cervical spinal cord in the rat was more or less effective than CLDR at 0.5-1 Gy/h, when the overall average dose rate during each day of PDR was close to the overall CLDR average dose rate. MATERIALS AND METHODS: PDR was simulated at a within-pulse dose rate of 4 Gy/h by filtered 18 MV X-rays from a linear accelerator. Two PDR schedules were used, 0.69 Gy at 1 h repetition (9 pulses per day) and 2 Gy at 3 h repetition (4 pulses per day), with overnight intervals of 16 and 15 h, respectively. The CLDR was delivered from iridium-192 wires in two concentric rings around a collar designed to fit the necks of rats so that they could eat and drink during the 72 h that was always the duration of the CLDR. Dose rate was then proportional to total CLDR dose. A range of doses was used to obtain dose response-curves, with a 15 Gy top-up dose (at 2 Gy/min, HDR) given on the day after the end of the PDR or CLDR irradiations. Animals were observed for at least 9 months to see whether fore-limb myelopathy developed. A total of 6-8 rats was irradiated per dose point, in two sets of experiments at an interval of 12 months. RESULTS: A set of 2 Gy fractions (at HDR) given daily, followed by the same top-up dose of 15 Gy at HDR, was available from a previous experiment for planning. Its ED50 was 61.2 Gy. The ED50 values found for the PDR schedules with 2 Gy at 3 h and 0.69 Gy at 1 h were 59.9 and 60.2 Gy, respectively. These were just 2% more effective than the daily HDR fractions, similar to expectations from theory if two components of repair are present. However, the CLDR irradiations resulted in no myelopathy even after doses up to 68 Gy at 0.94 Gy/h.. Thus PDR over 7 days (not at nights) appears to be more effective than CLDR over 3 days, with an effective dose-modifying factor of at least 1.1 to 1.17. DISCUSSION AND CONCLUSIONS: Reasons for this absence of effect with CLDR in these experiments are discussed, the most likely explanation being that a substantial component of repair with very short T1/2 (< 0.5 h) was present in spinal cord of these rats. There is evidence from other experiments elsewhere and in our laboratory for such a fast component of repair.     

Radiotherapy for carcinoma of the nasal cavity

Twenty-five patients with primary epithelial carcinoma of the nasal cavity without nodal or distant metastases were treated by irradiation between 1967 and 1978. Small field, beam-directed techniques delivered 6,000 to 7,000 rads with conventional fractionation. Control of the primary tumor was achieved in 21 (84%) patients after irradiation. All five treatment failures (one infield only, three infield recurrence with lymph node metastases, and one regional cervical node metastasis) were evident within six months; all five patients died of cancer. The adjusted actuarial survival rate at three years was 76%. Failure in the untreated neck was only 5% when the primary carcinoma was controlled and 16% overall. The literature has been reviewed with attention to tumor control rates and survival.     

CNS glia are targets for GDNF and neurturin

Carboplatin is one of the most common drugs used for radiochemotherapy of cancer. However, the best way to combine the drug with fractionated radiotherapy has not been established. In the present study the authors investigated which maximum tolerated daily bolus dose of carboplatin would allow safe radiopotentiation for 10 consecutive radiotherapy days, the scheme being repeated twice during the 6 weeks that a conventional radiotherapy scheme lasts. Seventy-two patients with lung or pelvis malignancies were included in a dose escalation study. Twenty-four patients comprised the first baseline cohort and were treated with radiotherapy alone. The daily dose of carboplatin was escalated starting from 38 mg/m2 daily (for 10 days) and increasing by 7 mg/m2 per day. Six patients were to be included in each cohort. All 12 patients treated at the 38 mg/m2 and 45 mg/m2 dose level completed two cycles of 10-day carboplatin treatment with no grade III-IV toxicity. Granulocyte colony-stimulating factor effectively averted the incidence of neutropenia and allowed the administration of the second carboplatin 10-day cycle in five of six patients at the 52 mg/m2 daily dose level. Platelet grade III-IV toxicity was observed in all 12 patients (six supported with granulocyte colony-stimulating factor and six with granulocyte colony-stimulating factor and recombinant human erythropoietin) treated at the 59 mg/m2 daily dose level and none of them received the second cycle of chemotherapy. Twelve patients were treated at the same dose level using amifostine 500 mg before carboplatin infusion. Two patients interrupted chemotherapy because of severe nausea and vomiting. Nine of 10 who accomplished the 10-day treatment had platelet levels more than 90,000/microl on day 28 and completed the second 10-day cycle without severe toxicity. Acute radiation toxicity did not increase in the carboplatin cohorts. In this study the authors established a high-dose fractionated carboplatin schedule that can be safely administered during radical radiotherapy.     

A clinico-pharmacological basis for optimizing the treatment of therapy-resistant forms of epilepsy

On 44 epileptic patients antiepileptic phenobarbital, finlepsin, diphenine, hexamidine were studied. The alterations in the level of free and bound fractions under the drug application in maximal tolerance daily doses, depending on changes in the administration frequency during the day, were recorded. It was established that level fluctuations of the total preparation occur mainly owing to level alterations in the fraction not bound to serum proteins. An increase in the drug administration frequency under the constant daily dose leads to a distinct reduction in the free fraction level fluctuations between doses, to a decrease in the intensity or removal of side effects, and makes it possible to further build up the daily dose to obtain the required effect.     

Laparoscopic resection of a benign true cyst of the spleen with the harmonic scalpel producing high levels of CA 19-9 and carcinoembryonic antigen

BACKGROUND: Oral ingestion of immunoglobulins in humans has been shown to be effective as prophylaxis against enteric infections. However, its therapeutic effect in children with infectious diarrhea has hitherto not been proven. We treated children with rotavirus diarrhea with immunoglobulins extracted from immunized bovine colostrum (IIBC) containing high titers of antibodies against four rotavirus serotypes. METHODS: In this double blind placebo-controlled trial, 80 children with rotavirus diarrhea were randomly assigned to receive orally either 10 g of IIBC (containing 3.6 g of antirotavirus antibodies) daily for 4 days or the same amount of a placebo preparation. The daily stool output (grams/kg/day), intake of oral rehydration solution (ml/kg/day), stool frequency (number of stools/day) and presence of rotavirus in stool were monitored for the 4 days during treatment. RESULTS: Children who received IIBC had significantly less daily and total stool output and stool frequency and required a smaller amount of oral rehydration solution than did children who received placebo (P < 0.05). Clearance of rotavirus from the stool was also earlier in the IIBC group compared with the placebo group (mean day, 1.5 vs. 2.9, P < 0.001). No adverse reactions from the colostrum treatment were observed. CONCLUSIONS: Treatment with antirotavirus immunoglobulin of bovine colostral origin is effective in the management of children with acute rotavirus diarrhea.