Photodynamic therapy provides local control of cholangiocarcinoma in patients awaiting liver transplantation.

Many transplant centers use endoscopically directed brachytherapy to provide locoregional control in patients with otherwise incurable cholangiocarcinoma (CCA) who are awaiting liver transplantation (LT). The use of endoscopic retrograde cholangiopancreatography (ERCP)-directed photodynamic therapy (PDT) as an alternative to brachytherapy for providing locoregional control in this patient population has not been studied. The aim of this study was to report on our initial experience using ERCP-directed PDT to provide local control in patients with unresectable CCA who were awaiting LT. Patients with unresectable CCA who underwent protocol-driven neoadjuvant chemoradiation and ERCP-directed PDT with the intent of undergoing LT were reviewed. Four patients with confirmed or suspected CCA met the inclusion criteria for protocol LT. All four patients (100%) successfully underwent ERCP-directed PDT. All patients had chemoradiation dose delays, and two patients had recurrent cholangitis despite PDT. None of these patients had progressive locoregional disease or distant metastasis following PDT. All four patients (100%) underwent LT. Intention-to-treat disease-free survival was 75% at mean follow-up of 28.1 months. In summary, ERCP-directed PDT is a reasonably well tolerated and safe procedure that may have benefit by maintaining locoregional tumor control in patients with CCA who are awaiting LT.

Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment.

The role of inhaled corticosteroids in the management of chronic obstructive pulmonary disease (COPD) remains controversial. The purpose of this study was to evaluate whether sputum eosinophilia (defined as eosinophils > or = 3%) predicts clinical benefit from inhaled corticosteroid treatment in patients with smoking-related clinically stable moderate-to-severe COPD. Forty consecutive patients with effort dyspnoea (mean age 67 yrs; 52 pack-yr smoking history; post-bronchodilator forced expiratory volume in one second (FEV1) <60% predicted, consistent with moderate-to-severe smoking-related chronic airflow limitation) were enrolled. Subjects were treated with inhaled placebo followed by inhaled budesonide (Pulmicort Turbuhaler 1,600 microg.day(-1)), each given for 4 weeks. While the treatment was single-blind (subject level), sputum cell counts before and after treatment interventions were double-blind, thus removing bias. Outcome variables included spirometry, quality-of-life assessment and 6-min walk test. Sputum eosinophilia was present in 38% of subjects. In these, budesonide treatment normalised the eosinophil counts and, in comparison to placebo treatment, resulted in clinically significant improvement in the dyspnoea domain of the disease-specific chronic respiratory questionnaire (0.8 versus 0.3) and a small but statistically significant improvement in post-bronchodilator spirometry (FEV1 100 mL versus 0 mL; p<0.05). In conclusion, sputum eosinophilia predicts short-term clinical benefit from high-dose inhaled corticosteroid treatment in patients with stable moderate-to-severe chronic obstructive pulmonary disease.

The effect of setup uncertainty on normal tissue sparing with IMRT for head-and-neck cancer.

PURPOSE: Intensity-modulated radiotherapy (IMRT) is being evaluated in the management of head-and-neck cancers at several institutions, and a Radiation Therapy Oncology Group study of its utility in parotid sparing is under development. There is an inherent risk that the sharper dose gradients generated by IMRT amplify the potentially detrimental impact of setup uncertainty. The International Commission on Radiation Units and Measurements Report 62 (ICRU-62) defined planning organ-at-risk volume (PRV) to account for positional uncertainties for normal tissues. The purpose of this study is to quantify the dosimetric effect of employing PRV for the parotid gland and to evaluate the use of PRV on normal-tissue sparing in the setting of small clinical setup errors. METHODS AND MATERIALS: The optimized nine-beam IMRT plans for three head-and-neck cancer patients participating in an institutional review board approved parotid-sparing protocol were used as reference plans. A second optimized plan was generated for each patient by adding a PRV of 5 mm for the contralateral parotid gland. The effect of these additions on the quality of the plans was quantified, in terms of both target coverage and normal-tissue sparing. To test the value of PRV in a worst-case scenario, systematic translational setup uncertainties were simulated by shifting the treatment isocenter 5 mm superiorly, inferiorly, left, right, anteriorly, and posteriorly, without altering optimized beam profiles. At each shifted isocenter, dose distributions were recalculated, producing a total of six shifted plans without PRV and six shifted plans with PRV for each patient. The effect of setup uncertainty on parotid sparing and the value of PRV in compensating for the uncertainty were evaluated. RESULTS: The addition of the PRV and reoptimization did not significantly affect the dose to gross tumor volume, spinal cord, or brainstem. In contrast, without any shift, the PRV did increase parotid sparing and reduce coverage of the nodal region adjacent to the parotid gland. As expected, when the plans were shifted, the greatest increase in contralateral parotid irradiation was noted with shifts toward the contralateral parotid gland. With these shifts, the average volume of contralateral parotid receiving greater than 30 Gy was reduced from 22% to 4% when a PRV was used. This correlated with a reduction in the average normal-tissue complication probability (NTCP) from 22% to 7%. CONCLUSIONS: The use of PRV may limit the volume of normal tissue structures, such as the parotid gland, exceeding tolerance dose as a result of setup errors. Consequently, it will be important to incorporate the nomenclature of ICRU-62 into the design of future IMRT studies, if the clinical gains of increased normal-tissue sparing are to be realized.

Atrial defibrillation thresholds of electrode configurations available to an atrioventricular defibrillator.

INTRODUCTION: Little investigation has been conducted to assess the atrial defibrillation thresholds of electrode configurations using electrodes designed for internal ventricular defibrillation (right ventricle [RV], superior vena cava [SVC], and pulse generator housing [Can]) combined with coronary sinus (CS) electrodes. We hypothesized that a CS-->SVC+Can electrode configuration would have a lower atrial defibrillation threshold than a standard configuration for defibrillation, RV-->SVC+Can. We also tested the atrial defibrillation thresholds of five other configurations. METHODS AND RESULTS: In 12 closed chest sheep, we situated a two-coil (RV, SVC) defibrillation catheter, a left-pectoral subcutaneous Can, and a CS lead. Atrial fibrillation was burst induced and maintained with continuous infusion of intrapericardial acetyl-beta-methylcholine chloride. Using fixed-tilt biphasic shocks, we determined the atrial defibrillation thresholds of seven test configurations in random order according to a multiple-reversal protocol. The peak voltage and delivered energy atrial defibrillation thresholds of CS-->SVC+Can (168+/-67 V, 2.68+/-2.40 J) were significantly lower than those of RV-->SVC+Can (215+/-88 V, 4.46+/-3.40 J). The atrial defibrillation thresholds of the other test configurations were RV+CS-->SVC+Can: 146+/-59 V, 1.92+/-1.45 J; RV-->CS+SVC+Can: 191+/-89 V, 3.53+/-3.19 J; CS-->SVC: 188+/-98 V, 3.77+/-4.14 J; SVC-->CS+ Can: 265+/-145 V, 7.37+/-9.12 J; and SVC-->Can: 516+/-209 V, 24.5+/-15.0 J. CONCLUSIONS: The atrial defibrillation threshold of CS-->SVC+Can is significantly lower than that of RV-->SVC+Can. In addition, the low atrial defibrillation threshold of RV+CS-->SVC+Can merits further investigation. Based on corroboration of low atrial defibrillation thresholds of CS-based configurations in humans, physicians might consider using CS leads with atrioventricular defibrillators.

Protective effects of fluticasone on allergen-induced airway responses and sputum inflammatory markers.

BACKGROUND: A direct comparison of the protective effects of single and regular doses of inhaled glucocorticoid on allergen-induced asthmatic responses and inflammation has not been made. OBJECTIVE: To compare the effects of pretreatment with fluticasone 250 microg 30 min before allergen inhalation and two weeks of 250 microg twice daily (last dose 24 h before challenge) with single and regular (twice daily) placebo doses on early and late asthmatic responses, induced sputum cell counts and measures of eosinophil activation at 7 h and 24 h, and methacholine airway responsiveness at 24 h. PATIENTS AND METHODS: Ten mild asthmatic patients were studied in a randomized, double-blind, placebo controlled crossover study. RESULTS: Regular fluticasone increased the baseline mean provocative concentration of methacholine to cause a 20% fall (PC20) in forced expiratory volume in 1 s (FEV1) from 2.6 to 6.4 mg/mL (P<0.05) and lowered the eosinophil count from 3.1% to 0.4% (P<0.05) compared with regular placebo. Neither single nor regular fluticasone had any effect on the early asthmatic response. Single fluticasone attenuated the late asthmatic response, the mean +/- SEM maximum percentage fall in FEV1 (10.8+/-3.6 compared with single placebo 18. 8+/-3.5, P=0.03), the allergen-induced increase of airway responsiveness (P<0.05), and the eosinophilia (P<0.005) and activated eosinophils at 7 h (P<0.01) but not at 24 h. Regular fluticasone also attenuated the late asthmatic response (11.1+/-2.5) compared with regular placebo (19.6+/-4.5), but this was not statistically significant and did not protect against the induced increase in airway responsiveness or the sputum eosinophilia. CONCLUSION: Two weeks of regular inhaled fluticasone discontinued 24 h before allergen challenge does not offer any additional protection against the early or late asthmatic responses, increased airway responsiveness or sputum eosinophilia compared with a single dose of 250 microg immediately before allergen challenge, despite increasing baseline PC20 and decreasing sputum eosinophilia prechallenge. The significance of the protective effect of a single dose of inhaled steroid before an allergen inhalation and the duration of the protective effect need further investigation.

Internal mammary node coverage: an investigation of presently accepted techniques.

PURPOSE: Recent publications have generated a renewed interest in regional nodal treatment to include the ipsilateral supraclavicular and internal mammary nodes (IMN). The purpose of this study is to evaluate three presently accepted treatment techniques for coverage of the intact breast and ipsilateral lymph node regions and to construct recommendations regarding the utilization of these techniques. METHODS AND MATERIALS: Anatomic data were obtained from five randomly selected patients with computerized tomography (CT) in treatment position. Three patients presented with cancer of the left breast and two with cancer of the right. Using the Pinnacle 3-D planning system, normal tissue volumes of breast, ipsilateral lung, heart, sternum, and the IMN target were delineated for each patient. Three accepted techniques used to treat ipsilateral breast, internal mammary and supraclavicular nodes (extended tangents, 5-field, partly wide tangents) were configured and compared to a supraclavicular field matched to standard tangential fields. A dosage of 50 Gy in 25 fractions was prescribed to the target volume. Dose-volume histograms (DVH) were generated and analyzed with regard to target volume coverage and lung/heart volumes treated. RESULTS: All of the treatment techniques covering IMN include at least 10% more lung and heart volume than that covered by standard tangential fields. The relative lung and heart volumes treated with each technique were consistent from patient to patient. The 5-field technique clearly treats the largest volume of normal tissue; however, most of this volume receives less than 50% of the dose prescribed. The percent of heart and ipsilateral lung treated to 20 Gy, 30 Gy, and 40 Gy have been calculated and compared. Due to the increase in chest wall thickness and depth of IMN superiorly, complete coverage was not achieved with any technique if the IMN target extended superiorly into the medial supraclavicular field where dose fall-off resulted in a significant underdosing at depth. For the same anatomic reasons, the 5-field technique underdosed 10-15% of the IMN target volume in 4 of the 5 cases. This technique also yielded a greater dose heterogeneity, which was not seen with the other techniques evaluated and correlated with the change of anterior chest wall thickness. CONCLUSIONS: Anatomic variation in chest wall thickness and IMN depth strongly suggests the routine use of multislice CT planning to ensure complete coverage of the target volume and optimal sparing of normal tissue. All of the techniques can be constructed to look acceptable at central axis. To cover the superior most aspect of the IMN chain either high tangential fields, a supraclavicular field photon beam of energy >6 MV, or an AP/PA supraclavicular setup should be considered. The 5-field technique has the most difficulty in compensating for the increased depth of the IMN in the superior aspect of the tangent fields with up to +/-40% variation of the dose noted in isolated areas within the target volume. Based on our evaluation, the partly wide tangent technique offers many advantages. It provides optimal coverage of the target volume, reduces coverage of normal tissue volumes to an acceptable level, and is easily reproducible with a high degree of dose homogeneity throughout the target.

Advances in radiotherapy for carcinoma of the head and neck.

Increasingly, progress in the radiotherapy of carcinomas of the head and neck is being driven by principles of radiobiology. This article discusses some of the major advances in head and neck radiotherapy, including altered fractionation, concomitant chemotherapy, and intensity-modulated radiotherapy, in the context of radiobiologic rationale, potential impact on tumor control, and normal tissue complications.

Detection of atrial arrhythmia for cardiac rhythm management by implantable devices.

Implantable atrial defibrillators (IAD) should provide pacing therapy whenever appropriate (ie, typical atrial flutter) to minimize shock-related patient discomfort. Additionally, IADs should provide diagnostics regarding atrial arrhythmia type and frequency of occurrence to enable improved physician management of atrial arrhythmia. To achieve this, IADs should accurately classify atrial arrhythmia such as atrial fibrillation (AF) and atrial flutter (AFL) This article evaluates the performance of an algorithm, atrial rhythm classification (ARC), designed to classify AF and AFL. The ARC algorithm uses maximum rate, standard deviation, and range of the 12 most recent atrial cycle lengths to plot a point in a three-dimensional space. A decision boundary divides the space into 2 regions--faster/unstable atrial cycle lengths (AF) or slower/stable cycle lengths (AFL). Classifications are made on a sliding window of 12 consecutive cycles until the end of the episode is reached. In this way, continuous episode feedback is provided that can be used to help guide device therapy, measure arrhythmia type and frequency of occurrence. Bipolar (1-cm) electrogram episodes of AF (n = 16) and AFL (n = 7) were acquired from 20 patients and retrospectively analyzed using the ARC algorithm. The sensitivity and specificity in this study was 0.993 and 0.982, respectively. The ARC algorithm would have appropriately guided atrial therapy and minimized discomfort associated with defibrillation shocks in this small patient data set warranting further studies. The ARC algorithm may also be beneficial as a diagnostic tool to assist physician management of atrial arrhythmia.

Radiotherapy and dosimetry of 64Cu-TETA-Tyr3-octreotate in a somatostatin receptor-positive, tumor-bearing rat model.

64Cu [T1/2 = 12.8 h; beta+ = 0.655 MeV (19%); beta- = 0.573 MeV (40%)] has shown promise as a radioisotope for targeted radiotherapy. It has been demonstrated previously that the somatostatin analogue 64Cu-TETA-octreotide (64Cu-TETA-OC, where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid) significantly inhibited the growth of somatostatin receptor-positive CA20948 rat pancreatic tumors in Lewis rats (C. J. Anderson et al., J. Nucl. Med., 39: 1944-1951, 1998). In this study, we evaluated the radiotherapeutic efficacy of a new 64Cu-labeled somatostatin analogue, 64Cu-TETA-Tyr3-octreotate (64Cu-TETA-Y3-TATE), in CA20948 tumor-bearing rats. A single dose of 15 mCi (555 MBq) of 64Cu-TETA-Y3-TATE was shown to be more effective in reducing tumor burden than the same dose of 64Cu-TETA-OC. In multiple dose experiments, tumor-bearing rats were administered three doses of either 10 or 20 mCi (370 or 740 MBq) of 64Cu-TETA-Y3-TATE at 48-h intervals. Rats given 3x10 mCi (3x370 MBq) showed extended mean survival times compared with rats given a single dose; however, no complete regressions occurred. Complete regression of tumors was observed for all rats treated with 3x20 mCi (3x740 MBq), with no palpable tumors for approximately 10 days; moreover, the mean survival time of these rats was nearly twice that of controls. Toxicity was determined by physical appearance and hematological and enzyme analysis, which revealed no overt toxicity and only transient changes in blood and liver chemistry. Absorbed dose estimates showed the dose-limiting organ to be the kidneys. The radiotherapy results, along with absorbed dose estimates to target and clearance organs, confirm that 64Cu-labeled somatostatin analogues warrant continued consideration as agents for targeted radiotherapy.

Protection against methacholine bronchoconstriction to assess relative potency of inhaled beta2-agonist.

The purposes of this study were to estimate the relative dose potency (RP) of two formulations of salbutamol pressurized metered-dose inhalers (Proventil-HFA and Ventolin-CFC MDIs) to protect against methacholine bronchoconstriction, to validate this method and provide recommendations. The protective effects of 100-, 200-, and 400-micrograms doses of Proventil-HFA were compared with the same doses of Ventolin-CFC in 18 adult asthmatics (mean FEV1, 92% predicted; mean baseline PC20 methacholine, 1.8 mg/ml), in a dose-level blind, balanced, eight-period, crossover, placebo-controlled study. The log-transformed PC20 values after each dose of the drugs were compared by repeated-measures analysis of variance (ANOVA). A significant dose-effect was present (p < 0.0001). Using the Finney assay, the RP of Proventil-HFA compared with Ventolin-CFC was 1.08 (90% CI, 0.81-1.46) (80% power). This was also estimated using a nonlinear Emax model to validate the Finney method. The most precise estimate of RP was obtained with the comparison between 100- and 200-micrograms doses (RP, 1.00; 90% CI, 0.77-1.31). There were no adverse events resulting from the drugs or methacholine. We conclude that Proventil-HFA salbutamol is bioequivalent to Ventolin-CFC salbutamol. Bronchoprotection to methacholine is a valid method of demonstrating bioequivalence. By this method, 100- and 200-micrograms doses of salbutamol inhalations from an MDI will suffice.

A preview of implantable cardioverter defibrillator systems in the next millennium: an integrative cardiac rhythm management approach.

The implantable cardioverter defibrillator (ICD), a primary therapeutic option for preventing sudden cardiac death, has rapidly evolved since being introduced clinically in 1980. Technologic advances in several key areas have enabled ICDs to provide more sophisticated rhythm management. Recent emphasis has been placed on dual-chamber ICDs possessing adaptive-rate pacing capabilities. Adoption of dual-chamber ICD systems has been rapid. The capabilities of future ICD systems will be governed by an integrative strategy that brings together sets of features specifically targeted at multifaceted rhythm disorders. The addition of atrial therapy will require more sophisticated rhythm discrimination algorithms. ICD technology will improve on several fronts including leads, integrated circuits, batteries, and capacitors. Additionally, state-of-the-art pacemaker technology will continue to be incorporated into ICDs. As these new ICD systems become increasingly sophisticated from an engineering viewpoint, tremendous emphasis will be placed on decreasing the complexity of programming, device interrogation, and patient monitoring during routine patient follow-up. Vast improvements in ICD programming systems may ultimately permit the 1-minute follow-up.

Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes.

Mismatch repair (MMR) proteins repair mispaired DNA bases and have an important role in maintaining the integrity of the genome [1]. Loss of MMR has been correlated with resistance to a variety of DNA-damaging agents, including many anticancer drugs [2]. How loss of MMR leads to resistance is not understood, but is proposed to be due to loss of futile MMR activity and/or replication stalling [3] [4]. We report that inactivation of MMR genes (MLH1, MLH2, MSH2, MSH3, MSH6, but not PMS1) in isogenic strains of Saccharomyces cerevisiae led to increased resistance to the anticancer drugs cisplatin, carboplatin and doxorubicin, but had no effect on sensitivity to ultraviolet C (UVC) radiation. Sensitivity to cisplatin and doxorubicin was increased in mlh1 mutant strains when the MLH1 gene was reintroduced, demonstrating a direct involvement of MMR proteins in sensitivity to these DNA-damaging agents. Inactivation of MLH1, MLH2 or MSH2 had no significant effect, however, on drug sensitivities in the rad52 or rad1 mutant strains that are defective in mitotic recombination and removing unpaired DNA single strands. We propose a model whereby MMR proteins - in addition to their role in DNA-damage recognition - decrease adduct tolerance during DNA replication by modulating the levels of recombination-dependent bypass. This hypothesis is supported by the finding that, in human ovarian tumour cells, loss of hMLH1 correlated with acquisition of cisplatin resistance and increased cisplatin-induced sister chromatid exchange, both of which were reversed by restoration of hMLH1 expression.

Optic neuritis in chronic relapsing experimental allergic encephalomyelitis in Biozzi ABH mice: demyelination and fast axonal transport changes in disease.

The encephalitogenicity of optic nerve tissue was demonstrated in Biozzi ABH (H-2(dq1)) mice. Acute experimental allergic encephalomyelitis (EAE) occurred in 11/14 animals and 4/5 exhibited relapse. The involvement of the optic nerve in spinal cord homogenate induced chronic relapsing EAE (CREAE) was demonstrated by mononuclear cell infiltration and myelin degradation in the optic nerve prior to and during clinical disease. During the relapse phase gross pathological assessment revealed swollen and translucent plaques on the optic nerves. Advanced lesions showed widespread demyelination, astrocytic gliosis and fibrotic changes of the blood vessels. Physiologically, the fast axonal transport of proteins from the retina to the optic nerve and superior colliculus was significantly decreased during relapse. The association of inflammation and demyelination with physiological deficit in the optic nerve highlights the usefulness of this model in the study of multiple sclerosis in which acute monosymptomatic unilateral optic neuritis is a common manifestation. Furthermore, the novel induction of CREAE with optic nerve homogenate suggests that optic neuritis is a common significant role in the pathophysiology and progression of neurological disease in CREAE which may be relevant to studies of optic neuritis in multiple sclerosis.

Relationship-specific and global perceptions of social support: associations with well-being and attachment.

Is one's global sense of social support largely a summation of the support perceived to exist within current social relationships, or is it a trait-like construct independent of current support levels? To address this issue, 183 college students completed measures of global support, support from four different social domains, attachment style, and several measures of well-being. Hierarchical regression analyses revealed that for two well-being measures (global and social loneliness), both global and domain support displayed significant unique associations; for emotional loneliness, only domain support had a significant unique influence. For the well-being measure reflecting generalized negative affect, only global support displayed such a unique association. Thus, global and domain support appear to be, to a considerable degree, independent constructs, each with its own sphere of influence in affecting well-being.

Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer.

PURPOSE: We performed a retrospective analysis to assess the durability of benefit derived from irradiation after prostatectomy for pT3N0 disease, and the possibility of cure. METHODS AND MATERIALS: We studied 88 patients who were irradiated after prostatectomy and had available prostate specific antigen (PSA) data, no known nodal or metastatic disease, no hormonal treatment, and follow-up of at least 12 months from surgery. Forty patients received adjuvant therapy for a high risk of local failure with undetectable PSA. Forty-eight patients received salvage therapy for elevated PSA levels. Mean follow up was 44 months from date of surgery and 31 months from irradiation. Biochemical failure was strictly defined as a confirmed rise in PSA of >10%, or as the ability to detect a previously undetectable PSA value. RESULTS: After salvage irradiation, 69% of patients attained an undetectable PSA. Eighty-eight percent of adjuvant patients were biochemically and clinically free of disease (bNED) at 3 years from prostatectomy. Sixty-eight percent of those receiving salvage irradiation were bNED 3 years after surgery. On univariate analysis, treatment group (adjuvant or salvage), pre-operative PSA, and the status of seminal vesicles were significant prognostic factors. The extent of PSA elevation in the salvage group was also significant. We did not demonstrate a significant difference between those salvage patients referred for persistently elevated PSA as compared to those with a late rise in PSA. On multivariate analysis, the only significant predictor of outcome was treatment group, with adjuvant irradiation having better outcome than salvage. CONCLUSION: More than two-thirds of this group of patients remain biochemically disease free at 3 years following irradiation, attesting to a number of potential cures. For patients with stage pT3N0 prostate cancer following radical prostatectomy, our data support the use of either routine postoperative adjuvant irradiation or close PSA follow-up with early salvage treatment.

Irradiation in the setting of collagen vascular disease: acute and late complications.

PURPOSE: Based on reports of greater toxicity from radiation therapy, collagen vascular diseases (CVDs) have been considered a contraindication to irradiation. We assessed the complications of radiation therapy in patients with CVD. PATIENTS AND METHODS: A total of 209 patients with documented CVD were irradiated between 1960 and 1995. One hundred thirty-one had rheumatoid arthritis (RA), 25 had systemic lupus erythematosus (SLE); 17 had polymyositis or dermatomyositis; 16 had scleroderma; eight had ankylosing spondylitis; five had juvenile RA; three had discoid lupus erythematosus; and four had 4 mixed connective tissue disorders (MCTD). The mean follow-up duration of curative cases was more than 6 years. Doses ranged from 10 to 87.6 Gy, with a median of 45 Gy. RESULTS: Overall, 263 sites were assessable in 209 patients. Significant (> or = grade 3) acute toxicity was seen in 10% of irradiated sites. Severe late effects were associated with significant acute reactions and with non-RA CVDs (6% v 21% at 5 years). No difference was seen in late effects according to timing of CVD onset, presence of concurrent vascular insults, radiation dose, or other technical factors, or by measures of disease activity. CONCLUSION: RA does not appear to have an elevated rate of late toxicity. While non-RA CVD is significantly associated with increased radiation late effects at standard doses, radiation-related mortality remains exceedingly rare. The choice of therapeutic modality in this radiosensitive group of patients should be made on a case-by-case basis.

Evaluation of single-dose inhaled corticosteroid activity with an allergen challenge model.

BACKGROUND: Inhaled corticosteroids are the most commonly used antiinflammatory agents for asthma. There is no simple way to compare objectively the relative potency of inhaled corticosteroids. The allergen-induced late asthmatic response (LAR) can be suppressed by a single dose of inhaled corticosteroid. OBJECTIVE: This study was undertaken to evaluate LAR as a model for the determination of the relative potency of single doses of inhaled corticosteroids. METHODS: We compared doses of 200 and 800 microg of a highly active inhaled corticosteroid (budesonide) with placebo and a marginally active investigational inhaled corticosteroid (D5159). Ten atopic patients with asthma completed a randomized, double-blind, double-dummy, multicenter, four-way, crossover trial. A standardized allergen challenge with the identical dose of allergen was performed 10 minutes after each of four blinded, single-dose treatments: 200 microg of budesonide, 800 microg of budesonide, 8 mg of D5159, and placebo, all administered from Turbuhaler. The LAR was recorded as the maximum percent fall in FEV1 between 4 and 7 hours, and the allergen-induced increase in methacholine airway responsiveness at 24 hours was recorded as the A log PC20 from the day before to the day after allergen challenge. RESULTS: There were no significant differences in the early asthmatic responses during the 4 days; the mean maximum percent in FEV1 fall ranged between 19.5% and 22%. D5159 produced a slight inhibition of the LAR with maximum percent fall in FEV1 recorded as 28.8% +/- 5.0% for D5159 versus 34.1% +/- 4.8% for placebo (p < 0.05). There was a greater reduction recorded after administration of the two doses of budesonide. The mean LAR was 15.1% +/- 3.8% for 200 microg of budesonide and 11.2% +/- 2.3% for 800 microg of budesonide (p < 0.01 compared with placebo and D5159). The two doses of budesonide were not statistically different. Airway responsiveness to methacholine increased by 1.07 doubling doses 24 hours after allergen challenge. This increased airway responsiveness was slightly, but not significantly, reduced by the three active treatments (0.6 to 0.91 doubling doses). CONCLUSION: The allergen-induced LAR model was able to differentiate a single dose of an active inhaled corticosteroid from placebo and a highly potent inhaled corticosteroid from a weak inhaled corticosteroid. The model did not differentiate between 2 fourfold doses of the highly active inhaled corticosteroid (at the doses used in this study), neither for the fall in FEV1 nor for the increase in airway hyperresponsiveness.

Characterization of the cellular and cytokine response in the central nervous system following Semliki Forest virus infection.

Cytokines are important mediators in the pathogenesis of central nervous system (CNS) inflammatory diseases including multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE), viral encephalitis and virus induced demyelinating diseases. We have used immunohistochemical techniques to characterize the mononuclear cell infiltrate and cytokine profiles in the CNS following infection of mice with the demyelinating A7(74) strain of Semliki Forest virus (SFV), an important viral model of MS. Mononuclear cell infiltrates in the CNS, first observed at 3 days and maximal during clearance of infectious virus, were comprised predominantly of CD8+ lymphocytes. F4/80+ macrophage/microglia and CD45/B220+ B lymphocytes were most numerous during the subsequent phase of demyelination. CD4+ T-lymphocytes were observed at low levels throughout infection. By immunostaining MHC class I, IL-1beta , IL-3 and TGF beta1 were constitutively expressed in normal mice and were upregulated following infection. MHC class II, IL-1alpha, IL-2, IL-2R, TNF-alpha and IL-6 were strongly upregulated in the CNS of SFV-infected mice and mice with chronic relapsing EAE. The spatial and temporal distribution of these cytokines during the course of disease was analysed. Whereas IL-1alpha, IL-1beta, IL-10, and TGF beta1 were observed on day 3 following infection GMCSF, IL-2 and TNF alpha were first apparent at day 7 when the cellular infiltration in the CNS was most intense. In contrast IFN gamma and IL-6 were first observed on day 10 prior to the demyelination phase of disease. Cytokines in the lesions of demyelination suggest a role in the pathogeneisis of myelin damage. Based on cytokine profiles no clear bias of either a Th1 or Th2 response was observed in the CNS during infection.