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Target volume dose considerations in proton beam treatment planning for lung tumors.

We performed a treatment planning study in order to gather basic insight in the effect of setup errors and breathing motion on the cumulative proton dose to a lung tumor. We used a simplified geometry that simulates a 50 mm diameter gross tumor volume (GTV) located centrally inside lung tissue. The GTV was expanded with a uniform 5 mm margin into a clinical target volume (CTV) and into a variety of planning target volume (PTV's). Proton beam apertures were designed to conform the prescribed dose laterally to the PTV while the range compensator was designed to provide distal coverage of the CTV. Different smearing distances were applied to the range compensators, and the cumulative dose in the CTV was evaluated for different combinations of breathing motion and systematic setup errors. Evaluation parameters were the dose to 99% of the CTV (D99) and the equivalent uniform dose (EUD), with a surviving fraction at 2 Gy of SF2 = 0.5. For a single proton field designed to a 15 mm expansion of the CTV and without smearing applied to the range compensator, D99 of the CTV reduced from 96% for no tumor displacement to 41% and 13% for systematic setup errors of 5 and 10 mm, respectively. For a representative clinical combination, of 5 mm systematic error and 10 mm breathing amplitude, the EUD of the CTV was about 40 Gy (prescribed dose 70 Gy) regardless the CTV to PTV margin, and without smearing. Smearing the range compensator increases the dose to the CTV substantially with a lateral margin and smearing distance of 7.5 mm providing ample tumor coverage. In this latter case, D99 of the target volume increased to 87% for a single field treatment plan. Smearing does, however, lead to an increase in dose to normal tissues distal to the clinical target volume. Next to countering geometric mismatches due to patient setup, smearing can also be used to counter the detrimental effects of breathing motion on the dose to the clinical target volume. We show that the lateral margin and smearing distance can be substantially smaller than the maximum tumor displacement due to setup errors and patient breathing, as measured by the D99 and the EUD.

Biophysical Phenomena↗

Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial.

BACKGROUND: We aimed to assess in patients with congestive heart failure whether dual inhibition of neutral endopeptidase and angiotensin-converting enzyme (ACE) with the vasopeptidase inhibitor omapatrilat is better than ACE inhibition alone with lisinopril on functional capacity and clinical outcome. METHODS: We did a prospective, randomised, double-blind, parallel trial of 573 patients with New York Heart Association (NYHA) class II-IV congestive heart failure, left-ventricular ejection fraction of 40% or less, and receiving an ACE inhibitor. Patients were randomly assigned omapatrilat at a daily target dose of 40 mg (n=289) or lisinopril at a daily target dose of 20 mg (n=284) for 24 weeks. The primary endpoint was improvement in maximum exercise treadmill test (ETT) at week 12. Secondary endpoints included death and comorbid events indicative of worsening heart failure. FINDINGS: Week 12 ETT increased similarly in the omapatrilat and lisinopril groups (24 vs 31 s, p=0.45). The two drugs were fairly well tolerated, but there were fewer cardiovascular-system serious adverse events in the omapatrilat group than in the lisinopril group (20 [7%] vs 34 [12%], p=0.04). There was a suggestive trend in favour of omapatrilat on the combined endpoint of death or admission for worsening heart failure (p=0.052; hazard ratio 0.53 [95% CI 0.27-1.02]) and a significant benefit of omapatrilat in the composite of death, admission, or discontinuation of study treatment for worsening heart failure (p=0.035; 0.52 [0.28-0.96]). Omapatrilat improved NYHA class more than lisinopril in patients who had NYHA class III and IV (p=0.035), but not if patients with NYHA class II were included. INTERPRETATION: Our findings suggest that omapatrilat could have some advantages over lisinopril in the treatment of patients with congestive heart failure. Thus use of vasopeptidase inhibitors could constitute a potentially important treatment for further improving the prognosis and well being of patients with this disorder.

Angiotensin II↗

Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial.

BACKGROUND: Beta blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. METHODS: In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0.35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. FINDINGS: The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86-1.02], p=0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. INTERPRETATION: Our results suggest that carvedilol extends survival compared with metoprolol.

Adrenergic beta-Antagonists↗

A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability.

In this double-blind, multicenter study, bupropion XL, a norepinephrine-dopamine reuptake inhibitor, and venlafaxine XR, a serotonin-norepinephrine reuptake inhibitor, were compared with regard to sexual functioning, efficacy, and tolerability. A total of 348 sexually active adult outpatients with depression were randomized to receive bupropion XL (titrated to a target dose of 300-450 mg/d) or venlafaxine XR (titrated to a target dose of 150-225 mg/d) for 12 weeks. Total scores on the primary dependent variable, the Changes in Sexual Functioning Questionnaire (self-report), increased for subjects receiving bupropion XL and decreased for those treated with venlafaxine XR; the mean change scores differed significantly between groups from week 2 onward. Among subjects with normal pretreatment sexual functioning, Changes in Sexual Functioning Questionnaire total scores remained essentially unchanged for the bupropion XL group but were decreased significantly for the venlafaxine XR group; mean change scores also differed between groups from week 2 onward. Although the therapies resulted in similar change on the 17-item Hamilton Depression Rating Scale, remission rates were significantly higher among those treated with bupropion XL (46%) versus venlafaxine XR (33%) (odds ratio, 1.93; 95% confidence interval, 1.07-3.46). Aside from adverse effects of venlafaxine XR on sexual function, both treatments were reasonably well tolerated. In conclusion, in this patient population (ie, relatively young, sexually active outpatients), bupropion XL was at least as effective as venlafaxine XR and had a significantly more favorable sexual side effect profile.

Adult↗

Do we need conventional angiography? The role of magnetic resonance imaging in verifying obliteration of arteriovenous malformations after Gamma Knife surgery.

Sixteen cerebral arteriovenous malformations (AVMs) were examined to determine the role of magnetic resonance (MR) imaging in verifying obliteration. The AVMs (mean volume 7.5 cm3, range 2-17 cm3) were treated with Gamma Knife surgery between March 1993 and May 1994. Integration of stereotactic MR and stereotactic conventional X-ray angiography (XRA) was used for targeting in the Gamma Knife surgery. All MR examinations both for targeting and follow-up, were performed on a 1.5-Tesla superconductive MR scanner (Signa). Multiple pulse sequences (spin echo T1- and T2-weighted MR imaging, and three-dimensional time-of-flight MR angiography) were used. The mean maximum target dose was 37.4 Gy (range 25.0-44.0 Gy). The mean minimum target dose was 20.1 Gy (range 17.5-25.2 Gy). Follow-up imaging was performed about every 6 months or when clinically warranted. XRA was performed when the AVM was no longer seen on MR images. The time from the last MR image to the XRA was within 1 month in nine patients, and longer in seven. MR imaging demonstrated regressing AVMs in all patients as early as 3 months after Gamma Knife surgery. For seven of the nine patients total obliteration on MR was confirmed on XRA within 1 month. In the other two, previous hemorrhage and adverse radiation effects probably caused overestimation of AVM obliteration. In the remaining seven patients, XRA confirmed the MR observation although the time intervals were longer. It is concluded that, for medium- to large-volume AVMs, MR can demonstrate not only the regressing AVMs but also verify total obliteration. However, verification has to be based on an integration of MR imgaging and MR angiography. The use of MR reduces the invasiveness of Gamma Knife surgery for cerebral AVMs.

Adolescent↗

What primary care physicians know about diagnosis and treatment of chronic heart failure.

BACKGROUND: The majority of patients with chronic heart failure (CHF) are treated by primary care physicians. Recent studies have shown that their knowledge about diagnosis and treatment of CHF is not satisfactory. AIM: To evaluate the knowledge of primary care physicians on the diagnosis and treatment of patients with CHF. METHODS: The survey consisting of 23 questions on the diagnosis and treatment of CHF, was filled in by 116 primary care physicians, practising in the city of Poznań. The questions dealt with the most typical characteristics of CHF, including history, physical examination, diagnosis of diastolic CHF and medical treatment, according to the recent guidelines of the European Society of Cardiology. RESULTS: More than 90% of physicians regarded history and physical examination as the most important elements required for establishing the diagnosis of CHF. Ankle oedema, dyspnea and fatigue were listed as the most typical CHF symptoms. Almost 80% of surveyed physicians routinely performed ECG and chest radiogram in order to diagnose CHF. Echocardiography was used by only 20% of physicians, and the term "diastolic CHF" was familiar to only one third of them. Angiotensin converting enzyme inhibitors (ACEI) were used by more than two thirds of doctors, and beta-blockers--by one third. The correct initial recommended dose of enalapril was known to more than half of the physicians, and the target dose--to only one fourth of them. The correct initial recommended dose of carvedilol was known to almost half of the physicians, and the target dose--to only 3% of them. Diuretics were prescribed by 62% of physicians, spironolactone--by half of them, and digitalis--by one third of them. CONCLUSIONS: Primary care physicians practising in the Poznań area diagnose CHF mainly on the basis of history, physical examination, ECG and chest radiogram. Echocardiography is underused which may hamper the accuracy of CHF diagnosis. ACEI and beta-blockers are also underused. These findings demonstrate that knowledge about diagnosis and treatment of CHF is insufficient among primary care physicians and indicate the need for educational and systematic changes, including a wider access to echocardiography.

Adrenergic beta-Antagonists↗

Ionizing irradiation quarantine treatment against plum curculio (Coleoptera: Curculionidae).

Plum curculio, Conotrachelus nenuphar (Herbst), is a quarantine pest of many temperate fruits, such as pomes, Malus spp.; stone fruits, Prunus spp.; and blueberries, Vaccinium spp.; in North America east of the Rocky Mountains and a small area in Utah. There are two strains, a northern univoltine one that undergoes obligate diapause as an adult and a southern multivoltine strain that usually has facultative diapause. Current quarantine treatments for shipment to areas that do not have the pest include methyl bromide fumigation and cold storage for several weeks. The cold storage treatment may not be effective against northern strain adults in diapause. The objective of this research was to develop an irradiation quarantine treatment against plum curculio. The estimated dose to kill southern strain plum curculio adults in one day is approximately 4 kGy. Diapausing northern strain plum curculios were prevented from reproducing with 40 Gy. Reproduction of southern strain plum curculios was prevented with a target dose of 80 Gy, and the dose recommended as a quarantine treatment, that would prevent adults from reproducing, is 92 Gy, the maximum absorbed dose measured when a target dose of 80 Gy was sought. At that dose, oviposition may still occur for up to 1 wk and some of the eggs may hatch, but there is no development beyond the first instar. Hosts of the plum curculio would tolerate that dose well. Immature plum curculios were prevented from reproducing with lower doses.

Animals↗

The problem of underdosing of angiotensin-converting enzyme inhibitors is markedly overrated: results from a study of patients discharged from hospital after an acute myocardial infarction.

OBJECTIVE: The use of angiotensin-converting enzyme (ACE) inhibitors has increased markedly during the last decade. It has been claimed that doses of ACE inhibitors prescribed in clinical practice are considerably lower than the target doses used in randomized clinical trials. The aim of the study was to investigate dosing of ACE inhibitors in patients discharged from the hospital after an acute myocardial infarction (AMI) and, furthermore, to compare these doses with the doses actually reached in clinical trials. METHODS: From 16 hospitals, we drew a sample of patients who were discharged alive with the diagnosis of AMI during a 3-month period in 1999/2000. From medical records, physicians in each hospital obtained the observed rate of cardiovascular drugs at discharge, including type and doses of ACE inhibitors. The clinicians' main indication for ACE inhibitor use was also reported. Outcome variables, including deaths and drug utilization with dosing after 6 months, were collected. RESULTS: Of a total of 767 patients discharged alive, 274 patients received an ACE inhibitor. The daily mean doses of the four ACE inhibitors used in the study were as follows: captopril 69.8+/-36.9 mg (n=44), enalapril 13.6+/-8.1 mg (n=75), lisinopril 11.0+/-7.2 mg (n=114), and ramipril 8.4+/-4.5 mg (n=38). The doses were unchanged after 6 months except for captopril, which showed a rise in mean daily dose to 84.4+/-36.7 mg. Ramipril compared most favorably with clinical trial medications, while captopril deviated most. The indication of hypertension was associated with slightly higher doses than the indication of secondary prevention. CONCLUSION: AMI patients were discharged from the hospital with ACE inhibitor doses fairly close to the ones achieved in clinical trials showing survival benefits for ACE inhibitors. A distinction should be made between target doses and doses actually obtained in clinical trials.

Acute Disease↗

Functional magnetic resonance imaging and radiosurgical dose planning.

OBJECTIVE: To assess the effect of functional magnetic resonance imaging (fMRI) on stereotactic radiosurgical (SRS) dose planning. METHODS: Patients included those undergoing SRS whose lesions were in or near areas that could be identified with fMRI. After processing, an fMR scan was registered to the anatomic scan, and this dataset was registered to a stereotactic CT scan. The imaged functional areas were contoured along with standard anatomical targets. Dose planning was done at first with the functional volumes rendered invisible; the plans were then adjusted as needed using the functional targets. Doses were measured using a dose-volume histogram tool. RESULTS: SRS was performed in 12 patients, 1 of whom also underwent SRT. Functional volumes studied included motor cortex in 8 patients, visual in 6 and language in 3; a total of 33 functional targets were imaged. Prescription doses ranged from 12 to 22.5 Gy (mean 19.5 Gy), and the maximum dose to functional volumes from 8 cGy to 18.5 Gy (mean 2.9 Gy). In 6 patients, arc adjustment using functional targets yielded a >50% reduction in dose to at least one functional volume; in all patients, the dose reduction to 50 and 75% of functional volumes averaged 4% (12 cGy) and 13% (30 cGy), respectively, while the reduction of maximal dose averaged 24% (50 cGy). CONCLUSIONS: fMRI can be used in SRS to reduce irradiation of eloquent brain using standard prescription doses. Appropriate arc adjustment may allow for escalation of the dose to the targeted lesion.

Adult↗

Long-term beta-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo.

PURPOSE: Bucindolol is a potent nonselective beta-blocking agent with vasodilatory properties. In this study, we evaluated the effects of long-term bucindolol therapy in the treatment of heart failure from idiopathic dilated cardiomyopathy. PATIENTS AND METHODS: Patients were eligible for enrollment if they had symptomatic heart failure, idiopathic dilated cardiomyopathy, and left ventricular ejection fraction less than 0.40. All patients received an initial test dose of 12.5 mg bucindolol orally every 12 hours for two or three doses. Patients tolerating the test dose were randomly assigned (double-blind) to receive bucindolol or placebo in a 3:2 ratio. Study medication was begun at a dose of 12.5 mg orally every 12 hours and gradually increased over a 1-month period until either a maximum tolerated dose or a target dose of 100 mg every 12 hours was reached. Study medication was then continued for an additional 2 months. RESULTS: A total of 24 patients were enrolled into the study. Twenty-three patients tolerated bucindolol test challenge; 14 were randomized to receive bucindolol, and nine were randomly assigned to receive placebo. The placebo group (age 56 +/- 2 years) was significantly older than the bucindolol group (46 +/- 3 years), but by all other clinical and hemodynamic parameters the two groups were comparable. Twenty-two of 23 patients completed the study. Patients treated with bucindolol had significant improvements in clinical heart failure symptoms and in resting hemodynamic function, including an increase of left ventricular ejection fraction (0.26 +/- 0.02 to 0.35 +/- 0.09, p = 0.003), cardiac index (2.2 +/- 0.1 to 2.5 +/- 0.4 L/minute/m2, p = 0.014), and left ventricular stroke work index (25 +/- 3 to 35 +/- 7 g.m/m2, p = 0.002) and a decrease in pulmonary artery wedge pressure (17 +/- 3 to 10 +/- 5 mm Hg, p = 0.005) and heart rate (86 +/- 3 to 75 +/- 9 beats/minute, p = 0.012). Patients treated with bucindolol also had a significant increase in exercise left ventricular ejection fraction (0.26 +/- 0.03 to 0.32 +/- 0.14, p = 0.015) and reduction in questionnaire-measured symptoms (p = 0.007) and New York Heart Association functional class (p less than 0.001). However, total treadmill exercise duration and maximal oxygen consumption with exercise did not change. No changes in rest or exercise parameters were observed in the placebo-treated group. Central venous plasma norepinephrine concentration decreased significantly in the bucindolol-treated group (423 +/- 79 to 212 +/- 101 pg/mL, p = 0.010), but was unchanged in the placebo-treated group. CONCLUSION: Bucindolol is well tolerated in patients with idiopathic dilated cardiomyopathy and congestive heart failure, and therapy for 3 months is associated with improved resting cardiac function, improved heart failure symptoms, and a reduction in venous norepinephrine concentration.

Adrenergic beta-Antagonists↗

Studies in dose-time-volume relationships in bladder and tongue radium implants.

The clinical results of 26 tongue and 31 bladder radium implants were analysed in terms of proposed dose specification parameters that describe the dose-time-volume relationships of the implant. Tongue cases that recurred within two years were mostly those with a relatively short treatment time and in which a relatively large dose reduction factor had to be applied. The dose-time factor did not differ significantly in the groups of bladder implants having different clinical results. A higher incidence of necrosis was noted in bladder cases. This was associated with a significantly higher mean dose and a somewhat greater degree of dose inhomogeneity. Recurrences were generally linked with greater mean dose, target volume and dose inhomogeneity. These unfavourable dose-volume relationships were frequently associated with poor distribution of needles. The reported experimental and clinical findings pertinent to the differential sparing of normal tissues associated with protraction of continuous irradiation are outlined. In the light of these, it is felt that the results of tongue implants could have been improved by omission of the dose-time adjustment factor for treatment time of 3-10 days without undue risk of necrosis. However, bladder results could have been improved by attainment of a better implantation technique while keeping the treatment time within 6-8 days in view of the lower tolerance.

Carcinoma, Squamous Cell↗

Statistical models for low dose exposure.

Extrapolation of health risks from high to low doses has received a considerable amount of attention in carcinogenic risk assessment over decades. Fitting statistical dose-response models to experimental data collected at high doses and use of the fitted model for estimating effects at low doses lead to quite different risk predictions. Dissatisfaction with this procedure was formulated both by toxicologists who saw a deficit of biological knowledge in the models as well as by risk modelers who saw the need of mechanistically-based stochastic modeling. This contribution summarizes the present status of low dose modeling and the determination of the shape of dose-response curves. We will address the controversial issues of the appropriateness of threshold models, the estimation of no observed adverse effect levels (NOAEL), and their relevance for low dose modeling. We will distinguish between quantal dose-response models for tumor incidence and models of the more informative age/time dependent tumor incidence. The multistage model and the two-stage model of clonal expansion are considered as dose-response models accounting for biological mechanisms. Problems of the identifiability of mechanisms are addressed, the relation between administered dose and effective target dose is illustrated by examples, and the recently proposed Benchmark Dose concept for risk assessment is presented with its consequences for mechanistic modeling and statistical estimation.

Age Factors↗

Plaque radiotherapy for selected orbital malignancies: preliminary observations: the 2002 Montgomery Lecture, part 2.

PURPOSE: To describe the principles and preliminary results of plaque brachytherapy for selected orbital malignancies. METHODS: A custom-designed Iodine-125 plaque, designed to deliver a target dose of 50 Gray, was placed surgically in the region from which an orbital malignancy was partially resected. The mean dose to the target area was 50 Gray. The initial and follow-up patient data were reviewed. RESULTS: Of the 8 patients, the diagnosis was adenoid cystic carcinoma of the lacrimal gland (4 cases), orbital invasion by basal cell carcinoma (2), orbital extension of conjunctival melanoma (1), and metastatic carcinoma (1). Of the 4 with adenoid cystic carcinoma, there was microscopic residual tumor after excision and orbital exenteration was considered. Three have tumor control with follow-up of 1, 3, and 6 years. One patient required exenteration for recurrence separate from the field of brachytherapy and is free of tumor after 10 years. All 4 patients are alive and well with tumor control. Of the 2 patients with orbital extension of basal cell carcinoma, tumor control without recurrence has been achieved in both after 2 years. The patient with orbital metastasis responded to plaque radiotherapy, with no orbital recurrence, but died of systemic metastasis. The patient with orbital melanoma had local orbital recurrence separate from the area of irradiation and is currently being treated for systemic metastasis. CONCLUSIONS: Based on preliminary observations, plaque radiotherapy appears to be a reasonable alternative to exenteration and external irradiation for selected orbital malignancies.

Adult↗

Smoothing intensity-modulated beam profiles to improve the efficiency of delivery.

Intensity-modulated beam profiles are generated by an inverse planning or optimization algorithm, a process that, being computationally complex and intensive, is inherently susceptible to noise and numerical artifacts. These artifacts make delivery of the beams more difficult, oftentimes for little, if any, observable improvement in the dose distributions. In this work we examine two approaches for smoothing the beam profiles. The first approach is to smooth the beam profiles subsequent to each iteration in the optimization process (method A). The second approach is to include a term within the objective function that specifies the smoothness of the profiles as an optimization criterion (method B). The two methods were applied to a phantom study as well as three clinical sites: paraspinal, nasopharynx, and prostate. For the paraspinal and nasopharynx cases, which have critical organs with low tolerance doses in close proximity, method B produced sharper dose gradients, better target dose homogeneity, and more critical organ sparing. In the less demanding prostate case, the two methods give similar results. In addition, method B is more efficient during optimization, requiring fewer iterations, but less efficient during DMLC delivery, requiring a longer beam-on time.

Algorithms↗

Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia.

We conducted a nonrandomized prospective phase II study of thalidomide in anemic patients with myelofibrosis with myeloid metaplasia (MMM), with or without preceding polycythemia vera or essential thrombocythemia, with a primary aim to improve anemia. Thalidomide was given in escalating doses with a target dose of 800 mg daily, but the median dose of thalidomide that was actually tolerated was 400 mg daily. Fifteen patients were entered into the study and 14 were evaluable for response. Five of 14 (36%) patients discontinued thalidomide before 3 mo because of side effects, and none of these five patients had a response at the time when thalidomide was stopped. When evaluated after 3 mo of therapy, none of the remaining nine patients exhibited a discernible clinical response. Three patients showed progressive disease defined as > 50% increase in the need for red cell transfusions. Treatment was poorly tolerated, with all patients reporting side effects of thalidomide, the most prominent being fatigue documented in 80% of patients. Two patients died while on study, one from acute myelogenous leukemia and one from pneumonia. We conclude that thalidomide given in doses employed in the treatment of multiple myeloma gives no clinically relevant hematological effects in advanced MMM and is hampered by a very high incidence of side effects.

Adult↗

Approaches to risk assessment of automotive engine exhausts.

Contributions of alkenes to cancer risk from urban air pollution were estimated on the basis of radiation dose equivalent of target dose. The latter was inferred from the incremental carboxyhaemoglobin (COHb) level in urban areas, the ratio of epoxide-haemoglobin adducts to COHb levels in smokers and the alkenes/CO level ratios in cigarette smoke and urban air. This model predicts some 200 and 5 cancer cases annually in Sweden from ethene and propene, respectively. This indicates that the risk from alkenes is of the same order of magnitude as that from the particulate fraction of the pollution.

Air Pollutants↗

All-trans retinoic acid for the treatment of AIDS-related Kaposi's sarcoma: results of a pilot phase II study.

Retinoids have anti-tumor activity in several malignant and premalignant conditions. Since Kaposi's sarcoma is regulated by steroid hormones both in vivo and in vitro, we hypothesized that retinoids may have anti-tumor effects in AIDS-related Kaposi's sarcoma. Thus, 27 patients with mucocutaneous, non-visceral AIDS-related Kaposi's sarcoma were treated with all-trans retinoic acid (tRA). Poor tolerance was observed at the initial starting dose of 150 mg/m2, and thus subsequent patients were treated using a weekly dose escalation, starting with 45 mg/m2 (given daily, in subdivided doses), to the target dose of 150 mg/m2 (given daily in three subdivided doses). Nearly half (46%) of the patients had extensive mucocutaneous disease with over 25 lesions. No patient had received prior cytotoxic chemotherapy. Ten patients had CD4 lymphocytes of 200/mm3 or greater (strata I); and 17 had under 200/mm3 CD4 lymphocytes (strata II). The median of the average daily tRA dose administered was 150 mg (90 mg/m2; there was no significant difference in the dose tolerance between the two strata). Adverse effects consisted of transient mild to moderate headaches in 65% of patients, mild to moderate skin dryness and cheilitis in 61%, and nausea and vomiting in 31%. Hematologic toxicities included hypertriglyceridemia in 62%, anemia in 23%, and neutropenia in 23%. Partial response to therapy was observed in 4/24 (17%) evaluable patients, occurring after 12, 20, 24, and 28 weeks of therapy, and lasting 4-24 weeks. Three responders had baseline CD4 lymphocyte counts < 200/mm3. Three additional patients experienced reduction in measured indicator lesions of greater than 25% but less than 50%, and seven patients experienced disease stabilization of 16 weeks or greater. In evaluable patients, the median time to disease progression was 22 weeks and the overall median survival in all patients was 27.3 months. No significant changes in CD4 lymphocyte counts, p24 antigen, and beta 2 microglobulin were observed over time. However, a statistically significant increase was observed in soluble IL-2 receptor levels while on tRA (p = 0.037). We conclude that tRA has activity in patients with mucocutaneous AIDS-related Kaposi's sarcoma with acceptable toxicity. tRA has immunological effects without upregulation of HIV parameters. Additional studies in combinations or with more active retinoids are warranted.

Acquired Immunodeficiency Syndrome↗

Relationship of lung adenoma prevalence and growth rate to acute urethan dose and target cell number.

Outbred Swiss Cox mice of both sexes were given single ip injections of 0.5--2.0 mg urethan/g body weight. Lung adenomas began to grow about 7 days after urethan administration. The relationship of plateau tumor level to dose was slightly concave upward. However, the relationship of average tumor number per 10(6) surviving target cells or alveolar type II cells to dose was markedly concave upward. Thus the definition of the urethan dose-lung adenoma prevalence curve should take into account the urethan cytotoxicity. Tumor diameters followed a log normal distribution pattern. The rate of change of geometric mean tumor diameter was independent of sex and urethan dose. In another experiment Swiss Cox mice received ip injections of 1.5 mg urethan/g body weight, and 4 weeks later chronic exposure to urethan in the drinking water was begun. The growth rate of adenomas induced by the single urethan injection was unaffected by subsequent chronic-urethan administration. The results support the common assumption that tumor growth rate is independent of the rate of chronic administration of a carcinogen.

Adenoma↗