A joint physics and radiobiology DREAM team vision - Towards better response prediction models to advance radiotherapy.

Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines.

Methodology paper: a novel phantom setup for commissioning of scanned ion beam delivery and TPS.

BACKGROUND: Commissioning of treatment planning systems (TPS) and beam delivery for scanned light ion beams is an important quality assurance task. This requires measurement of large sets of high quality dosimetric data in anthropomorphic phantoms to benchmark the TPS and dose delivery under realistic conditions. METHOD: A novel measurement setup is described, which allows for an efficient collection of a large set of accurate dose data in complex phantom geometries. This setup allows dose measurements based on a set of 24 small volume ionization chambers calibrated in dose to water and mounted in a holder, which can be freely positioned in a water phantom with various phantoms mounted in front of the water tank. The phantoms can be scanned in a CT and a CT-based treatment planning can be performed for a direct benchmark of the dose calculation algorithm in various situations. RESULTS: The system has been used for acceptance testing in scanned light ion beam therapy at Heidelberg Ion Beam Therapy Center for scanned proton and carbon ion beams. It demonstrated to be useful to collect large amounts of high quality data for comparison with the TPS calculation using various phantom geometries. CONCLUSION: The setup is an efficient tool for commissioning and verification of treatment planning systems. It is especially suited for dynamic beam delivery, as many data points can be obtained during a single plan delivery, but can be adapted also for other dynamic therapies, like rotational IMRT.

Integration and evaluation of automated Monte Carlo simulations in the clinical practice of scanned proton and carbon ion beam therapy.

Monte Carlo (MC) simulations of beam interaction and transport in matter are increasingly considered as essential tools to support several aspects of radiation therapy. Despite the vast application of MC to photon therapy and scattered proton therapy, clinical experience in scanned ion beam therapy is still scarce. This is especially the case for ions heavier than protons, which pose additional issues like nuclear fragmentation and varying biological effectiveness. In this work, we present the evaluation of a dedicated framework which has been developed at the Heidelberg Ion Beam Therapy Center to provide automated FLUKA MC simulations of clinical patient treatments with scanned proton and carbon ion beams. Investigations on the number of transported primaries and the dimension of the geometry and scoring grids have been performed for a representative class of patient cases in order to provide recommendations on the simulation settings, showing that recommendations derived from the experience in proton therapy cannot be directly translated to the case of carbon ion beams. The MC results with the optimized settings have been compared to the calculations of the analytical treatment planning system (TPS), showing that regardless of the consistency of the two systems (in terms of beam model in water and range calculation in different materials) relevant differences can be found in dosimetric quantities and range, especially in the case of heterogeneous and deep seated treatment sites depending on the ion beam species and energies, homogeneity of the traversed tissue and size of the treated volume. The analysis of typical TPS speed-up approximations highlighted effects which deserve accurate treatment, in contrast to adequate beam model simplifications for scanned ion beam therapy. In terms of biological dose calculations, the investigation of the mixed field components in realistic anatomical situations confirmed the findings of previous groups so far reported only in homogenous water targets. This work can thus be useful to other centers commencing clinical experience in scanned ion beam therapy.

Challenges of the Blackwood Basin, Western Australia.

Growing concern about the declining state of the catchment and river led to the formation of the Blackwood Basin Group in 1992. Funded primarily by the Natural Heritage Trust and using the river as the focus, the group aims to provide leadership and support to achieve sustainable management of natural resources in the catchment. Through an Integrated Catchment Management approach, the Blackwood Basin Group has managed a range of projects to improve the community's understanding and management of the Blackwood River and its catchment. A number of research, education, demonstration and on-ground action activities relating to river management have been undertaken in partnership with community and local, state and federal government organisations. Activities include demonstrations and evaluations of riparian restoration, funding riparian restoration activities, protection of high conservation value remnant vegetation, a flood risk study, zone action planning and monitoring the condition of the river and its tributaries.

Construction of a highly bioluminescent Nitrosomonas as a probe for nitrification conditions.

Cloned luciferase-encoding operons were transferred by conjugation to a natural isolate of the ammonia-oxidizing bacterial strain Nitrosomonas sp. RST41-3, thereby establishing conjugation as a tool for gene transfer into Nitrosomonas strains. Luminescence was dependent on the pH of the medium and the concentration of the substrate ammonium chloride. Moreover, the luminescence of the transconjugants was reduced immediately by micromolar concentrations of nitrapyrin and allylthiourea, which are specific inhibitors of nitrification. Our results indicate that luminescent Nitrosomonas strains may be useful as a probe to detect nitrification conditions in the natural environment as well as in sewage plants.

Reversed phase liquid chromatography with UV absorbance and flame ionization detection using a water mobile phase and a cyano propyl stationary phase Analysis of alcohols and chlorinated hydrocarbons.

The development of liquid chromatography with a commercially available cyano propyl stationary phase and a 100% water mobile phase is reported. Separations were performed at ambient temperature, simplifying instrumental requirements. Excellent separation efficiency using a water mobile phase was achieved, for example N=18 800, or 75 200 m(-1), was obtained for resorcinol, at a retention factor of k'=4.88 (retention time of 9.55 min at 1 ml min(-1) for a 25 cmx4.6 mm i.d. column, packed with 5 mum diameter particles with the cyano propyl stationary phase). A separation via reversed phase liquid chromatography (RP-LC) with a 100% water mobile phase of six phenols and related compounds was compared to a separation of the same compounds by traditional RP-LC, using octadecylsilane (ODS), i.e. C18, bound to silica and an aqueous mobile phase modified with acetonitrile. Nearly identical analysis time was achieved for the separation of six phenols and related compounds using the cyano propyl stationary phase with a 100% water mobile phase, as compared to traditional RP-LC requiring a relatively large fraction of organic solvent modifier in the mobile phase (25% acetonitrile:75% water). Additional understanding of the retention mechanism with the 100% water mobile phase was obtained by relating measured retention factors of aliphatic alcohols, phenols and related compounds, and chlorinated hydrocarbons to their octanol:water partition coefficients. The retention mechanism is found to be consistent with a RP-LC mechanism coupled with an additional retention effect due to residual hydroxyl groups on the cyano propyl stationary phase. Advantages due to a 100% water mobile phase for the chemical analysis of alcohol mixtures and chlorinated hydrocarbons are reported. By placing an absorbance detector in-series and preceding a novel drop interface to a flame ionization detector (FID), selective detection of a separated mixture of phenols and related compounds and aliphatic alcohols is achieved. The compound class of aliphatic alcohols is selectively and sensitively detected by the drop interface/FID, and the phenols and related compounds are selectively and sensitively detected by absorbance detection at 200 nm. The separation and detection of chlorinated hydrocarbons in a water sample matrix further illustrated the advantages of this methodology. The sensitivity and selectivity of the FID signal for the chlorinated hydrocarbons are significantly better than absorbance detection, even at 200 nm. This methodology is well suited to continuous and automated monitoring of water samples. The applicability of samples initially in an organic solvent matrix is explored, since an organic sample matrix may effect retention and efficiency. Separations in acetonitrile and isopropyl alcohol sample matrices compared well to separations with a water sample matrix.

Use of metabolically competent human hepatoma cells for the detection of mutagens and antimutagens.

The human hepatoma line (Hep G2) has retained the activities of various phase I and phase II enzymes which play a crucial role in the activation/detoxification of genotoxic procarcinogens and reflect the metabolism of such compounds in vivo better than experimental models with metabolically incompetent cells and exogenous activation mixtures. In the last years, methodologies have been developed which enable the detection of genotoxic effects in Hep G2 cells. Appropriate endpoints are the induction of 6-TGr mutants, of micronuclei and of comets (single cell gel electrophoresis assay). It has been demonstrated that various classes of environmental carcinogens such as nitrosamines, aflatoxins, aromatic and heterocyclic amines and polycyclic aromatic hydrocarbons can be detected in genotoxicity assays with Hep G2 cells. Furthermore, it has been shown that these assays can distinguish between structurally related carcinogens and non-carcinogens, and positive results have been obtained with rodent carcinogens (such as safrole and hexamethylphosphoramide) which give false negative results in conventional in vitro assays with rat liver homogenates. Hep G2 cells have also been used in antimutagenicity studies and can identify mechanisms not detected in conventional in vitro systems such as induction of detoxifying enzymes, inactivation of endogenously formed DNA-reactive metabolites and intracellular inhibition of activating enzymes.

Genotoxic effects of heavy metals: comparative investigation with plant bioassays.

The potential use of micronucleus assays in plants for the detection of genotoxic effects of heavy-metal ions was investigated. Three different plant systems were comparatively investigated in micronucleus tests with Tradescantia pollen mother cells (Trad MCN) and micronucleus tests with meristematic root tip cells of Allium cepa and Vicia faba (Allium/ Vicia MCN). As3+, Pb2+, Cd2+, Zn2+ caused a dose-dependent increase of MCN frequencies in all three test systems. Cu2+ gave consistently negative responses in all three tests; Zn2+ caused only a moderate, statistically not significant increase of MCN frequencies in Vicia. The ranking of genotoxic potencies in all three tests was in the descending order: As3+ > Pb2+ > Cd2+ > Zn2+ Cu2+. In experiments with Tradescantia, induction of MCN was observed in a concentration range between 1 and 10 mM, whereas in tests with root tip cells, higher concentrations (10-1,000 mM) were required to show significant effects. Further increase of the exposure levels caused toxic effects (reduction of root growth), cell division delays, and a decrease of MCN frequencies. Comparisons by linear regression analyses indicated that the sensitivity of the three bioassays for heavy metals decreases in the order: Trad MCN > Vicia root MCN > Allium root MCN. In further experimental series, a soil sample which contained high concentrations of the five metals and a control soil were investigated. Aqueous soil extracts induced only weak effects in Trad MCN tests and no effects in the root tip assays, whereas cultivation of the plants in the soils resulted in a pronounced induction of MCN in the Tradescantia system and moderate effects in Vicia and Allium. In conclusion, the results of the study indicate that the Trad MCN assay detects the genotoxic effects of heavy metals and can be used for biomonitoring metal-contaminated soils.

Bonded stationary phases for reversed phase liquid chromatography with a water mobile phase: application to subcritical water extraction.

Reversed phase high-performance liquid chromatography (RP-HPLC) is demonstrated for hydrophobic analytes such as aromatic hydrocarbons on a chemically bonded stationary phase and a mobile phase consisting of only water. Reversed phase liquid chromatography separations using a water-only mobile phase has been termed WRP-LC for water-only reversed phase LC. Reasonable capacity factors are achieved through the use of a non-porous silica substrate resulting in a chromatographic phase volume ratio much lower than usually found in RP-HPLC. Two types of bonded WRP-LC columns have been developed and applied. A brush phase was synthesized from an organochlorosilane. The other phase, synthesized from an organodichlorosilane, is termed a branch phase and results in a polymeric structure of greater thickness than the brush phase. A baseline separation of a mixture containing benzaldehyde, benzene, toluene, and ethyl benzene in less than 5 min is demonstrated using a water mobile phase with 12 000 plates generated for the unretained benzaldehyde peak. The theoretically predicted minimum reduced plate height is also shown to be approached for the unretained analyte using the brush phase. As an application, subcritical water extraction (SWE) at 200 degrees C is combined with WRP-LC. This combination allows for the extraction of organic compounds from solid matrices immediately followed by liquid chromatographic separation of those extracted compounds all using a solvent of 100% water. We demonstrate SWE/WRP-LC by spiking benzene, ethyl benzene, and naphthalene onto sand then extracting the analytes with SWE followed by chromatographic separation on a WRP column. A sand sample contaminated with gasoline was also analyzed using SWE/WRP-LC. This extraction process also provides kinetic information about the rate of analyte extraction from the sand matrix. Under the conditions employed, analytes were extracted at different rates, providing additional selectivity in addition to the WRP-LC separation.

Toxic effects of griseofulvin: disease models, mechanisms, and risk assessment.

Griseofulvin (GF) has been in use for more than 30 years as a pharmaceutical drug in humans for the treatment of dermatomycoses. Animal studies give clear evidence that it causes a variety of acute and chronic toxic effects, including liver and thyroid cancer in rodents, abnormal germ cell maturation, teratogenicity, and embroyotoxicity in various species. No sufficient data from human studies are available at present to exclude a risk in humans: therefore, attempts were made to elucidate the mechanisms responsible for the toxic effects of GF and to address the question whether such effects might occur in humans undergoing GF therapy. It is well documented that GF acts as a spindle poison and its reproductive toxicity as well as the induction of numerical chromosome aberrations and of micronuclei in somatic cells possibly may result from disturbance of microtubuli formation. Likewise, a causal relationship between aneuploidy and cancer has been repeatedly postulated. However, a critical survey of the data available on aneuploidogenic chemicals revealed insufficient evidence for such an association. Conceivably, other mechanisms may be responsible for the carcinogenic effects of the drug. The induction of thyroid tumors in rats by GF is apparently a consequence of the decrease of thyroxin levels and it is unlikely that such effects occur in GF-exposed humans. The appearance of hepatocellular carcinomas (HCC) in mice on GF-supplemented diet is preceded by various biochemical and morphological changes in the liver. Among these, hepatic porphyria is prominent, it may result from inhibition of ferrochelatase and (compensatory) induction of ALA synthetase. GF-induced accumulation of porphyrins in mouse liver is followed by cell damage and necrotic and inflammatory processes. Similar changes are known from certain human porphyrias which are also associated with an increased risk for HCC. However, the porphyrogenic effect of GF therapy in humans is moderate compared with that in the mouse model, although more detailed studies should be performed in order to clarify this relationship on a quantitative basis. A further important effect of GF-feeding in mice is the formation of Mallory bodies (MBs) in hepatocytes. These cytoskeletal abnormalities occur also in humans, although under different conditions; their appearance is associated with the induction of liver disease and HCC. Chronic liver damage associated with porphyria and MB formation, enhanced cell proliferation, liver enlargement, and enzyme induction all may contribute to the hepatocarcinogenic effect of GF in mice. In conclusion, further investigation is required for adequate assessment of health risks to humans under GF therapy.

Simultaneous flame ionization and absorbance detection of volatile and nonvolatile compounds by reversed-phase liquid chromatography with a water mobile phase.

A flame ionization detector (FID) is used to detect volatile organic compounds that have been separated by water-only reversed-phase liquid chromatography (WRP-LC). The mobile phase is 100% water at room temperature, without use of organic solvent modifiers. An interface between the LC and detector is presented, whereby a helium stream samples the vapor of volatile components from individual drops of the LC eluent, and the vapor-enriched gas stream is sent to the FID. The design of the drop headspace cell is simple because the water-only nature of the LC separation obviates the need to do any organic solvent removal prior to gas phase detection. Despite the absence of organic modifier, hydrophobic compounds can be separated in a reasonable time due to the low phase volume ratio of the WRP-LC columns. The drop headspace interface easily handles LC flows of 1 mL/min, and, in fact, compound detection limits are improved at faster liquid flow rates. The transfer efficiency of the headspace interface was estimated at 10% for toluene in water at 1 mL/min but varies depending on the volatility of each analyte. The detection system is linear over more than 5 orders of 1-butanol concentration in water and is able to detect sub-ppb amounts of o-xylene and other aromatic compounds in water. In order to analyze volatile and nonvolatile analytes simultaneously, the FID is coupled in series to a WRP-LC system with UV absorbance detection. WRP-LC improves UV absorbance detection limits because the absence of organic modifier allows the detector to be operated in the short-wavelength UV region, where analytes generally have significantly larger molar absorptivities. The selectivity the headspace interface provides for flame ionization detection of volatiles is demonstrated with a separation of 1-butanol, 1,1,2-trichloroethane (TCE), and chlorobenzene in a mixture of benzoic acid in water. Despite coelution of butanol and TCE with the benzoate anion, the nonvolatile benzoate anion does not appear in the FID signal, allowing the analytes of interest to be readily detected. The complementary selectivity of UV-visible absorbance detection and this implementation of flame ionization detection allows for the analysis of volatile and nonvolatile components of complex samples using WRP-LC without the requirement that all the components of interest be fully resolved, thus simplifying the sample preparation and chromatographic requirements. This instrument should be applicable to routine automated water monitoring, in which repetitive injection of water samples onto a gas chromatograph is not recommended.

Cerebral ischemia induced by compression tests during transcranial Doppler sonography.

Compression tests performed during transcranial Doppler sonography are intended for support in identifying vessels and measuring collateral circulation within the circle of Willis. The resulting information is thought to be valuable in patients with extracranial carotid stenoses, especially for planning carotid and extra-/intracranial bypass surgery. In a retrospective analysis of a series of 380 cases, two patients with symptomatic carotid artery stenoses suffered three compression-induced focal cerebral ischemias. In two instances, these ischemias started under compression. The resulting deficits were reversible. One patient developed an additional and persisting motor deficit whose onset was delayed. The diagnostic benefit of compression tests is not established nor its risk well defined. They should not be used routinely.

[Diagnosis and prognosis of carotid artery stenosis]. / Diagnose und Prognose der Carotisstenose.

The diagnosis of a carotid stenosis inevitably includes a neurological examination as well as CCT or MRI of the brain. Typical neurological and neuropsychological symptoms and signs as well as syndromes are described according to the vascular supply areas of the brain. CCT as well as MRI may identify cerebral infarction or other diseases and additionally give some information with regard to the underlying etiology or pathogenesis of an infarct. Satisfactory non-invasive demonstration of the carotid and vertebral arteries including their intracranial branches can be achieved by the use of sonographic methods (Dopplersonography, B-mode imaging, Duplex and colour-coded systems). Additionally, transcranial Dopplersonography is mandatory in most instances. Cerebral angiography is only justified preoperatively or for a disease which cannot be diagnosed reliably by other means, eg. cerebral venous thrombosis. The prognosis of a carotid stenosis depends not only on the degree of luminal narrowing and the shape of the stenosis but also on the clinical status of the patient (asymptomatic or symptomatic carotid stenosis, accompanying coronary artery disease etc.). Prophylactic treatment implies therapy of risk factors as well as antiaggregation, anticoagulation and carotid endarterectomy in selected cases.

Noninvasive assessment of CO2-induced cerebral vasomotor response in normal individuals and patients with internal carotid artery occlusions.

To evaluate the CO2-induced vasomotor reactivity of the cerebral vasculature, relative changes of blood flow velocity within the middle cerebral artery were measured by transcranial Doppler ultrasonography during normocapnia and various degrees of hypercapnia and hypocapnia. We studied 40 normal individuals and 40 patients with unilateral and 15 patients with bilateral internal carotid artery occlusions. When blood flow velocity changes as percent of normocapnic values were plotted against end-tidal CO2 volume percent, a biasymptotic curve (a tangent-hyperbolic function) gave the best fit of the scattergram. The distance between the upper and lower asymptotes was defined as cerebral vasomotor reactivity. In the normal individuals, mean +/- SD vasomotor reactivity was 85.63 +/- 15.96%. In patients with internal carotid artery occlusions, vasomotor reactivity was significantly lower than normal on both the occluded (mean 45.2%, median 50.4%; p less than 0.0001) and the nonoccluded (mean +/- SD 67.7 + 13.3%, p less than 0.01) sides in the unilateral group and on both sides (mean +/- SD 36.6 +/- 15.9% and 44.9 +/- 24.6%, p less than 0.0001) in the bilateral group. The difference between vasomotor reactivity for symptomatic and asymptomatic unilateral occlusions was also highly significant (mean 37.6% and 62.9%, p less than 0.006). Vasomotor reactivity was also significantly lower in patients with low-flow infarctions on computed tomography than in patients with normal scans (mean +/- SD 36.7 +/- 25% and 60.2 +/- 16.9%, p less than 0.008). A striking association of low-flow infarctions, ischemic ophthalmopathy, and hypostatic transient ischemic attacks was found with vasomotor reactivities of less than 34% or even paradoxical reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

[Laser trabeculoplasty in glaucoma chronicum simplex. Results of a prospective, clinical study]. / Lasertrabekuloplastik bei Glaucoma chronicum simplex. Ergebnisse einer prospektiven, klinischen Studie.

Between 1984 and 1986, 104 patients with open-angle glaucoma of various etiologies were treated by laser trabeculoplasty (LTP) in a prospective clinical study. In order to ensure that the group of patients studied was homogeneous, only the 85 consecutive patients (85 eyes) with primary open-angle glaucoma were included, using a specially designed software program. The number of patients with pseudoexfoliation glaucoma, aphakic glaucoma, and congenital glaucoma was too small to allow statistical comparison with those who had chronic open-angle glaucoma. Criteria for success were defined as follows: no progression of disk cupping or visual field defects, mean intraocular pressure below 24 mm Hg as calculated by a day profile, and no increase in medication. These conditions were satisfied by 76% of the patients after six months and by 64% after 12 months. Initially, coagulations were performed over 180 degrees in the inferior circumference. If this did not suffice, the upper 180 degrees were also coagulated. If LTP is to be effective, thorough coagulation with tender blanching effects is mandatory. Average preoperative pressure values of over 22 mm Hg and a postoperative pressure increase of between 5 and 14 mm Hg are favorable prognostic signs. None of the parameters age, sex, duration, intensity of glaucomatous disease, or preoperative medication had any influence on the efficacy of LTP. In 14 of the 45 patients in whom only one eye was treated a simultaneous decrease in pressure was also observed in the untreated eye. The side effects of LTP bear no relation to its benefits, so that LTP is very suitable as a therapy between medication and surgery. Careful follow-ups of the patients are necessary because of possible increases in intraocular pressure in the course of time.

[The so-called "ocular histoplasmosis syndrome"]. / Untersuchungen zum sogenannten "okulären Histoplasmose-Syndrom".

The authors describe seven patients presenting with ophthalmoscopic findings typical of "presumed ocular histoplasmosis syndrome." However, no humoral antibodies could be demonstrated. Moreover, the results of skin tests were all negative even after "boostering." Hence, the diagnosis of ocular histoplasmosis had to be ruled out. Tests for listeriosis, lues, leptospirosis, ornithosis, Toxocara canis, toxoplasmosis, Larva migrans, and Candida albicans were also negative. There are evidently other, so far unknown, agents which lead to an ophthalmoscopic picture that mimics ocular histoplasmosis with its typical "punched-out lesions" and central hemorrhagic chorioretinopathy. One of these agents may be Epstein-Barr virus, because two of six patients had increased antibody levels of Epstein-Barr nuclear antigen and early antigen, indicating an active or persistent state of viral infection.

Cardiac tamponade in medical patients: treatment and prognosis in the echocardiographic era.

Experience was reviewed in the management of pericardial tamponade in 36 patients with emphasis on factors governing short and long-term survival. Malignant pericardial effusion was the most common etiology and accounted for pericardial tamponade in 14 of the 36 patients (39%). Of the 36 patients, three received medical therapy alone, 18 were treated by one or more needle pericardiocentesis, pericardial drains were inserted in six patients, and thoracotomy was performed in nine. Needle pericardiocentesis was attempted as the initial therapy in all but two patients and was initially successful in relieving tamponade in 30 patients. Twenty-four patients died during a follow-up of from 1 day to 6 years. Delay in diagnosing tamponade was frequent and accounted for three deaths. Two more patients died from recurrent tamponade following initial relief. Eighteen patients died primarily from complications related to their basic illness, though recurrent pericardial effusion was a contributory factor in five. One patient died following pericardiectomy. The remaining 12 patients are well and free of pericardial disease. Short-term survival in pericardial tamponade is mostly dependent upon early diagnosis and relief of tamponade. Long-term survival depends upon the prognosis of the primary illness, irrespective of the mode of treatment used.

The solution of achromatic and chromatic Embedded Figures revisited.

Two samples of 20 males and 20 females each were drawn from two Eastern universities. Each of these two samples was presented with the 12-item Form B of Witkin's Embedded Figures Test, with half of each sex receiving the achromatic and half the chromatic format. As in the previous experiment (Bush & Coward, 1974), neither replication yielded a significant difference in mean solution time attributable to the effects of color. However, unlike the previous investigation, no sex differences were observed.

Spontaneous in vitro neoplastic transformation of adult human prostatic epithelium.

The possible significance of spontaneous transformation of epithelium from a benign prostatic adenoma containing glandular hyperplasia is discussed.