Altered fractionation outcomes for hypoxic head and neck cancer using the HYP-RT Monte Carlo model.

OBJECTIVE: Altered fractionation radiotherapy is simulated on a set of virtual tumours to assess the total doses required for tumour control compared with clinical head and neck data and the doses required to control hypoxic vs well-oxygenated tumours with different radiobiological properties. METHODS: The HYP-RT model is utilised to explore the impact of tumour oxygenation and the onset times of accelerated repopulation (AR) and reoxygenation (ROx) during radiotherapy. A biological effective dose analysis is used to rank the schedules based on their relative normal tissue toxicities. RESULTS: Altering the onset times of AR and ROx has a large impact on the doses required to achieve tumour control. Immediate onset of ROx and 2-week onset time of AR produce results closely predicting average human outcomes in terms of the total prescription doses in clinical trials. Modifying oxygen enhancement ratio curves based on dose/fraction significantly reduces the dose (5-10 Gy) required for tumour control for hyperfractionated schedules. HYP-RT predicts 10×1.1 Gy per week to be most beneficial, whereas the conventional schedule is predicted as beneficial for early toxicity but has average-poor late toxicity. CONCLUSION: HYP-RT predicts that altered radiotherapy schedules increase the therapeutic ratio and may be used to make predictions about the prescription doses required to achieve tumour control for tumours with different oxygenation levels and treatment responses. ADVANCES IN KNOWLEDGE: Oxic and hypoxic tumours have large differences in total radiation dose requirements, affected by AR and ROx onset times by up to 15-25 Gy for the same fractionation schedule.

The HYP-RT hypoxic tumour radiotherapy algorithm and accelerated repopulation dose per fraction study.

The HYP-RT model simulates hypoxic tumour growth for head and neck cancer as well as radiotherapy and the effects of accelerated repopulation and reoxygenation. This report outlines algorithm design, parameterisation and the impact of accelerated repopulation on the increase in dose/fraction needed to control the extra cell propagation during accelerated repopulation. Cell kill probabilities are based on Linear Quadratic theory, with oxygenation levels and proliferative capacity influencing cell death. Hypoxia is modelled through oxygen level allocation based on pO(2) histograms. Accelerated repopulation is modelled by increasing the stem cell symmetrical division probability, while the process of reoxygenation utilises randomised pO(2) increments to the cell population after each treatment fraction. Propagation of 10(8) tumour cells requires 5-30 minutes. Controlling the extra cell growth induced by accelerated repopulation requires a dose/fraction increase of 0.5-1.0 Gy, in agreement with published reports. The average reoxygenation pO(2) increment of 3 mmHg per fraction results in full tumour reoxygenation after shrinkage to approximately 1 mm. HYP-RT is a computationally efficient model simulating tumour growth and radiotherapy, incorporating accelerated repopulation and reoxygenation. It may be used to explore cell kill outcomes during radiotherapy while varying key radiobiological and tumour specific parameters, such as the degree of hypoxia.

Monte Carlo radiotherapy simulations of accelerated repopulation and reoxygenation for hypoxic head and neck cancer.

OBJECTIVE: A temporal Monte Carlo tumour growth and radiotherapy effect model (HYP-RT) simulating hypoxia in head and neck cancer has been developed and used to analyse parameters influencing cell kill during conventionally fractionated radiotherapy. The model was designed to simulate individual cell division up to 10(8) cells, while incorporating radiobiological effects, including accelerated repopulation and reoxygenation during treatment. METHOD: Reoxygenation of hypoxic tumours has been modelled using randomised increments of oxygen to tumour cells after each treatment fraction. The process of accelerated repopulation has been modelled by increasing the symmetrical stem cell division probability. Both phenomena were onset immediately or after a number of weeks of simulated treatment. RESULTS: The extra dose required to control (total cell kill) hypoxic vs oxic tumours was 15-25% (8-20 Gy for 5 × 2 Gy per week) depending on the timing of accelerated repopulation onset. Reoxygenation of hypoxic tumours resulted in resensitisation and reduction in total dose required by approximately 10%, depending on the time of onset. When modelled simultaneously, accelerated repopulation and reoxygenation affected cell kill in hypoxic tumours in a similar manner to when the phenomena were modelled individually; however, the degree was altered, with non-additive results. Simulation results were in good agreement with standard linear quadratic theory; however, differed for more complex comparisons where hypoxia, reoxygenation as well as accelerated repopulation effects were considered. CONCLUSION: Simulations have quantitatively confirmed the need for patient individualisation in radiotherapy for hypoxic head and neck tumours, and have shown the benefits of modelling complex and dynamic processes using Monte Carlo methods.

Biomedical engineering: issues and opportunity.

As defined by the National Institutes of Health (NIH), bioengineering is an interdisciplinary field that applies physical, chemical, and mathematical sciences and engineering principles to the study of biology, medicine, behavior, and health. It advances knowledge from the molecular to the organ systems level, and develops new and novel biologics, materials, processes, implants, devices, and informational approaches for the prevention, diagnosis, and treatment of disease for patient rehabilitation and for improving health.

The artificial heart: history and current status.

Twenty-years ago groups from California to Massachusetts were actively involved in the development of an artificial heart. From biomaterials development to biomedical power sources, the supporting industry and spin-off benefit was broad indeed. Young people were seeking careers in biomedical engineering and science. The National Institutes of Health was supporting artificial heart research at $10 to $12 million dollar levels. Groups at Andros, Inc. (now Baxter Novacor) and Stanford, Thoratec, Penn State and the Hershey Medical Center, Cleveland Clinic and the Division of Artificial Organs, the University of Utah, the Texas Heart Institute and the Baylor College of Medicine, Thermal Electron Corporation, and many more were the source of research and breakthrough development of pumps and systems for artificial hearts. We reported on performance criteria for an artificial heart pump at the First Biomechanics Symposium in 1973 [1]. By the beginning of the decade of the 90's, thousands of presentations had been made and manuscripts written reporting significant progress in the development of artificial heart pumps and systems. The Heart, Lung and Blood Institute of the National Institutes of Health was supporting an artificial heart contract research and development program at a level of $6 million dollars in 1991 [2]. Broad basic research grant activity also continues. The National Institutes of Health's artificial heart program received renewed support from the Institute of Medicine's special review in 1991 [3]. In December of 1992, the 16th Annual Cardiovascular Science and Technology Conference attracted over 500 attendees. This annual conference has provided a continuing forum for an update on progress in artificial heart development.

Depression and anxiety in medical, surgical, and pediatric interns.

The adaptive demands of a physicians' residency program include relocation to another area, mastery of a new organizational system, and a new level of role responsibility, in addition to education and patient care activities. This study examined the prevalence of significant psychiatric symptoms in medical, surgical, and pediatric interns for three four-month intervals. Following a cohort of 39 residents over the course of their first year, using the SCL-90--R, there was an elevated prevalence (M = 35%) of significant anxiety and depression throughout the year. Given the consistent high anxiety and depression, more research needs to be undertaken to understand the interaction of initial and ongoing adaptive demands.

Infrared spectroscopic studies on the phosphatidylserine bilayer interacting with calcium ion: effect of cholesterol.

Fourier transform infrared (IR) spectroscopic studies of phosphatidylserine/cholesterol/Ca2+ complexes are reported using the synthetic phosphatidylserines (PS) 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS), and 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS). IR spectra reveal that cholesterol does not significantly alter the binding nature of Ca2+ to PS molecules; Ca2+ binds to the phosphate ester group of PS in the presence of cholesterol up to 50 mol% as in the case of pure PS bilayers. However, the IR data indicate that the presence of cholesterol induces disorder of the acyl chain packing, increases the degree of immobilization of the interfacial and polar regions, and increases the degree of dehydration of the PS/Ca2+ complexes.

No safe place: parental alcoholism and adolescent suicide.

A child growing up in an alcoholic home develops either little self-consolidation (I-ness) and efficacy (I can) or a distorted self (I am insignificant). This results in a desperate search for a soothing-object (We-ness). The sadomasochistic behaviors, which a youth witnesses and is subjected to, become internalized as survival skills, but ultimately fail. These factors set the stage for a destructive modus operandi. When there is peer group attachment pressure, this teen does not find security when questioning, "Who am I?" because there is no "I" and no "We". Instead, this adolescent experiences fear, anxiety, and range, and wonders, "What's going to happen to me?" This propels the youth into frantic behaviors that are meant to confirm a sense of "We-ness" and competence. The result, however, is greater frustration and a mirroring of the opposite. Also, since there is a diminutive capacity for trust and an exiguous chance to reach out or respond to significant others, external soothingness becomes unobtainable. When the adolescent is confronted with aloneness, helplessness, and hopelessness, desperation results and a search for a safe place ensues. Suicide holds such an illusion. It is the embodiment of sadomasochism and permits the cognition "I am capable." A case study illustrates the problems.

Effect of tilting disk, heart valve orientation on flow through a curved aortic model.

The influence of tilting disk valve orientation on pulsatile flow through a curved tube model of the human aorta was studied. Simultaneous, two-component laser Doppler velocimeter measurements were made in a tube having a 22 mm diameter and 41 mm radius of curvature which simulated the average dimensions of the adult aorta. The blood analog fluid had a viscosity of 3.0 cp and matched the refractive index of the glass model aorta. Results at mid-arch showed low turbulence levels in early systole and no influence of valve orientation. During mid-systole, fluid from the ventricle reached mid-arch exhibiting strong influence of valve orientation and increased turbulence levels. With the major orifice of the valve adjacent to the inner curved wall, the peak turbulent shear stress was 307 dynes/cm2 at mid-arch during mid-systole. When the major orifice was rotated 180 degrees, the peak value was reduced to 91 dynes/cm2 at the same location and time. At the exit of the curved section, the flow was independent of the valve orientation and the turbulent shear the flow was independent of the value orientation and the turbulent shear stress levels were an order of magnitude lower than the peak value at the inlet. This study demonstrated that orienting the major orifice of a tilting disk valve adjacent to the outer curved wall minimized turbulent shear stress levels.

Influence of cardiac flow rate on turbulent shear stress from a prosthetic heart valve.

Elevated turbulent shear stresses associated with sufficient exposure times are potentially damaging to blood constituents. Since these conditions can be induced by mechanical heart valves, the objectives of this study were to locate the maximum turbulent shear stress in both space and time and to determine how the maximum turbulent shear stress depends on the cardiac flow rate in a pulsatile flow downstream of a tilting disk valve. Two-component, simultaneous, correlated laser velocimeter measurements were recorded at four different axial locations and three different flow rates in a straight tube model of the aorta. All velocity data were ensemble averaged within a 15 ms time window located at approximately peak systolic flow over more than 300 cycles. Shear stresses as high as 992 dynes/cm2 were found 0.92 tube diameters downstream of the monostrut, disk valve. The maximum turbulent shear stress was found to scale with flow rate to the 0.72 power. A repeatable starting vortex was shed from the disk at the beginning of each cycle.

Two-component laser velocimeter measurements downstream of heart valve prostheses in pulsatile flow.

Elevated turbulent shear stresses resulting from disturbed blood flow through prosthetic heart valves can cause damage to red blood cells and platelets. The purpose of this study was to measure the turbulent shear stresses occurring downstream of aortic prosthetic valves during in-vitro pulsatile flow. By matching the indices of refraction of the blood analog fluid and model aorta, correlated, simultaneous two-component laser velocimeter measurements of the axial and radial velocity components were made immediately downstream of two aortic prosthetic valves. Velocity data were ensemble averaged over 200 or more cycles for a 15-ms window opened at peak systolic flow. The systolic duration for cardiac flows of 8.4 L/min was 200 ms. Ensemble-averaged total shear stress levels of 2820 dynes/cm2 and 2070 dynes/cm2 were found downstream of a trileaflet valve and a tilting disk valve, respectively. These shear stress levels decreased with axial distance downstream much faster for the tilting disk valve than for the trileaflet valve.

The influence of suspension osmolarity and erythrocyte volume on cell deformability.

Erythrocytes were suspended in dextran solutions of phosphate buffered saline with solution osmolarities from 400 to 20 mosM/kg. The dilute suspensions were subjected to linear shear and their deformation determined by laser diffractometry (Ektacytometer). Cell volumes were measured using a Coulter counter following fixation in glutaraldehyde to eliminate the influence of deformability on the volume measurement. Minimum deformability generally agreed with the maximum cellular volume produced by hypotonic solutions. However, reduced deformability was observed for both hyperosmotic and hypoosmotic conditions. The oncotic effect of the dextran delayed hemolysis to surprisingly low values of solution osmolarity. In contrast with the usual osmotic fragility results, in the hypotonic dextran solutions there was no evidence of hemoglobin release. At low shear stresses, deformability was found to be enhanced by reducing intracellular viscosity (via osmotic water transport into the cell). However, the maximum cellular deformation obtained at high shear stress was always less than that for the normal discocyte at normal osmolarities.

The minimax problem of Personal Construct organization and schizophrenic thought disorder.

The minimax problem states that optimal construct organization involves two limiting levels of "too many" and "too few" available construct, dimensions for flexible, accurate discrimination of interpersonal events. Measures of thought disorder derived from personal construct theory, such as the Bannister-Fransella Grid, detect only "too many" constructs. The present study (N = 60) hypothesized that Ss with the least and most number of Functionally Independent Constructs (FIC) would evidence more thinking errors characteristic of a schizophrenic thought disorder than would Ss between the minimum and maximum groups. A grid form of the Role Construct Repertory Technique and the Whitaker Index of Schizophrenic Thinking (WIST; Forms A & B) were administered to 60 psychiatric inpatients. FIC scores were used to assign the Ss to five levels of construct organization and WIST scores served as the dependent variable. Two WIST scores confirmed the experimental hypothesis.

Purpose in life, depression, and locus of control.

Parallel to Frankl's theory of the search for meaning, which posits the separateness but intertwining of the psychological and existential realms, the Purpose In Life Test (PIL) has been found to have a low to moderate relationship with most conceptually related psychological measures. Extending separate correlational studies of the PIL with depression and locus of control, the current study inspected the relationship of individual PIL items to groups formed according to Zung Self-Rating Depression Scale and Rotter Internal-External Locus Of Control scores. One-hundred thirty-four Ss were split into four groups: Depressed external, depressed internals, nondepressed externals, and nondepressed internals. Although ungrouped correlational analysis of PIL items revealed only seven significant relationships with depression and two with locus of control, multiple discriminate analysis was successful in correctly classifying depressed externals about three-fourths of the time, and the overall "hit rate" for the four groups was above 60%. In addition to further validating the interaction of purpose in life with related psychological and social expectancy variables, results indicated a compounding effect between depression and external perception of reinforcement control with PIL scores in general, and two items (#4, 12) in particular, which appear to reflect the experience of current congruent involvement between the individual and his world.

Mechanical circulatory assistance for postoperative cardiogenic shock: a three year experience.

Retrospective analysis of 14 patients undergoing circulatory support for postcardiotomy cardiogenic shock during the past 3 yrs has demonstrated the ability of the profoundly depressed myocardium to recover. Four patients were totally weaned from circulatory support and 2 are long-term survivors. Our results suggest that improved survival is dependent on the absence of certain peri-operative complications. To improve future clinical results we suggest that prompt application of assist pumping is necessary to eliminate prolonged cardiopulmonary bypass times and subsequent massive bleeding; those circulatory support systems requiring systemic anticoagulation are of no value in the treatment of postcardiotomy cardiogenic shock; the use of atrial cannulation may be advantageous in certain patients to eliminate critical inflow obstruction, further prolongation of cardiopulmonary bypass, and additional myocardial damage; and that the high incidence of right ventricular failure that is refractory to medical therapy makes the ability to support both ventricles mandatory.

Pulsatile prosthetic valve flows.

The laser Doppler system has been established as a useful tool for eliciting the properties of simulated cardiovascular flows, and thus for comparative studies of flow properties of prosthetic valves. Significant differences among valve types and between models of one type have been documented. The complex variations of velocity profiles with time show that comparisons must be made for unsteady pulsatile rather than steady flow, despite the volume and complexity of the data required. Future studies will include methods of compacting the data presentation and improving the details of the experimental stimulation.