Plan Selection in Proton Therapy of Locally Advanced Prostate Cancer with Simultaneous Treatment of Multiple Targets

Purpose Intensity modulated proton therapy (IMPT) of locally advanced prostate cancer can spare the bowel considerably compared with modern photon therapy, but simultaneous treatment of the prostate (p), seminal vesicles (sv), and lymph nodes is challenging owing to day-to-day organ motion and range uncertainties. Our purpose was, therefore, to generate a plan library for use in adaptive IMPT to mitigate these uncertainties. Methods and Materials We retrospectively included 27 patients with a series of computed tomography scans throughout their treatment representing day-to-day variation. In 18 of the patients, target motion was analyzed using rigid shifts of prostate gold markers relative to bony anatomy. A plan library with different p and sv planning target volume (p/sv-PTV) positions was defined from the distribution and direction of these shifts. Delivery of IMPT using plan selection from the library was simulated for image guidance on bony anatomy, in the remaining patients and compared with nonadaptive IMPT. Results The plan library consisted of 3 small margin p/sv-PTVs: (1) p/sv-PTV shifted 1.5 systematic error (Σ) of the population mean in the anterior and cranial directions, (2) p/sv-PTV shifted 1.5Σ in the posterior and caudal directions, and (3) p/sv-PTV in the planning position. The conventional p/sv-PTV was also available for backup. Plan selection compared with nonadaptive IMPT resulted in a reduction of the rectum volume receiving 60 Gy relative biological effect (RBE) (V60GyRBE) from on average 12 mL to 9 mL. For the bladder the average V45GyRBE was reduced from 36% to 30%. Large and small bowel doses were also reduced, whereas target coverage was comparable or improved compared with nonadaptive IMPT. Conclusions Plan selection based on a population model of rigid target motion was feasible for all patients. Compared with conventional IMPT, plan selection resulted in significant dosimetric sparing of rectum and bladder without compromising target coverage.publishedVersio

Long-Term Predictors of Cardiovascular Disease (CVD) and CVD Related Mortality in Healthy Middle-Aged Norwegian Men

Background: Cardiovascular disease (CVD) is still the leading cause of mortality in the world, and more targeted prediction models are needed to improve CVD prevention. Aims: We hypothesized that heart rate reserve (difference between maximal heart rate and resting heart rate), temporal change in the chronotropic index ([achieved maximal heart rate – resting heart rate]/[estimated maximal heart rate – resting heart rate]), and physical fitness influenced long-term risks of CVD and CVD-related mortality. We also hypothesized that physical fitness had limited durability as a CVD risk predictor. Methods: Heart rate reserve, chronotropic index, and physical fitness were measured at two examinations, seven years apart, after symptom-limited bicycle ECG exercise tests of 2014 healthy middle-aged men in the 1970s. End-points were collected from scrutiny of hospital charts and the Norwegian Cause of Death Registry after 35 years of follow-up. Cox proportional hazard regression models adjusted for age and classical CVD risk factors were used to estimate risks. Results: Heart rate reserve was an independent predictor of CVD death. We found an interaction between heart rate reserve and physical fitness and after stratification by physical fitness level; the predictive abilities of heart rate reserve were confined to the group of men with low physical fitness. Temporal change in the chronotropic index was an independent predictor of CVD death and all-cause death. Physical fitness was an independent predictor of early CVD death, but the association wakened as time progressed. In contrast, classical CVD risk factors, and change in physical fitness during middle-age impacted CVD death risk in a full lifetime perspective. Conclusions: The findings presented within this thesis support our hypotheses and indicate that repeated testing of heart rate response during exercise and exercise capacity could strengthen long-term CVD risk assessment

ALICE TPC Upgrade Activities for LHC Run 3 and Beyond: "SAMPA ASIC Tests with GEM Detector Prototype"

The Time Projection Chamber (TPC) signal readout of the ALICE detector is being upgraded to accommodate the higher collision rates and -energies during LHC Run 3 in 2018. Due to the increased collision rates, the TPC drift time of about 100 μs will be 5 times longer than the average time between interactions, rendering the presently employed gating of the TPC wire-chambers insufficient. Therefore, a Gas Electron Multiplier (GEM) based system will be replacing the wire-chambers. In addition, the front-end electronics need to be replaced to match the new readout chamber technology and increased data rates. This will be done by the new SAMPA chip which combines the functionality of the previous PASA (PreAmplifier ShAper) and ALTRO (ALICE TPC ReadOut) chips currently used as front-end electronics. The focus of this work has been twofold: (1) Characterizing a SAMPA Chip 1 analog prototype for use in the upgraded ALICE TPC signal readout. (2) Construct and characterize a GEM detector prototype for use with the SAMPA Chip 1. A fully differential buffer has been designed and mounted on the Chip 1 carrier board for ADC readout capabilities. The buffer performed well and the ADC readout was successful. The power consumption of the SAMPA Chip 1 failed to reach the requirement of 6mW per channel, achieving no better than ~9mW per channel at the nominal supply voltage. Results from the gain and pulse shape stability showed linear gain and a stable pulse shape, with some deviations for low and high input charges as a result of poor signal-to-noise ratio and the amplifier saturating, respectively. The crosstalk measurement showed scattered results, but none of the carrier boards achieved the requirement of less than 0.2 %. The best crosstalk results averaged ~0.3 %, while the worst exceeded 1 %. Simulated noise for the SAMPA Chip 1 doesn’t fulfill the requirement of 385 ENC at 12 pF capacitance. When corrected for stray capacitances on the carrier boards, the measured noise coincided to some extent with the simulated values. The high noise levels seem to originate from the inside the SAMPA ASIC. A GEM detector has been designed and produced in close collaboration with the group stationed at the Wigner Research Institute in Budapest, Hungary. Testing of the GEM detector has been done at the Wigner Institute using both Fe-55 and Sr-90 radioactive sources, measuring the energy resolution of the detector and calibrating its gain. The gain was set to ~2000 and the energy resolution was measured to be ~8 %, which is below the 12 % requirement. Further testing of the prototype detector has been conducted in Bergen, establishing its gain for different gas mixtures and measuring the signal-to-noise ratio of the SAMPA Chip 1 for MIPs. This work has been done in close collaboration with Ganesh Jagannath Tambave, whose main focus has been on the signal readout and data acquisition of the SAMPA Chip 1. The signal-to-noise ratio measured to be 27:1, the requirement being 38:1. Increasing the drift gap of the detector will increase the signal-to-noise ratio

Plan Selection in Proton Therapy of Locally Advanced Prostate Cancer with Simultaneous Treatment of Multiple Targets

Purpose Intensity modulated proton therapy (IMPT) of locally advanced prostate cancer can spare the bowel considerably compared with modern photon therapy, but simultaneous treatment of the prostate (p), seminal vesicles (sv), and lymph nodes is challenging owing to day-to-day organ motion and range uncertainties. Our purpose was, therefore, to generate a plan library for use in adaptive IMPT to mitigate these uncertainties. Methods and Materials We retrospectively included 27 patients with a series of computed tomography scans throughout their treatment representing day-to-day variation. In 18 of the patients, target motion was analyzed using rigid shifts of prostate gold markers relative to bony anatomy. A plan library with different p and sv planning target volume (p/sv-PTV) positions was defined from the distribution and direction of these shifts. Delivery of IMPT using plan selection from the library was simulated for image guidance on bony anatomy, in the remaining patients and compared with nonadaptive IMPT. Results The plan library consisted of 3 small margin p/sv-PTVs: (1) p/sv-PTV shifted 1.5 systematic error (Σ) of the population mean in the anterior and cranial directions, (2) p/sv-PTV shifted 1.5Σ in the posterior and caudal directions, and (3) p/sv-PTV in the planning position. The conventional p/sv-PTV was also available for backup. Plan selection compared with nonadaptive IMPT resulted in a reduction of the rectum volume receiving 60 Gy relative biological effect (RBE) (V60GyRBE) from on average 12 mL to 9 mL. For the bladder the average V45GyRBE was reduced from 36% to 30%. Large and small bowel doses were also reduced, whereas target coverage was comparable or improved compared with nonadaptive IMPT. Conclusions Plan selection based on a population model of rigid target motion was feasible for all patients. Compared with conventional IMPT, plan selection resulted in significant dosimetric sparing of rectum and bladder without compromising target coverage

Exercise systolic blood pressure at moderate workload predicts cardiovascular disease and mortality through 35 years of follow-up in healthy, middle-aged men

Objective: There is an association between exercise systolic blood pressure (SBP) and cardiovascular disease and mortality. The aim of this study was to investigate this association, with 35 years of follow-up. Methods: Through 1972–75, 2014 healthy, middle-aged men underwent thorough medical examination and a bicycle exercise test. 1999 participants completed six minutes at 100 W. SBP was measured manually, both before the test and every two minutes during the test. Highest SBP measured during the first six minutes (SBP100W) was used in further analyses. Results: Participants were divided into quartiles (Q) based on their SBP100W; Q1: 100–160 mm Hg (n = 457), Q2: 165–175 mm Hg (n = 508), Q3: 180–195 mm Hg (n = 545) and Q4: 200–275 mm Hg (n = 489). After 35-years follow-up, there was a significant association between exercise SBP at baseline and cardiovascular disease and mortality. In the multivariate analysis adjusting for resting SBP, age, smoking status, total serum cholesterol and family history of coronary heart disease, as well as physical fitness, there is a 1.39-fold (CI: 1.00–1.93, p = 0.05) increased risk of cardiovascular mortality in Q4 compared to Q1. When not adjusting for physical fitness, there is a 1.29-fold (CI: 1.03–1.61, p = 0.02) increase in risk of cardiovascular disease between Q1 and Q4. Conclusions: The results of this study suggest that the association between exercise SBP at moderate workload and cardiovascular disease and mortality in middle-aged men extends through as long as 35 years and into old ages

Risk of radiation-induced secondary rectal and bladder cancer following radiotherapy of prostate cancer

<div><p>ABSTRACT</p><p><b>Background.</b> An elevated risk of radiation-induced secondary cancer (SC) has been observed in prostate cancer patients after radiotherapy (RT), rising to as high as one in 70 patients with more than 10 years follow-up. In this study we have estimated SC risks following RT with both previous and contemporary techniques, including proton therapy, using risk models based on different dose-response relationships.</p><p><b>Material and methods.</b> RT plans treating the prostate and seminal vesicles with either conformal radiotherapy (CRT), volumetric modulated arc therapy (VMAT) or intensity-modulated proton therapy (IMPT) were created for 10 patients. The risks of radiation-induced cancer were estimated for the bladder and rectum using dose-response models reflecting varying degrees of cell sterilisation: a linear model, a linear-plateau model and a bell-shaped model also accounting for fractionated RT.</p><p><b>Results.</b> The choice of risk models was found to rank the plans quite differently, with the CRT plans having the lowest SC risk using the bell-shaped model, while resulting in the highest risk applying the linear model. Considering all dose-response scenarios, median relative risks of VMAT versus IMPT were 1.1–1.7 for the bladder and 0.9–1.8 for the rectum. Risks of radiation-induced bladder and rectal cancers were lower from VMAT if exposed at 80 years versus IMPT if exposed at 50 years.</p><p><b>Conclusions.</b> The SC risk estimations for the bladder and rectum revealed no clear relative relationship between the contemporary techniques and CRT, with divergent results depending on choice of model. However, the SC risks for these organs when using IMPT were lower or comparable to VMAT. SC risks could be assessed when considering referral of prostate cancer patients to proton therapy, taking also general patient characteristics, such as age, into account.</p></div

Exercise Systolic Blood Pressure at Moderate Workload Is Linearly Associated With Coronary Disease Risk in Healthy Men

There is no consensus on the definition of an exaggerated increase in systolic blood pressure (SBP) during exercise. The aim was to explore a potential threshold for exercise SBP associated with increased risk of coronary heart disease in healthy men using repeated exercise testing. Two thousand fourteen healthy white male employees were recruited into the Oslo Ischemia Study during early 1970s. At follow-up 7 years later, 1392 men were still considered healthy. A bicycle exercise test at 100 W workload was performed at both visits. Cox regression analyses were performed with increasing cutoff levels of peak exercise SBP at 100 W workload (SBP100W) from 160 mm Hg to 200 mm Hg, adjusted for cardiovascular risk factors and physical fitness. Participants with SBP100W below cutoff level at both baseline and first follow-up were compared with participants with SBP100W equal to or above cutoff level at both visits. Compared with participants with SBP100W below all cutoff levels between 165 and 195 mm Hg, coronary heart disease risk was increased among participants with SBP100W equal to or above cutoff at all levels. There was no evidence of a distinct threshold level for coronary heart disease risk, and the relation between SBP100W and coronary heart disease appears linear. When investigating exercise SBP at moderate workload measured at 2 exercise tests in healthy middle-aged white men, there is increasing risk of coronary heart disease with increasing exercise SBP independent of SBP at rest. The association is linear from the low range of exercise SBP, and there is no sign of a distinct threshold level for increased coronary disease risk