Quantitative analysis of contribution of mild and moderate hyperthermia to thermal ablation and sensitization of irreversible electroporation of pancreatic cancer cells.

INTRODUCTION: Irreversible electroporation (IRE) is an ablation modality that applies short, high-voltage electric pulses to unresectable cancers. Although considered a non-thermal technique, temperatures do increase during IRE. This temperature rise sensitizes tumor cells for electroporation as well as inducing partial direct thermal ablation. AIM: To evaluate the extent to which mild and moderate hyperthermia enhance electroporation effects, and to establish and validate in a pilot study cell viability models (CVM) as function of both electroporation parameters and temperature in a relevant pancreatic cancer cell line. METHODS: Several IRE-protocols were applied at different well-controlled temperature levels (37 °C ≤ T ≤ 46 °C) to evaluate temperature dependent cell viability at enhanced temperatures in comparison to cell viability at T = 37 °C. A realistic sigmoid CVM function was used based on thermal damage probability with Arrhenius Equation and cumulative equivalent minutes at 43 °C (CEM43°C) as arguments, and fitted to the experimental data using "Non-linear-least-squares"-analysis. RESULTS: Mild (40 °C) and moderate (46 °C) hyperthermic temperatures boosted cell ablation with up to 30% and 95%, respectively, mainly around the IRE threshold Eth,50% electric-field strength that results in 50% cell viability. The CVM was successfully fitted to the experimental data. CONCLUSION: Both mild- and moderate hyperthermia significantly boost the electroporation effect at electric-field strengths neighboring Eth,50%. Inclusion of temperature in the newly developed CVM correctly predicted both temperature-dependent cell viability and thermal ablation for pancreatic cancer cells exposed to a relevant range of electric-field strengths/pulse parameters and mild moderate hyperthermic temperatures.

Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer.

BACKGROUND: Studies comparing upfront surgery with neoadjuvant treatment in pancreatic cancer may report only patients who underwent resection and so survival will be skewed. The aim of this study was to report survival by intention to treat in a comparison of upfront surgery versus neoadjuvant treatment in resectable or borderline resectable pancreatic cancer. METHODS: MEDLINE, Embase and the Cochrane Library were searched for studies reporting median overall survival by intention to treat in patients with resectable or borderline resectable pancreatic cancer treated with or without neoadjuvant treatment. Secondary outcomes included overall and R0 resection rate, pathological lymph node rate, reasons for unresectability and toxicity of neoadjuvant treatment. RESULTS: In total, 38 studies were included with 3484 patients, of whom 1738 (49·9 per cent) had neoadjuvant treatment. The weighted median overall survival by intention to treat was 18·8 months for neoadjuvant treatment and 14·8 months for upfront surgery; the difference was larger among patients whose tumours were resected (26·1 versus 15·0 months respectively). The overall resection rate was lower with neoadjuvant treatment than with upfront surgery (66·0 versus 81·3 per cent; P < 0·001), but the R0 rate was higher (86·8 (95 per cent c.i. 84·6 to 88·7) versus 66·9 (64·2 to 69·6) per cent; P < 0·001). Reported by intention to treat, the R0 rates were 58·0 and 54·9 per cent respectively (P = 0·088). The pathological lymph node rate was 43·8 per cent after neoadjuvant therapy and 64·8 per cent in the upfront surgery group (P < 0·001). Toxicity of at least grade III was reported in up to 64 per cent of the patients. CONCLUSION: Neoadjuvant treatment appears to improve overall survival by intention to treat, despite lower overall resection rates for resectable or borderline resectable pancreatic cancer. PROSPERO registration number: CRD42016049374.

Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer.

BACKGROUND: Locally advanced pancreatic cancer (LAPC) is associated with a very poor prognosis. Current palliative (radio)chemotherapy provides only a marginal survival benefit of 2-3 months. Several innovative local ablative therapies have been explored as new treatment options. This systematic review aims to provide an overview of the clinical outcomes of these ablative therapies. METHODS: A systematic search in PubMed, Embase and the Cochrane Library was performed to identify clinical studies, published before 1 June 2014, involving ablative therapies in LAPC. Outcomes of interest were safety, survival, quality of life and pain. RESULTS: After screening 1037 articles, 38 clinical studies involving 1164 patients with LAPC, treated with ablative therapies, were included. These studies concerned radiofrequency ablation (RFA) (7 studies), irreversible electroporation (IRE) (4), stereotactic body radiation therapy (SBRT) (16), high-intensity focused ultrasound (HIFU) (5), iodine-125 (2), iodine-125-cryosurgery (2), photodynamic therapy (1) and microwave ablation (1). All strategies appeared to be feasible and safe. Outcomes for postoperative, procedure-related morbidity and mortality were reported only for RFA (4-22 and 0-11 per cent respectively), IRE (9-15 and 0-4 per cent) and SBRT (0-25 and 0 per cent). Median survival of up to 25·6, 20·2, 24·0 and 12·6 months was reported for RFA, IRE, SBRT and HIFU respectively. Pain relief was demonstrated for RFA, IRE, SBRT and HIFU. Quality-of-life outcomes were reported only for SBRT, and showed promising results. CONCLUSION: Ablative therapies in patients with LAPC appear to be feasible and safe.

Correction: Time-Dependent Impact of Irreversible Electroporation on Pancreas, Liver, Blood Vessels and Nerves: A Systematic Review of Experimental Studies.

[This corrects the article DOI: 10.1371/journal.pone.0166987.].

Time-Dependent Impact of Irreversible Electroporation on Pancreas, Liver, Blood Vessels and Nerves: A Systematic Review of Experimental Studies.

INTRODUCTION: Irreversible electroporation (IRE) is a novel ablation technique in the treatment of unresectable cancer. The non-thermal mechanism is thought to cause mostly apoptosis compared to necrosis in thermal techniques. Both in experimental and clinical studies, a waiting time between ablation and tissue or imaging analysis to allow for cell death through apoptosis, is often reported. However, the dynamics of the IRE effect over time remain unknown. Therefore, this study aims to summarize these effects in relation to the time between treatment and evaluation. METHODS: A systematic search was performed in Pubmed, Embase and the Cochrane Library for original articles using IRE on pancreas, liver or surrounding structures in animal or human studies. Data on pathology and time between IRE and evaluation were extracted. RESULTS: Of 2602 screened studies, 36 could be included, regarding IRE in liver (n = 24), pancreas (n = 4), blood vessels (n = 4) and nerves (n = 4) in over 440 animals (pig, rat, goat and rabbit). No eligible human studies were found. In liver and pancreas, the first signs of apoptosis and haemorrhage were observed 1-2 hours after treatment, and remained visible until 24 hours in liver and 7 days in pancreas after which the damaged tissue was replaced by fibrosis. In solitary blood vessels, the tunica media, intima and lumen remained unchanged for 24 hours. After 7 days, inflammation, fibrosis and loss of smooth muscle cells were demonstrated, which persisted until 35 days. In nerves, the median time until demonstrable histological changes was 7 days. CONCLUSIONS: Tissue damage after IRE is a dynamic process with remarkable time differences between tissues in animals. Whereas pancreas and liver showed the first damages after 1-2 hours, this took 24 hours in blood vessels and 7 days in nerves.

Reliability of body-fat estimations from a four-compartment model by using density, body water, and bone mineral measurements.

Reliability of body-fat estimation by a four-compartment model was tested in 10 subjects. Body densities were measured by underwater weighing (UWW), total body water (TBW) by deuterium dilution, and total body bone mass (TBBM) by dual-energy x-ray absorptiometry in three sessions in 1 wk. Percent body fat was determined by [2.559/density -0.734 (TBW/weight) +0.983 (TBBM/weight) -1.841] x 100. Reliability coefficients were 0.991 and 0.994, and within-subjects standard deviations were +/- 1.0 and +/- 1.1 for percent body-fat estimations from Siri's two-compartment and the four-compartment models, respectively; fat mass was +/- 0.8 kg with both models. These data suggest that additive errors in the multicompartment model do not offset the improved accuracy of fat estimations over those obtained from UWW alone. The greatest source of error came from UWW procedure itself (+/- 0.002 g/cm3, or approximately 1.0% of body weight), followed by error in TBW (+/- 0.5 L). More reproducible passive methods that are not dependent on hydration or TBBM may be especially useful after validation against the four-compartment model.

An analysis of aerobic capacity in a large United States population.

This study presents a description of aerobic capacity in a large US population comprised of 1,514 men and 375 women. Such influencing factors as age, training state, occupation, and body composition were evaluated. The population consisted of new recruits entering the US Army from civilian life as well as soliders in a variety of assignments and physical training programs. Age ranged from 17 to 55 yr. With the exception of one older group, aerobic capacity was determined as maximal O2 uptake measured directly by the Douglas bag technique during a standard discontinuous treadmill running procedure. New male and female recruits representing a young civilian population entered the service with maximal O2 uptake of 51 and 37 ml X kg body wt-1 X min-1, respectively, and thereafter increased 5% during initial basic training. The difference between genders, 30% on an absolute basis, was 14% when expressed as a function of fat-free weight. Aerobic capacity was less after occupational training and continued to decrease with age at an average yearly rate of 10%, or 0.5 ml X kg body wt-1 X min-1. Aerobic capacity varied with intensity of the occupational physical demand, except in groups with significant physical training programs. This first large US population study of aerobic capacity, using a direct treadmill procedure, demonstrates levels consistent with any previously reported population.

Lower limit of body fat in healthy active men.

We examined body composition changes in 55 normal young men during an 8-wk Army combat leadership training course involving strenuous exercise and low energy intake, with an estimated energy deficit of 5.0 +/- 2.0 MJ/day and a resultant 15.7 +/- 3.1% weight loss. Percent body fat (BF) measured by dual-energy X-ray absorptiometry (DEXA) averaged 14.3% (range 6-26%) and 5.8 +/- 1.8% (range 4-11%) at the beginning and end of the course, respectively. Men who achieved a minimum percent BF (4-6%) by 6 wk demonstrated only small additional total and subcutaneous fat losses in the final 2 wk and sacrificed increasingly larger proportions of fat-free mass. Percent BF estimated from skinfold thicknesses reflected relative changes in fat mass, although actual percent BF was overestimated. Instead of reaching a plateau after fat stores were substantially depleted, abdominal, hip, and thigh girths continued to decline with body weight loss. Final percent BF for the leanest men was similar to that observed after a 25% body weight reduction in the 1950 Minnesota study (5.2% by underwater weighting), and height-corrected final fat mass was the same (1.0 +/- 0.2 vs. 0.9 +/- 0.7 kg fat/m2), suggesting that these values represent a minimal body fat content in healthy men and that weight loss subsequent to achieving this level is contributed from the fat-free mass. Our results suggest that 4-6% BF or approximately 2.5 kg fat represents the lower limit for healthy men, as assessed by DEXA or by underwater weighing.

Body fat assessment in women. Special considerations.

Methods of in vivo body fat estimation are based on simple assumptions about body composition which work reasonably well for men, while estimations in women have been largely extrapolated from the male studies so that women are treated as men with just more of the same fat. Compared to men, fat regulation in women is considerably more elaborate, with more and different sites for storage and a larger proportion of fat distributed to the extremities and in subcutaneous locations. Thus, a ratio of waist-to-hips girth which reflects increasing fatness in men only specifies 2 different extremes of a broader spectrum of possibilities for fat distribution in women. This complicates anthropometric prediction of total fatness and clearly limits the generalisability of any female equations. Anthropometric methods are further confounded by difficulties in the criterion methods against which they are developed. For example, the validity of assumptions about the fractional contributions of bone mineral and body water to fat-free mass and density may not hold through the reproductive cycles. Women athletes involved in weight-bearing or strength training may increase bone mineral content above average values but if they become amenorrhoeic, bone mineral density may fall significantly below average values. Fit premenopausal women distribute fat differently and have a higher bone mineral content than unfit postmenopausal women. Genetic factors which also affect criterion method assumptions in men are superimposed on these additional complications in women. Body fat in female athletes extends across almost the entire range of female fatness, with some of the lowest measurements in distance runners and body builders which fall into the normal male range, but also with some relatively high values in swimmers and strength athletes, which would classify these women as obese by male standards. Thus, total body fat reflects a more complex regulation and has a different meaning to health and performance in women than it does for men. Predictive equations for women athletes should be developed with a view to the specific group and ultimate purpose to which they will be applied.

Effects of acute cold exposure on submaximal endurance performance.

The purposes of this study were to assess VO2max and submaximal endurance time to exhaustion (ET) during acute cold-air exposure. Eight male subjects (means age = 19.9 yr) were alternately exposed in groups of four to chamber temperatures of +20 degrees C and -20 degrees C for 30 h each. A week was allowed between exposures. Maximum oxygen uptake was measured using a mechanically-braked cycle ergometer, and ET was determined on the same ergometer using a 17-min/3-min exercise/rest schedule until the subject was unable to maintain pedal rate. Maximum oxygen uptake was not significantly different between conditions: 3.43 +/- 0.09 l X min-1 at +20 degrees C and 3.35 +/- 0.10 l X min-1 at -20 degrees C. During endurance exercise, intensities equaled 77.1 +/- 1.4% and 78.9 +/- 2.0% of VO2max at +20 degrees C and -20 degrees C, respectively. Heart rate and VO2 values obtained between 8 and 10 min of the endurance run were not significantly different (156 +/- 2 bpm and 2.63 +/- 0.08 l X min-1 at +20 degrees C and 158 +/- 3 bpm and 2.65 +/- 0.11 l X min-1 at -20 degrees C). Endurance time to exhaustion however, decreased 38% (P less than 0.05) from 111.9 +/- 22.8 min at +20 degrees C to 66.9 +/- 13.6 min at -20 degrees C. The data support the contention that aerobic capacity is not altered by cold exposure but suggest a marked decrease in submaximal endurance performance.

Prevalence of coronary heart disease risk factors in a young military population.

This study was undertaken to determine the extent to which coronary heart disease risk factors are manifest in a young (17-35 years old) male military population. Approximately 360 individuals underwent medical and physical determination of body composition, blood cholesterol analysis, blood pressure measurement, history of smoking, and a maximal exercise stress test to assess maximal oxygen uptake (VO2 max) and the incidence of electrocardiographic abnormalities. Obesity (greater than 20% body fat), elevated blood cholesterol (greater than 200 mg/dl), and cigarette smoking (greater than 10 cigarettes/d) were the most predominant risk factors with incidences of 29, 32, and 36%, respectively. Only 2.4% of the sample had a positive stress test as indicated by an ST-segment depression of 1mm or greater. An inverse relationship between VO2 max and percent body fat was the only significant finding between level of aerobic power and risk factor prevalence. These data provide information on the prevalence of cardiovascular disease risk factors in an age group for which there has been only limited information.

Height, weight, percent body fat, and indices of adiposity for young men and women entering the U.S. Army.

The purpose of this investigation was to describe the height (H), weight (W), and percent body fat (%BF) of young men and women (ages 17-35 years) entering the U.S. Army and to determine an index of adiposity that fit criteria described in the literature. H and W were measured with a digital scale and anthropometer, respectively. %BF was calculated from four skinfolds thickness. Men and women were both separated into four age categories. Very little difference in H was found with increasing age. W and %BF increased progressively with age in the males but no increase in either parameter was seen within the three youngest age groups of women. For males, W/H2 was found to be the most appropriate index of adiposity of those studied, having a correlation with %BF of 0.75 and a standard error of estimate of +/- 3.4 %BF. W/H1.5 was the most appropriate index for females, having a correlation with %BF of 0.69 and a standard error of estimate of +/- 3.2 %BF. It was suggested that these indices could be used to replace or supplement the current H-W charts used in the Army. A table for predicting %BF from these indices has been provided.

Aerobic power and body fat of men and women during army basic training.

Maximal oxygen uptake (VO2 max) and percent body fat (%BF) were assessed in 87 males and 57 females before and after 7 weeks of Army basic training. VO2 max was determined using a running treadmill protocol and %BF was measured by skinfold technique. VO2 max increased 3.7% (50.7 vs. 52.3 ml/kg.min) and 10.5% (36.9 vs. 39.3 ml/kg.min) for males and females, respectively, with training. %BF decreased 11% in males and 7.1% in females while body weight increased in both. Analysis of variance revealed that, while these changes were significant, there was no quantitative difference in the response of the sexes undergoing the same training program. The data suggest that basic training presents an effective physical challenge for those males and females who have a VO2 max below the ranges of 49-52 ml/kg.min and 38-41 ml/kg.min, respectively, upon entry. In addition, it effectively reduces BF content of those who initially possess high percentages and increases the lean body mass particularly in women.

Psychological states and aerobic fitness of male and female recruits before and after basic training.

Psychological states and aerobic fitness were measured using a battery of psychological tests and a bicycle ergometer work test. A group of approximately two hundred male and female subjects were tested at the beginning of a six week basic training cycle and another group of two hundred were tested at the completion of basic training. A difference in mood, anxiety, self confidence and physical fitness was evident in the groups of male recruits, but not in the female recruits after training. A significant difference existed between males and females in terms of physical work capacity. These differences in work capacity and psychological responses should be considered in the assignment and selection of personnel for high work intensity military occupations.

Response of age forty and over military personnel to an unsupervised, self-administered aerobic training program.

The Army recently extended mandatory physical training and testing to include personnel 40 yrs of age and older. The purpose of this study was to describe the profile of aerobic fitness in a representative group from this age population and to evaluate the response of such a group to a self-administered, unsupervised training program. Maximal oxygen uptake (Vo2 max) and percent body fat (%BF) were assessed in 260 military personnel (40-53 yrs of age) before and after 6 mo of physical training consisting of a progressive walk/run mode of exercise. Before training the mean +/- S.D. for Vo2 max and %BF for all subjects was 38.1 +/- 6.2 ml/kg . min and 26.1 +/- 4.7%, respectively. Subjects were divided into three groups based upon their initial level of physical activity determined by interview as follows: inactive, moderately active and active. Upon retesting after 6 mo, 40% of the inactive group had not participated to any appreciable degree in the program and subjects of this group who did participate showed only a slight and insignificant increase (4.4%) in Vo2 max. The pretraining level of Vo2 max for the total population studied was similar to that reported in other studies on comparably aged subjects. However, changes with training were well below those seen with supervised group programs of 6 mo duration.

The influence of U.S. Army Basic Initial Entry Training on the muscular strength of men and women.

The influence of U.S. Army Basic Initial Entry Training on the maximum voluntary isometric strength (MVIS) and anthropometric parameters of men and women was investigated. Significant increases in weight and lean body mass (LBM) and decreases in percent body fat were found for both sexes during training. Significant increases in the MVIS of the upper torso (UT), leg extensors (LE), and trunk extensors (TE) were also found for both sexes. Females and males improved about the same amount on the LE (12.4% and 9.7%, respectively) but females improved significantly more than males on the UT (9.3% and 4.2%, respectively) and TE (15.9% and 8.1%, respectively). The greater gains in the females were presumably due to their lower initial strength levels and the consequently greater relative training stimulus. When strength was expressed relative to LBM, both sexes were able to exert similar amounts of strength on the LE and TE, suggesting that differences in strength between the sexes may primarily be a function of muscle mass.

Physiological effects of a military training program on male and female cadets.

Tested at the beginning and the end of the 6-week training program which all incoming cadets (plebes) undergo upon entering the U.S. Military Academy were 29 males and 26 females (17-21 years old). The aerobic training consisted of running for 30 min 5-6 d/week at varied speeds depending upon performance in an initial 1.5-mile run test. Females responded to training with a significant increase (p is less than 0.001) in VO2 max from 46.0 +/- 1.0 to 49.7 +/- 0.8 ml/kg.min (7.9%). Males did not increase their initial VO2 max (59.4 +/- 1.1 ml/kg.min) significantly. Both groups significantly reduced HRmax and percent body fat. Their initial VO2 max values and activity history accounted for the lack of a significant increase in this highly-fit population of males. Blood lactates were significantly decreased (p is less than 0.05) at the same two submaximal workloads after training. The initial difference in aerobic power between males and females was reduced from 22% to 18%.

Effects of travel across time zones (jet-lag) on exercise capacity and performance.

Eighty-one healthy male soldiers, aged 18-34, were studied for 5 d before and 5 d after an eastward deployment across six time zones to determine the effects of translocation on exercise capacity and performance. Fatigue, weakness, headache, sleepiness, irritability, and other commonly reported symptoms occurred in the majority of subjects. Most, but not all, of the symptoms were diminished or absent by the fifth day following the translocation. Cardiorespiratory function and perception of effort during both submaximal and maximal treadmill exercise were unaffected. Isometric strength of the upper torso, legs, and trunk extensor muscles also was not changed. Dynamic strength and endurance of elbow flexors declined significantly. Dynamic knee extensor strength and endurance scores exhibited a progressive decrement prior to translocation and were inconsistent suggesting that the stress of repetitive testing outweighed any jet-lag effects on performance capacity. Performance times for a 270 m sprint were increased for the first 4 d following translocation as were times for a 2.8 km run on the second and third days and for a 110 m lift and carry on the third day after deployment. Times for a 6.5 m rope climb did not change. These findings indicate that certain symptoms and physiological capacities are affected as a result of multiple time zone translocation. However, the specific mechanisms involved, the factors influencing the magnitude of any physiological alterations, and the ultimate impact of these capacity changes on actual physical performance remain to be clarified.

Validity of percent body fat predicted from circumferences: classification of men for weight control regulations.

Each of the military services classifies individuals in their weight control programs using percent body fat predicted by circumference-based equations. Although derived independently from service-specific samples, each of the male equations relies on waist circumference adjusted by a neck circumference. In this study, the authors examined the performance of the equations in 496 young (< 40 years) male soldiers, compared to percent body fat measured by dual-energy X-ray absorptiometry. The strength of the relationship to percent body fat improved from body mass index (weight/height2), to a waist circumference alone, to the difference between waist and neck circumferences. Overweight men who were misclassified by overestimation of total percent body fat using the equations (2.6% of the total sample) had normal neck circumferences and height but large waistlines, indicating that they were still classified appropriately to the goals of the weight control programs, all of which center on abdominal adiposity. The authors demonstrate that each of the service equations yield substantially similar results and discuss why a single equation could be easily agreed to and used by the Department of Defense for male body fat prediction.

Injuries associated with strenuous road marching.

Injuries were recorded during and up to 12 days after a maximal effort road march. Light infantry soldiers (N = 335) carried a total load of 46 kg over a 20 km course. Twenty-four percent of the soldiers suffered one or more injuries, resulting in 44 days of limited duty. All injuries involved the lower extremities and/or the back. Foot blisters and back problems were the most common complaints (35% and 23%, respectively, of the total injuries). These data indicate that units without recent road marching training can expect a high incidence of injuries as a result of a single demanding road march.