Comments on "Investigation of Histology Region Dielectric Measurements of Heterogeneous Tissues".

In the paper, "Investigation of histology region in dielectric measurements of heterogeneous tissues," by Porter and O'Halloran, the authors utilize a flexible phantom in a layered material dielectric property analysis to quantify the effective sensing volume of a coaxial dielectric probe. Ostensibly, this test has been used by others to characterize the region for which percent variation in the material composition in front of the probe corresponds to percent variation in the computed effective dielectric properties. By employing a compressible material, the authors fail to isolate features that are attributable solely to the probe, itself, and inadvertently incorporate confounding characteristics associated with the compressible nature of the material. The net effect is to exaggerate the probe's sensing volume which undermines conclusions drawn from the subsequent tissue dielectric property studies.

A photographic technique for quick assessment of mechanical isocenter of a linear accelerator.

Demands for mechanical accuracy of medical linear accelerators are increased due to the stereotactic and modulated rotational treatments. Mechanical inaccuracies affect the size and shape of the mechanical and radiation isocenters. In practice, the mechanical isocenter is defined by the intersection of rotational axes. However, there are no simple tools to check the properties of the mechanical isocenter in 3D. We introduce a new photography-based method for quick and sub-millimeter accurate determination of the mechanical isocenter. The method is based on image-processing algorithm and modified front pointer. The results demonstrate the quick measurement and visualization of the mechanical isocenter.

Open-Ended Coaxial Dielectric Probe Effective Penetration Depth Determination.

We have performed a series of experiments which demonstrate the effect of open-ended coaxial diameter on the depth of penetration. We used a two layer configuration of a liquid and movable cylindrical piece of either Teflon or acrylic. The technique accurately demonstrates the depth in a sample for which a given probe diameter provides a reasonable measure of the bulk dielectric properties for a heterogeneous volume. In addition we have developed a technique for determining the effective depth for a given probe diameter size. Using a set of simulations mimicking four 50 Ω coaxial cable diameters, we demonstrate that the penetration depth in both water and saline has a clear dependence on probe diameter but is remarkably uniform over frequency and with respect to the intervening liquid permittivity. Two different 50 Ω commercial probes were similarly tested and confirm these observations. This result has significant implications to a range of dielectric measurements, most notably in the area of tissue property studies.

Experimental and Analytical Comparisons of Tissue Dielectric Constant (TDC) and Bioimpedance Spectroscopy (BIS) in Assessment of Early Arm Lymphedema in Breast Cancer Patients after Axillary Surgery and Radiotherapy.

BACKGROUND: Early diagnosis of breast cancer treatment-related lymphedema (BCRL) is of great importance for longstanding treatment results. Tissue dielectric constant (TDC) and bioimpedance spectroscopy (BIS) both have a potential for early diagnosis, but have not been compared. METHODS AND RESULTS: One hundred women, treated for breast cancer with breast surgery, axillary dissection, and radiotherapy, were examined within one year after breast cancer treatment, as part of the follow-up procedure. Affected/at-risk and contralateral arms were measured with the TDC technique specific to localized skin water content and the BIS technique assessing arm extracellular fluid (ECF). Thirty-eight patients were clinically diagnosed for lymphedema (38.0%). The sensitivity and specificity for the TDC method were 65.8% and 83.9%, and for BIS method 42.1% and 93.5%, (p < 0.001 and NS), respectively. Of all lymphedema, 18.4% were detected only by TDC and 2.6% by BIS. Affected arm to contralateral arm TDC ratios for upper arm and forearm, 1.56 ± 0.49 and 1.28 ± 0.33, demonstrating the localized feature of the TDC measurements were significantly greater than the BIS arm ratio 1.12 ± 0.12 (both p < 0.001). CONCLUSIONS: Discrepancies between TDC and BIS techniques in assessing lymphedema are related to different measurement techniques and assessed tissue water components. Independently of selected technique-specific threshold limit, the TDC technique was more sensitive than the BIS technique in the early assessment of BCRL and demonstrated that nearly 20% of early lymphedema are only superficially localized. The results further supported the complementary role of TDC and arm volume measurements as a highly diagnostic method for early lymphedema.

Tangential volumetric modulated arc therapy technique for left-sided breast cancer radiotherapy.

BACKGROUND: The aim of the present study was to introduce a new restricted tangential volumetric modulated arc therapy (tVMAT) technique for whole breast irradiation and compare its dosimetric properties to other currently used breast cancer radiotherapy techniques. METHOD: Ten consecutive women with left-sided breast cancer were enrolled in this retrospective study. Four treatment plans were generated for each patient: 1) standard tangential field-in-field (FinF), 2) tangential intensity modulated radiotherapy (tIMRT), 3) tangential VMAT (tVMAT) with two dual arcs of 50-60° and 4) continuous VMAT (cVMAT) with a dual arc of 240°. The plans were created with Monaco® (tIMRT, tVMAT and cVMAT) and Oncentra® (FinF) treatment planning systems. RESULTS: With both VMAT techniques significantly higher cardiac avoidance, dose coverage and dose homogenity were achieved when compared with FinF or tIMRT techniques (p < 0.01). VMAT techniques also decreased the high dose areas (above 20 Gy) of ipsilateral lung. There were no significant differences in the mean dose of contralateral breast between the tVMAT, tIMRT and FinF techniques. The dose coverage (V47.5 Gy) was greatest with cVMAT. However, with cVMAT the increase of contralateral breast dose was significant. CONCLUSIONS: The present results support the hypothesis that the introduced tVMAT technique is feasible for treatment of left-sided breast cancer. With tVMAT dose to heart and ipsilateral lung can be reduced and the dose homogeneity can be improved without increasing the dose to contralateral breast or lung.

Role of microRNAs and DNA Methyltransferases in Transmitting Induced Genomic Instability between Cell Generations.

There is limited understanding of how radiation or chemicals induce genomic instability, and how the instability is epigenetically transmitted to the progeny of exposed cells or organisms. Here, we measured the expression of microRNAs (miRNAs) and DNA methyltransferases (DNMTs) in murine embryonal fibroblasts exposed to ionizing radiation or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which were previously shown to induce genomic instability in this cell line. Cadmium was used as a reference agent that does not induce genomic instability in our experimental model. Measurements at 8 and 15 days after exposure did not identify any such persistent changes that could be considered as signals transmitting genomic instability to the progeny of exposed cells. However, measurements at 2 days after exposure revealed findings that may reflect initial stages of genomic instability. Changes that were common to TCDD and two doses of radiation (but not to cadmium) included five candidate signature miRNAs and general up-regulation of miRNA expression. Expression of DNMT3a, DNMT3b, and DNMT2 was suppressed by cadmium but not by TCDD or radiation, consistently with the hypothesis that sufficient expression of DNMTs is necessary in the initial phase of induced genomic instability.

Dose- and time-dependent changes of micronucleus frequency and gene expression in the progeny of irradiated cells: two components in radiation-induced genomic instability?

Murine embryonic C3H/10T½ fibroblasts were exposed to X-rays at doses of 0.2, 0.5, 1, 2 or 5 Gy. To follow the development of radiation-induced genomic instability (RIGI), the frequency of micronuclei was measured with flow cytometry at 2 days after exposure and in the progeny of the irradiated cells at 8 and 15 days after exposure. Gene expression was measured at the same points in time by PCR arrays profiling the expression of 84 cancer-relevant genes. The micronucleus results showed a gradual decrease in the slope of the dose-response curve between days 2 and 15. The data were consistent with a model assuming two components in RIGI. The first component is characterized by dose-dependent increase in micronuclei. It may persist more than ten cell generations depending on dose, but eventually disappears. The second component is more persistent and independent of dose above a threshold higher than 0.2 Gy. Gene expression analysis 2 days after irradiation at 5 Gy showed consistent changes in genes that typically respond to DNA damage. However, the consistency of changes decreased with time, suggesting that non-specificity and increased heterogeneity of gene expression are characteristic to the second, more persistent component of RIGI.

Radiation-induced genomic instability in Caenorhabditis elegans.

Radiation-induced genomic instability has been well documented, particularly in vitro. However, the understanding of its mechanisms and their consequences in vivo is still limited. In this study, Caenorhabditis elegans (C. elegans; strain CB665) nematodes were exposed to X-rays at doses of 0.1, 1, 3 or 10Gy. The endpoints were measured several generations after exposure and included mutations in the movement-related gene unc-58, alterations in gene expression analysed with oligoarrays containing the entire C. elegans genome, and micro-satellite mutations measured by capillary electrophoresis. The progeny of the irradiated nematodes showed an increased mutation frequency in the unc-58 gene, with a maximum response observed at 1Gy. Significant differences were also found in gene expression between the irradiated (1Gy) and non-irradiated nematode lines. Differences in gene expression did not show clear clustering into certain gene categories, suggesting that the instability might be a chaotic process rather than a result of changes in the function of few specific genes such as, e.g., those responsible for DNA repair. Increased heterogeneity in gene expression, which has previously been described in irradiated cultured human lymphocytes, was also observed in the present study in C. elegans, the coefficient of variation of gene expression being higher in the progeny of irradiated nematodes than in control nematodes. To the best of our knowledge, this is the first publication reporting radiation-induced genomic instability in C. elegans.

Does the outcome of prostate cancer patients with large prostates differ from small prostate size in permanent seed, low dose-rate brachytherapy?

OBJECTIVE: Brachytherapy has good results in the treatment of early prostate cancer (PC). The procedure is challenging in large prostates, and the optimal prostate volume for brachytherapy was previously defined as ≤40 ml. This study analysed the outcome of PC patients with small (group A) and large (group B) prostate volume in prospective data. MATERIAL AND METHODS: The material consisted of 535 consecutive patients treated with brachytherapy in Kuopio University Hospital. The mean follow-up time was nearly 6 years. Prostate-specific antigen (PSA) failure was defined as PSA rising ≥2.0 µg/l above nadir. A PSA bounce was defined as a rise in PSA of ≥0.2 µg/l. The causes of death were recorded. RESULTS: A bounce was recorded more frequently in group A (30%) than in group B (18%) (p = 0.006). A bounce correlated with young age predicted a favourable outcome in both groups. PSA failure rate was similar in both groups: 13% and 12% in groups A and B, respectively. Post-treatment PSA ≤0.5 µg/l was the only independent prognostic factor associated with PSA failure in both groups (p < 0.0001, both groups). PC survival was 98.4% in both groups. Overall survival was 91% and 94% in groups A and B, respectively (p = not significant). CONCLUSIONS: There were no differences between the PC patients with small and large prostate volumes treated with brachytherapy with respect to PSA failure rate, PC survival or overall survival. All patients, independent of prostate size, are potential candidates for brachytherapy.

Interactive multiobjective optimization for anatomy-based three-dimensional HDR brachytherapy.

In this paper, we present an anatomy-based three-dimensional dose optimization approach for HDR brachytherapy using interactive multiobjective optimization (IMOO). In brachytherapy, the goals are to irradiate a tumor without causing damage to healthy tissue. These goals are often conflicting, i.e. when one target is optimized the other will suffer, and the solution is a compromise between them. IMOO is capable of handling multiple and strongly conflicting objectives in a convenient way. With the IMOO approach, a treatment planner's knowledge is used to direct the optimization process. Thus, the weaknesses of widely used optimization techniques (e.g. defining weights, computational burden and trial-and-error planning) can be avoided, planning times can be shortened and the number of solutions to be calculated is small. Further, plan quality can be improved by finding advantageous trade-offs between the solutions. In addition, our approach offers an easy way to navigate among the obtained Pareto optimal solutions (i.e. different treatment plans). When considering a simulation model of clinical 3D HDR brachytherapy, the number of variables is significantly smaller compared to IMRT, for example. Thus, when solving the model, the CPU time is relatively short. This makes it possible to exploit IMOO to solve a 3D HDR brachytherapy optimization problem. To demonstrate the advantages of IMOO, two clinical examples of optimizing a gynecologic cervix cancer treatment plan are presented.

Eight years experience of local prostate cancer treatment with permanent I125 seed brachytherapy--morbidity and outcome results.

BACKGROUND AND PURPOSE: There are only a limited number of reports of treatment of prostate cancer with permanent prostate seed I(125) brachytherapy (PPB) in Europe. We describe results from one Finnish institution having treated 444 patients with a follow-up of eight years. MATERIAL AND METHODS: Morbidity was evaluated by International Prostate Symptom Score and International Index of Erectile Function questionnaires. Urine flow, residual urine volume and the PSA values were measured pre-treatment and during follow-up. Any additional treatments were recorded. RESULTS: PPB was well tolerated. Median IPSS increased from 8 at baseline to 18 at three months post-therapy and returned to baseline score within 12 months. Median urine flow decreased from 15.2 ml/s at baseline to 10.2 ml/s at three months and returned to baseline value within two years. Acute urinary retention, potency preservation and severe proctitis were observed in 11%, 86% and 2% of patients, respectively. The PSA bounce was observed in 13% and PSA nadir < or =0.5 microg/l was reached by 81% of patients. Disease-free survival (DFS) was 90.2%. In the Cox regression analysis, the independent predictors of DFS were risk group and PSA nadir < or =0.5 microg/l (p<0.0001 for both). PC-specific survival was 98.5% and overall survival was 94.6%. CONCLUSIONS: Our results are in concordance and comparable with other reports on PPB.

Major reduction of monitor units with the avoidance of leaf-sequencing step by direct aperture based IMRT optimisation.

BACKGROUND AND PURPOSE: Compared with conventional 3D conformal radiotherapy (3D-CRT) the use of intensity-modulated radiation therapy (IMRT) has increased monitor units (MUs) in the delivery of prescribed dose to the patient and thus a potential risk of radiation-induced secondary cancer. Due to the elimination of the leaf-sequencing step in direct aperture based IMRT optimisation (DABO) the MUs in the beam delivery can be reduced. We compared MUs calculated by DABO with other IMRT techniques and 3D-CRT. MATERIAL AND METHODS: Treatment plans for five head and neck cancer patients using dynamic IMRT technique (DMLC) and step-and-shoot (SMLC) technique (Varian Helios Cadplan), 3D-CRT (Varian Eclipse) and a home-made DABO were produced. The total number of MUs, dose coverage and standard deviation of prescribed dose in planning target volume (PTV) between different techniques were compared. RESULTS: In all patients the PTV coverage and sparing of critical structures between the DABO, Helios DMLC and SMLC IMRT techniques was equivalent. Average MUs for beam delivery were 883 MU, 683 MU, 379 MU and 411 MU for DMLC, SMLC, DABO and 3D-CRT, respectively. CONCLUSIONS: The DABO IMRT technique is able to produce treatment plans equivalent in target coverage, dose uniformity and normal tissue sparing compared with the commercial IMRT techniques. The number of MUs with DABO were reduced with a factor of 2.3 (DMLC) and 1.8 (SMLC). The study suggests that with DABO IMRT technique the risk of secondary cancer can be reduced without compromise in the quality of treatment plans.

Comparison of conventional inserts and an add-on electron MLC for chest wall irradiation of left-sided breast cancer.

BACKGROUND: Collimation of irregularly shaped clinical electron beams is currently based on electron inserts made of low melting point alloys. The present investigation compares a conventional electron applicator with insert and add-on eMLC-based dose distributions in the postoperative chest wall irradiation of left-sided breast cancer. MATERIAL AND METHODS: Voxel Monte Carlo++ (VMC++) calculated dose distributions related to electron fields were compared with 10 left-sided breast cancer patients after radical mastectomy. The prescription dose was 50 Gy at a build-up maximum. The same dose was prescribed for the ipsilateral axillary, parasternal and supraclavicular lymph nodes that were treated with photons and calculated with a pencil beam algorithm. The insert beams were shaped with 1.5 cm thick Wood's metal electron inserts in an electron applicator of a Varian 2100 C/D linac. Doses for the eMLC-shaped beams were calculated for an eMLC prototype with 2 cm thick and 5 mm wide steel leaves. The same collimator-to-surface distance (CSD) of 5.8 cm was used for both collimators. RESULTS: The mean PTV dose was slightly higher for the eMLC plans (50.7 vs 49.5 Gy, p<0.001, respectively). The maximum doses assessed by D5% for the eMLC and insert were 60.9 and 59.1 Gy (p<0.001). The difference was due to the slightly higher doses near the field edges for the eMLC. The left lung V20 volumes were 34.5% and 34.0% (p<0.001). There was only a marginal difference in heart doses. DISCUSSION: Despite a slight increase of maximum dose in PTV the add-on electron MLC for chest wall irradiation results in practically no differences in dose distributions compared with the present insert-based collimation.

Reliability and validity of a bioimpedance measurement device in the assessment of UVR damage to the skin.

Ultraviolet radiation (UVR) is the primary cause of skin cancers. However, it is difficult to evaluate the amount of UVR absorbed into the skin retrospectively. Therefore, objective and non-invasive quantitative method would be valuable for epidemiological UVR exposure assessment. Photodamage reduces the amount of bound water in the skin, and thus, measuring the skin's dielectric constant can provide an opportunity for assessing the cumulative UVR exposure. The purpose of the study was to assess the reliability and validity of the bioimpedance device, Moisture Meter-D. The measurements were performed on 100 subjects at three separate measurement times. A questionnaire was used to obtain information on the host factors and on the past UVR exposure. The biological samples, to determine the elastin proportion of the dermis, were collected. Some long-term as well as seasonal variations in the dielectric constants were detected. Also, a weak relationship between the dielectric constant and the UVR exposure indicators and host factors was observed. The MoistureMeter-D appears not to measure structural alterations in the skin caused by photodamage, and thus it is not a valid instrument for the assessment of photodamage, i.e., past UVR exposure.

Dielectric measurement in experimental burns: a new tool for burn depth determination?

BACKGROUND: There has been a lack of methods to provide quantitative information of local tissue edema after burn injury. Noninvasive dielectric measurements provide this information. The measured value, the dielectric constant, is directly related to the amount of water in tissue. Using probes of different sizes, the measurements give information from different tissue depths. The aim of this study was to characterize edema formation at different tissue depths and to examine whether the dielectric measurements could be used to distinguish partial- and full-thickness burns in pigs. METHODS: An experimental animal study with pigs (n = 6) was performed in which dielectric measurements were taken of superficial, partial-thickness, and full-thickness burns for 72 hours. RESULTS: There was an increase in tissue water content in the superficial dermis in the partial-thickness burns at 48 hours. In whole dermis, the superficial burns resulted in increased tissue water content at 8 hours, and the partial-thickness burns resulted in increased tissue water content at 8, 24, and 72 hours. In deep burns, the water content was significantly decreased in the superficial dermis at 24 hours. All burns resulted in a considerable increase in fat water content. The dielectric probes could be used to differentiate partial- and full-thickness burns as early as 8 hours after burn. Receiver operating curve analysis of the measurements indicated 70 to 90 percent sensitivity and 80 to 100 percent specificity after 8 hours. CONCLUSIONS: The dielectric measurements provide a sensitive and noninvasive method for examining tissue edema and differentiate partial- and full-thickness burns in experimental burns. Thus, they are of clinical interest for early burn depth determination.

Radiation-induced changes in skin type I and III collagen synthesis during and after conventionally fractionated radiotherapy.

BACKGROUND AND PURPOSE: To measure local changes of collagen metabolism in irradiated breast skin and systemic changes in serum during and after radiotherapy and correlate these changes with skin thickness, erythema and palpable subcutaneous induration. PATIENTS AND METHODS: Aminoterminal propeptides of type I and type III procollagens (PINP and PIIINP, respectively) were measured from skin suction blister fluid (SBF) in 21 breast cancer patients with breast conserving surgery and conventionally fractionated radiotherapy (RT) to a total dose of 50Gy. Suction blisters were induced in the operated and contralateral breast skin before RT, at 2.5 weeks, at the end of RT, and at 1, 4, 7, 12 and 24 months post-treatment. Blood samples for serum were taken simultaneously with SBF induction. Skin thickness of the suction blister sites was measured with a high-frequency ultrasound device. The investigated sites were scored for erythema at the end of RT and palpable subcutaneous induration at 1 and 2 years post-treatment. RESULTS: In SBF the mean levels of PINP and PIIINP of the operated breast before RT were about 3-4 times higher than those in the contralateral breast due to the operation-related wound healing. The synthesis of PINP in irradiated breast after RT increased 7.7-fold (P < 0.001) 4 months post-irradiation. The PIIINP synthesis was at maximum at 1 month post-irradiation (P < 0.001). Both synthesis stayed elevated until 2 years. The level of PINP correlated significantly with the palpable skin induration at 1 and 2 years (P = 0.038 and P = 0.003, respectively). The skin thickness of the irradiated breast was highest at 4 months post-treatment and significantly elevated until 1 year. The skin thickness correlated with the PINP level until 7 months and with PIIINP between 4 and 18 months. The PINP/PIIINP ratio reached the maximum at 4 months and stayed elevated until 2 years. No change in mean serum level of PINP was found during or after RT. CONCLUSIONS: We demonstrated a maximum and elevated levels for PINP and PIIINP skin collagen metabolism determined from SBF during the 2 years' follow-up. Elevated levels of PINP and PIIINP correlated with the thickening of the skin and subcutaneous induration but not with erythema.

Measurement of hydration in the stratum corneum with the MoistureMeter and comparison with the Corneometer.

BACKGROUND/PURPOSE: MoistureMeter is a novel capacitive device for measuring the hydration of stratum corneum (SC). The capacitor 'plates' are formed by the probe material and the well-conducting epidermal-dermal skin layers, while the dry layer of SC acts as an 'insulator' of the capacitor. Due to this measurement principle, the measurement depth is not constant, but equal to the thickness of the dry layer of SC. The present study was undertaken to test the MoistureMeter SC-2 in an experimental setup simulating the uppermost skin structure. The sensitivity of the MoistureMeter was compared with a conventional device Corneometer CM 820 in eight healthy volunteers. METHODS: The experimental setup consisted of a polyethene foil simulating SC and a mixture of cellulose and saline simulating the underlying skin layers with a high water content. The hydration of SC of volar forearm was measured in eight healthy volunteers both with the MoistureMeter SC-2 and Corneometer CM 820 after the application of three different skin formulations: base, base plus salt (2 wt% NaCl), base plus salt and glycerin (5 wt%). In the sorption-desorption test, the skin was wetted with a drop of water and the dehydration was followed with both devices for 2 min. RESULTS: The test with the experimental setup agreed with the results predicted by the mathematical capacitance model. The hydration values of the MoistureMeter SC-2 and Corneometer CM 820 correlated well (R=0.75), but the relative range of readings with the MoistureMeter was approximately three times larger than with Corneometer. The MoistureMeter was insensitive for the salt (2 wt% NaCl) of the formulation and differentiated the hydration effect of glycerin better than the Corneometer. In the sorption-desorption test, the MoistureMeter demonstrated the individual differences between the volunteers, whereas with the Corneometer the differences were minimal. CONCLUSION: The capacitive measuring principle of the MoistureMeter was demonstrated in an experimental arrangement. Although both instruments yielded equivalent data with the base formulation, the MoistureMeter was a more sensitive device than the Corneometer CM 820 and independent of added salt in the formulations.

Dielectric constant of skin and subcutaneous fat to assess fluid changes after cardiac surgery.

The ability to objectively determine the degree of tissue edema and to monitor on-line fluid balance in critically ill patients would be a clinical benefit. In this prospective descriptive trial, we evaluated a new noninvasive method--dielectric constant of skin and subcutaneous fat (SSF)--in assessing fluid balance during cardiac surgery. The dielectric constant at the applied high radiofrequency is a direct measure of tissue water content. Twenty-nine patients with elective cardiac surgery participated in the study. Dielectric constants on forearm, thigh and abdomen were measured before surgery, within 1 h after surgery and in the first, second, third and fourth postoperative morning. At the same time the patients were weighed, except immediately after the operation and the first postoperative day when fluid balances were calculated. A statistically significant correlation (r = 0.60, p < 0.01) was found between the increase of the dielectric constant of SSF and weight gain of the patients from the baseline to the second postoperative morning. From the second to the fourth postoperative day when the patients were losing the weight, a statistical significant correlation between the dielectric constant and weight loss was not found. The results suggest that the measurement of the dielectric constant is a promising new method in assessing the fluid status of operated patients during the time the patients cannot be weighed.