Tumour-stroma ratio to predict pathological response to neo-adjuvant treatment in rectal cancer.

INTRODUCTION: Management of rectal cancer has advanced, with an increasing use of neoadjuvant chemoradiotherapy (nCRT). This opens options for organ preserving treatment for those with a major response to nCRT. However, the degree of clinical response, based on MRI and post-treatment biopsies, only poorly matches the degree of actual pathological response. In order to select patients with major pathological response without surgical resection, it is of importance to define tumour markers predicting the degree of pathological response to nCRT. The intra-tumoural tumour-stroma ratio (TSR) might be this marker. METHODS: TSR in pre-treatment biopsies was estimated according to the method described by van Pelt et al. The degree of pathological response was assessed on the tumour resection according to tumour regression grading (TRG) by Mandard. The primary endpoint of this study was the difference in pathological response to nCRT between TSR-high and TSR-low groups. RESULTS: We found that 26.2% of patients with major response was classified as TSR-high, while 73.8% of patients were classified as TSR-low. A high TSR in pre-treatment biopsies was associated with a lower chance of major-response to nCRT (OR = 0.37, 95%CI; 0.19-0.73), p = 0.004), independent of tumour stage and time between nCRT and surgery. CONCLUSION: In rectal cancer, TSR in pre-treatment biopsies predicts pathologic response to nCRT, with a high TSR bringing twice the risk of poor to no response compared to low TSR. In future, assessment of TSR may fulfil a role in a therapeutic algorithm identifying patients who will or will not respond to nCRT prior to treatment initiation.

A high tumour-stroma ratio (TSR) in colon tumours and its metastatic lymph nodes predicts poor cancer-free survival and chemo resistance

PurposeDespite known high-risk features, accurate identification of patients at high risk of cancer recurrence in colon cancer remains a challenge. As tumour stroma plays an important role in tumour invasion and metastasis, the easy, low-cost and highly reproducible tumour-stroma ratio (TSR) could be a valuable prognostic marker, which is also believed to predict chemo resistance.MethodsTwo independent series of patients with colon cancer were selected. TSR was estimated by microscopic analysis of 4 µm haematoxylin and eosin (H&E) stained tissue sections of the primary tumour and the corresponding metastatic lymph nodes. Patients were categorized as TSR-low (≤ 50%) or TSR-high (> 50%). Differences in overall survival and cancer-free survival were analysed by Kaplan–Meier curves and cox-regression analyses. Analyses were conducted for TNM-stage I–II, TNM-stage III and patients with an indication for chemotherapy separately.ResultsWe found that high TSR was associated with poor cancer-free survival in TNM-stage I–II colon cancer in two independent series, independent of other known high-risk features. This association was also found in TNM-stage III tumours, with an additional prognostic value of TSR in lymph node metastasis to TSR in the primary tumour alone. In addition, high TSR was found to predict chemo resistance in patients receiving adjuvant chemotherapy after surgical resection of a TNM-stage II–III colon tumour.ConclusionIn colon cancer, the TSR of both primary tumour and lymph node metastasis adds significant prognostic value to current pathologic and clinical features used for the identification of patients at high risk of cancer recurrence, and also predicts chemo resistance.

A high tumour-stroma ratio (TSR) in colon tumours and its metastatic lymph nodes predicts poor cancer-free survival and chemo resistance.

PURPOSE: Despite known high-risk features, accurate identification of patients at high risk of cancer recurrence in colon cancer remains a challenge. As tumour stroma plays an important role in tumour invasion and metastasis, the easy, low-cost and highly reproducible tumour-stroma ratio (TSR) could be a valuable prognostic marker, which is also believed to predict chemo resistance. METHODS: Two independent series of patients with colon cancer were selected. TSR was estimated by microscopic analysis of 4 µm haematoxylin and eosin (H&E) stained tissue sections of the primary tumour and the corresponding metastatic lymph nodes. Patients were categorized as TSR-low (≤ 50%) or TSR-high (> 50%). Differences in overall survival and cancer-free survival were analysed by Kaplan-Meier curves and cox-regression analyses. Analyses were conducted for TNM-stage I-II, TNM-stage III and patients with an indication for chemotherapy separately. RESULTS: We found that high TSR was associated with poor cancer-free survival in TNM-stage I-II colon cancer in two independent series, independent of other known high-risk features. This association was also found in TNM-stage III tumours, with an additional prognostic value of TSR in lymph node metastasis to TSR in the primary tumour alone. In addition, high TSR was found to predict chemo resistance in patients receiving adjuvant chemotherapy after surgical resection of a TNM-stage II-III colon tumour. CONCLUSION: In colon cancer, the TSR of both primary tumour and lymph node metastasis adds significant prognostic value to current pathologic and clinical features used for the identification of patients at high risk of cancer recurrence, and also predicts chemo resistance.

The rationale of opportunistic bilateral salpingectomies (OBS) during benign gynaecological and obstetric surgery: a consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG).

Ovarian cancer (OC), is a disease difficult to diagnose in an early stage implicating a poor prognosis. The 5-year overall survival in Belgium has not changed in the last 18 years and remains 44 %. There is no effective screening method (secondary prevention) to detect ovarian cancer at an early stage. Primary prevention of ovarian cancer came in the picture through the paradigm shift that the fallopian tube is often the origin of ovarian cancer and not the ovary itself. Opportunistic bilateral salpingectomy (OBS) during benign gynaecological and obstetric surgery might have the potential to reduce the risk of ovarian cancer by as much as 65 %. Bilateral risk-reducing salpingectomy during a benign procedure is feasible, safe, appears to have no impact on the ovarian function and seems to be cost effective. The key question is whether we should wait for a RCT or implement OBS directly in our daily practice. Guidelines regarding OBS within our societies are therefore urgently needed. Our recommendation is to inform all women without a child wish, undergoing a benign gynaecological or obstetrical surgical procedure about the pro's and the con's of OBS and advise a bilateral salpingectomy. Furthermore, there is an urgent need for a prospective registry of OBS. The present article is the consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG) regarding OBS.

Correction to: Extreme ST-segment elevations in seemingly no significant angiographic coronary artery abnormalities: a case report.

Following publication.

Extreme ST-segment elevations in seemingly no significant angiographic coronary artery abnormalities: a case report.

BACKGROUND: Obstructive coronary artery disease is found in approximately 97% of patients presenting with ST-elevation myocardial infarction and 92% of patients with non ST-elevation myocardial infarction (Bainey KR, Welsh RC, Alemayehu W, Westerhout CM, Traboulsi D, Anderson T, et al. Int J Cardiol 264: 12-17, 2018). Recent studies showed that myocardial infarction without obstructive coronary atherosclerosis (MINOCA) is also associated with a long-term risk of adverse events (Bainey KR, Welsh RC, Alemayehu W, Westerhout CM, Traboulsi D, Anderson T, et al. Int J Cardiol 264: 12-17, 2018).. The following case illustrates that MINOCA may also be associated with short term adverse events (depending on the underlying mechanism). CASE PRESENTATION: A 49-year old Caucasian male with no significant medical history was referred to our cardiac emergency department with acute chest pain. The ambulance ECG showed extreme ST-segment elevation anterolateral ('tombstone sign'), which had resolved completely at arrival in the hospital. Coronary angiography showed no obstructive coronary artery disease. Conservative (medical) therapy was started and patient was discharged. Two days later he presented with recurrent cardiac ischemia with ventricular fibrillation. Coronary angiography showed no changes compared with earlier presentation. During admission to the ICU his clinical condition gradually deteriorated, eventually leading to his death. Post-mortem studies showed no significant atherosclerotic lesions. Massive myocardial infarction was found, probably caused by temporary occlusion of the left main coronary artery. CONCLUSIONS: Several pathophysiological mechanisms are recognized in MINOCA, of which vasospasm is the most probable one in this case. MINOCA is associated with increased over-all mortality and risk of ventricular arrhythmias. Therefore, additional testing should be considered when there is no explanation for the mismatch between ST-elevations (STEMI) and (no significant) coronary abnormalities.

Do mathematical model studies settle the controversy on the origin of cardiac synchronous trans-thoracic electrical impedance variations? A systematic review.

Impedance cardiography (ICG) is a method to evaluate cardiac-stroke volume and cardiac-output by measuring the cardiac-synchronous changes in the dynamic trans-thoracic electrical impedance (ΔZ). Clinical evaluations on the accuracy of ICG showed varying results. Consequently, the classic assumption in ICG-the aorta as a main source of ΔZ-is questioned and subsequently investigated in simulation studies using mathematical models of the electrical resistivity of the human body. The aim is to review the consensus in mathematical modelling studies that investigate the origin of the ΔZ as measured in ICG. In a systematic literature search, studies were identified and surveyed with reference to characteristics, such as included organs and their resistivity and geometries, electrode positions and calculation of ΔZ, to review the consensus between mathematical modelling studies that investigate the origin of the ΔZ as measured in ICG. Thirteen papers showed considerable variation in the model's characteristics with varying or contradicting outcomes for the ΔZ 's origin. For instance, 11 studies excluded perfused muscle tissue, implying implicitly their insignificance, while 3 other studies included muscle tissue and indicated it as the most important origin of ΔZ. In conclusion, the reviewed papers show a lack of consensus with respect to both the modelled characteristics as well as the model outcomes and, as a result, these studies failed to settle the controversy on ΔZ 's origin. Recommendations have been added to improve future mathematical model studies.

Chorangiocarcinoma of the placenta: a case report and clinical review.

OBJECTIVE: We describe a case of chorangiocarcinoma, a complex lesion consisting of a trophoblastic proliferation within a chorangioma, presenting in a term placenta. MATERIALS AND METHODS: The lesion was diagnosed by ultrasound at a second trimester check-up after amniocentesis, performed because of increased combined risk at first trimester screening for trisomy 21. After uncomplicated vaginal delivery, a healthy child was born and the placenta was expelled spontaneously. RESULTS: Gross examination of the placenta showed a well-demarcated mass, bulging paracentrally from the fetal surface. Histology revealed a trophoblastic proliferation inside a chorangioma, consisting of multiple nodules with characters of focal multinucleation and pleomorphic cell nuclei, extensive central necrosis and high mitotic activity. Immunohistochemical staining showed strong intensity for hCG; Ki-67 (MIB-1) demonstrated a high proliferation index. Histopathological and immunohistochemical profile was compatible with a malignant trophoblastic proliferation. CONCLUSIONS: This is only the fifth reported case of so-called "chorangiocarcinoma" of the placenta (Table 1). However, histopathologically only one reported case was identical to ours. A proliferation of atypical trophoblast was observed inside a chorangioma, which formed as it were a shield around the trophoblast. No extravascular stromal invasion was present. Follow-up revealed no metastases, either in the mother or the child, up to 3 months after birth.

An analysis of 5'-inosine and 5'-guanosine monophosphate taste in rats.

Inosine monophosphate (IMP) and guanosine monophosphate (GMP) elicit an umami taste in humans and synergistically increase the intensity of the umami taste of monosodium glutamate (MSG). Conditioned taste aversion (CTA) studies in rodents indicate that these nucleotides and MSG elicit quite similar tastes, but recent physiological evidence suggests that these nucleotides and MSG may not activate the same population of taste receptors and therefore may not elicit identical taste qualities. This study reports the findings of several behavioral experiments with rats that compared the taste properties of IMP and GMP with each other and with those of MSG. Well-trained rats were able to detect both nucleotides at nanomolar concentrations, but they did not respond to either nucleotide in two-bottle preference tests or brief-access CTA tests at concentrations less than 0.5 mM. Discrimination experiments found that the tastes of these nucleotides could not be discriminated from each other, but both could be discriminated from MSG, even when the taste of Na(+) was controlled. Overall, these experiments indicate the taste properties of the two 5'-ribonucleotides are quite similar to each other, and even though they may elicit an umami sensation, these sensations are not identical to the taste of MSG.

A histopathological contribution to supratentorial glioma grading, definition of mixed gliomas and recognition of low grade glioma with Rosenthal fibers.

BACKGROUND: Previous glioma studies have described separate grading systems for oligodendrogliomas and astrocytomas. Many of these gliomas contain mixtures of neoplastic astrocytes and oligodendrocytes. Prognosis may be related to the percentages of these neoplastic components. Previous survival/grading studies have been limited to histopathological features but have not evaluated the importance of percentages of neoplastic components. This study attempted to perceive the relative importance of percentages of neoplastic astrocytes and oligodendrocytes for definition of astroglial, oligodendroglial and mixed oligoastroglial tumors. After determination of these limits we explored the possibility to develop a grading system for common supratentorial gliomas based on reproducible histopathological features. METHODS: A retrospective study was performed of 362 cases of unselected supratentorial glioma. One hundred and thirty-eight binary and nine continuous histopathological variables, amongst which percentages of neoplastic astrocytes and oligodendrocytes, were scored and related to survival. Only well reproducible histological features were accepted in Cox regression to define glioma grades. RESULTS AND CONCLUSIONS: Supratentorial gliomas appeared to be composed of variable percentages of neoplastic oligodendrocytes and astrocytes, but this spectrum did not correspond to a continuous change in prognosis. Gliomas containing 30% or more neoplastic oligodendrocytes had a slightly better outcome (p < 0.0432) but higher percentages did not further improve prognosis. Percentages of neoplastic astrocytes were not correlated to survival. We therefore propose to designate gliomas containing 30% or more neoplastic oligodendrocytes as oligodendroglial tumors, and others as astroglial tumors. From a prognostic point of view there is no need to recognize mixed oligoastrocytomas. An interesting finding was the recognition of a low grade glioma group with Rosenthal fibers, which had the longest postoperative survival. Another prognosticator of interest concerns the mitotic rate as a continuous variable. Atypical mitoses indicated the worst survival, after necrosis. It was possible to develop a grading system for all supratentorial gliomas using six reproducible histological parameters: necrosis, atypical mitoses, the mitotic rate, endothelial proliferative activity, percentage of neoplastic oligodendrocytes and Rosenthal fibers. This resulted in four grades for astroglial tumors (p < 0.002) and three grades for oligodendroglial tumors (p < 0.008) which differed significantly within each group with respect to survival.

The boundary element method in the forward and inverse problem of electrical impedance tomography.

In this paper, a new formulation of the reconstruction problem of electrical impedance tomography (EIT) is proposed. Instead of reconstructing a complete two-dimensional picture, a parameter representation of the gross anatomy is formulated, of which the optimal parameters are determined by minimizing a cost function. The two great advantages of this method are that the number of unknown parameters of the inverse problem is drastically reduced and that quantitative information of interest (e.g., lung volume) is estimated directly from the data, without image segmentation steps. The forward problem of EIT is to compute the potentials at the voltage measuring electrodes, for a given set of current injection electrodes and a given conductivity geometry. In this paper, it is proposed to use an improved boundary element method (BEM) technique to solve the forward problem, in which flat boundary elements are replaced by polygonal ones. From a comparison with the analytical solution of the concentric circle model, it appears that the use of polygonal elements greatly improves the accuracy of the BEM, without increasing the computation time. In this formulation, the inverse problem is a nonlinear parameter estimation problem with a limited number of parameters. Variants of Powell's and the simplex method are used to minimize the cost function. The applicability of this solution of the EIT problem was tested in a series of simulation studies. In these studies, EIT data were simulated using a standard conductor geometry and it was attempted to find back this geometry from random starting values. In the inverse algorithm, different current injection and voltage measurement schemes and different cost functions were compared. In a simulation study, it was demonstrated that a systematic error in the assumed lung conductivity results in a proportional error in the lung cross sectional area. It appears that our parametric formulation of the inverse problem leads to a stable minimization problem, with a high reliability, provided that the signal-to-noise ratio is about ten or higher.

Determination of stroke volume by means of electrical impedance tomography.

ECG-gated electrical impedance tomography (EIT) is a non-invasive imaging technique, developed to monitor blood volume changes. This study is the first in comparing this non-invasive technique in measuring stroke volume with established techniques. The objective of this study was to validate EIT variables derived from the EIT images with paired obtained stroke volume measurements by thermodilution and MRI. After right cardiac catheterization, EIT measurements were performed in 25 patients. Regression analysis was used to analyse the relation between the EIT results and stroke volume determined by thermodilution. From the regression line an equation was derived to estimate stroke volume (in ml) by EIT. A strong correlation was found between EIT and stroke volume measured by the thermodilution method (r = 0.86). In a group of 11 healthy subjects this equation was validated to MRI. The mean and standard deviation of the difference between EIT and MRI was 0.7 ml and 5.4 ml respectively. These data indicate that EIT is a valid and reproducible method for the assessment of stroke volume.

Monitoring of recruitment and derecruitment by electrical impedance tomography in a model of acute lung injury.

OBJECTIVE: To evaluate a noninvasive system for obtaining information about alveolar recruitment and derecruitment in a model of acute lung injury. DESIGN: Prospective experimental study. SETTING: Animal research laboratory. SUBJECTS: Nine anesthetized pigs. INTERVENTIONS: Electrical impedance tomography measurements were performed. Electrical impedance tomography is an imaging technique that can register the ventilation-induced impedance changes in different parts of the lung. In nine anesthetized pigs, repeated lung lavages were performed until a PaO2 of <80 mm Hg was reached. Thereafter, the lungs were recruited according to two different recruitment protocols: the open lung approach and the open lung concept. Five time points for measurements were chosen: healthy (reference), lavage (atelectasis), recruitment, derecruitment, and maintain recruited (final). MEASUREMENTS AND MAIN RESULTS: After lavage, there was a significant increase in the impedance ratio, defined as the ventilation-induced impedance changes of the anterior part of the lung divided by that of the posterior part (from 1.75 +/- 0.63 to 4.51 +/- 2.22; p < .05). The impedance ratio decreased significantly after performing the recruitment protocol (from 4.51 +/- 2.22 to 1.18 +/- 0.51). During both recruitment procedures, a steep increase in baseline impedance change was seen. Furthermore, during derecruitment, a decrease in the slope in baseline impedance change was seen in the posterior part of the lung, whereas the anterior part showed no change. CONCLUSION: Electrical impedance tomography is a technique that can show impedance changes resembling recruitment and derecruitment of alveoli in the anterior and posterior parts of the lung. Therefore, electrical impedance tomography may help in determining the optimal mechanical ventilation in a patient with acute lung injury.

The electric resistivity of human tissues (100 Hz-10 MHz): a meta-analysis of review studies.

The electric resistivity of various human tissues has been reported in many studies, but on comparison large differences appear between these studies. The aim of this study was to investigate systematically the resistivities of human tissues as published in review studies (100 Hz-10 MHz). A data set of 103 resistivities for 21 different human tissues was compiled from six review studies. For each kind of tissue the mean and its 95% confidence interval were calculated. Moreover, an analysis of covariance showed that the calculated means were not statistically different for most tissues, namely skeletal (171 omega cm) and cardiac (175 omega cm) muscle, kidney (211 omega cm), liver (342 omega cm), lung (157 omega cm) and spleen (405 omega cm), with bone (> 17,583 omega cm), fat (3,850 omega cm) and, most likely, the stratum corneum of the skin having higher resistivities. The insignificance of differences between various tissue means could imply an equality of their resistivities, or, alternatively, could be the result of the large confidence intervals which obscured real existing differences. In either case, however, the large 95% confidence intervals reflected large uncertainties in our knowledge of resistivities of human tissues. Applications based on these resistivities in bioimpedance methods, EEG and EKG, should be developed and evaluated with these uncertainties in mind.

A meta-analysis of three decades of validating thoracic impedance cardiography.

OBJECTIVE: To provide a meta-analysis of current literature concerning the validation of thoracic impedance cardiography (TIC) and to explain the variations in the reported results from the differences in the studies. DATA SOURCES: A computer-assisted search of English-language, German, and Dutch literature was performed for the period January 1966 to April 1997. Moreover, references from review articles were obtained. STUDY SELECTION: A total of 154 studies comparing measurements of cardiac output or related variables obtained from TIC and a reference method were analyzed. DATA EXTRACTION: Articles were classified by differences in TIC methodology, reference method, and subject characteristics. Fisher's Zf transformed correlation coefficients were used to compare results. Data were pooled using the random-effects method. DATA SYNTHESIS: An overall pooled r2 value of .67 (95% confidence interval, 0.64-0.71) was found. However, the correlation was higher in repeated-measurement designs than in single-measurement designs (r2 = .53; 95% confidence interval, 0.43-0.62). Further research using analysis of variance revealed a significant influence of the reference method and the subject characteristics on the correlation coefficient. The correlation was significantly better in animals than in cardiac patients. Subgroup analysis revealed that TIC correlated significantly better to the indirect Fick method than to echocardiography in healthy subjects. No significant influence of the applied TIC methodology was found. DISCUSSION: The overall r2 value of .67 indicates that TIC might be useful for trend analysis of different groups of patients. However, for diagnostic interpretation, a r2 value of .53 might not meet the required accuracy of the study. Great care should be taken when TIC is applied to the cardiac patient. However, because the applied reference method was of significant influence, differences between TIC and the reference method are incorrectly attributed to errors in TIC alone.

Estimation of extracellular volume by a two-frequency measurement.

An approach to determine intra- and extracellular conduction on the basis of Bode analysis is presented. Estimation of the ratio between intra- and extracellular conduction could be performed by phase measurement only, midrange in the bandwidth of interest. An important feature is that the relation between intra- and extracellular conduction can be continuously monitored by phase measurement and no curve fitting whatsoever is required. Based on a two-frequency measurement determining Re at 4 kHz and phi max at 64 kHz, it proved possible to estimate extracellular volume (ECV) in 23 patients. Reference values on ECV were determined by sodium bromide. The results show a good correlation (r = 0.90) with the reference method. The average error of ECV estimation was -3.6% (SD 8.4).

A meta-analysis of published studies concerning the validity of thoracic impedance cardiography.

UNLABELLED: Our aim was to provide a meta-analysis of the literature concerning the validation of thoracic impedance cardiography (TIC) and to explain variations in reported results from differences in the studies. One hundred fifty-four studies (164 Fisher's Z-transformed correlation coefficients) comparing measurements of cardiac output or related parameters from TIC and a reference method were analyzed. Papers were classified according to differences in TIC methodology, reference method, and subject characteristics. Pooling using the random-effects method yielded an overall correlation of r = 0.82 (95% confidence interval: 0.80-0.84). ANOVA revealed a significant influence of the reference method and the subject characteristics on the correlation coefficient. In cardiac patients, the correlation was significantly decreased. No influence of the applied TIC methodology was found. CONCLUSION: TIC might be useful for trend analysis of different groups of patients. However, since the reference method was of significant influence, differences between TIC and the reference method are incorrectly attributed to TIC alone.

Towards a theoretical understanding of stroke volume estimation with impedance cardiography.

In electrical impedance cardiography, Kubicek's formula is often used to measure stroke volume from thoracic impedance variations synchronously to heart activity. To calculate stroke volume from impedance variations, the so-called outflow problem should be adequately solved. This outflow problem refers to the joint causes of impedance change due to blood entering the aorta from the heart, as well as blood leaving the aorta due to arterial runoff. The aim of this study was to investigate the Kubicek formula as a solution of the outflow problem. Kubicek's formula was theoretically investigated using a simple model of the volume-conducting properties of the thorax (two-cylinder model), as well as the hemodynamics of the systemic circulation (three-element "windkessel" model). The mathematical analysis showed that the outflow problem was not solved by the Kubicek formula. Moreover, this theoretical result was experimentally confirmed.

The influence of extravascular lung water on cardiac output measurements using thoracic impedance cardiography.

The purpose of this study was to investigate the influence of pulmonary oedema as measured with the double indicator dilution technique on the accuracy of cardiac output (CO) measurement using thoracic impedance cardiography (TIC) compared with thermodilution in thirteen sepsis patients. Differences in the Kubicek and Sramek-Bernstein equation with respect to pulmonary oedema were explored theoretically and experimentally. From a parallel two cylinder model a hypothesis can be derived that CO determined with the Kubicek equation is oedema independent, whereas CO determined using the Sramek-Bernstein equation is oedema dependent. Experimentally, CO determined using Kubicek's equation correlated better with thermodilution CO (r = 0.75) than CO determined with the Sramek-Bernstein equation (r = 0.25). The effect of oedema on the accuracy of TIC was investigated by comparing the differences in the CO of impedance and thermodilution to the extravascular lung water index. For the Kubicek equation the difference was not influenced by oedema (r = 0.04, p = 0.84), whereas for the Sramek-Bernstein equation the difference was affected by oedema (r = 0.39, p = 0.05). Thus, the effects of pulmonary oedema on the accuracy of TIC measurements can better be understood with the parallel cylinder model. Moreover, the Kubicek equation still holds when pulmonary oedema is present, in contrast to the Sramek-Bernstein equation.

Extra-cellular volume estimation by electrical impedance--phase measurement or curve fitting: a comparative study.

In order to determine body fluid shifts between the intra- and extra-cellular spaces, multifrequency impedance measurement is performed. According to the Cole-Cole extrapolation, lumped values of intra- and extra-cellular conduction can be estimated which are commonly expressed in resistances Ri and Re respectively. For this purpose the magnitude and phase of the impedance under study are determined at a number of frequencies in the range between 5 kHz and 1 MHz. An approach to determine intra- and extra-cellular conduction on the basis of Bode analysis is presented in this article. On this basis, estimation of the ratio between intra- and extra-cellular conduction could be performed by phase measurement only, midrange in the bandwidth of interest. An important feature is that the relation between intra- and extra-cellular conduction can be continuously monitored by phase measurement and no curve fitting whatsoever is required. Based on a two frequency measurement determining Re at 4 kHz and phi(max) at 64 kHz it proved possible to estimate extra-cellular volume (ECV) more accurately compared with the estimation based on extrapolation according to the Cole-Cole model in 26 patients. Reference values of ECV were determined by sodium bromide. The results show a correlation of 0.90 with the reference method. The average error of ECV estimation was -3.6% (SD 8.4), whereas the Cole-Cole extrapolation showed an error of 13.2% (SD 9.5). An important feature of the proposed approach is that the relation between intra- and extra-cellular conduction can be continuously monitored by phase measurement and no curve fitting whatsoever is required.