Tomaž Jarm

Antitumor effectiveness of electrochemotherapy: A systematic review and meta-analysis

BACKGROUND This systematic review has two purposes: to consolidate the current knowledge about clinical effectiveness of electrochemotherapy, a highly effective local therapy for cutaneous and subcutaneous tumors; and to investigate the differences in effectiveness of electrochemotherapy with respect to tumor type, chemotherapeutic drug, and route of drug administration. METHODS All necessary steps for a systematic review were applied: formulation of research question, systematic search of literature, study selection and data extraction using independent screening process, assessment of risk of bias, and statistical data analysis using two-sided common statistical methods and meta-analysis. Studies were eligible for the review if they provided data about effectiveness of single-session electrochemotherapy of cutaneous or subcutaneous tumors in various treatment conditions. RESULTS In total, 44 studies involving 1894 tumors were included in the review. Data analysis confirmed that electrochemotherapy had significantly (p < .001) higher effectiveness (by more than 50%) than bleomycin or cisplatin alone. The effectiveness was significantly higher for intratumoral than for intravenous administration of bleomycin (p < .001 for CR%, p = .028 for OR%). Bleomycin and cisplatin administered intratumorally resulted in equal effectiveness of electrochemotherapy. Electrochemotherapy was more effective in sarcoma than in melanoma or carcinoma tumors. CONCLUSIONS The results of this review shed new light on effectiveness of electrochemotherapy and can be used for prediction of tumor response to electrochemotherapy with respect to various treatment conditions and should be taken into account for further refinement of electrochemotherapy protocols.

Parameters of Postocclusive Reactive Hyperemia Measured by Near Infrared Spectroscopy in Patients with Peripheral Vascular Disease and in Healthy Volunteers

AbstractThe main purpose of our study was to determine the parameters of the postocclusive reactive hyperemia test that could help and provide the clinician with information about the tissue oxygenation, the severity of the disease, and the results of the applied therapies. Near infrared spectroscopy (NIRS) proved to be a valid noninvasive trend monitor useful for investigating the physiology of oxygen transport to tissue. Important advantages of NIRS over transcutaneous oximetry (TcpO2) are: (a) a more dynamic nature of the NIRS signals which reflects more closely the actual response of the peripheral vasculature to the occlusive provocation; (b) larger sampling volume; and (c) the ability of assessing tissue oxygenation at deeper tissue levels. We demonstrated that the time parameters of reactive hyperemia, the rate of reactive hyperemia, and the maximal change during reactive hyperemia, all calculated from the oxyhemoglobin (HbO2) signal of the NIRS, clearly distinguish between healthy volunteers and patients with vascular disorder. The time parameters of reactive hyperemia were significantly longer (p < 0.01), and the rate of reactive hyperemia (p = 0.01) as well as the maximal change during reactive hyperemia (p = 0.02) were significantly lower in patient group compared to healthy volunteers. These parameters were also in good correlation with the values of ankle brachial index (ABI) and the resting values of oxygen partial pressure (TcpO2). Values of the chosen parameters obtained from the HbO2 signal were further compared between groups of diabetic and nondiabetic patients with peripheral vascular disease. Although longer time parameters of reactive hyperemia and lower rates of hyperemic response were detected, the difference between both groups was not statistically significant.

Reproducibility of parameters of postocclusive reactive hyperemia measured by near infrared spectroscopy and transcutaneous oximetry

The purpose of this study was to investigate postocclusive hyperemic response using near infrared spectroscopy (NIRS) and transcutaneous oximetry TcpO2 Five minute arterial occlusion on the calf muscle was performed in six healthy volunteers (mean age 29, range 23-34 years, mean TcpO2 at rest 53 mmHg, range 47-58 mmHg, and ankle brachial index between 1 and 1.2). Oxygen partial pressure at rest, oxygen consumption VO2 during ischemia, recovery times and resaturation rates after arterial occlusion were determined and new parameters for evaluation of the level of vascular disorders of lower limbs are suggested. The reproducibility of the signals was studied by repeating the same protocol on each subject four to six times. Repeated measurements showed no significant difference among trials, indicating that the measurements were reproducible. The mean values of the coefficient of variability for suggested parameters varied between 6% and 30% (mean value 17%). Interindividual variations of parameters are higher and can be explained by differences in fat/muscle ratio and in the measured tissue volume of the NIRS signal. Simultaneous measurements of NIRS and TcpO2 showed different responses to ischemic conditions, due to the different physiological levels of oxygen assessment. The combined use of both methods yields deeper insight into conditions of blood flow and tissue oxygenation.

Postocclusive Reactive Hyperemia in Healthy Volunteers and Patients With Peripheral Vascular Disease Measured by Three Noninvasive Methods

Postocclusive reactive hyperemia (PORH) was evaluated in three healthy volunteers and in three patients with different etiologies and suffering from peripheral arterial occlusive disease (PAOD). Three noninvasive methods were used: transcutaneous oximetry (TcPO2), near-infrared spectroscopy (NIRS), and laser Doppler flowmetry (LDF). Changes in perfusion and oxygenation of tissue were measured on foot before, during, and after arterial occlusion on thigh. Numerical parameters were derived from measured signals for quantification of the PORH response. Results of all three methods provided distinction between healthy volunteers and patients. The experimental optical techniques of NIRS and LDF demonstrated more clearly than the well-established TcPO2 method the difference between healthy volunteers and patients. The dynamics of the PORH response proved to be a better indicator of peripheral vascular disorder than the amplitude of responses.

Mathematical modelling of tumor growth in mice following electrotherapy and bleomycin treatment

In treatment of subcutaneous solid tumors in mice locally applied electrotherapy by direct current and i.v. administered bleomycin were combined. The study showed the interaction of both treatments in a way, that the antitumour effect of both was more than additive when compared to single treatments. The electrotherapy by means of 0.6 mA of one hour duration, as single treatment significantly delayed tumour growth in comparison to control group (growth delay GD = 6.7 ± 1.2 days), whereas therapy by 250 μg bleomycin i.v. injection had only moderate effect on tumour growth (GD = 0.5 ± 0.2 days). When both treatments were combined the tumour growth delay observed was 10.8±1.9 days. A model was developed in which the pharmacokinetic model of bleomycin was extended and transformed to the level of macroscopic biologically detectable effect i.e. tumour growth retardation. The data on tumor growth in control group was used to determine parameters of the Gompertz model (V0, αv0 and β). For modelling of both single treatments the extended Gompertz equation was used. In the case of electrotherapy a two component effect had to be introduced in order to obtain satisfactory fit. The effect of bleomycin on tumour growth was obtained by introducing the influential parameter which transferred the bleomycin concentration in tumour tissue obtained from pharmacokinetic model to the effect on tumour growth.

An algorithm for synchronization of in vivo electroporation with ECG

The combined treatment of tumours in which delivery of a chemotherapeutic agent is followed by high voltage electroporation pulses has been termed electrochemotherapy. The electrochemotherapy of tumours located relatively close to the heart muscle can lead to fibrillation of the heart, especially if electroporation pulses are delivered in the vulnerable period of the heart or in coincidence with heart arrhythmias. We built an electroporation pulse delivery algorithm that enables safer use of electrochemotherapy. The algorithm is designed to deliver pulses outside the vulnerable period and to prevent pulses from being generated in the presence of heart arrhythmias. We evaluated the algorithms performance using records of the Long-Term ST Database, thus simulating real-world conditions. The results of the evaluation, a sensitivity of 91.751%, a positive predictivity of 100.000% and a delivery error rate of 8.268% for electroporation pulse delivery (medians), suggest that the algorithm is accurate and appropriate for application in electrochemotherapy of tumours regardless of tumour location.

Blood Perfusion of Subcutaneous Tumours in Mice Following the Application of Low-Level Direct Electric Current

Electrotherapy with low-level direct electric current has been proved to be an effective local treatment of solid tumours. In the presented study an attempt was made to evaluate the effect of a single treatment with electrotherapy on blood perfusion of solid subcutaneous fibrosarcoma Sa-1 tumours in A/J mice. The tissue-staining method with Patent blue-violet dye, the rubidium extraction technique, and the noninvasive near-infrared spectroscopy method were used for this purpose. Results of all methods indicate that perfusion and subsequently oxygenation of tumours were reduced due to application of electrotherapy.

Monte-Carlo Simulation of Light Transport for NIRS Measurements in Tumors of Elliptic Geometry

Propagation of light in a highly scattering medium such as biological tissue is difficult to study. For complex geometry and multilayer structures computer simulation has to be used for light transport analysis. A Monte Carlo model of light propagation in tissue has been applied for the purpose of better understanding of the results of near-infrared spectroscopy (NIRS) measurements in experimental tumors. The major objective was to determine the percentage and location of the illuminated area in tumor and to estimate fraction of NIRS signal originating from the underlying tissues. Values of optical parameters used in the model were taken from literature. Tumor shape was approximated with a rotational ellipsoid. Computer simulations were made for two positions of optodes: reflectance and transmittance mode. Results of simulations indicate that in both configurations the majority of signal originates from tumor and not from surrounding tissue. In reflectance mode collected light comes from limited area near the optode whereas in transmittance mode the collected light illuminate almost whole tumor. This difference between the two modes is valid for all tissue parameters.

Effect of Hydralazine on Blood Flow, Oxygenation, and Interstitial Fluid Pressure in Subcutaneous Tumors

Many experimental and clinical solid tumors are known to exhibit poor oxygenation and high interstitial fluid pressure (IFP) in comparison to normal surrounding tissues. Oxygenation and IFP in addition to abnormal blood flow influence the response of tumors to various therapies and are also important for development and progression of malignant growth.“ Hydralazine (HYZ) is an arteriolar vasodilating drug which is used for treatment of hypertension in humans. HYZ can decrease both tumor blood flow and tumor IFP. These two changes may have opposite effects on drug delivery and oxygenation in tumors. In our study we evaluated the effect of HYZ on blood flow, oxygenation, and IFP in a murine tumor model. Oxygenation was measured by a relatively new method which has recently become available, the OxyLite system.

Proper Patient and Treatment Parameters Selection for Electrochemotherapy of Deep Seated Head and Neck Tumors

Treatment with electrochemotherapy is by far used for treatment of cutaneous cancers. Its potential for treating deep-seated head and neck lesions, but also those in other areas of the body is yet to be fully understood and appreciated. Emphasizing the importance of proper patient and treatment parameters selection, their education about the possible drawbacks of treatment and, last but not least, outcomes are of utmost importance. We present two patients, both with squamous cell carcinomas of head and neck, but with very different outcomes.