A computational study of the relation between the power density in the tumor and the maximum temperature in the scalp during Tumor Treating Fields (TTFields) therapy.

In this work we investigated the relation between the power density in the tumor and the maximum temperature reached in the scalp during TTFields treatment for glioblastoma. We used a realistic head model to perform the simulations in COMSOL Multiphysics and we solved Pennes' equation to obtain the temperature distribution. Our results indicate that there might be a linear relation between these two quantities and that TTFields are safe from a thermal point of view.

Microbial growth inhibition by alternating electric fields in mice with Pseudomonas aeruginosa lung infection.

High-frequency, low-intensity electric fields generated by insulated electrodes have previously been shown to inhibit bacterial growth in vitro. In the present study, we tested the effect of these antimicrobial fields (AMFields) on the development of lung infection caused by Pseudomonas aeruginosa in mice. We demonstrate that AMFields (10 MHz) significantly inhibit bacterial growth in vivo, both as a stand-alone treatment and in combination with ceftazidime. In addition, we show that peripheral (skin) heating of about 2 degrees C can contribute to bacterial growth inhibition in the lungs of mice. We suggest that the combination of alternating electric fields, together with the heat produced during their application, may serve as a novel antibacterial treatment modality.

Microbial growth inhibition by alternating electric fields.

Weak electric currents generated using conductive electrodes have been shown to increase the efficacy of antibiotics against bacterial biofilms, a phenomenon termed "the bioelectric effect." The purposes of the present study were (i) to find out whether insulated electrodes that generate electric fields without "ohmic" electric currents, and thus are not associated with the formation of metal ions and free radicals, can inhibit the growth of planktonic bacteria and (ii) to define the parameters that are most effective against bacterial growth. The results obtained indicate that electric fields generated using insulated electrodes can inhibit the growth of planktonic Staphylococcus aureus and Pseudomonas aeruginosa and that the effect is amplitude and frequency dependent, with a maximum at 10 MHz. The combined effect of the electric field and chloramphenicol was found to be additive. Several possible mechanisms underlying the observed effect, as well as its potential clinical uses, are discussed.

Disruption of cancer cell replication by alternating electric fields.

Low-intensity, intermediate-frequency (100-300 kHz), alternating electric fields, delivered by means of insulated electrodes, were found to have a profound inhibitory effect on the growth rate of a variety of human and rodent tumor cell lines (Patricia C, U-118, U-87, H-1299, MDA231, PC3, B16F1, F-98, C-6, RG2, and CT-26) and malignant tumors in animals. This effect, shown to be nonthermal, selectively affects dividing cells while quiescent cells are left intact. These fields act in two modes: arrest of cell proliferation and destruction of cells while undergoing division. Both effects are demonstrated when such fields are applied for 24 h to cells undergoing mitosis that is oriented roughly along the field direction. The first mode of action is manifested by interference with the proper formation of the mitotic spindle, whereas the second results in rapid disintegration of the dividing cells. Both effects, which are frequency dependent, are consistent with the computed directional forces exerted by these specific fields on charges and dipoles within the dividing cells. In vivo treatment of tumors in C57BL/6 and BALB/c mice (B16F1 and CT-26 syngeneic tumor models, respectively), resulted in significant slowing of tumor growth and extensive destruction of tumor cells within 3-6 days. These findings demonstrate the potential applicability of the described electric fields as a novel therapeutic modality for malignant tumors.

Using computational phantoms to improve delivery of Tumor Treating Fields (TTFields) to patients.

This paper reviews the state-of-the-art in simulation-based studies of Tumor Treating Fields (TTFields) and highlights major aspects of TTFields in which simulation-based studies could affect clinical outcomes. A major challenge is how to simulate multiple scenarios rapidly for TTFields delivery. Overcoming this challenge will enable a better understanding of how TTFields distribution is correlated with disease progression, leading to better transducer array designs and field optimization procedures, ultimately improving patient outcomes.

Reflectance pulse oximetry from core body in neonates and infants: comparison to arterial blood oxygen saturation and to transmission pulse oximetry.

OBJECTIVE: To compare pulse oximetry oxygen saturation (SpO(2)) measured by a novel reflectance method from core body to arterial oxygen saturation (SaO(2)) in neonates and infants. Transmission pulse oximetry (TPO) was measured for comparison. STUDY DESIGN: We monitored 18 infants by the two pulse oximeters simultaneously. The reflectance pulse oximetry (RPO) (PRO2, ConMed, Utica, NY) was measured on the upper back or chest, while the TPO (N395-Nellcor, Pleasanton, CA) was measured from the finger of the infant on the left hand or feet. Data from the two methods were compared to functional SaO(2) derived from blood sample drawn from arterial line for patient care and measured by a Co-oximeter (Ilex, Instrument Lab. Lexington, MA). The potential advantage of the RPO is demonstrated in a case of a premature infant with hypovolemic shock, where SaO(2) or TPO could not be obtained but oximetry was available from the RPO. RESULTS: We used for analysis 56 RPO and 32 TPO measurements. SpO(2) obtained from the RPO was 88.3+/-9.8%, from the TPO 84.2+/-10.1%, and functional SaO(2) was 88.2+/-11.7%, with correlation coefficient of 0.93 and 0.88, respectively (p<0.0001). The mean difference (bias) and standard deviation of the differences (precision) between the RPO and the TPO compared to functional SaO(2) were -0.09+/-4.5% and 1.26+/-5.9% and the absolute errors were 3.2+/-3.1%, and 4.4+/-4.0%, respectively. The accuracy of both RPO and TPO was diminished when SaO(2) was <85%, but only the RPO remained correlated with the functional SaO(2). CONCLUSIONS: Reflectance pulse oximetry measured from core body of neonates and infants is accurate and reliable and is comparable to the transmission SpO(2) when compared to functional SaO(2). We speculate that the reflectance method might be advantageous in cases of poor peripheral perfusion in neonates and infants.

Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs.

Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100-200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors.

Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields).

BACKGROUND: The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial. METHODS: Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients. RESULTS: The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.

We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro. Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines [human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299)] and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.

Multi-wavelength reflectance pulse oximetry.

The performance of current reflectance pulse oximeters is hindered by poor signal-to-noise ratio. To overcome this problem a new reflectance oximeter has been developed with a sensor which consists of three LEDs and two continuous photodetector rings placed equidistant from the center of the LEDs. In addition, ultra low noise electronics and adaptive algorithm assure improved performance. A validation study was performed on 10 healthy volunteers. Sensors were placed on several sites and measurements were compared to reference arterial blood samples. During the study progressive hypoxemia was induced by lowering the inspired oxygen concentration (FiO2) to 10%, followed by a recovery phase. Twelve blood samples were taken during each cycle, yielding a total of 120 measured data points. Data from randomly selected 5 subjects was used for calibration and subsequently tested on the other 5 subjects. Results proved to be well within clinically acceptable boundaries for all 3 sampling sites with high correlation (R2 > 0.9) and SD around 2%. In conclusion, a new 3 wavelength reflectance pulse oximeter with unique sensor geometry and improved algorithms provides enhanced performance and is less susceptible to poor signal to noise conditions when compared to existing reflectance oximetry systems.