A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer.

BACKGROUND: 5-fluorouracil (5-FU) combined with a folate remains an essential treatment component for metastatic colorectal cancer (mCRC). Leucovorin is the folate most often used, but requires intracellular conversion to a reduced folate, and has high pharmacokinetic variability and limited bioavailability in patients with low folate pathway gene expression. Arfolitixorin is an immediately active form of folate, [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF), and may improve outcomes. PATIENTS AND METHODS: This open-label, multicenter, phase I/II study in patients with mCRC (NCT02244632) assessed the tolerability and efficacy of first- or second-line arfolitixorin (30, 60, 120, or 240 mg/m2 intravenous) with 5-FU alone, or in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan, every 14 days. Safety, efficacy, and pharmacokinetics were assessed before and after four cycles (8 weeks) of treatment. RESULTS: In 105 treated patients, investigators reported 583 adverse events (AEs) in 86 patients (81.9%), and 256 AEs (43.9%) were potentially related to arfolitixorin and 5-FU. Dose adjustments were required in 16 patients (15.2%). At 8 weeks, 9 out of 57 patients assessed for efficacy achieved an objective response (15.8%), and all 9 achieved a partial response. Six of these nine patients had received arfolitixorin as a first-line treatment. A further 33 patients (57.9%) achieved stable disease. Pharmacokinetics were assessed in 35 patients. The average tmax was 10 min, and area under the plasma concentration-time curve from time 0 to 1 h increased linearly between 30 and 240 mg/m2. No accumulation was observed for [6R]-MTHF following repeated administration, and there were no major pharmacokinetic differences between cycle 1 and cycle 4 at any dose. CONCLUSIONS: Arfolitixorin is a well-tolerated moderator of 5-FU activity. It is suitable for further investigation in mCRC and has the potential to improve treatment outcomes in patients with low folate pathway gene expression. Arfolitixorin can easily be incorporated into current standard of care, requiring minimal changes to chemotherapy regimens.

IEEE Committee on Man and Radiation-COMAR Technical Information Statement: Health and Safety Issues Concerning Exposure of the General Public to Electromagnetic Energy from 5G Wireless Communications Networks.

This COMAR Technical Information Statement (TIS) addresses health and safety issues concerning exposure of the general public to radiofrequency (RF) fields from 5G wireless communications networks, the expansion of which started on a large scale in 2018 to 2019. 5G technology can transmit much greater amounts of data at much higher speeds for a vastly expanded array of applications compared with preceding 2-4G systems; this is due, in part, to using the greater bandwidth available at much higher frequencies than those used by most existing networks. Although the 5G engineering standard may be deployed for operating networks currently using frequencies extending from 100s to 1,000s of MHz, it can also operate in the 10s of GHz where the wavelengths are 10 mm or less, the so-called millimeter wave (MMW) band. Until now, such fields were found in a limited number of applications (e.g., airport scanners, automotive collision avoidance systems, perimeter surveillance radar), but the rapid expansion of 5G will produce a more ubiquitous presence of MMW in the environment. While some 5G signals will originate from small antennas placed on existing base stations, most will be deployed with some key differences relative to typical transmissions from 2-4G base stations. Because MMW do not penetrate foliage and building materials as well as signals at lower frequencies, the networks will require "densification," the installation of many lower power transmitters (often called "small cells" located mainly on buildings and utility poles) to provide for effective indoor coverage. Also, "beamforming" antennas on some 5G systems will transmit one or more signals directed to individual users as they move about, thus limiting exposures to non-users. In this paper, COMAR notes the following perspectives to address concerns expressed about possible health effects of RF field exposure from 5G technology. First, unlike lower frequency fields, MMW do not penetrate beyond the outer skin layers and thus do not expose inner tissues to MMW. Second, current research indicates that overall levels of exposure to RF are unlikely to be significantly altered by 5G, and exposure will continue to originate mostly from the "uplink" signals from one's own device (as they do now). Third, exposure levels in publicly accessible spaces will remain well below exposure limits established by international guideline and standard setting organizations, including ICNIRP and IEEE. Finally, so long as exposures remain below established guidelines, the research results to date do not support a determination that adverse health effects are associated with RF exposures, including those from 5G systems. While it is acknowledged that the scientific literature on MMW biological effect research is more limited than that for lower frequencies, we also note that it is of mixed quality and stress that future research should use appropriate precautions to enhance validity. The authorship of this paper includes a physician/biologist, epidemiologist, engineers, and physical scientists working voluntarily and collaboratively on a consensus basis.

Electromagnetic Fields Associated with Commercial Solar Photovoltaic Electric Power Generating Facilities.

The southwest region of the United States is expected to experience an expansion of commercial solar photovoltaic generation facilities over the next 25 years. A solar facility converts direct current generated by the solar panels to three-phase 60-Hz power that is fed to the grid. This conversion involves sequential processing of the direct current through an inverter that produces low-voltage three-phase power, which is stepped up to distribution voltage (∼12 kV) through a transformer. This study characterized magnetic and electric fields between the frequencies of 0 Hz and 3 GHz at two facilities operated by the Southern California Edison Company in Porterville, CA and San Bernardino, CA. Static magnetic fields were very small compared to exposure limits established by IEEE and ICNIRP. The highest 60-Hz magnetic fields were measured adjacent to transformers and inverters, and radiofrequency fields from 5-100 kHz were associated with the inverters. The fields measured complied in every case with IEEE controlled and ICNIRP occupational exposure limits. In all cases, electric fields were negligible compared to IEEE and ICNIRP limits across the spectrum measured and when compared to the FCC limits (≥0.3 MHz).

Very-low-frequency and low-frequency electric and magnetic fields associated with electric shuttle bus wireless charging.

Tests conducted to date at the University of Tennessee at Chattanooga (UTC) indicate that wireless charging of the Chattanooga Area Regional Transportation Authority's (CARTA) downtown shuttle bus, currently operating with off-board battery charging technology, offers significant improvements in performance and cost. The system operates at a frequency of 20 kHz and a peak power of 60 kW. Because the system's wireless charging is expected to occur during a nominal 3-min charging period with passengers on-board, the magnetic and electric fields associated with charging were characterised at UTC's Advanced Vehicle Test Facility and compared with established human exposure limits. The two most prominent exposure limits are those published by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) and the Institute for Electrical and Electronic Engineers (IEEE). Both organisations include limits for groups who are trained (workers in specific industries) to be aware of electromagnetic environments and their potential hazards, as well as a lower set of limits for the general public, who are assumed to lack such awareness. None of the magnetic or electric fields measured either within or outside the bus during charging exceeded either the ICNIRP or the IEEE exposure limits for the general public.

Radiofrequency contact currents: sensory responses and dosimetry.

The process of setting science-based exposure standards (or guidelines) for radiofrequency (RF) contact current exposure has been disadvantaged by a lack of relevant data. The authors first review the essential features and results of the available studies and illustrate the apparent discrepancies among them. Then, they examine the manner in which current was administered in these studies and suggest as to how the physical relationship of a contacting finger to the current electrode may play a role in affecting sensory thresholds specific to those configurations. A major factor in this analysis relates to whether current density is uniformly distributed across the contact area or whether an electrode's 'edge effects' enhance currents with a net effect of decreasing apparent thresholds, when expressed as the bulk current entering a subject. For an exposure with a clear hazard potential, thresholds of human sensory response to RF currents require further investigation.

ELF magnetic fields in electric and gasoline-powered vehicles.

We conducted a pilot study to assess magnetic field levels in electric compared to gasoline-powered vehicles, and established a methodology that would provide valid data for further assessments. The sample consisted of 14 vehicles, all manufactured between January 2000 and April 2009; 6 were gasoline-powered vehicles and 8 were electric vehicles of various types. Of the eight models available, three were represented by a gasoline-powered vehicle and at least one electric vehicle, enabling intra-model comparisons. Vehicles were driven over a 16.3 km test route. Each vehicle was equipped with six EMDEX Lite broadband meters with a 40-1,000 Hz bandwidth programmed to sample every 4 s. Standard statistical testing was based on the fact that the autocorrelation statistic damped quickly with time. For seven electric cars, the geometric mean (GM) of all measurements (N = 18,318) was 0.095 µT with a geometric standard deviation (GSD) of 2.66, compared to 0.051 µT (N = 9,301; GSD = 2.11) for four gasoline-powered cars (P < 0.0001). Using the data from a previous exposure assessment of residential exposure in eight geographic regions in the United States as a basis for comparison (N = 218), the broadband magnetic fields in electric vehicles covered the same range as personal exposure levels recorded in that study. All fields measured in all vehicles were much less than the exposure limits published by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) and the Institute of Electrical and Electronics Engineers (IEEE). Future studies should include larger sample sizes representative of a greater cross-section of electric-type vehicles.

Radiofrequency fields associated with the Itron smart meter.

This study examined radiofrequency (RF) emissions from smart electric power meters deployed in two service territories in California for the purpose of evaluating potential human exposure. These meters included transmitters operating in a local area mesh network (RF LAN, ∼250 mW); a cell relay, which uses a wireless wide area network (WWAN, ∼1 W); and a transmitter serving a home area network (HAN, ∼70 mW). In all instances, RF fields were found to comply by a wide margin with the RF exposure limits established by the US Federal Communications Commission. The study included specialised measurement techniques and reported the spatial distribution of the fields near the meters and their duty cycles (typically <1 %) whose value is crucial to assessing time-averaged exposure levels. This study is the first to characterise smart meters as deployed. However, the results are restricted to a single manufacturer's emitters.

Differential splenic cytokine responses to dietary immune modulation by diverse chicken lines.

Nutritional modulation of the immune system is an often exploited but poorly characterized process. In chickens and other food production animals, dietary enhancement of the immune response is an attractive alternative to antimicrobial use. A yeast cell wall component, beta-1,3/1,6-glucan, augments the response to disease in poultry and other species; however, the mechanism of action is not clear. Ascorbic acid and corticosterone are better characterized immunomodulators. In chickens, the spleen acts both as reservoir and activation site for leukocytes and, therefore, splenic gene expression reflects systemic immune function. To determine effects of genetic line and dietary immunomodulators, chickens of outbred broiler and inbred Leghorn and Fayoumi lines were fed either a basal diet or an experimental diet containing beta-glucans, ascorbic acid, or corticosterone from 56 to 77 d of age. Spleens were harvested, mRNA was isolated, and expression of interleukin (IL)-4, IL-6, IL-18, macrophage inflammatory protein-1beta, interferon-gamma, and phosphoinositide 3-kinase p110gamma transcripts was measured by quantitative reverse transcription PCR. Effects of diet, genetic line, sex, and diet x genetic line interaction on weight gain and gene expression were analyzed. At 1, 2, and 3 wk after starting the diet treatments, birds fed the corticosterone diet had gained less weight compared with birds fed the other diets (P < 0.001). Sex affected expression of IL-18 (P = 0.010), with higher levels in males. There was a significant interaction between genetic line and diet on expression of IL-4, IL-6, and IL-18 (P = 0.021, 0.006, and 0.026, respectively). Broiler line gene expression did not change in response to the experimental diet. Splenic expression of IL-6 was higher in Leghorns fed the basal or ascorbic acid diets, rather than the beta-glucan or corticosterone diets, whereas the opposite relationship was observed in the Fayoumi line. Expression of IL-4 and IL-18 responded to diet only within the Fayoumi line. The differential splenic expression of birds from diverse genetic lines in response to nutritional immunomodulation emphasizes the need for further study of this process.

Magnetic fields from steel-belted radial tires: implications for epidemiologic studies.

Magnetic fields emanate from radial tires due to the presence of reinforcing belts which are made of magnetized steel wire. When these tires spin, they generate alternating magnetic fields of extremely low frequency (ELF), usually below 20 Hz. The fundamental frequency of these fields is determined by tire rotation rate and has a sinusoidal waveform with a high harmonic content. The static field of radial tires can exceed 500 microT at the tread, and the tire-generated alternating fields can exceed 2.0 microT at seat level in the passenger compartment of vehicles. Degaussing the tires reduces both the static and alternating fields to low levels, but the fields increase gradually over time after degaussing. The tire-generated fields are below the frequencies detected by most of the magnetic field meters used in previous studies of power frequency magnetic field health effects. If these fields are biologically active, failure to detect them could compromise exposure assessments associated with epidemiologic studies.

Comparison between radiation-induced cell cycle delay in lymphocytes and radiotherapy response in head and neck cancer.

A study was made evaluating the use of radiation-induced cell cycle delay in lymphocytes to predict tumour response to radiotherapy. Peripheral blood lymphocytes were isolated from whole blood from 49 patients with head and neck cancer before treatment with radiotherapy and from 25 healthy donors. The clinical response to radiotherapy was assessed at 0-2 months after treatment. The level of radiation-induced cell cycle delay was measured using flow cytometry after mitogen stimulation of lymphocytes. The analysis of ten normal donors gave no significant difference in variability between the intra-assay and the intra-donor samples. However, the cell cycle data for lymphocytes from these healthy donors showed significant inter-individual differences in G2 phase accumulation. Patients showing no response to radiotherapy had a high level of S-phase cells compared with partial (P < 0.001) and complete responders (P = 0.016). An inverse relationship was found when analysing the fraction of cells in G2 (P = 0.009 and 0.034 respectively). In general, healthy donors had similar cell cycle kinetics compared with the non-responders. In conclusion, the result indicates that radiation-induced cell cycle delay in lymphocytes is inversely correlated with tumour response to radiotherapy in head and neck cancer patients. However, the value of the present test for predicting individual tumour response is limited, because of assay variability and overlap between groups.

Hypothyroidism after external radiotherapy for head and neck cancer.

PURPOSE: To study the development of thyroid hypofunction in patients with head and neck cancers admitted for external radiotherapy. METHODS AND MATERIALS: Between November 1990 and July 1996, thyroid function was measured in 264 consecutive patients, where the entire thyroid gland or part of it was included in the target volume. The time to development of hypothyroidism (HT) was calculated from the start of the radiotherapy. RESULTS: The median follow-up period was 19 months. Seventeen patients (6%) developed elevated serum thyroid-stimulating hormone levels with depressed (free) thyroxine levels (i.e., clinical HT). Elevated serum thyroid-stimulating hormone level with normal (free) thyroxine levels (i.e., chemical HT) developed in 57 (22%). The median time to clinical HT was 15 months (range: 7 to 32). The median time to chemical HT was also 15 months (range: 2 to 28). The actuarial risk of developing clinical or chemical HT 3 years after treatment was 15 and 40%, respectively. The incidence of chemical HT was significantly higher (p = 0.041) when the whole thyroid was included in the target volume compared to patients where only part of the thyroid was irradiated. The same trend was seen as regards clinical HT (p = 0.063). For those 20 patients who underwent laryngectomy, there was an increased risk of both chemical and clinical HT (p = 0.011 and 0.019, respectively). Increasing age was associated with an increased risk of chemical HT (p = 0.001), but not of clinical HT (p = 0.553). Sex, tumor site, radiation dose, and combination of radiotherapy and chemotherapy were not significant factors for thyroid hypofunction. CONCLUSION: Depressed thyroid function is common after external radiotherapy for cancers of the head and neck. Routine testing for possible thyroid hypofunction should be included in the follow-up procedures, even many years after end of radiotherapy.

VDTs: field levels, epidemiology, and laboratory studies.

As the use of video display terminals (VDTs) has expanded, questions have been raised as to whether working at a VDT affects the risk of adverse pregnancy outcome. A particular focus for these questions has been the very low frequency (VLF) magnetic field produced by a VDT's horizontal deflection coil. VDTs also produce VLF electric fields, extremely low frequency (ELF) electric and magnetic fields, and static electric fields, Ten studies of pregnancy outcome in VDT operators have been conducted in six countries, and with one exception, none has concluded that magnetic fields from VDTs may predispose pregnant operators to spontaneous abortion or congenital malformation. The epidemiologic studies conducted thus far do not provide a basis for concluding that VDT work and adverse pregnancy outcome are associated. Studies of fetal resorptions and malformations in rodents exposed to VLF magnetic fields have produced inconsistent findings. Two laboratories in Sweden that studied mice have reported positive results, one laboratory showing field-related malformations (but not resorptions) and the other showing field-related resorptions (but not malformations). Two Canadian laboratories have reported negative results in rats and mice. Studies of avian embryos have also yielded inconsistent results, but lacking a maternal-fetal placental interface, avian embryos are a questionable model for evaluating human reproductive risks. Finally, VLF electric and magnetic fields measured at the operator position are in compliance with field strength standards and guidelines that have been established around the world.

Long-term cytotoxicity of orthodontic direct-bonding adhesives.

The purpose of this study was to examine the potential toxic effects of several orthodontic adhesives immediately after polymerization and at various time intervals up to 2 years postopolymerization by means of an in vitro overlay assay. Adhesive samples were incubated on tissue cultures containing an agar overlay with a vital dye (neutral red). Viable cells were stained red; nonviable cells were unstained. The circular pattern of nonviable cells demonstrated a zone of inhibition that was measured and compared. All materials tested showed cytotoxic effects immediately after polymerization and the toxic effect decreased with time postpolymerization. However, 2 years after initial polymerization, significant zones of inhibition indicating continued in vitro toxicity were still evident in all but one of the adhesives.

Optical fiber communication experiment at 5 Gbit/sec.

A Gbit/sec optical fiber communication experiment was performed. The maximum speed was 3 Gbit/sec with a BH laser and 5 Gbits/sec with a TJS laser. A 500-m single-mode fiber was used, and the power was coupled by mounting the laser butt-end to the fiber, giving a minimum loss of 10 dB. The receiver employed a Si-avalanche photodiode with an impulse-response width of 210 psec (FWHM) and a 10-Gbit/sec and gate built from GaAs MESFETs. Bit-error-rate measurement values of <10(-9) prove the feasibility of optical fiber transmission at 5 Gbit/sec.

A review of selected biological effects and dosimetric data useful for development of radiofrequency safety standards for human exposure.

This report examines the bases for developing radiofrequency exposure standards which can be related to the thermogenic properties of electromagnetic fields. A review of selected biological effects, including dosimetric data and simulation of human thermodyanmic characteristics that are pertinent to standards development, is presented. Based on the analogy of thermal-stress standards that have been developed for hot industrial environments, limits on increases of body temperature are proposed as criteria for limiting exposure to radiofrequency fields, i.e., occupational exposures involving deep heating of the whole body should not increase core temperature in excess of 1 degree C. Since energy deposition from exposure to some RF fields is likely to be non-uniform and may be high in tissues that are not adapted to high rates of absorption or dissipation of thermalizing energy, means are needed to adjust focal thermal loading against the whole-body averages. A limit on core temperature is inadequate when focal elevations of temperature are close to the limits for protein denaturation, as may well occur even though the core temperature may rise less than 1 degree C. Safety limits for the general population are also discussed and here the permissible thermal load should be low enough to cause no more than an insignificant increase in core temperature. Areas needing further research to reduce the uncertainties in developing safe exposure limits for man are delineated. Even in highly adverse environmental conditions the gross thermal load and consequential heat stress from exposure to radiofrequency fields at the 10 mW/cm2 level will be small compared with that generated by any physical effort. On the basis of available data, it is concluded that the safe value for continuous exposure to 10 mW/cm2, widely used in Western countries, appears to provide an adequate margin of safety for both occupational and environmental exposure for frequencies above about 1 GHz. This limit may well be too high (perhaps by an order of magnitude) for some frequencies below 1 GHz where body resonances cause a significant increase in energy deposition and where local temperature rises occur. At the same time the present averaging period of 0.1 h seems unjustifiably short.