Charge and membrane potential

In brief

What membrane potential actually is

A living cell keeps different salt concentrations inside and outside itself. Potassium is concentrated inside, sodium outside, and the membrane lets some ions through and not others at any given moment. Because the ions carry charge, that imbalance shows up as a voltage across the membrane, with the inside negative relative to the outside. This is the resting membrane potential, and it is the reason a cell can be described as electrically charged without any mysticism being involved ^1,2.

The gradients are not free. They are held up by a pump in the membrane that spends the cell's chemical fuel, adenosine triphosphate, to push sodium out and bring potassium in. Jens Skou found the responsible enzyme in crab nerve and published it in 1957 under the deliberately cautious title "The influence of some cations on an adenosine triphosphatase from peripheral nerves" ³; in his Nobel lecture he explained that the word pump was left out of that title because it was thought too provocative ⁴. In the same year Post and Jolly reported that sodium, potassium and ammonium transport across the human red cell membrane were linked to one another ⁵.

The voltage is not the same in every cell, and the textbook figure of about -70 mV is a round number rather than a constant of nature. In one type of neuron (Type I) in the bed nucleus of the stria terminalis, a small region deep in the mouse forebrain, the resting value was about -70 mV in young animals and about -80 mV in aged ones ⁶. In a series of mouse hippocampal pyramidal neurons the resting value was -54.6 plus or minus 2.3 mV, and an anesthetic shifted it to -58.7 plus or minus 2.1 mV ⁷. Malaria parasites freed from their red cells and measured with a radiolabeled probe sat at -95 plus or minus 2 mV ³⁴. Any sentence that gives one number for all cells is simplifying.

Two more distinctions matter before anything else in this page makes sense. Depolarization means the voltage moving toward zero, so the inside becomes less negative; hyperpolarization means it moving further from zero, more negative. And membrane potential is not surface charge. Surface charge, usually reported as zeta potential, is the electrical charge sitting on the outside face of the cell, measured by watching the cell drift in a field; it is a different quantity, with different causes, and confusing the two is the single commonest error in popular writing about this subject ^27,28. A 2025 study characterized both on the same cells, HeLa cervical cancer cells against primary cervical epithelial cells from patients, measuring zeta potential directly and deriving membrane potential from dielectrophoresis alongside membrane capacitance, conductance and cytoplasm conductivity, and called the five-property combination an electrome ³⁵; putting them side by side is the only way to keep the two quantities apart.

The whole history, including the reversals

The electrical story of cells was settled in nerve before anyone applied it to cancer. Hodgkin and Huxley's 1952 paper gave a quantitative description of membrane current and used it to explain conduction and excitation in nerve ¹; Skou's 1957 enzyme gave the pump that holds the gradients up ^3,4; and in 1976 Neher and Sakmann recorded single channel currents from denervated frog muscle, so the doors themselves could be watched opening ³⁶. From that point the physics was not in doubt. What was in doubt was whether any of it mattered to tissues that do not fire.

Clarence Cone made the leap in the early 1970s, in a series of papers in Oncology and the Journal of Theoretical Biology arguing that the transmembrane potential level is a basic mechanism of mitosis control and, in a 1971 paper, offering a unified theory of normal mitotic control and oncogenesis ^43,44,45. With Tongier he showed that simulating a change in the potential level changed whether cultured cells divided ⁴⁶. In 1976 he and C M Cone published the most striking result of the program in Science: fully differentiated central nervous system neurons, which do not normally divide, began synthesizing DNA and went through nuclear mitosis after sustained depolarization with agents that raised internal sodium and lowered potassium, mostly ending as binucleate cells because division of the cell body did not complete ⁴⁷. Cone summarized the program in a 1974 review on the role of the surface electrical transmembrane potential in normal and malignant mitogenesis ⁴⁸, and in 1978 he and C M Cone reported evidence of normal mitosis with complete cytokinesis in central nervous system neurons under sustained depolarization with ouabain ⁴⁹, which tempers the 1976 finding that most cells ended binucleate. None of the early papers carries an abstract in PubMed, so the detail has to be read in the originals ^{43,44,45,46,48,49}.

The measurement that people usually mean when they say cancer cells are depolarized came in 1985, from Binggeli and Weinstein, who recorded intracellularly with high-impedance micropipettes from normal and malignant quail and rat cell pairs. In high-density cultures the cancer cells sat at -20.7 mV against -40.1 mV for normal quail cells and -30.7 against -61.9 mV for the rat pair, and the key observation was dynamic: normal cells held a low potential through several divisions and then suddenly jumped to a high value, while cancer cells never made that jump at any density ⁸. The following year the same authors turned it into a hypothesis about a threshold potential separating resting from proliferating cells, with sodium channels and gap junctions, the direct channels that join neighboring cells, as the machinery ⁵⁰.

After that the field split into three streams that are still running, and each has had its reversals. The channel stream produced genuine oncology targets and one spectacular correction. The device stream produced a negative pivotal trial, a post hoc rescue, positive pivotal trials in three organs, a second negative pivotal trial, and a 2026 argument that the whole evidence base has a hole in it ^{20,21,22,23,33}. And the frog stream, Michael Levin's, produced the only experiments in which changing the voltage changed the tumor outcome ^9,10,13.

What the voltage does inside a cell

The reason a standing voltage can matter to growth is that several things a cell needs to do are themselves voltage-sensitive. Channels open and close with voltage. Transporters that carry nutrients in alongside ions run faster or slower with it. And charged lipids in the membrane itself move. The clearest demonstration of the last is a 2015 paper in Science: depolarizing the plasma membrane reorganized phosphatidylserine and one phosphoinositide at the nanometer scale, which made K-Ras, a growth-switch protein mutated in many cancers, cluster more tightly and amplified mitogen-activated protein kinase (MAPK) signaling, a relay of enzymes that carries growth signals to the nucleus, in fibroblasts, in neuroblastoma cells and in fly neurons in a living animal; repolarizing broke the clusters and inhibited the signaling ³⁷. The authors describe the membrane as acting like a field-effect transistor, with voltage setting the gain on a growth circuit.

In the frog work, the downstream route was different and just as concrete. Hyperpolarizing cells that carried human oncogenes returned their voltage to normal and significantly reduced the number of tumor-like structures, and the effect was transduced through a voltage-regulated sodium-butyrate exchanger named SLC5A8, implicating butyrate, a histone deacetylase inhibitor, meaning a chemical that changes how tightly DNA is packed and so which genes are read, in the suppression ⁹. Depolarized voltage also marked precursor sites before any lesion was visible, which is why the authors call it a diagnostic as well as a control ⁹. A companion paper reported that oncogene-induced tumors in the same model had aberrantly high sodium content, and that susceptibility was reduced not only by forcing hyperpolarizing channels but by a drug acting on the animal's own chloride channels, which is the first hint that this could ever be pharmacology rather than gene therapy ¹⁰.

Reviews place these findings in a general rule for non-excitable cells: hyperpolarized, more negative voltages go with settled, differentiated cells and depolarized ones with dividing cells, with voltage controlling mitotic activity and cell cycle progression in many systems ^2,32. The honest version of the rule includes its limits. The review most often cited for the cancer claim states that electrophysiological analyses in many cancer cell types show a depolarized voltage that favors proliferation, while describing the data on a role in migration as only emerging ¹². And the 2021 synthesis frames the whole subject as tissue-level patterns of voltage processing morphogenetic information, not as a single number per cell ¹³.

There is one more route that deserves its own name, because it is the most physiologically solid electrical story in cancer and it is less than a decade old: the first direct demonstrations of synapses onto glioma cells were published in 2019 ^57,58. High-grade gliomas integrate into neural circuits. They form genuine synapses with neurons, driven by AMPA-type glutamate receptors, and they also receive non-synaptic potassium currents amplified through gap junctions into an electrically coupled network; depolarizing the tumor membranes in a living mouse promoted proliferation, and blocking the signaling slowed tumors and lengthened survival ⁵⁷. The parallel paper showed the same synapses by electron microscopy, located on the thin tubes that connect tumor cells, and found that genetic disruption of AMPA receptors in the tumor cells reduced invasiveness and growth, while the antiepileptic AMPA receptor antagonist perampanel reduced tumor growth and anesthesia reduced invasion ⁵⁸. In people, the degree of functional connectivity between a glioblastoma and the rest of the brain predicted both worse survival and worse performance on language tasks ⁶⁷. Since then the wiring story has widened. Human glioblastoma organoids transplanted into mice integrate into local and long-range circuits across the brain, receiving neuromodulatory as well as glutamate inputs, including cholinergic synapses from the basal forebrain that make the cells more motile ⁶⁸; in 2025 two papers in Nature showed that small cell lung cancer, a tumor outside the nervous system, forms genuine synapses with neurons and grows faster with neuronal activity, with cutting the vagus nerve slowing primary lung tumors ^69,70; a brain-wide connectivity map of childhood diffuse midline glioma predicted survival in two independent cohorts ⁷¹; and a 2026 study found longer survival in children with diffuse midline glioma taking the antiseizure drug levetiracetam, which in models acts on GABAergic synapses onto the tumor cells rather than through its antiseizure target ⁷². That last finding is worth setting beside the perampanel pilot that found no difference from levetiracetam ⁷³, since the comparator may itself have been active. A 2026 review in Cell surveys the whole field, now called cancer neuroscience ⁷⁴.

Ion channels as cancer targets, and the corrections

If voltage matters, the proteins that set it should matter too, and the search for cancer-relevant ion channels is now a large field with its own vocabulary: a 2018 review in Physiological Reviews proposes calling the hallmarks of cancer oncochannelopathies, on the argument that uncontrolled proliferation, resistance to cell death, invasion and angiogenesis all depend in part on channel function ⁷⁵. That is a framework, not a finding, and the honest assessment has to be done channel by channel. A 2024 systematic review from Levin's group cataloged 109 drugs that act on ion channels, pumps or gap junctions and have reported effects on the cancer phenotype, many of them nervous-system drugs already on the market, and proposed them for repurposing; it is a catalog of preclinical effects, not of trials ⁷⁶.

The founding example is ether-a-go-go, also called Eag1, Kv10.1 or by its gene name KCNH1. Transfecting it into mammalian cells conferred a transformed phenotype, and the transfected cells favored tumor progression in immune-depressed mice ⁵⁴. In human tissue, purpose-made antibodies and quantitative PCR found expression limited in normal tissue to specific brain areas and restricted cell populations, but overexpressed in tumors at high frequency, up to 80% depending on the tissue source, with proliferation reduced when expression was inhibited in tumor lines ⁷⁷. In cervical samples the protein appeared in 67% of low-grade and 92% of high-grade intraepithelial lesion cytologies against 27% of normal samples, a graded pattern that makes a marker credible ⁷⁸. The same paper found the protein in almost half of normal women taking estrogens, which is exactly the specificity problem that sinks screening markers ⁷⁸.

Then came the correction. Heterozygous missense mutations in KCNH1 cause Zimmermann-Laband syndrome, a developmental disorder with gum overgrowth, intellectual disability, underdeveloped nails and terminal finger bones, and excess hair; patch-clamp recordings supported gain of function for the syndrome mutants ⁵⁶. Inheriting an overactive version of the canonical oncochannel does not give you cancer. It changes how a body is built. Separately, a 2014 paper extending the channel to liposarcoma is listed in PubMed as a retracted publication, so its numbers are not evidence ⁵⁵.

Sodium channels have held up better as markers of invasion. A neonatal splice form of Nav1.5 was upregulated in metastatic human breast cancer cells and tissues, its activity potentiated directional motility, endocytosis and invasion in vitro, and expression correlated with clinically assessed lymph node metastasis ⁷⁹. In colon cancer, blocking the same channel pharmacologically or by RNA interference reduced invasive potential, patient biopsies stained strongly for the protein with little or none in matched normal colon, and probabilistic modeling placed the gene at the top of an invasion network whose predicted downstream members, when knocked down, also reduced invasion ⁸⁰. Potassium channels have been manipulated the other way: changing resting voltage in triple-negative breast cancer cells by altering potassium channel expression increased invasion in vitro and tumor growth and metastasis in mice, with cadherin-11 and MAPK signaling in the path, and the authors repurposed an approved potassium channel blocker against metastasis in that model ⁸¹.

The calcium side is the least settled. A review of transient receptor potential channels in breast cancer proposes TRPC1 and TRPM8 as markers of well-differentiated tumors, TRPM7 as a proliferative marker of poorly differentiated ones and TRPV6 as a marker of aggressive cancers, while noting that high TRPC3 goes with a favorable prognosis in lung adenocarcinoma ⁸². Channels point in different directions in different tissues, which is a reason to distrust any single story about charge and cancer.

The other charge: the outside of the cell

When people say cancer cells are negatively charged they usually mean the outside, not the membrane voltage, and this is where the popular version is weakest. The outside of a cell is coated in sugars, many of them ending in sialic acid, a sugar that carries a negative charge; that coat is the glycocalyx. Tumors are often hypersialylated, and the consequence that has turned out to matter is immunological rather than electrostatic: dense tumor sialoglycans engage inhibitory Siglec receptors on immune cells, which behave like the checkpoints already targeted by antibodies, and the same trick is used by microorganisms ⁸⁷.

The coat also matters mechanically. A bulky glycocalyx on tumor cells funnels active integrins, the proteins a cell uses to grip its surroundings, into adhesions and applies tension to matrix-bound ones, promoting focal adhesion assembly and integrin-dependent growth factor signaling independent of the cell's own contractility; large glycoproteins were abundant on circulating tumor cells from patients with advanced disease ⁸⁸. So the coat does something real. What it does is not explained by net charge.

The surface-charge idea is older than the voltage idea. In 1956 James, Ambrose and Lowick reported in Nature that tumor cells carried a different electrical charge from their normal counterparts, measured by watching them drift in a field ⁵¹, and it is this measurement, not membrane voltage, that most popular claims about negatively charged cancer cells descend from. The electrophoretic evidence since is genuinely mixed, and the show should say so. In pigmented hamster melanoma, tumors contained two subpopulations with different mobilities, the difference was abolished by stripping sialic acid with neuraminidase, the faster and more negative fraction grew with tumor size and was remarkably elevated in metastatic nodules ⁸⁹. Against that, a 1985 study of Lewis lung tumor lines found higher total and surface sialic acid in the highly metastatic line and stated that despite the increase on the cell surface, the electrophoretic mobility of the cells was unchangeable ⁹⁰. More surface sialic acid does not automatically mean a more negative measured cell. In a 2024 study, exosomes, the tiny membrane-wrapped packets that cells shed, from a prostate carcinoma line were smaller, more numerous and more negative in zeta potential than those from a benign line, with more alpha-2,3 and alpha-2,6 sialylated glycans ⁹¹; that is one cell-line pair, not a diagnostic.

One surface change does have a drug attached to it, and the drug failed. Phosphatidylserine, normally kept on the inner face of the membrane, appears on the outside of tumor cells: three tumorigenic human lines expressed three to seven times more of it in the outer leaflet than normal keratinocytes, and loading normal cells with it made activated monocytes bind them ⁹². An antibody against that exposed lipid, bavituximab, went to a 597-patient randomized phase 3 trial with docetaxel in previously treated non-squamous lung cancer. Median overall survival was 10.5 versus 10.9 months, HR 1.06 (95% CI 0.88-1.29), p = 0.533, with no difference in progression-free survival ⁹³. A real surface difference, a rationally designed antibody, and a negative pivotal trial is the most useful single lesson on this page.

How it is found and measured

Resting voltage in a single cell is measured by putting a glass pipette on it or in it, which is how the matched cancer-versus-normal numbers were obtained and how single channels were first seen ^8,36. That method cannot be applied to a tumor in a patient, which is the practical reason the human version of the depolarization claim is still missing. Voltage-sensitive dyes are the workaround: one described pair reports resting rather than spiking voltage and can be used on whole embryos and cultures over long periods, with subcellular resolution and recordings lasting days, though the protocol does not address calibration to absolute millivolts ⁹⁴. High-throughput imaging with such reporters is what revealed that the voltage of breast cancer cells moves rather than sitting still ⁶¹.

At the tissue level the measurable proxy is sodium. A magnetic resonance scan tuned to the sodium nucleus gave absolute tissue sodium concentrations in 20 patients with malignant gliomas: 103 plus or minus 36 millimoles per kilogram wet weight in tumor against 68 plus or minus 11 in uninvolved contralateral tissue, with gray matter at 61 plus or minus 8 and white matter at 69 plus or minus 10, all differences from tumor at p < 0.002 ⁹⁵. In mouse breast tumors, sodium imaging distinguished tumor from non-tumor, the rise was traced to sodium inside cells rather than outside, two drugs blocking inward sodium conductance did not change it, and effective chemotherapy did reduce it ⁹⁶. Raised tissue sodium is therefore a real and treatment-responsive signal, and it is not the same measurement as membrane voltage. It is not universal either: in a 2026 prospective series of 46 men scanned for suspected prostate cancer, tissue sodium in the biopsy-proven cancers was lower than in the healthy contralateral gland, 32.2 plus or minus 5.5 against 36.1 plus or minus 3.9 millimoles per liter, p = 0.018 ⁹⁷, so tumors have more sodium is a finding about particular tumors rather than a law.

Two commercial attempts to read malignancy electrically are worth knowing in detail, because both show what happens when a physical difference is turned into a test. The first commercial attempt was a skin test. In 661 women scheduled for breast biopsy at eight European centers, sensors on the skin recorded surface electropotentials, and a depolarization index rose stepwise from non-proliferative benign lesions (median 0.398) through proliferative benign lesions (0.531) to cancer (0.644); at 90% sensitivity the specificity was 55% for palpable lesions ⁵³. The device never entered routine use, which is the lesson: a real electrical gradient can still make a poor test. Electrical impedance spectroscopy of pigmented skin lesions, in a blinded prospective study of 1951 patients and 1943 evaluable lesions including 265 melanomas, reached sensitivity 96.6% with a one-sided 95% lower bound of 94.2%, and specificity of 34.4% (95% CI 32.0-36.9), giving a positive predictive value of 21.1% and a negative predictive value of 98.2% ⁹⁸. It is a rule-out test, not a rule-in one. And the microwave contrast that motivated a generation of breast imaging work turns out to depend on what the tumor is compared with: against fatty tissue the contrast reached 10 to 1, but against normal glandular or fibroconnective tissue it was no more than about 10% ⁹⁹.

The other negative result in this section is about sorting rather than diagnosis. Dielectrophoresis, which moves cells with non-uniform fields, was measured across the whole NCI-60 panel, the US National Cancer Institute's standard set of 60 human cancer cell lines: capacitance varied with cell size and with how folded the membrane was, and the behavior reflected the surface area and volume the cells had at their growth sites, so the property being read is exterior morphology rather than a malignant electrical signature ¹⁰⁰. That is still useful, because morphology differs between circulating tumor cells and blood cells, but it is not what the marketing language implies.

• Intracellular microelectrode or patch clampA fine glass pipette either impales the cell or seals onto it, and reads the voltage directly; the sealed-pipette method also resolves single channels ^8,36.The reference method for resting voltage; it is how the matched cancer-versus-normal values were obtained ⁸Definitive for the cell it is on, to within a few millivolts ⁸One cell at a time, in culture or a slice. It cannot be done on an intact human tumor in a clinic, which is why the human version of the claim is still missing ¹²
• Voltage-sensitive fluorescent dyesDyes whose brightness tracks membrane voltage, read under a microscope, including a pair described for resting rather than spiking voltage in frog embryos and cultured cells in frog embryos and cultured cells ⁹⁴.To map voltage across whole tissues and over hours or days, and to screen many cells at once ^61,94The protocol lists advantages over electrodes, including subcellular resolution, whole-tissue monitoring in vivo and long recording periods; it does not address absolute calibration, which is left to the user ⁹⁴High-throughput imaging of breast cancer lines showed the voltage fluctuates in several patterns rather than holding one value, so a single snapshot can mislead ⁶¹
• Sodium MRIA magnetic resonance scan tuned to the sodium nucleus instead of hydrogen, giving tissue sodium concentration in millimoles per kilogram ⁹⁵.In 20 patients with malignant gliomas, tumor sodium averaged 103 plus or minus 36 against 68 plus or minus 11 in uninvolved contralateral tissue ⁹⁵Differences from gray matter, white matter, cerebrospinal fluid and contralateral brain all reached p < 0.002 ⁹⁵It measures total sodium, not voltage. In mouse breast tumors the raised signal came from sodium inside cells, and two inhibitors of sodium entry did not change it, while effective chemotherapy did ⁹⁶
• Electrical impedance spectroscopy of skin lesionsA handheld probe passes tiny alternating currents through a mole at many frequencies and scores the result; sold as Nevisense ⁹⁸.As an adjunct before deciding to excise a pigmented lesion, in 1951 patients and 1943 evaluable lesions including 265 melanomas ⁹⁸Sensitivity 96.6%, 256 of 265 melanomas, with a one-sided 95% lower bound of 94.2% ⁹⁸Specificity was 34.4% (95% CI, the range within which the true value plausibly lies, 32.0-36.9) and positive predictive value 21.1%, so four of five positives were not melanoma ⁹⁸
• Dielectrophoretic sortingA non-uniform electric field pushes cells according to their electrical properties, proposed as a way to pull tumor cells out of blood ¹⁰⁰.Measured across the whole NCI-60 panel, the US National Cancer Institute's standard set of 60 human cancer cell lines and compared with blood cell populations ¹⁰⁰Reproducible, and genuinely able to separate cells of similar size from different tissues ¹⁰⁰The property it reads is cell size and how folded the membrane is, inherited from where the cell grew, not a malignant electrical signature ¹⁰⁰

What is actually done with electricity in cancer care

Tumor treating fields are a wearable device: adhesive arrays on the skin deliver low-intensity alternating electric fields, 200 kHz for the head ²⁰ and 150 kHz for the chest ¹⁹, continuously, with a recommendation of at least 18 hours a day ^19,20; the pancreatic trial's abstract does not state its frequency ⁶³, and the ovarian trial used 200 kHz on the abdomen ²³, so the figure is not simply one frequency per region. The claimed mechanism began as interference with the mitotic spindle, the scaffold of protein fibers that pulls a dividing cell's chromosomes apart, in dividing cells ^39,40 and modeling supports forces on microtubules and ionic effects around them as the leading physical candidates ⁴¹; a 2026 review adds innate immune sensing through the cGAS-STING and AIM2 pathways, the cell's alarm systems for stray DNA, immunogenic cell death and macrophage reprogramming, and states plainly that the evidence for this broader picture is largely preclinical ⁴².

The trial record, in order, is this. The first phase 3, in recurrent glioblastoma, was negative: 6.6 versus 6.0 months, HR 0.86 (95% CI 0.66-1.12), p = 0.27, with severe adverse events lower on the device, 6% versus 16% ²¹. A post hoc analysis restricted to patients who completed at least one cycle reported 7.7 versus 5.9 months, HR 0.69, p = 0.0093, and its authors noted the contrast with the original intention-to-treat result, in which everyone is analyzed in the group they were assigned to ²². The second phase 3, EF-14, in newly diagnosed glioblastoma after radiochemotherapy, was positive on both endpoints in 695 patients: 20.9 versus 16.0 months overall survival, HR 0.63 (95% CI 0.53-0.76), p < 0.001 ²⁰. A simulation study on 340 of those patients found longer survival above a modeled dose threshold of 0.77 mW/cm³ and above an average field of 1.06 V/cm, which is the basis for talking about a dose at all ²⁴.

The trials after that widened the organs. A single-arm phase 2 in pleural mesothelioma reported median overall survival of 18.2 months in 80 patients with no control group, which the authors themselves describe as warranting a randomized trial ¹⁸. LUNAR in lung cancer and PANOVA-3 in pancreatic cancer were positive for overall survival, by 3.3 and 2.0 months respectively, and PANOVA-3 improved pain-free survival and, in a post hoc analysis, distant progression-free survival (13.9 versus 11.5 months, HR 0.74, 95% CI 0.57-0.96, p = 0.022), while progression-free survival, local progression-free survival and response rate were unchanged, so the survival gain is not matched by any pre-specified tumor-control endpoint ^19,63. The widening also produced a second negative pivotal trial: in 558 women with platinum-resistant ovarian cancer, adding 200 kHz fields to weekly paclitaxel gave median overall survival of 12.2 versus 11.9 months, HR 1.01 (95% CI 0.83-1.24), p = 0.89, with no benefit in the intention-to-treat population and only a post hoc subgroup signal ²³. With EF-11, two pivotal phase 3 trials of this device are negative on their primary endpoint. METIS delayed intracranial progression after radiosurgery for lung cancer brain metastases, HR 0.72, p = 0.044, with the effect more marked in the 118 patients also receiving immune checkpoint inhibitors, and with no deterioration in quality of life or cognition ⁶⁴.

The criticisms are specific and they are published. Every pivotal trial is open-label, because a convincing dummy array is hard, and a 2026 review argues that without sham control the device cannot be separated from the 24-hour support, home deliveries and regular visits that come with it; it also identifies suboptimal control arms in half of the six pivotal trials, including two of the positive ones, notes protocol changes and unusual censoring patterns, and points out that one company has produced the main evidence base with no replication by a competitor ³³. Uptake reflects that: in two large academic neuro-oncology programs the device was used in 3 to 12% of newly diagnosed and 0 to 16% of recurrent glioblastoma patients, and among 30 respondents at an educational session, 60% were convinced it prolongs survival and only 30% viewed it as definitively standard of care ¹⁰². The cost is real: a manufacturer-affiliated cost-utility analysis in pancreatic cancer put lifetime costs at $351,400 against $220,000, for 0.34 additional quality-adjusted life years, meaning years of life weighted by their quality with a year in perfect health counting as one, an incremental cost-effectiveness ratio, the extra cost per extra quality-adjusted year, of $387,300 ¹⁰³.

Practical details matter for anyone combining treatments. Arrays left in place during radiotherapy attenuated dose at depth by about 2 to 4% down to 10 cm and raised surface dose by a factor of 1.81 to 1.87 by solid-state detector, with repositioning cutting peak surface dose by up to 40% but leaving it 1.6 to 2.3 times baseline ¹⁰⁴. Starting the fields before and during radiotherapy was feasible in a 20-patient cohort with no protocol-defined treatment-limiting toxicity, 0 of 20 with an exact 95% confidence interval of 0 to 16.8%, though grade 3 or higher adverse events, mostly blood counts from chemoradiation, occurred in 12 patients ¹⁰⁵. Laboratory work suggests field strength and exposure time trade off against each other in cell lines, which is the kind of finding that could eventually reduce wear time ¹⁰⁶, and simulation says adequate intensities may be reachable in brainstem tumors with scalp-only arrays ¹⁰⁷. A randomized phase 2 trial has now tested that same idea against a control arm: in 66 patients with newly diagnosed glioblastoma, adding the fields during chemoradiation did not meet its primary endpoint, with one-year progression-free survival of 28.7% versus 17.3% (p = 0.146), median progression-free survival 5.4 versus 4.1 months (p = 0.14) and median overall survival 18.5 versus 16.5 months (p = 0.95) in the intention-to-treat population; a significant difference appeared only in an exploratory evaluable subset of 54 patients, 9.9 versus 4.1 months (p = 0.016) ⁶⁵.

Electroporation: electricity that works by breaking the membrane

Two older electrical treatments are more straightforwardly physical, because they work by making holes. Electrochemotherapy applies brief high-voltage pulses to make the membrane transiently leaky so that a drug, almost always bleomycin, floods in. The founding experiment was done in rats in 1987: a single impulse at 5 kV/cm lasting 2 milliseconds, given after bleomycin, shrank a hepatocellular carcinoma to an average of 17% of its initial mass in four days, while neither the pulse nor the drug alone inhibited growth at all ¹¹⁰. Mice followed in 1991, with tumors reduced and sometimes eradicated by intramuscular bleomycin plus local pulses ¹¹¹. In people, the pan-European registry reports 2482 lesions in 987 patients with an overall response of 85% and complete response of 70%, varying by tumor type from 64% complete in melanoma metastases to 91% in Kaposi sarcoma ¹¹².

Irreversible electroporation uses pulses strong enough that the holes do not reseal, killing tissue without heating it. A registry of 200 patients with stage III pancreatic cancer reported median overall survival of 24.9 months against historical controls ¹¹³. A 2026 meta-analysis of 31 studies and 1296 patients put median overall survival after irreversible electroporation for unresectable locally advanced pancreatic cancer at 16.3 months (95% CI 14.2-18.4), with an apparent advantage over non-electroporation comparators (mean difference 6.97 months, 95% CI 0.79-13.15, p = 0.03) that the authors themselves grade as low-to-moderate certainty because almost all the input is uncontrolled ¹¹⁴. When it was compared head to head with stereotactic radiotherapy in a randomized phase 2 trial, median overall survival was 16.1 months for radiotherapy against 12.5 for electroporation, HR 1.39 (95% CI 0.84-2.30), p = 0.21, and the trial was stopped early for futility ¹⁰⁸. That trial's immune substudy found each modality activating immunity differently, with antigen-specific T cell responses in nine of sixteen immunocompetent participants, which is a reason to keep studying it rather than a reason to use it ¹¹⁵. The one place where this physics is clearly winning is not oncology at all: in atrial fibrillation, pulsed field ablation was non-inferior to conventional thermal ablation in 607 randomized patients, 73.3% against 71.3% free of the composite endpoint at one year ¹⁰⁹. Pulsed field ablation received its first FDA device approval in December 2023 and has been taken up quickly, against three decades of slower uptake for electroporation in oncology ¹¹⁶.

The devices that borrow the language

Every one of the numbers above exists because somebody ran a trial, and that is exactly what the frequency-generator industry has never done. The claim attached to Rife machines and their descendants is that each organism, including each tumor and each parasite, has a resonant frequency at which it can be destroyed from outside, leaving the patient untouched. A search of the biomedical literature returns no clinical trial of such a device for cancer, either for or against. That absence is itself the finding, and it should be stated that way on air: after roughly ninety years of commerce, there is nothing to review.

The closest thing to a serious version of the idea has been studied, and its results are instructive. A group administered 27.12 MHz radiofrequency fields amplitude-modulated at what they called tumor-specific frequencies, identified by a biofeedback examination, intrabuccally, that is inside the mouth ¹¹⁷. In 41 patients with advanced hepatocellular carcinoma and few options, the open-label single-group study reported no grade 2 or higher toxicity, 14 patients (34.1%) with stable disease beyond six months, median progression-free survival 4.4 months (95% CI 2.1-5.3), median overall survival 6.7 months (3.0-10.2), three partial and one near-complete response ¹¹⁸. A companion review describes the approach and the in vitro work behind it ¹¹⁷. One uncontrolled single-group study in a disease with heterogeneous natural history cannot establish an effect; the authors call it a phase I/II safety and effectiveness study, which is the right label.

Where related devices have been tested blind, they have failed. Electrodermal testing with a Vegatest device was compared with skin prick testing in 30 volunteers, half of them allergic, across three operators and three sessions, 54 tests each: the results did not correlate with skin prick tests, could not distinguish allergic from non-allergic participants, no operator did better than any other, and no single participant was consistently diagnosed correctly. The conclusion in the paper is that electrodermal testing cannot be used to diagnose environmental allergies ³⁰. A 2014 placebo-controlled, double-blind trial of a proprietary bioresonance device for smoking cessation in 190 people did report higher quit rates, 28.6% against 16.1% at one year ¹¹⁹; a co-author is listed in the record without any affiliation and no funding or conflict statement was retrievable, so the independence of that evaluation is unverified, and smoking cessation is not cancer treatment.

The reason to be blunt about this is not tidiness. Among patients with non-metastatic breast, prostate, lung or colorectal cancer who chose alternative medicine as their only anticancer treatment, matched two to one against patients receiving conventional treatment, the hazard ratio for death was 2.50 (95% CI 1.88-3.27) overall, 5.68 (3.22-10.04) in breast cancer, 2.17 (1.42-3.32) in lung and 4.57 (1.66-12.61) in colorectal cancer ³¹. The devices are not harmless objects that happen not to work. They are sold into the window in which a curable cancer is still curable.

What was believed, and is not

This field has corrected itself more often than its popular version admits, and the corrections are the most useful part of it. Several of them came from the same laboratories that had argued the opposite, which is how the process is supposed to work and is not a reason to distrust the whole subject. What follows is the short list of beliefs that were once reasonable, were published, were repeated, and are now either overturned or substantially narrowed. Each card gives the claim, what replaced it, and when. Where a correction is widely ignored in popular writing, that is said; where the original observation survives and only the interpretation fell, that is said too, because the two are often confused.

One pattern runs through all of them. In every case the physical observation held up and the inference about cancer did not. Cancer cells really are less negative in culture ⁸; the channel really is overexpressed in tumors ⁷⁷; the sugar coat really is denser ⁸⁷; the lipid really is exposed ⁹²; the fields really do slow dividing cells in a dish ³⁹. What failed was the step from there to a cause, a test or a treatment, and it failed in a particular way each time: a marker turned out to be present in healthy people too ⁷⁸, a target turned out to do something else in the body ⁵⁶, an antibody against a real difference did not help patients ⁹³. That is the shape of the error to listen for.

What is still unknown

The largest gap is the simplest. Nobody has published a prospective study measuring resting membrane voltage in freshly obtained human tumor cells and matched normal cells from the same patients, with blinded pathology. The claim that cancer cells are depolarized rests on cell lines, on amphibian embryos, on reviews of both ^12,13, and on one small unmatched human biopsy series ¹¹. The two measurements usually cited as the human evidence are from quail and rat cells in culture ⁸. Until the paired human study exists, the right sentence on air is that this is true in the models and untested in people.

The second gap is dose. Field dose in therapy is assigned by simulation on head models derived from scans, with compliance and delivered current taken from device logs ²⁴, and the 2026 critique names the absence of validated human in vivo dosimetry as a limit on biological plausibility ³³. Nobody can yet tell a patient how many volts per centimeter reached their tumor yesterday. A sham-controlled trial is the other missing piece; it is technically hard with a wearable device but not impossible, and until one exists the contribution of the device and of the intensive support around it cannot be separated ³³.

The third gap is mechanism, in both directions. For applied fields, the account has drifted from pure spindle disruption to include immune effects ^41,42. Academic groups with no manufacturer author have reproduced the antiproliferative effect in cell lines, in glioblastoma kinome profiling ¹⁶, across a panel of low-passage colorectal lines ¹²¹ and on a purpose-built exposure platform ¹²², but nobody has validated the mechanism in a human tumor, and the 2026 critique notes that a single company has generated the main evidence base with no substantial replication from competing manufacturers ³³. For endogenous voltage, the frog results are strong but the translation is unknown: no one has shown that pharmacologically hyperpolarizing a human tumor changes its behavior, even though the frog work showed that manipulating the animal's own chloride channels was enough ¹⁰.

On the parasite side, one claimed absence has to be withdrawn and two stated plainly. Helminth surfaces have been examined, and they are negatively charged like almost every biological surface, though in cytochemistry rather than in numbers. Cationized ferritin, a positively charged marker that sticks to negative surfaces, binds the outer coat of adult Schistosoma mansoni ¹²³ and of its cercariae, where the binding survived removal of sialic acid but not of protein or chondroitin ¹²⁴; the larval epicuticles of Strongyloides ratti and Trichinella spiralis both carry a net negative charge, dense and uniform in Strongyloides ¹²⁵; the surface coat of Toxocara canis larvae ¹²⁶ and the sheath of Wuchereria bancrofti microfilariae ¹²⁷ bind the same marker; and the glycocalyx of juvenile Fasciola gigantica is polyanionic throughout its depth ¹²⁸. The only numbers found are for eggs: in 2026, Ascaris lumbricoides eggs measured about -21.9 mV and Taenia eggs about -18.4 mV by zeta potential, against -28 mV for Giardia cysts ²⁹. No zeta potential of a living adult worm tegument was found, and the rest of the surface-charge data in parasitology are protozoan ^27,28,129. None of this links worms to tumors: a negative surface is the default state of cells, eggs, cysts and spores alike. There is no paper documenting a shared bioelectric signature between tumors and parasites; searches combining those terms return nothing, so that linkage is a hypothesis, not literature. And there is no in vivo human measurement of the reversed proton gradient that reviews describe qualitatively ⁸³, which matters because acid-base claims and charge claims are often blended together in popular accounts.

The parasite connection, at its true strength

Parasites belong on this page for a precise reason, and it is not a shared electrical signature. It is that two of the most widely used worm drugs, praziquantel and ivermectin, both work by opening an ion channel, so a large part of successful antiparasitic therapy is, mechanically, bioelectric medicine that already works. Not all of it is: the benzimidazoles albendazole and mebendazole, which carry most mass treatment of soil-transmitted worms, bind the worm's tubulin, the protein of its internal scaffolding, and have nothing to do with voltage ¹³⁰. A review of nematode channel pharmacology does report that the majority of antinematodal drugs target ion channels of one kind or another, nicotinic acetylcholine receptors among them ¹³¹, so the generalization is defensible as long as the benzimidazoles are named as the exception. Praziquantel, developed in the 1970s and in clinical use since about 1980 with an unknown mechanism ¹³², was shown in 2019 to activate a schistosome transient receptor potential channel of the melastatin family at nanomolar concentrations, with the right stereochemical preference, meaning it favors one mirror-image form of the drug, and the right downstream consequences for muscle contraction and surface damage ⁵⁹. A genome-wide association study in a laboratory-selected resistant parasite line mapped reduced response to that same channel, found the trait recessive, and produced marker-selected lines differing more than 377-fold in drug response, with resistant parasites expressing the channel 2.25-fold less ⁶⁰.

The structural detail is worth hearing because it explains which worms the drug treats. The binding pocket is conserved across parasitic flatworms, and a single acidic residue in one domain acts as a gatekeeper: an aspartate permits potent activation, which is why flukes and the cyclophyllidean tapeworms are sensitive, while a glutamate in other flatworms goes with lower sensitivity, across a roughly 300-fold range ¹³³. In 2026, whole-genome sequencing of 570 field samples across eight countries found four naturally occurring variants of that channel associated with reduced drug sensitivity, together with instances of treatment failure after mass drug administration, which is standing variation for resistance rather than established clinical resistance ¹³⁴. An older hypothesis, that the drug acted through unusual calcium channel beta subunits, remains in the literature and was supported by those subunits conferring drug sensitivity on an otherwise insensitive mammalian channel ¹³⁵; the melastatin channel now has the stronger genetic support. The same residue explains why praziquantel fails against liver flukes of the genus Fasciola, and in 2024 the same group used the Fasciola channel as a target to find a different chemical series that activates it, a target-based flukicide active across every fluke they profiled ¹³⁶. A second, distinct schistosome channel of the same family is activated by the benzodiazepine meclonazepam, which, unlike praziquantel, retains activity against juvenile worms, though its human side effects rule it out as a drug as it stands ¹³⁷. A public database, TRPtracker, now collects channel variants, their geography and frequency, and their measured praziquantel sensitivity, for surveillance ¹³⁸.

Ivermectin is the cleaner story. Expression cloning from Caenorhabditis elegans identified an avermectin-sensitive glutamate-gated chloride channel, a channel found in invertebrates and not vertebrates ¹³⁹, and the three-dimensional structure solved at 3.3 angstroms showed ivermectin binding in the transmembrane domain and stabilizing an open pore ¹⁴⁰. Open chloride channels hold the worm's membrane at a negative voltage and it cannot fire or move. The reason this is safe in people is a pump: mice lacking the mdr1a P-glycoprotein of the blood-brain barrier were 100-fold more sensitive to ivermectin than normal mice ¹⁴¹. The drug is selective because of a channel the host does not have and a barrier the host does. A newer drug, emodepside, acts on SLO-1 potassium channels and, unlike ivermectin, killed adult filarial worms, the thread-like worms of the group that causes river blindness, in cattle by 18 months after treatment at 0.15 and 0.75 mg/kg; that cattle work comes from the developer's own laboratories ¹⁴², but the drug has since reached people. In a 2025 phase 2a randomized, placebo-controlled trial in 202 adults in Laos infected with Strongyloides stercoralis, the dose-response curve plateaued at a single 15 mg dose with a predicted cure rate of 89.1% (95% CI 81.6-93.7), against 88.0% observed with ivermectin and 0% with placebo, and transient drowsiness and blurred vision were the commonest effects ¹⁴³.

Parasite membrane potential itself has been measured where the organism can be isolated, and worms are included. Microelectrodes advanced through the back of an adult male Schistosoma mansoni meet three electrical compartments: about -51 mV across the outer tegumental membrane, about -28 mV in the muscle beneath and about -10 mV in the space between ¹⁴, with a second series giving -45.9 plus or minus 2.5 mV for the tegument ¹⁵. Both the tegument and the muscle potentials are primarily potassium-dependent and are held up by the sodium-potassium pump, since ouabain, which blocks that pump, depolarizes them ^14,52; praziquantel depolarizes all three compartments ¹⁴ while causing a rapid sustained contracture of the worm's musculature at one micromolar, with calcium accumulating in the parasite ¹⁴⁴. Those 1980 to 1982 recordings are the physiology that the 2019 channel discovery finally explained. In the giant roundworm Ascaris the muscle resting potential is odd: it is relatively insensitive to the potassium, sodium and chloride in the bath and appears to be set largely by an electrogenic pump ¹⁴⁵. Among protozoa, the malaria parasite, isolated from its host red cell and measured with a radiolabeled probe, sat at -95 plus or minus 2 mV, and the voltage was reduced by a specific inhibitor of its proton pump, by a proton ionophore and by glucose deprivation, consistent with electrogenic proton extrusion at the parasite surface countered by potassium influx ³⁴. Surface charge has been measured in protozoa: Cryptosporidium oocysts had a zeta potential of about -25 mV at pH 6 to 6.5, becoming -35 mV at alkaline pH and reaching zero at pH 2.5 ²⁷; Leishmania promastigotes about -15 mV, and notably stripping sialic acid did not change it, so their negativity is not sialic-acid driven ²⁸; and across three Trichomonas vaginalis and five Tritrichomonas fetus strains there was no difference between species but significant differences between strains, with the strains more pathogenic to mice carrying a more negative surface ¹²⁹. These are ordinary values. Everything in biology carries a surface charge in this range, which is why finding one in a parasite proves nothing about cancer.

Electric fields do kill parasites, in food rather than in people. Pulsed electric fields at 3 kV/cm and 50 kJ/kg inactivated close to 100% of Anisakis larvae, the fish worm, in hake while disturbing moisture, water-holding capacity and cooking loss less than freezing and thawing did ¹⁴⁶; the European food safety assessment that reviewed this work concluded that freezing and heating remain the most efficient methods, that pulsed electric field is a promising technology needing further development, and that ultrasound treatments were not effective ¹⁴⁷. Electrical measurement is also now a laboratory tool against parasites: microfluidic chips read the viability of schistosome larvae from their impedance, replacing a human observer watching worms under a microscope ¹⁴⁸.

Finally, the one place where antiparasitic drugs and cancer electricity genuinely touch. Ivermectin kills leukemia cells in the laboratory at low micromolar concentrations, and the mechanism reported is exactly the one this page is about: chloride influx, increased cell size, and hyperpolarization of the plasma membrane with no change in mitochondrial membrane potential, plus reactive oxygen species that were needed for the killing, with delayed tumor growth in three mouse leukemia models and synergy with cytarabine and daunorubicin ¹⁴⁹. That is a real bioelectric anticancer mechanism for an antiparasitic drug. It is also, as of October 2026, in vitro and mouse work: a 2026 review of antiparasitic agents in oncology lists ivermectin's effects across breast, ovarian and colorectal models, including activation of chloride channels, and concludes that clinical translation faces pharmacokinetic limits, heterogeneous dosing and a paucity of adequately powered randomized clinical trials ¹²⁰. The honest summary for the season is that the parasite-cancer link in this area is a drug mechanism, not a shared electrical signature, and that nobody has shown a human cancer responding to a channel-opening antiparasitic in a randomized trial.

Where it connects

Sources

149 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1. 1
   HODGKIN AL, HUXLEY AF. A quantitative description of membrane current and its application to conduction and excitation in nerve.J Physiol · 1952 · 117(4):500-44doi:10.1113/jphysiol.1952.sp004764 · PMID 12991237

   The quantitative description of membrane current in nerve. The record carries no abstract, so the content must be read in the paper; it is cited here for the existence and date of the framework, not for a specific number.

2. 2
   Blackiston DJ, McLaughlin KA, Levin M. Bioelectric controls of cell proliferation: ion channels, membrane voltage and the cell cycle.Cell Cycle · 2009 · 8(21):3527-36doi:10.4161/cc.8.21.9888 · PMID 19823012

   Review establishing that all cells hold steady voltage gradients and that voltage both controls and is controlled by cell cycle progression. A review, with no pooled estimates.

3. 3
   Skou JC. The influence of some cations on an adenosine triphosphatase from peripheral nerves.Biochim Biophys Acta · 1957 · 23(2):394-401doi:10.1016/0006-3002(57)90343-8 · PMID 13412736

   The original 1957 paper identifying the enzyme in crab nerve; no abstract in the record. Reprinted in J Am Soc Nephrol 1998;9(11):2170-7 (PMID 9808107, doi 10.1681/ASN.V9112170).

4. 4
   Skou JC. The Identification of the Sodium-Potassium Pump (Nobel Lecture).Angew Chem Int Ed Engl · 1998 · 37(17):2320-2328PMID 29710959

   Skou's own account, including that the word pump was omitted from the 1957 title as too provocative. A retrospective lecture, not primary data. Identified here by PubMed ID only: the registered DOI contains angle brackets that break markup.

5. 5
   POST RL, JOLLY PC. The linkage of sodium, potassium, and ammonium active transport across the human erythrocyte membrane.Biochim Biophys Acta · 1957 · 25(1):118-28doi:10.1016/0006-3002(57)90426-2 · PMID 13445725

   The other 1957 paper, establishing that these transports are linked in human red cells. No abstract in the record, so no stoichiometry is quoted here.

6. 6
   Smithers HE, Terry JR, Brown JT, Randall AD. Aging-Associated Changes to Intrinsic Neuronal Excitability in the Bed Nucleus of the Stria Terminalis Is Cell Type-Dependent.Front Aging Neurosci · 2017 · 9:424doi:10.3389/fnagi.2017.00424 · PMID 29311907

   The concrete anchor for about -70 mV: one neuron type rested near that value in young mice and near -80 mV in aged ones. Mouse brain slices, two age cohorts of female animals.

7. 7
   Zhao W, Zhang M, Liu J, Liang P, Wang R, Hemmings HC, Zhou C. Isoflurane Modulates Hippocampal Cornu Ammonis Pyramidal Neuron Excitability by Inhibition of Both Transient and Persistent Sodium Currents in Mice.Anesthesiology · 2019 · 131(1):94-104doi:10.1097/ALN.0000000000002753 · PMID 31166240

   Resting potential of -54.6 plus or minus 2.3 mV in mouse hippocampal pyramidal neurons, hyperpolarized to -58.7 plus or minus 2.1 mV by an anesthetic. Cited to show that the textbook -70 mV is a round number, not a universal value.

8. 8
   Binggeli R, Weinstein RC. Deficits in elevating membrane potential of rat fibrosarcoma cells after cell contact.Cancer Res · 1985 · 45(1):235-41PMID 3965134

   The matched measurements: -20.7 versus -40.1 mV in quail and -30.7 versus -61.9 mV in rat cells at high density, and the failure of cancer cells to make the normal jump to a high potential. Quail and rat cells in culture, not human tissue.

9. 9
   Chernet BT, Levin M. Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in a Xenopus model.Dis Model Mech · 2013 · 6(3):595-607doi:10.1242/dmm.010835 · PMID 23471912

   The strongest evidence that voltage is instructive: depolarization marked oncogene-induced tumor-like structures and their precursor sites, and forced hyperpolarization significantly reduced their formation through SLC5A8. Frog embryos; no effect sizes with confidence intervals are given.

10. 10
    Lobikin M, Chernet B, Lobo D, Levin M. Resting potential, oncogene-induced tumorigenesis, and metastasis: the bioelectric basis of cancer in vivo.Phys Biol · 2012 · 9(6):065002doi:10.1088/1478-3975/9/6/065002 · PMID 23196890

    Shows high sodium content in oncogene-induced frog tumors and that susceptibility fell with forced hyperpolarization or with a drug acting on the animal's own chloride channels. Frog model; no numeric effect sizes in the abstract.

11. 11
    Marino AA, Iliev IG, Schwalke MA, Gonzalez E, Marler KC, Flanagan CA. Association between cell membrane potential and breast cancer.Tumour Biol · 1994 · 15(2):82-9doi:10.1159/000217878 · PMID 8184256

    Membrane potentials in biopsy tissue from 9 women with infiltrating ductal carcinoma were significantly depolarized against 8 women with benign disease; transformed breast cells were especially sensitive to potassium channel blockers. Small, unmatched, and from an orthopedic-surgery laboratory.

12. 12
    Yang M, Brackenbury WJ. Membrane potential and cancer progression.Front Physiol · 2013 · 4:185doi:10.3389/fphys.2013.00185 · PMID 23882223

    The review most often cited for the statement that cancer cells are depolarized, including the mesenchymal stem cell differentiation results. It is a review of other people's measurements; it contains no new human data, and it is explicit that the migration link is weaker than the proliferation link.

13. 13
    Levin M. Bioelectric signaling: Reprogrammable circuits underlying embryogenesis, regeneration, and cancer.Cell · 2021 · 184(8):1971-1989doi:10.1016/j.cell.2021.02.034 · PMID 33826908

    The field's current synthesis: voltage distributions across tissues process morphogenetic information. A review and a research program, not evidence of clinical effect.

14. 14
    Bricker CS, Pax RA, Bennett JL. Microelectrode studies of the tegument and sub-tegumental compartments of male Schistosoma mansoni: anatomical location of sources of electrical potentials.Parasitology · 1982 · 85(Pt 1):149-61doi:10.1017/s0031182000054226 · PMID 7122122

    Locates three electrical compartments in the worm by marking the electrode track, and reports that ouabain and praziquantel depolarize all three. The tegument and muscle potentials are primarily potassium-dependent.

15. 15
    Thompson DP, Pax RA, Bennett JL. Microelectrode studies of the tegument and sub-tegumental compartments of male Schistosoma mansoni: an analysis of electrophysiological properties.Parasitology · 1982 · 85(Pt 1):163-78doi:10.1017/s0031182000054238 · PMID 7122123

    The companion paper, giving -45.9 plus or minus 2.5 mV for the tegument with input resistances and time constants, and showing the tegument and the compartment beneath it behave as electrical syncytia.

16. 16
    Jones AB, Schanel TL, Rigsby MR, Griguer CE, McFarland BC, Anderson JC, et al. Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities.Cells · 2023 · 12(17):2171doi:10.3390/cells12172171 · PMID 37681903

    An academic group with no manufacturer author reproducing the antiproliferative effect in temozolomide-sensitive and -resistant lines, and profiling the kinases that shift. Also states the recurrent and newly diagnosed glioblastoma indications. Cell lines only.

17. 17
    Sarkari A, Korenfeld S, Deniz K, Ladner K, Wong P, Padmanabhan S, et al. Treatment with tumor-treating fields (TTFields) suppresses intercellular tunneling nanotube formation in vitro and upregulates immuno-oncologic biomarkers in vivo in malignant mesothelioma.Elife · 2023 · 12:e85383doi:10.7554/eLife.85383 · PMID 37955637

    States that the device is in active clinical use for glioblastoma and malignant mesothelioma; one author is at the manufacturer. Cited here for the indication, not for its laboratory findings.

18. 18
    Ceresoli GL, Aerts JG, Dziadziuszko R, Ramlau R, Cedres S, van Meerbeeck JP, et al. Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial.Lancet Oncol · 2019 · 20(12):1702-1709doi:10.1016/S1470-2045(19)30532-7 · PMID 31628016

    Median overall survival 18.2 months in 80 patients, with skin reaction the only device-related event. Single-arm and manufacturer-funded; the authors themselves call for a randomized trial.

19. 19
    Leal T, Kotecha R, Ramlau R, Zhang L, Milanowski J, Cobo M, et al. Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study.Lancet Oncol · 2023 · 24(9):1002-1017doi:10.1016/S1470-2045(23)00344-3 · PMID 37657460

    A significant 3.3-month survival gain in 276 patients, with serious adverse events of any cause higher on the device arm. Open-label, manufacturer-funded, and the investigator's-choice control mixed immune checkpoint inhibitors with docetaxel; only 32% of patients had received a previous checkpoint inhibitor.

20. 20
    Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial.JAMA · 2017 · 318(23):2306-2316doi:10.1001/jama.2017.18718 · PMID 29260225

    The positive pivotal trial, 695 patients, with both endpoints significant. Randomized and open-label, with manufacturer employees among the authors; it cannot separate the device from the care around it.

21. 21
    Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, et al. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality.Eur J Cancer · 2012 · 48(14):2192-202doi:10.1016/j.ejca.2012.04.011 · PMID 22608262

    The first phase 3, negative for overall survival, with lower severe toxicity and better quality of life on the device. Author list includes manufacturer staff.

22. 22
    Kanner AA, Wong ET, Villano JL, Ram Z. Post Hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A system versus best physician's choice chemotherapy.Semin Oncol · 2014 · 41 Suppl 6:S25-34doi:10.1053/j.seminoncol.2014.09.008 · PMID 25213871

    The post hoc rescue of the negative trial, which the authors themselves contrast with the original intention-to-treat result. Published in a supplement by trial investigators; no funding statement in the record.

23. 23
    Vergote I, Copeland LJ, Van Gorp T, Laenen A, Scambia G, Thaker PH, et al. Tumor Treating Fields therapy in platinum-resistant ovarian cancer: Results of the ENGOT-ov50/GOG-3029/INNOVATE-3 pivotal phase 3 randomized study.Eur J Cancer · 2025 · 219:115306doi:10.1016/j.ejca.2025.115306 · PMID 40010134

    The negative pivotal trial in ovarian cancer: 558 patients, HR 1.01 for death. Open-label and manufacturer-funded; the only positive finding is a post hoc subgroup.

24. 24
    Ballo MT, Urman N, Lavy-Shahaf G, Grewal J, Bomzon Z, Toms S. Correlation of Tumor Treating Fields Dosimetry to Survival Outcomes in Newly Diagnosed Glioblastoma: A Large-Scale Numerical Simulation-Based Analysis of Data from the Phase 3 EF-14 Randomized Trial.Int J Radiat Oncol Biol Phys · 2019 · 104(5):1106-1113doi:10.1016/j.ijrobp.2019.04.008 · PMID 31026557

    The dose-response analysis that makes it possible to speak of a field dose at all, with thresholds of 0.77 mW/cm3 and 1.06 V/cm. Dose was simulated on head models rather than measured in patients, and four of six authors were at the manufacturer.

25. 25
    Edd JF, Horowitz L, Davalos RV, Mir LM, Rubinsky B. In vivo results of a new focal tissue ablation technique: irreversible electroporation.IEEE Trans Biomed Eng · 2006 · 53(7):1409-15doi:10.1109/TBME.2006.873745 · PMID 16830945

    A single 20 ms pulse at 1000 V/cm produced non-thermal tissue death in rat liver, with sharp borders corresponding to 300 to 500 V/cm and large vessel architecture preserved. Rat liver; the numbers are the basis for the field-strength scale used here.

26. 26
    Neumann E, Schaefer-Ridder M, Wang Y, Hofschneider PH. Gene transfer into mouse lyoma cells by electroporation in high electric fields.EMBO J · 1982 · 1(7):841-5doi:10.1002/j.1460-2075.1982.tb01257.x · PMID 6329708

    The paper that named electroporation, using 8 kV/cm pulses of 5 microseconds to drive DNA into cells. It establishes the field strengths at which electricity becomes a hole-punch.

27. 27
    Drozd C, Schwartzbrod J. Hydrophobic and electrostatic cell surface properties of Cryptosporidium parvum.Appl Environ Microbiol · 1996 · 62(4):1227-32doi:10.1128/aem.62.4.1227-1232.1996 · PMID 8919783

    Zeta potential about -25 mV at pH 6 to 6.5, -35 mV at alkaline pH, zero at pH 2.5, with little variation by conductivity. A measurement made for water treatment purposes; it says nothing about cancer.

28. 28
    Silva Filho FC, Saraiva EM, Santos MA, de Souza W. The surface free energy of Leishmania mexicana amazonensis.Cell Biophys · 1990 · 17(2):137-51doi:10.1007/BF02990493 · PMID 1705480

    Zeta potential about -15 mV in both virulent and avirulent promastigotes, unchanged by neuraminidase, so the negativity is not sialic-acid driven. Surface free energies of adhesion differed between virulent and avirulent forms.

29. 29
    de Castro Novelli QH, Soares FA, Margatho VS, Fernandes EP, Suzuki CTN, Sabadini E, et al. The Evaluation of Surface Charges of Ascaris Lumbricoides, Giardia Duodenalis, and Taenia spp., in Preserved Fecal Samples Processed in Natura.Acta Parasitol · 2026 · 71(5)doi:10.1007/s11686-026-01367-1 · PMID 42726392

    Zeta potentials of -28, -21.9 and -18.4 mV for Giardia cysts, Ascaris eggs and Taenia eggs in formalin-preserved stool; measured for diagnostic reasons, and on eggs and cysts rather than living worms.

30. 30
    Lewith GT, Kenyon JN, Broomfield J, Prescott P, Goddard J, Holgate ST. Is electrodermal testing as effective as skin prick tests for diagnosing allergies? A double blind, randomised block design study.BMJ · 2001 · 322(7279):131-4doi:10.1136/bmj.322.7279.131 · PMID 11159567

    A blinded trial in which a commercial electrodermal device could not distinguish allergic from non-allergic volunteers across 1620 planned individual tests (30 volunteers, 54 tests each), 1584 of which were completed to protocol. It tests allergy diagnosis, not cancer treatment, and is the nearest rigorous evidence on devices of this family.

31. 31
    Johnson SB, Park HS, Gross CP, Yu JB. Use of Alternative Medicine for Cancer and Its Impact on Survival.J Natl Cancer Inst · 2018 · 110(1)doi:10.1093/jnci/djx145 · PMID 28922780

    281 patients who used alternative medicine as sole treatment for non-metastatic cancer, matched two to one, had a hazard ratio for death of 2.50 overall and 5.68 in breast cancer. Observational and subject to confounding by unmeasured factors, with low comorbidity scores in the alternative group.

32. 32
    Sundelacruz S, Levin M, Kaplan DL. Role of membrane potential in the regulation of cell proliferation and differentiation.Stem Cell Rev Rep · 2009 · 5(3):231-46doi:10.1007/s12015-009-9080-2 · PMID 19562527

    Review arguing that distinct voltage controls are found in cancer cells and precursor cells, and that bioelectric properties can serve as markers and control mitotic activity. Narrative review.

33. 33
    Ranganathan S, van Doorn-Khosrovani SBVW, Hammond A, Ellsworth SG, Olivier T. Tumor treating fields: Will the evidence gap ever be filled?Eur J Cancer · 2026 · 244:116897doi:10.1016/j.ejca.2026.116897 · PMID 42341618

    The published critique: no sham-controlled trials, limited plausibility without human in vivo dosimetry, suboptimal control arms in half of six pivotal trials including two positive ones, and protocol changes with unusual censoring. A review and argument, not new data.

34. 34
    Allen RJW, Kirk K. The membrane potential of the intraerythrocytic malaria parasite Plasmodium falciparum.J Biol Chem · 2003 · 279(12):11264-72doi:10.1074/jbc.M311110200 · PMID 14630911

    A measured parasite membrane potential of -95 plus or minus 2 mV, attributed to electrogenic proton extrusion countered by potassium influx. Isolated parasites in a defined solution, not inside an intact infected person.

35. 35
    Hoque R, Cirovic S, Hughes MP, Labeed FH. Electrophysiological fingerprints of healthy cervical epithelial and HeLa cells: Membrane potential, zeta potential and passive electrical properties.PLoS One · 2025 · 20(12):e0337538doi:10.1371/journal.pone.0337538 · PMID 41406114

    Five electrical properties on the same cells, HeLa against clinically derived primary cervical epithelial cells. Zeta potential was measured directly and membrane potential derived from dielectrophoresis rather than recorded with an electrode; one cancer line against primary cells, not a diagnostic.

36. 36
    Neher E, Sakmann B. Single-channel currents recorded from membrane of denervated frog muscle fibres.Nature · 1976 · 260(5554):799-802doi:10.1038/260799a0 · PMID 1083489

    The first recordings of individual channel openings. No abstract in the record; cited for the achievement and date.

37. 37
    Zhou Y, Wong CO, Cho KJ, van der Hoeven D, Liang H, Thakur DP, Luo J, Babic M, Zinsmaier KE, Zhu MX, Hu H, Venkatachalam K, Hancock JF. SIGNAL TRANSDUCTION. Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling.Science · 2015 · 349(6250):873-6doi:10.1126/science.aaa5619 · PMID 26293964

    The physical route from voltage to an oncogene: depolarization reorganizes phosphatidylserine, K-Ras nanoclusters and MAPK signaling is amplified; repolarization reverses it. Fibroblasts, neuroblastoma cells and fly neurons, not human tumors.

38. 38
    Blackiston D, Adams DS, Lemire JM, Lobikin M, Levin M. Transmembrane potential of GlyCl-expressing instructor cells induces a neoplastic-like conversion of melanocytes via a serotonergic pathway.Dis Model Mech · 2010 · 4(1):67-85doi:10.1242/dmm.005561 · PMID 20959630

    Depolarizing a sparse set of chloride-channel-expressing cells drove normal melanocytes into an invasive over-proliferating phenotype at a distance, through serotonin transport. A similar effect was seen in cultured human melanocytes; it is not a claim about human disease.

39. 39
    Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Disruption of cancer cell replication by alternating electric fields.Cancer Res · 2004 · 64(9):3288-95doi:10.1158/0008-5472.can-04-0083 · PMID 15126372

    The founding preclinical paper: 100 to 300 kHz fields inhibited eleven tumor cell lines and mouse tumors, selectively affecting dividing cells. The authors were at the manufacturer; this is in vitro and mouse work.

40. 40
    Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.Proc Natl Acad Sci U S A · 2007 · 104(24):10152-7doi:10.1073/pnas.0702916104 · PMID 17551011

    The ten-patient pilot with median time to progression 26.1 weeks and median overall survival 62.2 weeks against historical controls. Uncontrolled, ten patients, manufacturer-affiliated authors.

41. 41
    Tuszynski JA, Wenger C, Friesen DE, Preto J. An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields.Int J Environ Res Public Health · 2016 · 13(11):1128doi:10.3390/ijerph13111128 · PMID 27845746

    Computational assessment concluding that ionic condensation waves around microtubules and dielectrophoretic effects on microtubule dipoles are the most likely explanations, with actin filaments and ion channels less likely. Modeling, not measurement in tissue.

42. 42
    Donnini F, Battaglia G, Chibbaro S, Marampon F, Minniti G, Tini P. Tumor Treating Fields and the Glioblastoma Microenvironment: Mechanistic Convergences with Radiotherapy.Cancers (Basel) · 2026 · 18(13)doi:10.3390/cancers18132069 · PMID 42449613

    The current mechanistic review, adding innate immune sensing, immunogenic cell death and macrophage reprogramming to the anti-mitotic account, and stating that the available evidence is largely preclinical. It also gives median survival in glioblastoma as roughly 15 to 20 months with multimodal treatment.

43. 43
    Cone CD. Variation of the transmembrane potential level as a basic mechanism of mitosis control.Oncology · 1970 · 24(6):438-70doi:10.1159/000224545 · PMID 5495918

    The founding proposal that voltage level controls division. No abstract in the record; cited for the claim's existence and date, not its content.

44. 44
    Cone CD. Unified theory on the basic mechanism of normal mitotic control and oncogenesis.J Theor Biol · 1971 · 30(1):151-81doi:10.1016/0022-5193(71)90042-7 · PMID 5555269

    The theoretical extension to oncogenesis. No abstract in the record.

45. 45
    Cone CD. Maintenance of mitotic homeostasis in somatic cell populations.J Theor Biol · 1971 · 30(1):183-94doi:10.1016/0022-5193(71)90043-9 · PMID 5555270

    The companion theoretical paper to the unified theory, in the same volume; no abstract in the record.

46. 46
    Cone CD, Tongier M. Control of somatic cell mitosis by simulated changes in the transmembrane potential level.Oncology · 1971 · 25(2):168-82doi:10.1159/000224567 · PMID 5148061

    The experimental companion, in cultured cells. No abstract in the record.

47. 47
    Cone CD, Cone CM. Induction of mitosis in mature neurons in central nervous system by sustained depolarization.Science · 1976 · 192(4235):155-8doi:10.1126/science.56781 · PMID 56781

    Sustained depolarization of differentiated neurons in culture induced RNA synthesis within an hour, DNA synthesis within three and nuclear mitosis, mostly without completing cell division. In vitro, chick embryo neurons; it does not show that depolarization causes tumors.

48. 48
    Cone CD. The role of the surface electrical transmembrane potential in normal and malignant mitogenesis.Ann N Y Acad Sci · 1974 · 238:420-35doi:10.1111/j.1749-6632.1974.tb26808.x · PMID 4613241

    Cone's own review of the program; no abstract in the record.

49. 49
    Cone CD, Cone CM. Evidence of normal mitosis with complete cytokinesis in central nervous system neurons during sustained depolarization with ouabain.Exp Neurol · 1978 · 60(1):41-55doi:10.1016/0014-4886(78)90167-x · PMID 566213

    Follow-up to the 1976 Science paper, reporting complete cell division in some depolarized neurons. Chick embryo neurons in culture; no abstract in the record.

50. 50
    Binggeli R, Weinstein RC. Membrane potentials and sodium channels: hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions.J Theor Biol · 1986 · 123(4):377-401doi:10.1016/s0022-5193(86)80209-0 · PMID 2443763

    The threshold hypothesis built from literature values plus sodium permeability and gap junctions. Explicitly two hypotheses, not a measurement.

51. 51
    JAMES AM, AMBROSE EJ, LOWICK JH. Differences between the electrical charge carried by normal and homologous tumour cells.Nature · 1956 · 177(4508):576-7doi:10.1038/177576a0 · PMID 13321908

    The founding observation of the surface-charge story, by cell electrophoresis. The record carries no abstract, so it is cited for the existence and date of the observation.

52. 52
    Fetterer RH, Pax RA, Bennett JL. Na+-K+ transport, motility and tegumental membrane potential in adult male Schistosoma mansoni.Parasitology · 1981 · 82(1):97-109doi:10.1017/s0031182000041895 · PMID 7208106

    Ouabain, lithium substitution and cooling all depolarize the tegument and raise muscle tension, which is the evidence that the sodium-potassium pump holds the worm's voltage up and may be electrogenic. The founding characterization is Fetterer RH, Pax RA, Bennett JL, Schistosoma mansoni: characterization of the electrical potential from the tegument of adult males, Exp Parasitol 1980;49(3):353-65 (PMID 7371737, doi 10.1016/0014-4894(80)90071-5), which carries no abstract.

53. 53
    Cuzick J, Holland R, Barth V, Davies R, Faupel M, Fentiman I, et al. Electropotential measurements as a new diagnostic modality for breast cancer.Lancet · 1998 · 352(9125):359-63doi:10.1016/s0140-6736(97)10002-2 · PMID 9717923

    661 women, eight centers; a graded depolarization index but specificity of only 55% at 90% sensitivity for palpable lesions. Industry-supported device evaluation; the test did not survive.

54. 54
    Pardo LA, del Camino D, Sanchez A, Alves F, Bruggemann A, Beckh S, Stuhmer W. Oncogenic potential of EAG K(+) channels.EMBO J · 1999 · 18(20):5540-7doi:10.1093/emboj/18.20.5540 · PMID 10523298

    Transfection conferred a transformed phenotype and favored tumor progression in SCID (severe combined immunodeficient) mice. Cell culture plus xenograft; no human clinical evidence. No conflict-of-interest statement was required by the journal in 1999.

55. 55
    Wu J, Zhong D, Wei Y, Wu X, Kang L, Ding Z. Potassium channel ether a go-go1 is aberrantly expressed in human liposarcoma and promotes tumorigenesis.Biomed Res Int · 2014 · 2014:345678doi:10.1155/2014/345678 · PMID 25136578

    RETRACTED PUBLICATION, so listed by PubMed. Cited here only as a retraction in this literature; none of its reported figures should be used as evidence.

56. 56
    Kortum F, Caputo V, Bauer CK, Stella L, Ciolfi A, Alawi M, et al. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome.Nat Genet · 2015 · 47(6):661-7doi:10.1038/ng.3282 · PMID 25915598

    The decisive correction: germline gain-of-function mutations in the canonical oncochannel cause a developmental syndrome, not cancer. It also puts the vacuolar proton pump in a developmental role.

57. 57
    Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, et al. Electrical and synaptic integration of glioma into neural circuits.Nature · 2019 · 573(7775):539-545doi:10.1038/s41586-019-1563-y · PMID 31534222

    AMPA-receptor-dependent neuron-glioma synapses, gap-junction-amplified potassium currents, and optogenetic depolarization promoting proliferation, with blockade inhibiting xenografts and extending mouse survival. Mouse xenografts plus human intraoperative recordings.

58. 58
    Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression.Nature · 2019 · 573(7775):532-538doi:10.1038/s41586-019-1564-x · PMID 31534219

    Shows bona fide chemical synapses onto glioma cells with typical ultrastructure, synchronized calcium transients in connected networks, and reduced invasion and growth with AMPA receptor blockade including perampanel. Animal models and human tumor material.

59. 59
    Park SK, Gunaratne GS, Chulkov EG, Moehring F, McCusker P, Dosa PI, Chan JD, Stucky CL, Marchant JS. The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel.J Biol Chem · 2019 · 294(49):18873-18880doi:10.1074/jbc.AC119.011093 · PMID 31653697

    Identifies the channel the drug activates, with nanomolar sensitivity and the expected stereoselectivity. Heterologous expression and parasite pharmacology; it does not by itself prove the channel is the only target.

60. 60
    Le Clec'h W, Chevalier FD, Mattos ACA, Strickland A, Diaz R, McDew-White M, et al. Genetic analysis of praziquantel response in schistosome parasites implicates a transient receptor potential channel.Sci Transl Med · 2021 · 13(625):eabj9114doi:10.1126/scitranslmed.abj9114 · PMID 34936381

    Maps drug response to the same channel by genome-wide association in a selected line, with marker-selected populations differing more than 377-fold and resistant parasites expressing the channel 2.25-fold less. Laboratory selection, with a survey of 259 field parasites.

61. 61
    Quicke P, Sun Y, Arias-Garcia M, Beykou M, Acker CD, Djamgoz MBA, Bakal C, Foust AJ. Voltage imaging reveals the dynamic electrical signatures of human breast cancer cells.Commun Biol · 2022 · 5(1):1178doi:10.1038/s42003-022-04077-2 · PMID 36369329

    Shows that cancer cell resting voltage fluctuates in four machine-learning-defined classes, with transient hyperpolarizations blocked by tetrodotoxin, apamin and iberiotoxin. Cell lines only; it undermines any single-number description.

62. 62
    Badwe RA, Parmar V, Nair N, Joshi S, Hawaldar R, Pawar S, et al. Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer.J Clin Oncol · 2023 · 41(18):3318-3328doi:10.1200/JCO.22.01966 · PMID 37023374

    A randomized trial in which blocking sodium channels with lidocaine before surgery improved disease-free and overall survival. Open-label; the sodium channel rationale is the authors' mechanism, not a measured endpoint.

63. 63
    Babiker HM, Picozzi V, Chandana SR, Melichar B, Kasi A, Gang J, et al. Tumor Treating Fields With Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study.J Clin Oncol · 2025 · 43(21):2350-2360doi:10.1200/JCO-25-00746 · PMID 40448572

    A 2.0-month survival gain and better pain-free survival in 571 patients, with progression-free survival, local progression-free survival and response rate unimproved; distant progression-free survival improved only in a post hoc analysis. Open-label; the discordance between survival and the pre-specified tumor-control endpoints is unexplained.

64. 64
    Mehta MP, Gondi V, Ahluwalia MS, Roberge D, Sio TTW, Trifiletti DM, et al. Tumor Treating Fields Therapy After Stereotactic Radiosurgery for Brain Metastases From Non-Small Cell Lung Cancer: Final Results of the Phase 3 METIS Study.Int J Radiat Oncol Biol Phys · 2025 · 124(2):278-293doi:10.1016/j.ijrobp.2025.08.066 · PMID 41033612

    Significantly delayed intracranial progression in 298 patients, with no deterioration in quality of life or cognition. Time to distant intracranial progression was not significant, and several supportive analyses are labeled post hoc.

65. 65
    Limon D, Bokstein F, Blumenthal DT, Ram Z, Grossman R. Prospective randomized trial of tumor-treating fields with chemoradiation in newly diagnosed glioblastoma.Neurooncol Adv · 2026 · 8(1):vdag106doi:10.1093/noajnl/vdag106 · PMID 42239656

    Primary endpoint not met in 66 patients; the positive finding is in a post hoc evaluable cohort, the same pattern as the EF-11 reanalysis.

66. 66
    In brief: Optune Pax - a portable device for pancreatic cancer.Med Lett Drugs Ther · 2026 · 68(1752):e64doi:10.58347/tml.2026.1752g · PMID 41961539

    A formulary brief on the abdominal device for pancreatic cancer, with keywords covering efficacy, safety and adverse effects. The record carries no abstract, so nothing beyond the title and keywords can be verified from the database.

67. 67
    Krishna S, Choudhury A, Keough MB, Seo K, Ni L, Kakaizada S, et al. Glioblastoma remodelling of human neural circuits decreases survival.Nature · 2023 · 617(7961):599-607doi:10.1038/s41586-023-06036-1 · PMID 37138086

    In awake humans, functional connectivity between tumor and brain predicted worse survival and worse language performance, and highly connected regions were enriched for a synaptogenic subpopulation secreting thrombospondin-1. Observational in patients, with mechanism from cell biology.

68. 68
    Sun Y, Wang X, Zhang DY, Zhang Z, Bhattarai JP, Wang Y, et al. Brain-wide neuronal circuit connectome of human glioblastoma.Nature · 2025 · 641(8061):222-231doi:10.1038/s41586-025-08634-7 · PMID 39821165

    Human glioblastoma organoids transplanted into mice integrate into local and long-range circuits, including cholinergic inputs from the basal forebrain that make the cells more motile. Human cells, mouse brain.

69. 69
    Sakthivelu V, Schmitt A, Odenthal F, Ndoci K, Touet M, Shaib AH, et al. Functional synapses between neurons and small cell lung cancer.Nature · 2025 · 646(8087):1243-1253doi:10.1038/s41586-025-09434-9 · PMID 40931078

    The first demonstration of neuron-to-cancer synapses in a tumor outside the nervous system, with NMDA- and GABA-receptor-mediated inputs. Mouse and in vitro work.

70. 70
    Savchuk S, Gentry KM, Wang W, Carleton E, Biagi-Junior CAO, Luthria K, et al. Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis.Nature · 2025 · 646(8087):1232-1242doi:10.1038/s41586-025-09492-z · PMID 40931074

    Vagus nerve transection inhibits primary lung tumor development, and depolarization of the cancer cells is itself enough to promote growth in the brain. Mouse models.

71. 71
    Sidpra J, Lind V, Cohen AL, Schaper FLWVJ, Stone TJ, Grabovska Y, et al. A prognostic human brain network for diffuse midline glioma.Nature · 2026 · 655(8123):769-779doi:10.1038/s41586-026-10631-3 · PMID 42271051

    A brain-wide connectivity map of childhood diffuse midline glioma that predicted overall survival in two external validation cohorts. Imaging and retrospective outcome data, not an intervention.

72. 72
    Barron T, Drexler R, Mochizuki A, Cantor E, Shamardani K, Woo PJ, et al. Levetiracetam therapeutically targets GABAergic synapses in diffuse midline glioma.Nat Med · 2026doi:10.1038/s41591-026-04646-6 · PMID 42754728

    Retrospective real-world survival data in children plus mouse xenografts, with the effect specific to diffuse midline glioma and independent of the drug's antiseizure target. Not a randomized trial.

73. 73
    Tobochnik S, Regan MS, Dorotan MKC, Reich D, Lapinskas E, Hossain MA, et al. Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma.Clin Cancer Res · 2024 · 30(23):5365-5373doi:10.1158/1078-0432.CCR-24-1849 · PMID 39499201

    High-frequency oscillation rates were similar with perampanel and with standard levetiracetam, and the trial was terminated early after a planned interim analysis with outcomes in 11 patients. Peritumoral glutamate correlated with high-gamma oscillation rates.

74. 74
    Winkler F, Heuer S, Althammer F, Augustin H, Beleggia F, Demir IE, et al. Cancer neuroscience: The past, the present, and the road ahead.Cell · 2026 · 189(8):2464-2489doi:10.1016/j.cell.2026.03.018 · PMID 41997131

    The current review of the field. A review, so it is cited for the state of the field rather than for any single result.

75. 75
    Prevarskaya N, Skryma R, Shuba Y. Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies?Physiol Rev · 2018 · 98(2):559-621doi:10.1152/physrev.00044.2016 · PMID 29412049

    The framework paper arguing that the hallmarks of cancer can be classed as channel disorders. The authors present it as a point of view to substantiate, not as a demonstration.

76. 76
    Kofman K, Levin M. Bioelectric pharmacology of cancer: A systematic review of ion channel drugs affecting the cancer phenotype.Prog Biophys Mol Biol · 2024 · 191:25-39doi:10.1016/j.pbiomolbio.2024.07.005 · PMID 38971325

    109 channel-acting drugs with reported cancer-relevant effects, systematically reviewed and proposed for repurposing. A preclinical catalog with no pooled clinical estimates.

77. 77
    Hemmerlein B, Weseloh RM, Mello de Queiroz F, Knotgen H, Sanchez A, Rubio ME, et al. Overexpression of Eag1 potassium channels in clinical tumours.Mol Cancer · 2006 · 5:41doi:10.1186/1476-4598-5-41 · PMID 17022810

    Human tissue evidence that the channel is near-tumor-specific, overexpressed in up to 80% of samples depending on tissue. Association in tissue, not causation; the authors generated the antibodies used and hold the position that the channel is a drug target.

78. 78
    Ortiz CS, Montante-Montes D, Saqui-Salces M, Hinojosa LM, Gamboa-Dominguez A, Hernandez-Gallegos E, et al. Eag1 potassium channels as markers of cervical dysplasia.Oncol Rep · 2011 · 26(6):1377-83doi:10.3892/or.2011.1441 · PMID 21887469

    A graded association from 27% of normal samples to 92% of high-grade lesions. It also found the protein in almost half of normal patients taking estrogens, which the authors propose as a risk indicator and which is better read as a specificity problem.

79. 79
    Fraser SP, Diss JKJ, Chioni AM, Mycielska ME, Pan H, Yamaci RF, et al. Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis.Clin Cancer Res · 2005 · 11(15):5381-9doi:10.1158/1078-0432.CCR-05-0327 · PMID 16061851

    Identifies the neonatal Nav1.5 splice form, its functional effects on motility and invasion in vitro, and a correlation with clinically assessed lymph node metastasis. Correlation coefficients and p values are not given in the abstract.

80. 80
    House CD, Vaske CJ, Schwartz AM, Obias V, Frank B, Luu T, et al. Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion.Cancer Res · 2010 · 70(17):6957-67doi:10.1158/0008-5472.CAN-10-1169 · PMID 20651255

    Blockade reduced invasion in colon cancer lines, biopsies stained strongly against little or none in matched normal colon, and network modeling placed the gene upstream of an invasion program. In vitro plus tissue staining; no clinical outcome data.

81. 81
    Payne SL, Ram P, Srinivasan DH, Le TT, Levin M, Oudin MJ. Potassium channel-driven bioelectric signalling regulates metastasis in triple-negative breast cancer.EBioMedicine · 2021 · 75:103767doi:10.1016/j.ebiom.2021.103767 · PMID 34933180

    Changing resting voltage by manipulating potassium channels increased invasion in vitro and tumor growth and metastasis in mice, with cadherin-11 and MAPK in the path, and an approved blocker was repurposed in the model. Mouse and cell work only.

82. 82
    Ouadid-Ahidouch H, Dhennin-Duthille I, Gautier M, Sevestre H, Ahidouch A. [TRP calcium channel and breast cancer: expression, role and correlation with clinical parameters].Bull Cancer · 2012 · 99(6):655-64doi:10.1684/bdc.2012.1595 · PMID 22640890

    Review, in French with an English abstract, proposing several TRP channels as markers of differentiation and aggressiveness and noting that high TRPC3 is favorable in lung adenocarcinoma. Narrative review of the authors' own series among others.

83. 83
    Reshkin SJ, Cardone RA, Harguindey S. Na+-H+ exchanger, pH regulation and cancer.Recent Pat Anticancer Drug Discov · 2013 · 8(1):85-99doi:10.2174/15748928130108 · PMID 22738122

    Review arguing that cancers reverse the normal inside-to-outside pH gradient early and that NHE1 is a primary driver. No pH values or effect sizes; published in a patent-focused journal and advocating anti-NHE1 protocols, which is a stated commercial interest.

84. 84
    Sennoune SR, Bakunts K, Martinez GM, Chua-Tuan JL, Kebir Y, Attaya MN, Martinez-Zaguilan R. Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity.Am J Physiol Cell Physiol · 2004 · 286(6):C1443-52doi:10.1152/ajpcell.00407.2003 · PMID 14761893

    Locates the proton pump at the surface of highly metastatic breast cancer cells and shows inhibitors reduce invasion and migration. Cell lines; no numeric effect sizes in the abstract.

85. 85
    Heuer S, Burghaus I, Gose M, Kessler T, Sahm F, Vollmuth P, et al. PerSurge (NOA-30) phase II trial of perampanel treatment around surgery in patients with progressive glioblastoma.BMC Cancer · 2024 · 24(1):135doi:10.1186/s12885-024-11846-1 · PMID 38279087

    A published protocol for a placebo-controlled phase 2 trial of blocking neuron-glioma synapses, 66 patients planned. A plan, not a result.

86. 86
    Eschen JT, Jensen LL, Hausmann D, Lind ANR, Lukacova S, Weischenfeldt J, et al. SENIPERA Phase 0/1 randomized window-of-opportunity clinical trial of SENIcapoc and PERAmpanel mono- and combination therapy of newly diagnosed glioblastoma: a trial protocol.BMC Cancer · 2026 · 26(1)doi:10.1186/s12885-026-15784-y · PMID 41981510

    A protocol combining an AMPA receptor antagonist with a KCa3.1 potassium channel blocker in 27 to 36 patients. Shows the channel-targeting idea reaching early trials; it contains no efficacy data.

87. 87
    Adams OJ, Stanczak MA, von Gunten S, Laubli H. Targeting sialic acid-Siglec interactions to reverse immune suppression in cancer.Glycobiology · 2018 · 28(9):640-647doi:10.1093/glycob/cwx108 · PMID 29309569

    Review establishing that tumor hypersialylation acts through inhibitory Siglec receptors similar to known immune checkpoints. It reframes the negative sugar coat as immunology rather than electrostatics.

88. 88
    Paszek MJ, DuFort CC, Rossier O, Bainer R, Mouw JK, Godula K, et al. The cancer glycocalyx mechanically primes integrin-mediated growth and survival.Nature · 2014 · 511(7509):319-25doi:10.1038/nature13535 · PMID 25030168

    A bulky glycocalyx funnels integrins into adhesions and applies tension independent of contractility, and large glycoproteins were abundant on circulating tumor cells from patients with advanced disease. Mechanics, not charge.

89. 89
    Hyrc K, Wilczek A, Cieszka K. Electrophoretic heterogeneity of pigmented hamster melanoma cells.Pigment Cell Res · 1993 · 6(2):100-10doi:10.1111/j.1600-0749.1993.tb00588.x · PMID 8321866

    The strongest positive surface-charge result: mobility differences caused by sialic acid, with the more negative fraction rising with tumor size and in metastatic nodules. Hamster melanoma; no numeric mobility values in the abstract.

90. 90
    Furesz J, Pal K, Budavari I, Lapis K. The physico-chemical properties of tumor cells with different metastatic potential.Neoplasma · 1985 · 32(6):689-94PMID 4088388

    The counterweight: more total and surface sialic acid in the highly metastatic line, with the electrophoretic mobility described as unchangeable. Mouse Lewis lung lines; no numbers in the abstract.

91. 91
    Kosutova N, Lorencova L, Hires M, Jane E, Orovcik L, Kollar J, et al. Negative Charge-Carrying Glycans Attached to Exosomes as Novel Liquid Biopsy Marker.Sensors (Basel) · 2024 · 24(4):1128doi:10.3390/s24041128 · PMID 38400284

    Carcinoma-derived exosomes were smaller, more numerous and more negative in zeta potential than those from a benign line, with more sialylated glycans. One cell-line pair; no numeric zeta values in the abstract and no patient samples.

92. 92
    Utsugi T, Schroit AJ, Connor J, Bucana CD, Fidler IJ. Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes.Cancer Res · 1991 · 51(11):3062-6PMID 2032247

    Three tumorigenic human lines expressed three to seven fold more of the exposed lipid than normal keratinocytes, and loading normal cells with it made activated monocytes bind them. Cell culture.

93. 93
    Gerber DE, Horn L, Boyer M, Sanborn R, Natale R, Palmero R, et al. Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer.Ann Oncol · 2018 · 29(7):1548-1553doi:10.1093/annonc/mdy177 · PMID 29767677

    The pivotal negative trial of targeting exposed phosphatidylserine: 597 patients, median overall survival 10.5 versus 10.9 months, HR 1.06, p = 0.533. Subset signals in high beta-2 glycoprotein 1 patients and in those later given checkpoint inhibitors were not significant for the former and exploratory for the latter.

94. 94
    Adams DS, Levin M. Measuring resting membrane potential using the fluorescent voltage reporters DiBAC4(3) and CC2-DMPE.Cold Spring Harb Protoc · 2012 · 2012(4):459-64doi:10.1101/pdb.prot067702 · PMID 22474652

    A protocol for measuring resting rather than spiking voltage with dyes, in culture and in frog embryos. It describes advantages and does not validate absolute calibration.

95. 95
    Ouwerkerk R, Bleich KB, Gillen JS, Pomper MG, Bottomley PA. Tissue sodium concentration in human brain tumors as measured with 23Na MR imaging.Radiology · 2003 · 227(2):529-37doi:10.1148/radiol.2272020483 · PMID 12663825

    The human numbers for tissue sodium in malignant gliomas against normal structures and contralateral tissue. It shows raised sodium in tumors; it says nothing about the membrane voltage of individual cells.

96. 96
    James AD, Leslie TK, Kaggie JD, Wiggins L, Patten L, Murphy O'Duinn J, et al. Sodium accumulation in breast cancer predicts malignancy and treatment response.Br J Cancer · 2022 · 127(2):337-349doi:10.1038/s41416-022-01802-w · PMID 35462561

    Shows raised tumor sodium driven by the intracellular compartment, unchanged by two inhibitors of inward sodium conductance, and reduced by effective chemotherapy. Mouse models; it measures sodium, not voltage.

97. 97
    Adlung A, Westhoff N, Hausmann D, Schoenberg SO, Nörenberg D, Zöllner FG, Tollens F. Decreased Tissue Sodium Concentration in Suspected Prostate Cancer Detected by Internal-Reference 23Na MRI: A Prospective Exploratory Study.Diagnostics (Basel) · 2026 · 16(7):1064doi:10.3390/diagnostics16071064 · PMID 41975775

    Nine biopsy-proven cancers in eight of 46 men scanned; sodium lower in tumor than in the healthy contralateral gland. Small and exploratory, but it reverses the direction seen in brain and breast.

98. 98
    Malvehy J, Hauschild A, Curiel-Lewandrowski C, Mohr P, Hofmann-Wellenhof R, Motley R, et al. Clinical performance of the Nevisense system in cutaneous melanoma detection: an international, multicentre, prospective and blinded clinical trial on efficacy and safety.Br J Dermatol · 2014 · 171(5):1099-107doi:10.1111/bjd.13121 · PMID 24841846

    Sensitivity 96.6% and specificity 34.4% across 1943 evaluable lesions including 265 melanomas, giving a positive predictive value of 21.1%. An industry evaluation of the device; it supports ruling out, not ruling in.

99. 99
    Lazebnik M, Popovic D, McCartney L, Watkins CB, Lindstrom MJ, Harter J, et al. A large-scale study of the ultrawideband microwave dielectric properties of normal, benign and malignant breast tissues obtained from cancer surgeries.Phys Med Biol · 2007 · 52(20):6093-115doi:10.1088/0031-9155/52/20/002 · PMID 17921574

    Contrast of up to 10 to 1 against fatty tissue but no more than about 10% against glandular or fibroconnective tissue, measured from 0.5 to 20 GHz. It corrects earlier claims of large contrast.

100. 100
     Gascoyne PRC, Shim S, Noshari J, Becker FF, Stemke-Hale K. Correlations between the dielectric properties and exterior morphology of cells revealed by dielectrophoretic field-flow fractionation.Electrophoresis · 2013 · 34(7):1042-50doi:10.1002/elps.201200496 · PMID 23172680

     Across the NCI-60 panel, dielectric behavior was largely determined by cell size and membrane folding from the growth site. It supports dielectrophoresis as a sorting method and removes the idea of a malignant electrical signature.

101. 101
     Tong T, Hendriksen JD, Elbæk KJ, Molnar K, Christiansen FV, Ozsvar A, et al. Combined patch-clamp electrophysiology and single-cell genomic analysis reveal spiking tumor cells at the neocortical glioblastoma interface in humans.Neuro Oncol · 2026 · 28(6):1442-1457doi:10.1093/neuonc/noag059 · PMID 41857760

     Human glioblastoma cells recorded in acute and cultured slices of patient tissue; more than half of the cells at the leading edge fired aberrant action potentials, and tumor and non-tumor cells shared the phenotype. Human tissue, but slices, not an intact tumor in a patient.

102. 102
     Lassman AB, Joanta-Gomez AE, Pan PC, Wick W. Current usage of tumor treating fields for glioblastoma.Neurooncol Adv · 2020 · 2(1):vdaa069doi:10.1093/noajnl/vdaa069 · PMID 32666048

     Retrospective usage of 3 to 12% in newly diagnosed and 0 to 16% in recurrent glioblastoma at two academic centers, with a 30-respondent survey showing persistent skepticism. A small survey at one meeting, not a representative sample of oncologists.

103. 103
     Guzauskas GF, Picozzi V, Nino de Rivera Guzman JF, Wang BCM. Estimating the cost-effectiveness of tumor treating fields for locally advanced pancreatic cancer patients.J Med Econ · 2026 · 29(1):2031-2045doi:10.1080/13696998.2026.2707046 · PMID 42517235

     A cost-utility model giving $351,400 versus $220,000 in lifetime costs for 0.34 added quality-adjusted life years, an incremental cost-effectiveness ratio of $387,300 per quality-adjusted life year. Two of four authors are employed by the manufacturer, and the paper argues for judging value beyond conventional thresholds.

104. 104
     Ashmeg S, Taylor J, Lalonde R, Wadi-Ramahi S. Dosimetric impact of radiofrequency tumor treating field arrays on dose on surface and at depth.J Appl Clin Med Phys · 2026 · 27(7):e70704doi:10.1002/acm2.70704 · PMID 42418435

     Arrays left on during photon irradiation attenuated dose 2 to 4% to 10 cm depth and raised surface dose 1.81 to 1.87 fold, with repositioning cutting peak surface dose by up to 40% but leaving it 1.6 to 2.3 times baseline. Phantom measurements, not patients.

105. 105
     Kebir S, Oster C, Sharma S, Jekel L, Schmidt T, Grieger J, et al. Safety and feasibility of tumor treating fields initiated before and during radiotherapy for newly diagnosed glioblastoma: results from the Arm A feasibility cohort of a phase I/II trial (PriCoTTF).BMC Cancer · 2026 · 26(1)doi:10.1186/s12885-026-16613-y · PMID 42538542

     No protocol-defined treatment-limiting toxicity in 20 patients starting the fields before radiotherapy, with median usage 76.5%. The authors state that the toxicity definition was narrow and the efficacy analyses exploratory, so this is feasibility data only.

106. 106
     Heo J, Yoon M. Intensity- and time-dependent anticancer effects of alternating electric fields in non-small cell lung cancer cell lines.Oncol Lett · 2026 · 31(6):238doi:10.3892/ol.2026.15593 · PMID 42038346

     Cell-line work on trading field strength against exposure time, and the source used here for the statement that the therapy has been approved for metastatic non-small cell lung cancer. One author is at a company developing field-therapy dosimetry products.

107. 107
     Chen AY, Shah R, Shi W, Urman N, Shapira N, Avgeropoulos N, et al. Feasibility evaluation of tumor treating fields for brainstem gliomas.J Neurooncol · 2026 · 178(3)doi:10.1007/s11060-026-05697-y · PMID 42406140

     A seven-patient simulation study of array layouts for brainstem tumors, and the source used here for the statement that the therapy is approved for supratentorial glioblastoma. Simulation only, with manufacturer-affiliated co-authors.

108. 108
     Timmer FEF, Geboers B, Ruarus AH, Vroomen LGPH, Schouten EAC, van der Lei S, et al. MRI-guided stereotactic ablative body radiotherapy versus CT-guided percutaneous irreversible electroporation for locally advanced pancreatic cancer (CROSSFIRE): a single-centre, open-label, randomised phase 2 trial.Lancet Gastroenterol Hepatol · 2024 · 9(5):448-459doi:10.1016/S2468-1253(24)00017-7 · PMID 38513683

     The head-to-head randomized comparison, stopped early for futility, with no difference in overall survival or adverse events and a point estimate favoring radiotherapy. Funded in part by a device manufacturer; the authors call for comparison against chemotherapy alone.

109. 109
     Reddy VY, Gerstenfeld EP, Natale A, Whang W, Cuoco FA, Patel C, et al. Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation.N Engl J Med · 2023 · 389(18):1660-1671doi:10.1056/NEJMoa2307291 · PMID 37634148

     Pulsed electric field ablation was non-inferior to thermal ablation in 607 randomized patients. Not oncology; included as the clearest demonstration that electroporation does a defined clinical job. Industry funded.

110. 110
     Okino M, Mohri H. Effects of a high-voltage electrical impulse and an anticancer drug on in vivo growing tumors.Jpn J Cancer Res · 1987 · 78(12):1319-21PMID 2448275

     A single 5 kV/cm, 2 ms pulse after bleomycin shrank rat hepatocellular carcinoma to an average of 17% of initial mass in four days, while neither treatment alone worked. The founding experiment for electrochemotherapy, in rats.

111. 111
     Mir LM, Orlowski S, Belehradek J, Paoletti C. Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses.Eur J Cancer · 1991 · 27(1):68-72doi:10.1016/0277-5379(91)90064-k · PMID 1707289

     Local pulses after intramuscular bleomycin reduced and sometimes eradicated transplanted mouse tumors. Mouse work; it establishes the principle, not clinical efficacy.

112. 112
     Clover AJP, de Terlizzi F, Bertino G, Curatolo P, Odili J, Campana LG, et al. Electrochemotherapy in the treatment of cutaneous malignancy: Outcomes and subgroup analysis from the cumulative results from the pan-European International Network for Sharing Practice in Electrochemotherapy database for 2482 lesions in 987 patients (2008-2019).Eur J Cancer · 2020 · 138:30-40doi:10.1016/j.ejca.2020.06.020 · PMID 32836172

     Overall response 85% and complete response 70% across 2482 lesions, varying by histology and lesion size. A prospective registry, not a randomized comparison with alternatives.

113. 113
     Martin RCG, Kwon D, Chalikonda S, Sellers M, Kotz E, Scoggins C, McMasters KM, Watkins K. Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy.Ann Surg · 2015 · 262(3):486-94doi:10.1097/SLA.0000000000001441 · PMID 26258317

     A multicenter registry of 200 patients with median overall survival 24.9 months and local recurrence in 3%, after induction chemotherapy in all and chemoradiation in half. Compared with historical controls, not randomized.

114. 114
     Hajibandeh S, Hussain M, Abu Taha K, Sujathan V, Finch LM, Hajibandeh S, et al. Survival After Irreversible Electroporation in Unresectable Locally Advanced Pancreatic Cancer: A Meta-analysis.J Surg Res · 2026 · 327:39-48doi:10.1016/j.jss.2026.08.030 · PMID 42743900

     Single-arm and comparative meta-analysis of 31 studies; the authors grade their own certainty as low to moderate and call for randomized trials.

115. 115
     Geboers B, Timmer F, Vos D, Scheffer H, Bakker J, Ruarus A, et al. Systemic immunomodulation by irreversible electroporation versus stereotactic ablative body radiotherapy in locally advanced pancreatic cancer: the CROSSFIRE trial.J Immunother Cancer · 2025 · 13(3)doi:10.1136/jitc-2024-010222 · PMID 40139834

     The immune substudy: 20 patients per arm, with different immune activation patterns and tumor-antigen-specific T cell responses in 9 of 16 immunocompetent participants, associated with longer survival. Exploratory, small, and hypothesis-generating.

116. 116
     Miklavcic D, Cindric H, Davalos RV, Deschamps F, Gehl J, Kos B, et al. Non-thermal ablation and drug delivery by electroporation: expanding current indications beyond cancer and cardiac treatment.Radiol Oncol · 2026 · 60(3):307-322doi:10.2478/raon-2026-0040 · PMID 42583772

     Expert opinion from the Ljubljana group that developed much of the field; gives the December 2023 first FDA device approval for cardiac pulsed field ablation against three decades of slower uptake in oncology. An opinion paper, not a systematic review.

117. 117
     Zimmerman JW, Jimenez H, Pennison MJ, Brezovich I, Morgan D, Mudry A, Costa FP, Barbault A, Pasche B. Targeted treatment of cancer with radiofrequency electromagnetic fields amplitude-modulated at tumor-specific frequencies.Chin J Cancer · 2013 · 32(11):573-81doi:10.5732/cjc.013.10177 · PMID 24206915

     The authors' own review of the biofeedback-derived frequency approach and its in vitro work. A review by the group that developed the method; no controlled clinical evidence is presented.

118. 118
     Costa FP, de Oliveira AC, Meirelles R, Machado MCC, Zanesco T, Surjan R, et al. Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields.Br J Cancer · 2011 · 105(5):640-8doi:10.1038/bjc.2011.292 · PMID 21829195

     The only patient data for the frequency-specific idea: 41 patients, single group, open label, no toxicity above grade 1, median overall survival 6.7 months, four objective responses. Uncontrolled, so it establishes tolerability rather than efficacy.

119. 119
     Pihtili A, Galle M, Cuhadaroglu C, Kilicaslan Z, Issever H, Erkan F, Cagatay T, Gulbaran Z. Evidence for the efficacy of a bioresonance method in smoking cessation: a pilot study.Forsch Komplementmed · 2014 · 21(4):239-45doi:10.1159/000365742 · PMID 25231565

     A placebo-controlled double-blind pilot in 190 smokers reporting higher quit rates with a proprietary bioresonance device. A co-author is listed without affiliation and no funding or conflict statement was retrievable, so independence is unverified; the outcome is smoking cessation, not cancer.

120. 120
     Al-Zoubi RM, Farhan A, Hanbali B, Al-Zoubi SR, Khan A, Shkoor M, et al. Antiparasitic agents in oncology: Innovative mechanisms, emerging evidence and clinical potential in cancer treatment.Eur J Med Chem · 2026 · 316:118987doi:10.1016/j.ejmech.2026.118987 · PMID 42217373

     The current review of repurposing antiparasitics in oncology, including chloride channel activation by ivermectin, and explicit that clinical translation faces a paucity of adequately powered randomized trials. A narrative review with no pooled estimates.

121. 121
     Su Z, Liu M, Krohn M, Ostermann J, Schwarz S, Hahn O, et al. NAALADL1 modulates cellular resistance to Tumor Treating Fields in colorectal cancer.NPJ Precis Oncol · 2026 · 10(1)doi:10.1038/s41698-026-01492-0 · PMID 42191816

     The first systematic test across a large panel of low-passage colorectal lines, from an academic group with no manufacturer author; finds wide heterogeneity in response and a resistance gene. Cell lines only.

122. 122
     Senturk F, Kocum IC, Aksan ES, Duzen U. A programmable electroculture platform for direction-dependent alternating electric field delivery in cancer cell models.Phys Med Biol · 2026 · 71(16)doi:10.1088/1361-6560/ae99a6 · PMID 42594945

     A purpose-built exposure system, independent of the manufacturer's hardware, reproducing the antiproliferative effect at 200 kHz and 3 V/cm in glioblastoma and neuroblastoma lines with endothelial cells less sensitive. Cell lines only.

123. 123
     Wilson RA, Barnes PE. The formation and turnover of the membranocalyx on the tegument of Schistosoma mansoni.Parasitology · 1977 · 74(1):61-71doi:10.1017/s0031182000047533 · PMID 402626

     The outer coat of the adult worm can be labeled with cationized ferritin, a positively charged marker, and turns over with a half-life of 2 to 3 hours. Cytochemistry, not a numeric surface charge.

124. 124
     Cavalcanti MGS, Araújo HRC, Paiva MHS, Silva GM, Barbosa CCGS, Silva LF, et al. Ultrastructural and cytochemical aspects of Schistosoma mansoni cercaria.Micron · 2008 · 40(3):394-400doi:10.1016/j.micron.2008.09.006 · PMID 19081261

     Cationized ferritin stains the cercarial surface strongly; removing sialic acid with neuraminidase did not abolish it, but trypsin or chondroitinase did. Cytochemistry on the infective larva.

125. 125
     Murrell KD, Graham CE, McGreevy M. Strongyloides ratti and Trichinella spiralis: net charge of epicuticle.Exp Parasitol · 1983 · 55(3):331-9doi:10.1016/0014-4894(83)90030-9 · PMID 6221941

     Both larval epicuticles carry a net negative charge; in Strongyloides it is dense and uniform and behaves like a highly sulfated mucopolysaccharide, while in Trichinella it tracks carboxyl groups instead. A sign of charge, not a number.

126. 126
     Page AP, Rudin W, Fluri E, Blaxter ML, Maizels RM. Toxocara canis: a labile antigenic surface coat overlying the epicuticle of infective larvae.Exp Parasitol · 1992 · 75(1):72-86doi:10.1016/0014-4894(92)90123-r · PMID 1639165

     The larval surface coat binds cationized ferritin and ruthenium red, indicating a net negative charge, and is shed when antibody binds it. Cytochemistry and immuno-electron microscopy.

127. 127
     de Souza W, Souto-Padrón T, Dreyer G, de Andrade LD. Fine structure and localization of anionic sites on the surface of microfilaria of Wuchereria bancrofti.J Submicrosc Cytol Pathol · 1989 · 21(1):121-9PMID 2649230

     Cationized ferritin binds the sheath and the epicuticle of the microfilaria. No DOI is registered for this record, so it is identified by PubMed ID; cytochemistry, not a numeric surface charge.

128. 128
     Hanna REB, Moffett D, Robinson MW, Jura WGZO, Brennan GP, Fairweather I, Threadgold LT. Fasciola gigantica: Ultrastructural cytochemistry of the tegumental surface in newly-excysted metacercariae and in vitro-penetrated juvenile flukes informs a concept of parasite defence at the interface with the host.Vet Parasitol · 2019 · 274:108923doi:10.1016/j.vetpar.2019.108923 · PMID 31542719

     The juvenile fluke's glycocalyx is polyanionic and carbohydrate-rich throughout its depth, with a thick capsule not seen in adults. Cytochemistry on larvae, and the authors read it as immune defense rather than as electrostatics.

129. 129
     Costa e Silva Filho F, Elias CA, de Souza W. Further studies on the surface charge of various strains of Trichomonas vaginalis and Tritrichomonas foetus.Cell Biophys · 1986 · 8(3):161-76doi:10.1007/BF02788492 · PMID 2425974

     No difference between the two species but significant differences between strains, with more mouse-pathogenic strains carrying a more negative surface, and enzyme treatment showing a sialoglycoconjugate contribution. Protozoa, with pathogenicity measured in a subcutaneous mouse assay.

130. 130
     Lacey E. The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles.Int J Parasitol · 1988 · 18(7):885-936doi:10.1016/0020-7519(88)90175-0 · PMID 3066771

     The standard review of the benzimidazole mechanism, which is tubulin binding and has nothing to do with voltage; no abstract in the record.

131. 131
     Choudhary S, Kashyap SS, Martin RJ, Robertson AP. Advances in our understanding of nematode ion channels as potential anthelmintic targets.Int J Parasitol Drugs Drug Resist · 2021 · 18:52-86doi:10.1016/j.ijpddr.2021.12.001 · PMID 35149380

     Review stating that the majority of antinematodal drugs target ion channels, and cataloging them by class.

132. 132
     Waechtler A, Cezanne B, Maillard D, Sun R, Wang S, Wang J, Harder A. Praziquantel - 50 Years of Research.ChemMedChem · 2023 · 18(12):e202300154doi:10.1002/cmdc.202300154 · PMID 37009677

     Industry-authored history of the drug from the Bayer-Merck cooperation onward; cited here for dates only.

133. 133
     Rohr CM, Sprague DJ, Park SK, Malcolm NJ, Marchant JS. Natural variation in the binding pocket of a parasitic flatworm TRPM channel resolves the basis for praziquantel sensitivity.Proc Natl Acad Sci U S A · 2022 · 120(1):e2217732120doi:10.1073/pnas.2217732120 · PMID 36574686

     Explains why flukes and cyclophyllidean tapeworms are sensitive and other flatworms less so, through a single gatekeeper residue, across a roughly 300-fold range. Functional profiling of orthologs, not clinical data. Epub 27 Dec 2022; the volume and issue carry a 3 January 2023 cover date.

134. 134
     Berger DJ, Park SK, Crellen T, Vianney TJ, Kabatereine NB, Cotton JA, et al. Extensive parasite transmission and variation in a functional receptor associated with drug resistance in endemic Schistosoma mansoni.Sci Adv · 2026 · 12(29):eadt3721doi:10.1126/sciadv.adt3721 · PMID 42467774

     570 sequenced samples across eight countries, with four naturally occurring channel variants associated with reduced drug sensitivity and instances of treatment failure. It shows standing variation for resistance; it does not establish widespread clinical resistance.

135. 135
     Kohn AB, Anderson PA, Roberts-Misterly JM, Greenberg RM. Schistosome calcium channel beta subunits. Unusual modulatory effects and potential role in the action of the antischistosomal drug praziquantel.J Biol Chem · 2001 · 276(40):36873-6doi:10.1074/jbc.C100273200 · PMID 11500482

     The earlier calcium channel hypothesis, supported by schistosome beta subunits conferring drug sensitivity on an otherwise insensitive mammalian channel. Heterologous expression; now largely superseded by the channel genetics.

136. 136
     Sprague DJ, Park SK, Gramberg S, Bauer L, Rohr CM, Chulkov EG, et al. Target-based discovery of a broad-spectrum flukicide.Nat Struct Mol Biol · 2024 · 31(9):1386-1393doi:10.1038/s41594-024-01298-3 · PMID 38714890

     A single amino acid change in the target explains why praziquantel fails against Fasciola, and the Fasciola channel was then used as a target to find a new chemical series active across the profiled flukes. In vitro and ex vivo parasites, no animal efficacy study here.

137. 137
     Park SK, Sprague DJ, Rohr CM, Chulkov EG, Petrow I, Kumar S, Marchant JS. The anthelmintic meclonazepam activates a schistosome transient receptor potential channel.J Biol Chem · 2023 · 300(1):105528doi:10.1016/j.jbc.2023.105528 · PMID 38043794

     A second, distinct schistosome TRPM channel as the target of a benzodiazepine that, unlike praziquantel, retains activity against juvenile worms. The compound's human side effects rule it out as a drug as it stands.

138. 138
     Rohr CM, Park SK, Aguiar-Martins K, Anderson TJC, Berger DJ, Berriman M, et al. TRPtracker: a community database for monitoring praziquantel sensitivity at TRPM variants.Int J Parasitol Drugs Drug Resist · 2026 · 30:100639doi:10.1016/j.ijpddr.2026.100639 · PMID 41865684

     A shared database of natural channel variants, their geography and frequency, and their measured praziquantel sensitivity in a heterologous expression system. A surveillance resource, not evidence of clinical resistance.

139. 139
     Cully DF, Vassilatis DK, Liu KK, Paress PS, Van der Ploeg LHT, Schaeffer JM, Arena JP. Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans.Nature · 1994 · 371(6499):707-11doi:10.1038/371707a0 · PMID 7935817

     Establishes the invertebrate-specific target of ivermectin. All authors were at the company that discovered and markets the drug, so the paper defining its selectivity comes from the manufacturer.

140. 140
     Hibbs RE, Gouaux E. Principles of activation and permeation in an anion-selective Cys-loop receptor.Nature · 2011 · 474(7349):54-60doi:10.1038/nature10139 · PMID 21572436

     The 3.3 angstrom structure showing ivermectin bound in the transmembrane domain and stabilizing an open pore. Structural biology; it explains the mechanism without addressing clinical use.

141. 141
     Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs.Cell · 1994 · 77(4):491-502doi:10.1016/0092-8674(94)90212-7 · PMID 7910522

     Mice lacking the barrier pump were 100-fold more sensitive to ivermectin. The reason a drug that targets an invertebrate channel is safe in mammals, shown in mice.

142. 142
     Bah GS, Schneckener S, Hahnel SR, Bayang NH, Fieseler H, Schmuck GM, et al. Emodepside targets SLO-1 channels of Onchocerca ochengi and induces broad anthelmintic effects in a bovine model of onchocerciasis.PLoS Pathog · 2021 · 17(6):e1009601doi:10.1371/journal.ppat.1009601 · PMID 34077488

     A potassium channel drug that killed adult filarial worms in cattle by 18 months, which ivermectin does not do. Eight of eighteen authors work for the developer, and the model is cattle.

143. 143
     Taylor L, Many S, Jeanguenat H, Hattendorf J, Sayasone S, Keiser J. Efficacy and safety of ascending doses of emodepside in comparison with ivermectin in adults infected with Strongyloides stercoralis in Laos: a phase 2a, dose-ranging, randomised, parallel-group, placebo-controlled, single-blind clinical trial.Lancet Infect Dis · 2025 · 25(11):1254-1264doi:10.1016/S1473-3099(25)00255-5 · PMID 40580974

     202 adults in eight arms of about 25; emodepside matched ivermectin from 15 mg upward, with transient drowsiness and blurred vision the commonest effects. Academic funding (European Research Council, Uniscientia Foundation); single-blind, and a phase 2a dose-finding study rather than a pivotal trial.

144. 144
     Fetterer RH, Pax RA, Bennett JL. Praziquantel, potassium and 2,4-dinitrophenol: analysis of their action on the musculature of Schistosoma mansoni.Eur J Pharmacol · 1980 · 64(1):31-8doi:10.1016/0014-2999(80)90366-0 · PMID 7449814

     Praziquantel at one micromolar causes a rapid sustained contracture with calcium accumulation in the parasite, blocked by lanthanum. Isolated worms in a bath.

145. 145
     Brading AF, Caldwell PC. The resting membrane potential of the somatic muscle cells of Ascaris lumbricoides.J Physiol · 1971 · 217(3):605-24doi:10.1113/jphysiol.1971.sp009588 · PMID 5098084

     The roundworm muscle potential is relatively insensitive to the potassium, sodium and chloride of the bath, and the authors suggest an electrogenic pump supplies most of it.

146. 146
     Abad V, Alejandre M, Hernandez-Fernandez E, Raso J, Cebrian G, Alvarez-Lanzarote I. Evaluation of Pulsed Electric Fields (PEF) Parameters in the Inactivation of Anisakis Larvae in Saline Solution and Hake Meat.Foods · 2023 · 12(2):264doi:10.3390/foods12020264 · PMID 36673356

     3 kV/cm and 50 kJ/kg inactivated close to 100% of larvae in hake while affecting moisture, water-holding capacity and cooking loss less than freezing. Food processing, not treatment of an infected person.

147. 147
     EFSA Panel on Biological Hazards; Koutsoumanis K, Allende A, Alvarez-Ordonez A, Bover-Cid S, Chemaly M, et al. Re-evaluation of certain aspects of the EFSA Scientific Opinion of April 2010 on risk assessment of parasites in fishery products, based on new scientific data. Part 1: ToRs1-3.EFSA J · 2024 · 22(4):e8719doi:10.2903/j.efsa.2024.8719 · PMID 38650612

     The official assessment: freezing and heating remain the most efficient ways to kill parasites in fish, pulsed electric field is promising but needs development, and ultrasound was not effective. A regulatory opinion, not a trial.

148. 148
     Chawla K, Modena MM, Ravaynia PS, Lombardo FC, Leonhardt M, Panic G, Burgel SC, Keiser J, Hierlemann A. Impedance-Based Microfluidic Assay for Automated Antischistosomal Drug Screening.ACS Sens · 2018 · 3(12):2613-2620doi:10.1021/acssensors.8b01027 · PMID 30426744

     Electrical impedance used to read the size and motility of schistosome larvae automatically, replacing subjective visual scoring. A laboratory tool; the electricity measures the parasite rather than treating it.

149. 149
     Sharmeen S, Skrtic M, Sukhai MA, Hurren R, Gronda M, Wang X, et al. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells.Blood · 2010 · 116(18):3593-603doi:10.1182/blood-2010-01-262675 · PMID 20644115

     The clearest bioelectric anticancer mechanism for an antiparasitic drug: chloride influx, plasma membrane hyperpolarization without change in mitochondrial potential, reactive oxygen species, and delayed tumor growth in three mouse models. Low micromolar concentrations in cells and mice; no human trial.