Background: Brain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofrequency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF). Methods: 27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metastasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to animals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic underpinnings associated with cancer inhibition was identified using an agnostic approach. Findings: Animal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca 2+ influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, activated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of β-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H. Interpretation: We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.

Summary Anticipatory nausea and vomiting (ANV) after repeated cycles of cytotoxic chemotherapy is thought to be a conditioned response to a conditioning stimulus. Good control of acute and delayed emesis may result in a lower incidence of ANV. We have analysed data from 574 chemotherapy patients who received granisetron as their antiemetic treatment during repeat cycle chemotherapy. Per treatment cycle, less than 10% of patients displayed symptoms of anticipatory nausea and 2% or less had symptoms of anticipatory vomiting. It is concluded that the use of granisetron as an antiemetic during the acute phase of chemotherapy may result in a lower incidence of ANV in patients undergoing repeat cycle chemotherapy.The treatment of many forms of malignant disease often involves the use of cytotoxic agents whose toxic effects include nausea and/or vomiting. Andrykowski et al. (1985) showed that, in patients undergoing the initial phase of chemotherapy, emesis is an unconditioned response. However, after a few cycles of emetogenic chemotherapy during which the patient experiences emesis, the association of factors linked with chemotherapy (visual, gustatory, olfactory, environmental) may themselves initiate emesis. These factors are considered to be conditioned stimuli eliciting a conditioned response (emesis). Typically, these factors may precipitate emesis prior to the administration of chemotherapy, and this emesis is referred to as anticipatory nausea and vomiting (ANV). The incidence of ANV may vary widely from centre to centre owing to heterogeneity of patients and treatments. Early reviews of the prevalence of ANV showed that it ranges from 28.3% (Nicholas, 1982) to 44% (Nesse et al., 1980). Love et al. (1982) reported a prevalence of anticipatory vomiting of 38%. The percentage of patients who reported ANV was subdivided by Morrow et al. (1982) into 24% who experienced anticipatory nausea and 9% anticipatory vomiting. The relationship between the development of ANV and the number of chemotherapy treatments has also been documented (Redd & Andresen, 1981;Nicholas, 1982;Redd et al., 1982).Chang (1981) showed that ANV is poorly responsive to treatment with conventional antiemetics, and much effort has been put into understanding the aetiology of ANV by Morrow et al. (1991). Behavioural treatment (Morrow & Morrell, 1982) to desensitise patients by means of counselling or by relaxation techniques has been considered.It is now accepted that the development of ANV is a function of the emetogenicity and frequency of chemotherapy treatments. In a study by Wilcox et al. (1982), prevention of post-chemotherapy nausea and vomiting by conventional antiemetics was associated with the prevention of symptoms of ANV. The recent introduction of the potent and selective 5-HT3 antagonists as antiemetics (granisetron, ondansetron and tropisetron) has been regarded as being a significant advance in the control of acute emesis. In this paper we analyse the incidence of the symptoms of ANV of patients who have undergone repeat cycle...

The combination of dexamethasone plus ondansetron is more effective in protecting chemotherapy-naive patients undergoing their first course of highly emetogenic chemotherapy with cisplatin and chemotherapy-pretreated patients refractory to standard antiemetics from chemotherapy-induced nausea and vomiting compared to ondansetron plus placebo.

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We conclude that MDL 73.147 EF is a well tolerated and possibly effective antiemetic.