Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the secretory glands. Conventional chemotherapy has poor effectiveness against metastatic ACC. Thus, a novel effective therapy is needed against metastatic ACC. A majority of ACCs (up to 94%) express c-kit. Imatinib is monoclonal antibody with specific activity against c-kit but has not been found to be effective in treating patients with ACC in which c-kit is overexpressed and activated. The NF-κB and mTOR pathways have been shown that ubiquitously and concurrently activated, indicating that the inhibition of these pathways may represent a novel treatment approach for patients with ACC. Curcumin has been shown to inhibit NF-κB and NF-κB-related pathways. 43-year-old patient was diagnosed ACC from submandibular salivary gland. After complete resection of tumor adjuvant radiotherapy was initiated. Seven years later multiple lung metastases were detected and ACC was confirmed by re-biopsy. First-line chemotherapy failed. NF-κB and c-kit were overexpressed in the metastatic specimens. Therefore, we treated the patient with metastatic chemoresistant ACC with imatinib 400mg/day and intravenous curcumin 225mg/m(2) twice a week plus oral bioavailable curcumin Arantal(®) 2×84mg/day. At 24 months, we observed near complete anatomic and complete metabolic response. To our knowledge, this is the first report of a patient with a c-kit-positive ACC that is successfully treated with the combination of imatinib and curcumin in an integrative approach.

Background: Tumor-specific DNA repair defects are ubiquitous in cancerous tissue, which offers a potential for clinical gain to build on these perturbations. Intravenous high-dose vitamin C (IVC) triggers the formation of hydrogen peroxide (H₂O₂), which contributes to Fenton chemistry producing hydroxyl radicals (-OH), causing selective damage to DNA. Herein, we evaluated the therapeutic response to IVC and PARP inhibitors (PARPi) in combination in 8 patients with a deficiency of homologous recombination repair system (dHRR) in a 3-year period. Material and Methods: Eight patients with progressive stage IV malignancy, who were pre-treated with conventional methods, were admitted to our clinic. Subsequent therapy has included IVC at a dose that was set to be in the range of 1 to 1.5 g/kg, although 1.25 g/kg was dominantly administered. Furthermore, following genomic evaluation, PARPi (niraparib or olaparib or talazoparib) was chosen to be used in combination with IVC which was administered 2 to 4 times a week. Results: In the present study, we achieved partial response in 5 patients and complete response in 3 patients. Grade 2 anemia and fatigue toxicities were observed in some cases, while grade 3 toxicity was not found in any of the patients. Conclusion: Our 8 patient case study shows that IVC could be a plausible additional therapy for HRR deficiency. Although the single agent PARPi therapy is effective for metastatic disease, an overall survival (OS) advantage has not been demonstrated. Our results suggest that adding IVC can improve PARPi therapy outcomes. To fully endorse the results stated above, combinatorial therapy of intravenous high dose vitamin C and PARP inhibitors needs to be reviewed in broader cohorts of patients.

Hyperthermia has been shown to be a medically useful procedure applicable for different indications. For the connection between clinical effects and heat, it is important to understand the actual temperatures achieved in the tissue. There are limited temperature data available when using capacitive hyperthermia devices even though this is worldwide the most widespread method for loco-regional heating. Hence, this study examines temperature measurements using capacitive heating. Bioequivalent phantoms were used for the measurements, which, however, do not consider perfusion in live tissue. In general, the required temperature impact for an effective cancer therapy should need an increase of 0.2°C/min, which has been achieved. In the described tests on the non-perfused dummy, on average, the temperature increases by approximately 2°C in the first 12 min. The temperature difference relative to the starting temperature was 10–12°C within a therapy time of 60 min (rising from the initial room temperature between 20–24°C and 32–34°C). The average deviation with three individual measurements each on different days in a specified localization was 2°C. The minimum temperature difference was 4.2°C, and the maximum value was reached in the liver with 10.5°C. These values were achieved with a moderate energy input of 60–150 watts, with much higher performance outputs still available. These results show that the tested capacitive device is capable of achieving quick temperature increase with a sufficient impact into the depth of a body.

Ewing’s sarcoma (ES) is a bone and soft tissue tumor that mainly occurs at a young age. The underlying cause of Ewing’s sarcoma is the formation of fusion proteins between FET family genes and ETS family genes. Tumors with FET/ETS fusion genes can have defects in the DNA damage response and are sensitive to PARP inhibitors (PARPi). However, several studies have shown that PARPi alone is not sufficient to induce a meaningful antitumor response and that combinations of DNA-damaging agents with PARPi are required to achieve efficacy. Accordingly, preclinical studies have reported dramatic responses to PARPi treatment in combination with DNA-damaging agents such as temozolomide or irinotecan. Similarly, it has been previously reported that by generating reactive oxygen species, high-dose intravenous vitamin C (IVC) can induce DNA damage. This suggests that the combination of IVC with PARPi may increase genotoxic stress and enhance the antitumor response. In addition, unlike chemotherapeutic agents, IVC induces DNA damage selectively in cancer cells, and the side effects are significantly milder than those of chemotherapy. As ETS fusion-positive ES is deficient in faithful DNA repair, partly due to the interaction between ETS fusion products and PARP1, a PARPi plus IVC seems to be a logical and effective combination for the treatment of ETS fusion-positive ES. This paper reports significant responses to IVC (1–1.5 g/kg) in combination with PARPi (olaparib 300 mg BID or talazoparib 1 mg/day) in two patients with metastatic Ewing’s sarcoma. The observations highlight an unmet therapeutic need for patients with advanced metastatic ES. The combination of PARPi with a selective DNA-damaging agent was effective in these cases. This case experience suggests that IVC may be incorporated into PARPi-based therapeutic strategies. Further studies are needed to confirm the efficacy of this combination in the treatment of Ewing sarcoma with ETS fusions.

Complete response to Trametinib in a heavily-pretreated sarcoma: RAF1 as a predictor of MEKi Response