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This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum-based intravenous chemotherapy. Twelve patients with operable, recurrent platinum-sensitive EOC (recurrence !6 months after first-line therapy) were included according to the classical 313 dose-escalation design at three dose levels-60, 80 and 100 mg=m 2 . After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41-43 C. Postoperatively, all patients were treated with standard intravenous platinum-based combination chemotherapy. One of six patients experienced a dose-limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg=m 2 . The remaining five patients treated with 100 mg=m 2 tolerated their treatment well. The recommended phase II dose was established at 100 mg=m 2 . The mean peritoneal-to-plasma AUC ratio was 19Á5 at the highest dose level. Cisplatin-induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1-3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum-based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg=m 2 has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinumsensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg=m 2 . The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

Background The cholinergic anti‐inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non‐invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. Methods Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c‐fos+ cells. Gene and protein expression of IL‐6, MCP‐1, IL‐1β as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL‐6, TNFα, and IL‐1β serum levels were analyzed 3 hours after lipopolysaccharide administration. Results tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia‐induced IL‐6 and TNF‐α release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. Conclusion tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non‐invasive approach for treatment of POI.