A phase I, single-arm, open-label, dose escalation study of intraperitoneal cisplatin and doxorubicin in patients with recurrent ovarian cancer and peritoneal carcinomatosis.

OBJECTIVE: We performed a phase I, single-arm, non-randomized, open-label, dose-escalation trial to determine the dose-limiting toxicity of intraperitoneal cisplatin and doxorubicin applied as pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with recurrent ovarian cancer. METHODS: We used a standard 3 + 3 dose-escalation design with doxorubicin 1.5 mg/m2, cisplatin 7.5 mg/m2 q 4 to 6 weeks for 3 cycles and subsequent dose escalation steps (20% increment per step) in patients with recurrent ovarian cancer and peritoneal carcinomatosis. Toxicity and clinical efficacy were monitored. The primary endpoint was the maximum-tolerable dose. Secondary endpoints included histologic tumor regression and serum parameters. RESULTS: 15 evaluable patients (3, 7, and 5 in cohorts 1, 2, and 3, respectively) on average received 2.3 PIPAC cycles. No dose limiting toxicities were found. Adverse side effects were 1 grade 3 event (colon perforation) and 85 grade 1/2 events including fatigue (n = 19), abdominal pain (n = 18), nausea/vomiting (n = 14), sleep disorder (n = 8), diarrhea (n = 5), and fever (n = 2). Liver and renal toxicity was not observed in any of the 3 cohorts (AST 19.1 ±â€¯3.2, 25.8 ±â€¯6.5, and 22.1 ±â€¯4.5 IU/L, respectively; ALT 14.7 ±â€¯3.5, 18.5 ±â€¯5.6, and 23.3 ±â€¯13.0 IU/L, respectively; GGT 45.7 ±â€¯35.1, 25.2 ±â€¯10.3, and 43.9 ±â€¯26.4 IU/L, respectively; serum creatinine 1.06 ±â€¯0.23, 0.80 ±â€¯0.17, and 0.89 ±â€¯0.35 mg/dL, respectively). No systemic hematologic toxicity, alopecia, or neurotoxicity was noted. The maximum tolerable dose was not reached. Histologic tumor regression was observed in 7/11 (64%) patients who underwent ≥2 PIPAC cycles. CONCLUSIONS: PIPAC with cisplatin and doxorubicin may be safely used at an intraperitoneal dose of 10.5 mg/m2 and 2.1 mg/m2, respectively. Systemic toxicity of this therapy is low.

The Liver and Small Intestine Can Partly Compensate Severe Normovolemic Hemodilution in a Rat Model.

BACKGROUND: Knowing the individual critical hematocrit for every organ is essential in operative scenarios in which extensive blood losses are expected. In the past, experimental settings were very heterogeneous resulting in the publication of widely differing values even for one organ in the same species. This study aimed to investigate the compensatory capacity of the liver and the small intestine in a rat model of severe normovolemic hemodilution. MATERIALS AND METHODS: Male rats were subjected to a stepwise hemodilution with a succinylated gelatin-containing solution to a final hematocrit of 10%, being observed for additional 150 min. During the course of the experiment, blood glucose and L-lactate, as well as D-lactate and intestinal fatty acid-binding protein-2 measurements, were performed eight times in total. The amino acids alanine and glutamine were measured during dilution and at the end of the experiment (four times in total). Hemodilutional effects on the blood and oxygen supply of the liver and the small intestine were measured in a minimally invasive manner. RESULTS: In the liver and the small intestine, there were no substantial changes in the blood flow of the microcirculation. Plasma glucose and lactate levels rose transiently, whereas lactate values did not exceed the upper threshold of aerobic metabolism. Plasma levels of the amino acids alanine and glutamine rose significantly and stayed elevated, whereas D-lactate and intestinal fatty acid-binding protein-2 were not significantly increased at any point during the whole experimental time compared to the initial value. CONCLUSIONS: Severe hemodilution with a succinylated gelatin-containing solution is tolerated at a profoundly low hematocrit value of 10% during the experimental phase of 150 min.

Histidine and other amino acids in blood and urine after administration of Bretschneider solution (HTK) for cardioplegic arrest in patients: effects on N-metabolism.

Bretschneider (histidine-tryptophan-ketoglutarate, HTK) solution employed for induction of cardioplegic arrest possesses a high histidine concentration (198 mM). Due to the large volume administered, massive amounts of histidine are incorporated. The aim of the study was to evaluate alterations in amino acid and nitrogen metabolism originating from histidine degradation. Between 07/2014 and 10/2014, a total of 29 consecutive patients scheduled for elective isolated coronary artery bypass grafting with cardiopulmonary bypass (CPB) were enrolled in this prospective observational study. The patients received 1.6 L cardioplegic Bretschneider solution on average. Blood gas and urine samples obtained were analyzed for amino acid as well as urea and ammonium concentrations. After CPB initiation, plasma histidine concentration greatly increased to 21,000 µM to reach 8000 µM at the end. Within the operative period, plasma concentrations of aspartate, glutamate, asparagine, alanine, and glutamine increased variable in magnitude. During the same time, urinary analysis revealed histidine excretion of 19,500 µmol in total and marked elevations in glutamate and glutamine excretion. The absolute amounts of urea and ammonium excreted additionally were 3 mmol and 8 mmol, respectively. Already during CPB, distinct amounts of the histidine administered are metabolized, mainly to other amino acids, but only small amounts to urea and ammonia. Thus, the impact of the histidine incorporated on acid-base status in the intraoperative phase is minor. On the other hand, intraoperative provision of several amino acids arising from histidine metabolism might mitigate postaggression syndrome.

Concentrations of cisplatin and doxorubicin in ascites and peritoneal tumor nodules before and after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with peritoneal metastasis.

INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new means of delivering chemotherapy into the abdomen of patients with peritoneal carcinomatosis (PC). The amount of drug uptake in ascites and peritoneum after PIPAC is unknown. METHODS: Retrospective cohort study of women with PC from gynecological tumors comparing the concentrations of cisplatin and doxorubicin in ascites and peritoneum before and after PIPAC. Concentrations were measured using gas chromatography. Peritoneal tumor samples were assessed for histological tumor regression. RESULTS: 59 PIPAC procedures were performed in 32 women with PC. The concentrations of doxorubicin and cisplatin in ascites significantly increased after PIPAC (140.2 ± 671.5 vs 9035.7 ± 5328.6 ng/ml; p < 0.0001 and 95.2 ± 106.4 vs 24,770.8 ± 11,710.8 ng/ml; p < 0.0001, respectively). Concentrations of doxorubicin and cisplatin in peritoneal tissue also significantly increased after PIPAC (5.1 ± 0.7 vs 19.2 ± 38.6 ng/g; p = 0.007, and 81.9 ± 7.8 vs 131.5 ± 134.4 ng/g; p = 0.005, respectively). On an individual patient level, a significant uptake (>2-fold) of doxorubicin and cisplatin was observed in 57/59 (97%) and 58/59 (98%) of cases in ascites and in 23/59 (39%) and 13/59 (22%) of cases in the peritoneum. Uptake of cisplatin and doxorubicin were significantly correlated (Spearman correlation coefficient: 0.33; p = 0.011). After repeated PIPACs, doxorubicin uptake increased in peritoneal tumor tissue (p = 0.008). CONCLUSIONS: PIPAC leads to a significant chemotherapy uptake in both ascites and peritoneum, suggesting a bimodal cytotoxic effect of PIPAC via direct tissue uptake into peritoneal tumor nodules and via ascites. Consecutive PIPAC applications lead to peritoneal accumulation of doxorubicin, suggesting a cumulative cytotoxic effect of doxorubicin after repeated PIPACs.

Transient dilutional acidosis but no lactic acidosis upon cardiopulmonary bypass in patients undergoing coronary artery bypass grafting.

INTRODUCTION: Dilutional acidosis may result from the introduction of a large fluid volume into the patients' systemic circulation, resulting in a considerable dilution of endogenous bicarbonate in the presence of a constant carbon dioxide partial pressure. Its significance or even existence, however, has been strongly questioned. Blood gas samples of patients operated on with standard cardiopulmonary bypass (CPB) were analyzed in order to provide further evidence for the existence of dilutional acidosis. MATERIAL AND METHODS: Between 07/2014 and 10/2014, a total of 25 consecutive patients scheduled for elective isolated coronary artery bypass grafting with CPB were enrolled in this prospective observational study. Blood gas samples taken regularly after CPB initiation were analyzed for dilutional effects and acid-base changes. RESULTS: After CPB initiation, hemoglobin concentration dropped from an average initial value of 12.8 g/dl to 8.8 g/dl. Before the beginning of CPB, the mean value of the patients' pH and base excess (BE) value averaged 7.41 and 0.5 mEq/l, respectively. After the onset of CPB, pH and BE values significantly dropped to a mean value of 7.33 (p < 0.0001) and -3.3 mEq/l (p < 0.0001), respectively, within the first 20 min. In the following period during CPB they recovered to 7.38 and -0.5 mEq/l, respectively, on average. Patients did not show overt lactic acidosis. CONCLUSIONS: The present data underline the general existence of dilutional acidosis, albeit very limited in its duration. In patients undergoing coronary artery bypass grafting it seems to be the only obvious disturbance in acid-base homeostasis during CPB.