The effects of hypoxia and reoxygenation on action potentials (AP), contractions, and certain biochemical parameters were studied in isolated rat ventricular myocytes in monolayer culture in the presence and absence of glucose. Substrate deprivation alone had no influence on the basal properties. In the presence of glucose, a 4-h hypoxic treatment caused only a moderate decrease in AP amplitude and rate. In substrate-free conditions, hypoxia induced a gradual decline in plateau potential level and in AP duration and rate, followed by rhythm abnormalities and a failure of the electromechanical coupling. Spontaneous AP generation then ceased, and the resting potential decreased with increased duration of hypoxia. These alterations were associated with a decrease in ATP content, an increase in the lactate production, and a leakage of about 50% of the total cellular lactate dehydrogenase (LDH). Cells reoxygenated after 150 min hypoxia recovered near-normal function, while the ATP depletion ceased and the rate of lactate and LDH loss was diminished. Conversely, cells reoxygenated after 4 h hypoxia exhibited a further decrease of the residual resting polarization and no change in the decline of intracellular ATP and in the efflux of cytosolic lactate and LDH. The results of this study indicate that (1) the sequence and the extent of functional alterations are dependent on the duration of hypoxia in the absence of exogenous substrate and (2) ATP depletion and the amount of lactate and LDH released during hypoxia are related to the shift from reversibly to irreversibly damaged cells.

Early stage epithelial ovarian carcinoma is defined pathologically as a tumor strictly limited to one or both ovaries without any extra‐ovarian disease (i.e., Stage IA or B of the International Federation of Gynecology and Obstetrics (FIGO) classification). This diagnosis can be obtained only after an exhaustive surgical staging procedure, performed as soon as the diagnosis of epithelial invasive ovarian carcinoma is established. This staging surgery currently encompasses a peritoneal cytology, the thorough inspection of all the visceral and parietal peritoneal surfaces with biopsy of any abnormality, total abdominal hysterectomy and bilateral salpingo‐oophorectomy (TAH + BSO), random peritoneal biopsies, omentectomy, appendectomy and bilateral pelvic and para‐aortic lymphadenectomies, up to the left renal vein. The results of this staging procedure and its indications are discussed. In all of the cases, the radical removal of the pathologic adnexa is indicated, along with the complete peritoneal and retroperitoneal staging. While fertility‐sparing surgery (avoiding hysterectomy and contralateral adnexectomy, if possible) seems to be safe for young women, a TAH + BSO is the rule for the others. Adjuvant chemotherapy can be omitted in well‐differentiated tumors with a negative staging operation, but currently it remains indicated in all other cases. Indeed, the ultimate goal in early stage ovarian carcinoma is to not impair by inadequate management the high chance of a cure. Semin. Surg. Oncol. 19:36–41, 2000. © 2000 Wiley‐Liss, Inc.

The cytotoxicity of 48 compounds included in the MEIC (Multicenter Evaluation of In Vitro Cytotoxicity) list was determined in cultures of rat hepatocytes, McCoy, and MDBK cells. The average minimum concentration of each compound inducing cytotoxicity was measured in each cell type. The cytotoxicity values were then compared with published oral LD50 values for rats and mice. The logarithmic transformation of in vivo toxic doses and the corresponding in vitro cytotoxic concentrations showed a statistically significant correlation between the in vitro and in vivo values. The results show that an accurate in vivo LD50 dose could be predicted from in vitro data for at least 75% of the selected compounds. It is hoped that this finding will not only stimulate others to pursue in vitro technique but will eventually lead to elimination of the in vivo LD50 test.

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5512 Background: Nintedanib, an oral inhibitor of VEGF-FGF-PDGF receptors, has been shown to prolong progression-free survival (PFS) when added to adjuvant chemotherapy after primary surgery (duBois A, Lancet Oncol 2015). CHIVA trial explored the role of nintedanib in combination with NACT. Methods: Patients (pts) with FIGO stage IIIC-IV chemotherapy-naive AEOC considered as unresectable after laparoscopic evaluation were randomized (2:1) to be treated with 3 to 4 cycles (cy) of carboplatin (AUC 5 mg/mL/min) and paclitaxel (175 mg/m²) (CP) before interval debulking surgery (IDS) followed by 2 to 3 cy of CP for a total of 6 cy, plus either 200 mg of Nin (armA) or placebo (armB) twice daily on days 2–21 q3week at cy 1&2, 5&6 and maintenance therapy for up to 2 years. The primary endpoint was PFS. Results: Between Jan. 2013 and May 2015, 188 pts were included (124 arm A, 64 arm B) with a median Peritoneal Cancer Index of 22 (range 19-27). Pts characteristics were well balanced between both arms. Median PFS was 14.4 mos (95%CI 12.2-15.4) and 16.8 (13.3-21.4) in arm A and B respectively (HR:1.50, p=0.02). Median OS was 37.7 mos (29.8-41.0) and 44.1 (32.7-not reached) in arm A and B respectively (HR:1.54, p=0.053). Arm A was associated with more toxicity compared to arm B respectively (Grade 3&4 adverse events: 92 versus 71%), with increased early treatment discontinuation before the 3rd cy (14.5 vs 6.2%) & CP dose reduction (12% vs 0%). Pts in Arm A reported inferior RECIST ORR to pre-IDS therapy compared to Arm B (35.1 vs 55.9%). IDS was performed significantly less frequently in arm A (58.1%) vs arm B (76.6%). However among pts who underwent IDS, complete surgical cytoreduction rate (76%) and peri/postoperative complication rate (11.2%) were similar in both arms. Conclusions: The addition of nintedanib to NACT increases toxicity and compromise chemotherapy efficacy leading to a reduced rate of IDS and worse PFS and OS for advanced EOC patient. Clinical trial information: 2011-006288-23.