Laparoscopy-assisted fetoscopy for laser surgery in twin-twin transfusion syndrome with anterior placentation.

OBJECTIVE: To compare a laparoscopy-assisted fetoscopic approach with an ultrasound-directed percutaneous approach for laser photocoagulation of placental anastomoses in cases of twin-twin transfusion syndrome (TTTS) with anterior placentation. METHOD: We performed a retrospective review of all cases that underwent laser ablation of placental anastomoses for TTTS with an anterior placenta at Texas Children's Fetal Center from November 2006 to November 2008. The two cohorts were identified by chart review based on the type of approach: laparoscopy-assisted vs. ultrasound-guided percutaneous uterine entry for fetoscopy. Operative and outcome data were extracted and the groups were compared using statistical methods, taking P < 0.05 as statistically significant. RESULTS: In the 100 cases of TTTS studied, 48 had an anterior placenta. Fifteen (31%) of these underwent laparoscopy-assisted fetoscopy (LAF) while a percutaneous approach was used in the remaining 33 (69%) cases. The total procedure time was longer in the LAF group than in the percutaneous group (96.1 +/- 25 vs. 67.9 +/- 28 min; P < 0.01). There was no difference in the rate of preterm premature rupture of membranes up to 2 weeks and 4 weeks after surgery (7 vs. 15% and 13 vs. 21%, for the LAF group vs. the percutaneous group, respectively; P = 0.7). The gestational ages at delivery were similar: 30.3 +/- 4.5 weeks in the LAF group and 29.2 +/- 4.6 weeks in the percutaneous group (P = 0.32). The overall survival rate at birth was tending towards better survival in the laparoscopic group than in the percutaneous group (80 vs. 61%, respectively; P = 0.06). The neonatal survival rate was better with the LAF approach than with the percutaneous approach (80 vs. 59%, respectively; P = 0.045). CONCLUSION: Laparoscopy-assisted entry of the uterus is associated with improved neonatal survival for laser photocoagulation in cases of TTTS with a complete anterior placentation.

Effects of retinoids on cancerous phenotype and apoptosis in organotypic cultures of ovarian carcinoma.

BACKGROUND: Retinoic acid analogues, called retinoids, have shown promise in clinical trials in preventing breast and ovarian cancers. Classic retinoids bind to retinoic acid receptors, which regulate cell growth. Some novel retinoids, such as fenretinide, i.e., N-(4-hydroxyphenyl)retinamide (4-HPR), induce apoptosis through retinoic acid receptor-independent mechanisms; however, they appear to do so only at concentrations above those achieved in clinical chemoprevention trials. At lower concentrations (< or =1 microM), 4-HPR acts like classic retinoids, by inducing differentiation through a receptor-dependent mechanism. Our goal was to compare the effects of novel receptor-independent (apoptotic) retinoids with those of classic growth-inhibitory retinoids at clinically achievable doses on growth, differentiation, and apoptosis in ovarian tissue. METHODS: Four receptor-independent (apoptotic) and seven growth-inhibitory retinoids, including synthetic, low-toxicity compounds called heteroarotinoids, were administered at concentrations of 1 microM to organotypic cultures of ovarian primary and cancer cell lines: OVCAR-3, Caov-3, and SK-OV-3. After fixation, embedding, and sectioning, the growth fraction was quantified by measuring expression of the proliferation marker Ki-67/myb, differentiation was assessed by expression of mucin, and apoptosis was evaluated by the TUNEL assay. Spearman correlation analysis was performed on the data, and all P values were two-sided. RESULTS: All 11 retinoids reversed characteristics associated with the cancerous phenotype in all neoplastic cultures. Glandular structures were observed consistently in retinoid-treated, but not in untreated, OVCAR-3 and Caov-3 cultures. All retinoids decreased growth fractions, and some increased mucin expression. All receptor-independent retinoids and two receptor-dependent retinoids induced apoptosis, and the induction correlated significantly with increased expression of the mucin MUC1 (r =.83; P =.03). Retinoids with ester-linking groups did not induce apoptosis but decreased the growth fraction in correlation with MUC1 induction (r = -.93; P =.02). CONCLUSIONS: At clinically achievable concentrations, all retinoids tested decrease the growth fraction, induce differentiation and apoptosis. Induction of MUC1 expression is implicated in the mechanisms of action.

Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.

Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.