Deltoid-Spring Ligament Reconstruction in Adult Acquired Flatfoot Deformity With Medial Peritalar Instability.

BACKGROUND: A spring ligament tear is commonly present in advanced stages of adult acquired flatfoot deformity (AAFD). Previous anatomic studies have demonstrated that the superficial deltoid ligament blends with the superomedial spring ligament, forming the tibiocalcaneonavicular ligament (TCNL). Adding allograft TCNL reconstruction to osseous correction has been suggested to augment medial peritalar stability in advanced AAFD with large spring ligament tears. We aimed to investigate the clinical and radiographic outcomes of TCNL reconstruction for flexible AAFD with medial peritalar instability. METHODS: Fourteen feet in 12 patients who underwent osseous and TCNL reconstructions for advanced AAFD (stage IIB with large spring ligament tears or stage IV) were recruited for the study. The mean postoperative follow-up was 24 (range, 12-33) months. Pre- and postoperative clinical outcomes were assessed by the Foot and Ankle Ability Measure (FAAM), SF-36, and Patient-Reported Outcomes Measurement Information System (PROMIS). Correction of forefoot abduction and the sagittal arch were measured from pre- and postoperative weightbearing radiographs. RESULTS: The FAAM Activities of Daily Living improved from 69.3 to 90.1 (P = .001). The SF-36 Physical Function (PF) and Pain subscales both improved significantly (39.4 to 87.8 and 44.6 to 93.1, respectively, P < .001 for each). The PROMIS PF improved from 38.2 to 46.8 (P = .002) and the PROMIS Pain Interference (PI) from 62.6 to 50.1 (P = .003). Radiographic measures showed an improved anterior-posterior (AP) talo-first metatarsal angle of 24.7 to 11.8 degrees (P < .001) and talonavicular coverage angle of 47.4 to 23.1 degrees (P < .01). An improved Meary's angle of 29.7 to 12.5 degrees (P < .001) and a calcaneal pitch angle of 11.7 to 16.9 degrees (P = .14) were noted in the lateral view. CONCLUSION: Considering the anatomic characteristics of the deltoid-spring ligament complex, TCNL reconstruction may play a significant role in maintaining peritalar stability when performed with osseous correction. Deltoid-spring ligament (TCNL) reconstruction is a viable surgical option for those with advanced stage AAFD with medial peritalar instability that leads to improved functional and radiographic outcomes. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib.

Sunitinib is a multitargeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. We hypothesized that sunitinib undergoes metabolic activation to form chemically reactive, potentially toxic metabolites which may contribute to development of sunitinib-induced hepatotoxicity. The purpose of this study was to define the role of cytochrome P450 (P450) enzymes in sunitinib bioactivation. Metabolic incubations were performed using individual recombinant P450s, human liver microsomal fractions, and P450-selective chemical inhibitors. Glutathione (GSH) and dansylated GSH were used as trapping agents to detect reactive metabolite formation. Sunitinib metabolites were analyzed by liquid chromatography-tandem mass spectrometry. A putative quinoneimine-GSH conjugate (M5) of sunitinib was detected from trapping studies with GSH and dansyl-GSH in human liver microsomal incubations, and M5 was formed in an NADPH-dependent manner. Recombinant P450 1A2 generated the highest levels of defluorinated sunitinib (M3) and M5, with less formation by P450 3A4 and 2D6. P450 3A4 was the major enzyme forming the primary active metabolite N-desethylsunitinib (M1). In human liver microsomal incubations, P450 3A inhibitor ketoconazole reduced formation of M1 by 88%, while P450 1A2 inhibitor furafylline decreased generation of M5 by 62% compared to control levels. P450 2D6 and P450 3A inhibition also decreased M5 by 54 and 52%, respectively, compared to control. In kinetic assays, recombinant P450 1A2 showed greater efficiency for generation of M3 and M5 compared to that of P450 3A4 and 2D6. Moreover, M5 formation was 2.7-fold more efficient in human liver microsomal preparations from an individual donor with high P450 1A2 activity compared to a donor with low P450 1A2 activity. Collectively, these data suggest that P450 1A2 and 3A4 contribute to oxidative defluorination of sunitinib to generate a reactive, potentially toxic quinoneimine. Factors that alter P450 1A2 and 3A activity may affect patient risk for sunitinib toxicity.