Radiographic Outcomes, Union Rates, and Complications Associated With Plantar Implant Positioning for Midfoot Arthrodesis.

BACKGROUND: Midfoot arthrodesis has long been successfully included in the treatment paradigm for a variety of pathologic foot conditions. A concern with midfoot arthrodesis is the rate of nonunion, which historically has been reported between 5% and 10%. Plantar plating has also been noted to be more biomechanically stable when compared to traditional dorsal plating in previous studies. Practical advantages of plantar plating include less dorsal skin irritation and the ability to correct flatfoot deformity from the same medial incision. The purpose of this study is to report the arthrodesis rate, the success of deformity correction, and the complications associated with plantar-based implant placement for arthrodesis of the medial column. METHODS: A retrospective review was undertaken of all consecutive patients between 2012 and 2019 that underwent midfoot arthrodesis with plantar-positioned implants. Radiographic outcomes and complications are reported on 62 patients who underwent midfoot arthrodesis as part of a correction for hallux valgus deformity, flatfoot deformity, degenerative arthritis, Lisfranc injury, or Charcot neuroarthropathy correction. RESULTS: Statistically significant improvement was seen in the lateral talus-first metatarsal angle (Meary angle) and medial arch sag angle for patients treated for flatfoot deformity correction. In patients treated for hallux valgus deformity, there was a reduction in the intermetatarsal angle from 15.4 to 6.8 degrees. The overall nonunion rate was 6.45% in all patients. The rate of nonunion was higher at the NC joint compared to the TMT joint and with compression claw plates. One symptomatic nonunion required revision surgery (1.7%). There were no nonunions when excluding neuroarthropathy patients and smokers. The odds ratio (OR) for nonunion in patients with neuroarthropathy was 6.05 (P < .05), and in active smokers the OR was 2.33 (P < .05). CONCLUSION: Plates placed on the plantar bone surface for midfoot arthrodesis achieved and maintained deformity correction with rare instances of symptomatic hardware for a variety of orthopedic conditions. An overall clinical and radiographic union rate of 94% was achieved. The radiographic union rate improved to 100% when excluding both neuroarthropathy patients and smokers. The incidence of nonunion was higher in smokers, neuroarthropathy patients, naviculocuneiform joint fusions, use of compression claw plates, and when attempting to fuse multiple joints. Incisional healing complications were rarely seen other than in active smokers. LEVEL OF EVIDENCE: Level IV, case series.

Pharmacological reversal of histone methylation presensitizes pancreatic cancer cells to nucleoside drugs: in vitro optimization and novel nanoparticle delivery studies.

We evaluated the potential of an investigational histone methylation reversal agent, 3-deazaneplanocin A (DZNep), in improving the chemosensitivity of pancreatic cancer to nucleoside analogs (i.e., gemcitabine). DZNep brought delayed but selective cytotoxicity to pancreatic cancer cells without affecting normal human pancreatic ductal epithelial (HPDE) cells. Co-exposure of DZNep and gemcitabine induced cytotoxic additivity or synergism in both well- and poorly-differentiated pancreatic cell lines by increased apoptosis. In contrast, DZNep exerted antagonism with gemcitabine against HPDE cells with significant reduction in cytotoxicity compared with the gemcitabine-alone regimen. DZNep marginally depended on purine nucleoside transporters for its cytotoxicity, but the transport dependence was circumvented by acyl derivatization. Drug exposure studies revealed that a short priming with DZNep followed by gemcitabine treatment rather than co-treatment of both agents to produce a maximal chemosensitization response in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. DZNep rapidly and reversibly decreased trimethylation of histone H3 lysine 27 but increased trimethylation of lysine 9 in an EZH2- and JMJD1A/2C-dependent manner, respectively. However, DZNep potentiation of nucleoside analog chemosensitization was found to be temporally coupled to trimethylation changes in lysine 27 and not lysine 9. Polymeric nanoparticles engineered to chronologically release DZNep followed by gemcitabine produced pronounced chemosensitization and dose-lowering effects. Together, our results identify that an optimized DZNep exposure can presensitize pancreatic cancer cells to anticancer nucleoside analogs through the reversal of histone methylation, emphasizing the promising clinical utilities of epigenetic reversal agents in future pancreatic cancer combination therapies.

Asymmetric synthesis of (-)-nupharamine and (-)-(5S,8R,9S)-5-(3-furyl)-8-methyloctahydroindolizidine from beta-amino ketones and the intramolecular Mannich reaction.

The asymmetric synthesis of the 2,3,6-trisubstituted piperidine core of the antitumor Nuphar alkaloids was readily achieved by using the intramolecular Mannich reaction and a sulfinimine-derived beta-amino ketone.