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Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate. more...

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential. more...

The surgical method of repairing distal tibial fractures remains controversial. Open reduction and plating is a popular method that can result in good fixation and retention of the achieved position. The usual approach for open plating is anterior. Although it offers good exposure to the tibia, the medial plating is at high risk of wound problems and nonunions. Also, if fixation of the fibula is required, an additional incision must be made on the lateral side of the shin. Lateral plating using a single lateral approach for treating distal tibial and fibular fractures has been reported to have good results; however, most of these studies were small series. We retrospectively evaluated and compared the clinical outcomes of distal tibial fractures treated with medial plating using an anterior approach and lateral plating using a lateral approach. Eighty-eight patients with distal tibial fractures treated with medial or lateral plating were retrospectively reviewed. The 88 fractures were divided into 2 groups: the medial plating group used an anterior approach and included 49 patients and the lateral plating group used a lateral approach and included 39 patients. Both groups were similar with respect to injury mechanism, union rate, malunion rate, operative time, functional score, and range of ankle motion (P>or=.14). Both medial and lateral plating for treating distal tibial fractures achieved good functional outcomes with a low malunion rate; however, the lateral plating group had a lower complication rate (P=.047) and fewer hardware problems (P more...

Removal of intrauterine devices (IUDs) in early pregnancy, when the IUDs threads are not visible at the cervical canal and the patient wishes to continue her pregnancy, remains a problem. Thirty-three patients using IUDs with nonvisible filaments on examination under-went flexible hysteroscopy for retrieval of the devices and follow-up until delivery. In all cases, hysteroscopies were performed without cervical dilatation and anesthesia. In 30 patients, the devices were found within the uterine cavity, and 28 IUDs were removed. In the remaining 3 patients, no IUD was observed. Twenty-four healthy children have been born. Six other patients requested a dilatation and curettage (D & C) about 1–2 weeks later after successful IUD removal. In 2 women, examinations were done at 22 and 29 weeks antepartum, and these 2 patients were lost to follow up. Operative fiberoptic hysteroscopy is proposed as a useful and effective method of retrieval of IUDs in early pregnancy when the filaments of the IUD are ab... more...

Summary Objective Intrauterine adhesion remains a common complication post dilatation and curettage (D&C) in reproductive females. Internal cervical orifice adhesion (ICA) is also observed incidentally after D&C. Here, we introduce a novel adjunctive management for ICA with cross-type nelaton catheter. Materials and Methods In this study, 20 patients suffering from amenorrhea and ICA after D&C were included. All individuals underwent flexible hysteroscopy to confirm their simple ICA statuses. All women accepted the insertion of simple cross-type nelaton catheter. Two weeks post insertion, the catheter was removed and a secondlook hysteroscopy was performed. Three months post catheter removal, the menstruation statuses and the efficiency of nelaton catheter in preventing ICA were evaluated. Results Nineteen patients had 3-month follow-up. Seventeen individuals (89.4%) had normal menstruation flow as well as the impact internal orifice of cervical canal. Only two patients (10.5%) had hypomenorrhea and fibrotic narrowing of the internal orifice of the cervix, which required resectoscopy to remove the internal cervical adhesions. All patients appeared the competence of endurance for these procedures. Conclusion The novel cross-type nelaton catheter is a simple, well tolerated, and highly effective method for the management of ICA after D&C. more...