Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identifi ed as a potent, selective, and covalent KRAS G12C inhibitor that exhibits favorable drug-like properties, selectively modifi es mutant cysteine 12 in GDPbound KRAS G12C , and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRAS G12C -positive cell line-and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRAS G12C -positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profi ling in sensitive and partially resistant nonclinical models identifi ed mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. SIGNIFICANCE :The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRAS G12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identifi cation of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target’s resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.

KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.

Background: Umbilical and epigastric hernia repairs are frequently performed surgical procedures with an expected low complication rate. Nevertheless, the optimal method of repair with best short-and long-term outcomes remains debatable. The aim was to develop guidelines for the treatment of umbilical and epigastric hernias. Methods: The guideline group consisted of surgeons from Europe and North America including members from the European Hernia Society and the Americas Hernia Society. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, the Scottish Intercollegiate Guidelines Network (SIGN) critical appraisal checklists, and the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument were used. A systematic literature search was done on 1 May 2018, and updated on 1 February 2019. Results: Literature reporting specifically on umbilical and epigastric hernias was limited in quantity and quality, resulting in a majority of the recommendations being graded as weak, based on low-quality evidence. The main recommendation was to use mesh for repair of umbilical and epigastric hernias to reduce the recurrence rate. Most umbilical and epigastric hernias may be repaired by an open approach with a preperitoneal flat mesh. A laparoscopic approach may be considered if the hernia defect is large, or if the patient has an increased risk of wound morbidity. Conclusion: This is the first European and American guideline on the treatment of umbilical and epigastric hernias. It is recommended that symptomatic umbilical and epigastric hernias are repaired by an open approach with a preperitoneal flat mesh.

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Background Rare locations of hernias, as well as primary ventral hernias under certain circumstances (cirrhosis, dialysis, rectus diastasis, subsequent pregnancy), might be technically challenging. The aim was to identify situations where the treatment strategy might deviate from routine management. Methods The guideline group consisted of surgeons from the European and Americas Hernia Societies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used in formulating the recommendations. The Scottish Intercollegiate Guidelines Network (SIGN) critical appraisal checklists were used to evaluate the quality of full‐text papers. A systematic literature search was performed on 1 May 2018 and updated 1 February 2019. The Appraisal of Guidelines for Research and Evaluation (AGREE) instrument was followed. Results Literature was limited in quantity and quality. A majority of the recommendations were graded as weak, based on low quality of evidence. In patients with cirrhosis or on dialysis, a preperitoneal mesh repair is suggested. Subsequent pregnancy is a risk factor for recurrence. Repair should be postponed until after the last pregnancy. For patients with a concomitant rectus diastasis or those with a Spigelian or lumbar hernia, no recommendation could be made for treatment strategy owing to lack of evidence. Conclusion This is the first European and American guideline on the treatment of umbilical and epigastric hernias in patients with special conditions, including Spigelian and lumbar hernias. All recommendations were weak owing to a lack of evidence. Further studies are needed on patients with rectus diastasis, Spigelian and lumbar hernias.

Post-operative complications pose a significant set-back for patients undergoing breast reconstruction. This study aims to characterize factors associated with postoperative complications following breast reconstruction using the National Surgical Quality Improvement Program (ACS-NSQIP) database from 2005-2010. The 2005-2010 ACS-NSQIP databases were reviewed, identifying encounters for CPT codes including either implant-based reconstruction (immediate, delayed, and tissue expander) or autologous reconstruction (pedicled transverse rectus abdominus myocutaneous (TRAM), free TRAM, and latissimus dorsi flap with or without implant). Complications were characterized into three categories: major surgical complications, wound complications, and medical complications. During the study period 16,063 breast reconstructions were performed. Autologous reconstructions were performed in 20.7% of patients and implant-based in 79.3%. The incidence of major surgical complications was 8.4%, whereas the incidence of medical and wound complications was 1.6% and 3.5%, respectively. Independent risk factors for major surgical complications included: immediate and autologous reconstructions, obesity, smoking, previous percutaneous cardiac surgery (PCS), recent weight loss, bleeding disorder, recent surgery, ASA ≥ 3, intra-operative transfusion, and prolonged operative times. Risk factors for medical complications included: autologous reconstruction, obesity, tumor involving CNS, bleeding disorders, recent surgery, ASA ≥ 3, intra-operative transfusion, and prolonged operative times. This study characterizes the incidence of surgical and medical complications following breast reconstruction using a large, prospective multicentre dataset. Key identifiable risk factors associated with both surgical and medical morbidity included: autologous breast reconstruction, obesity, ASA ≥ 3, bleeding disorders, and prolonged operative time. Data derived from this cohort can be used to risk-stratify patients and to enhance perioperative decision-making.

This study evaluated clinical factors and postoperative complications to determine which ones were associated with 30-day unplanned hospital readmission among patients undergoing surgery for malignant tumors of the head and neck. Further understanding of which complications are associated with unplanned readmission after head and neck surgery will allow for improved risk stratification and development of postoperative care protocols to reduce unplanned hospital readmission.