Primary Human Papillomavirus Testing and Other New Technologies for Cervical Cancer Screening.

Cervical cancer screening has saved the lives of millions in regions where routine gynecologic care is readily accessible. As screening continues to evolve away from cervical cytology to primary human papillomavirus (HPV) testing, robust prospective cohort data have allowed for precise risk stratification and improved our ability to identify those at greatest risk of high-grade dysplasia and decrease unnecessary diagnostic procedures. New technologies such as p16/Ki-67 dual stain testing and HPV methylation panels, which offer comparable performance to co-testing and can be developed into high-throughput workflows, could lead to a fully molecular Pap test. Self-sampling in the United States, where the initial screen can be done in the home, in conjunction with new screening technologies, may decrease the existing hurdles of routine cervical cancer screening. Implementation barriers include issues with workflow, workforce, and cost. These need to be addressed to achieve an improved and more equitable cervical cancer screening program in the United States.

Tumor deposits are associated with a higher risk of peritoneal disease in non-metastatic colorectal cancer patients.

BACKGROUND AND OBJECTIVES: Tumor deposit (TD) is a poor prognostic factor in colorectal cancer (CRC) patients. This study aimed to determine whether TD carry the same risk of peritoneal recurrence as known high-risk (HR) features in CRC patients. METHODS: A retrospective cohort-study of stage I-III CRC patients from 2010 to 2015 was conducted. TD group was defined by the presence of TD on histopathology whereas HR group was defined by the presence of obstruction, perforation, or T4-stage. RESULTS: A total of 151 patients with CRC were identified, of which 50 had TD and 101 had a HR feature. The overall risk of peritoneal recurrence was higher in the TD group versus HR group (36.0% vs. 19.8%, p = 0.03). The risk of peritoneum as the site of first recurrence was also higher in the TD group (22.0% vs. 12.9%, p = 0.03). Overall cancer recurrence at any site was also higher in the TD group (56.0% vs. 34.7%, p = 0.01). Median time to first recurrence was 1.2 (0.7-1.9) years in the TD group compared to 1.4 (0.8-2.1) years in the HR group (p = 0.31). CONCLUSIONS: In non-metastatic CRC patients, TD might have a higher risk of tumor recurrence versus their HR counterparts. Alternative strategies for surveillance and treatment should be considered.

Improved survival with combination chemotherapy and external beam radiation therapy in uterine carcinosarcoma.

OBJECTIVES: To evaluate differences in survival and recurrence patterns in stage I-IV uterine carcinosarcoma patients treated with surgery followed by adjuvant chemotherapy alone, radiation alone, or a combination of both chemotherapy and radiation therapy. METHODS: A multicenter retrospective analysis of patients with surgically staged carcinosarcoma receiving adjuvant therapy from January 2000 to December 2019 was conducted. Inclusion criteria were patients with carcinosarcoma who had received primary surgical treatment, followed by adjuvant therapy with chemotherapy alone, radiation therapy alone, or a combination of chemoradiation. Patients were excluded for incomplete surgical staging data, adjuvant brachytherapy alone, adjuvant chemotherapy and brachytherapy without external beam radiation therapy, receipt of neoadjuvant chemotherapy and/or pre-operative pelvic radiation, and death due to non-cancer causes. Sites of recurrence were analyzed by adjuvant treatment modality using Pearson's χ2 test. Progression-free and overall survival were calculated using Kaplan-Meier estimates. Multivariate analysis was performed using Cox proportional hazards model. RESULTS: Of 176 evaluable patients, 27% (n=47) had stage I, 14% (n=24) stage II, 37% (n=66) stage III, and 22% (n=39) stage IV disease. Among them, 33% (n=59) received chemotherapy alone, 17% (n=29) received radiation therapy alone, and 50% (n=88) received chemoradiation. Patients with stage I disease recurred less frequently (64%) versus stage II (83%), stage III (85%), and stage IV (90%) (p<0.001). Stage I disease demonstrated improved progression-free and overall survival relative to all other stages (p<0.01). Across all stages, patients receiving chemoradiation experienced superior progression-free (p=0.01) and overall survival (p=0.05) versus single modality therapy. However, when analyzed in a stage-specific manor, stage III disease derived the greatest survival benefit from chemoradiation versus all other stages (p<0.01). On multivariant analysis, only stage and receipt of chemoradiation were independent predictors of survival. CONCLUSION: Stage I disease demonstrated improved survival compared with other stages regardless of adjuvant treatment modality. Chemoradiation was associated with improved survival and better distant and local disease control for all stages of disease. Patients with stage III disease derived the most benefit from chemoradiation.

Optimal cytoreduction followed by chemoradiation in stage IVB uterine serous carcinoma.

OBJECTIVES: The prognosis of patients presenting with stage IVB uterine serous carcinoma (USC) remains extremely poor, with a reported 5-year survival of <20%. Here were evaluate the survival impact of cytoreductive surgery and identify other prognostic factors in stage IVB USC. METHODS: A multicenter retrospective analysis of patients with stage IVB USC was conducted from 2000 to 2018. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking; followed by adjuvant chemotherapy+/-external beam radiation therapy (EBRT). Optimal cytoreduction (R1) was defined as residual disease ≤1 cm at completion of surgery, and suboptimal cytoreduction (R2) was defined as >1 cm. Progression free survival (PFS) and overall survival (OS) analysis was performed using Kaplan-Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. RESULTS: Final analysis included 68 patients. There was no difference in the frequency of treatment delays between regimens (p = 0.832). 96% of patients received platinum-based chemotherapy. There was no difference in the age (p = 0.227), race (p = 0.936), type of radiotherapy (p = 0.852) or chemotherapy regimen received (p = 0.996) between R1 and R2 cohorts. The median PFS for all patients was 8 months and the median OS was 13 months. Cytoreduction to R1 was associated with a median PFS of 9 months, compared to R2 with a median PFS of 4 months (p < 0.001, HR 0.32, 95% CI 7.4-14.1). Median OS was also improved with R1 vs. R2 cytoreduction (17 months vs. 7 months, respectively) (p < 0.001, HR 0.21, 95% CI 13.7-26.4). Compared to R1, cytoreduction to R0 was not associated with a survival benefit. The R0 median OS was 17 months versus 18 months in R1 (p = 0.67). The combination of adjuvant chemoradiation was associated with improved PFS (11 months vs. 7 months) (p = 0.024, HR 0.41, 95% CI 6.5-9.4) and OS (22 months vs 13 months) (p = 0.65, HR 0.25, 95% CI 10.5-15.4) compared to chemotherapy-alone, respectively. On MVA, only the amount of residual disease (p = 0.003, HR 0.39, 95% CI 0.2-0.7) and receipt of adjuvant chemoradiation (p = 0.010, HR 0.09, 95% CI 0.01-0.58) were independent predictors of survival. CONCLUSIONS: In stage IVB USC, optimal cytoreduction should be the goal at the time of primary surgery. The combination of chemoradiation was associated with superior survival compared to chemotherapy alone and should be further investigated in this patient population.

Weighing the Risk Profile of Cervical Spine MRI in Evaluating Pediatric Cervical Spine Injuries.

OBJECTIVE: Screening for cervical spine injury after blunt trauma is common, but there remains varied practice patterns and clinical uncertainty regarding adequate radiographic evaluation. An oft-cited downside of MRI is the added risk compared to CT in the pediatric population; however, these specific risks have not yet been reported. This study examines the risks of cervical spine MRI in pediatric trauma patients in the context of what value MRI adds. METHODS: This was a retrospective observational study of all pediatric blunt trauma patients who were evaluated with a cervical spine MRI over a 4-year period at a level 1 pediatric trauma center. Clinical and radiographic data were abstracted, as well as anesthesia requirements and MRI-related major adverse events. CT and MRI results were compared for their ability to detect clinically unstable injuries - those requiring halo or surgery. RESULTS: There was one major adverse event related to MRI among the 269 patients who underwent cervical spine MRI - a rate of 0.37%. While 55% of children had an airway and anesthesia for MRI, only 57% of these airways were newly placed for the MRI. None of the 85 patients newly intubated for MRI developed aspiration pneumonitis or ventilator-associated pneumonia, and no patients had a significant neurologic event while at MRI. Another area of the body was imaged concurrently with the cervical spine MRI in 64% of patients and 83% of MRIs were performed within 48 h. CT and MRI were both 100% sensitive for injuries requiring halo or operative intervention. Eighty-three patients had an MRI performed after a negative CT, 11% (9/83) of these patients had a clinically stable injury detected on subsequent MRI, and none of these patients presented for delayed cervical spine complications. CONCLUSIONS: Overall, the safety profile of MRI in this setting is excellent and less than one-third of patients need new airway and anesthesia solely for MRI. In this clinical scenario, MRIs can happen relatively quickly and many patients require another body part to be imaged concurrently anyway. MRI and CT were both 100% sensitive for clinically unstable injuries. In the appropriate patients, MRI remains a safe and radiation-free alternative to CT.

Cutaneous metastasis of PD-L1 positive cervical carcinoma.

•Cutaneous metastases in cervical cancer are rare and associated with a poor prognosis.•Treatment is typically palliative, utilizing chemotherapy and radiation.•We report a case of PD-L1 positive cervical cancer with cutaneous metastases that developed after initial recurrence.•For patients on checkpoint inhibitor therapy who develop skin toxicity, it is important to rule out cutaneous metastases.

Evaluation of the incidence and clinical significance of WT-1 expression in uterine serous carcinoma.

BACKGROUND: Wilms tumor gene 1 (WT1) expression is a hallmark of ovarian serous carcinoma and considered to be diagnostic marker of these tumors, differentiating them from uterine serous carcinoma (USC), historically thought to rarely express WT1. However, more recent data indicates a significant percentage of USC may express WT1. The clinical implications of WT1 positivity in USC remain unclear. METHODS: A multicenter retrospective analysis of patients with USC was conducted from 2000 to 2019. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking with archival tissue available for WT1 assessment via immunohistochemistry (IHC). Chemosensitive patients were defined as those recurring >6 months from last platinum-based chemotherapy. Progression free survival (PFS) and overall survival (OS) analysis was performed using Kaplan-Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. RESULTS: WT1 status was evaluated in 61 patients with USC. 13 (21.3%) were positive for WT1 by IHC. Stage distribution included 32% stage I, 5% stage II, 25% stage III and 38% stage IV. There was no difference in the stage (p = 0.158), race (p = 0.227) or distribution of recurrence sites (p = 0.581) between WT1 positive and WT1 negative tumors. The majority of patients were chemosensitive (63%). Chemosensitivity was significantly improved in WT1 positive (92.3%) vs. WT1 negative tumors (55.8%) (p = 0.016). We observed a trend towards improved PFS among WT1 positive tumors (21 vs. 16-months, respectively) (p = 0.544). On MVA, stage (p < 0.001) and chemosensitivity (p < 0.001) were independent predictors of PFS. CONCLUSIONS: WT1 positivity is observed in over 20% of USC. WT1 expression is associated with improved chemosensitivity which may contribute to improvements in PFS.

Rationally Designed Magnetic Nanoparticles for Cochlear Drug Delivery: Synthesis, Characterization, and In Vitro Biocompatibility in a Murine Model.

Hypothesis: Magnetic nanoparticles (MNPs) for cochlear drug delivery can be precisely engineered for biocompatibility in the cochlea. Background: MNPs are promising drug delivery vehicles that can enhance the penetration of both small and macromolecular therapeutics into the cochlea. However, concerns exist regarding the application of oxidative, metal-based nanomaterials to delicate sensory tissues of the inner ear. Translational development of MNPs for cochlear drug deliver requires specifically tuned nanoparticles that are not cytotoxic to inner ear tissues. We describe the synthesis and characterization of precisely tuned MNP vehicles, and their in vitro biocompatibility in murine organ of Corti organotypic cultures. Methods: MNPs were synthesized via 2-phase ligand transfer process with precise control of nanoparticle size. Core and hydrodynamic sizes of nanoparticles were characterized using electron microscopy and dynamic light scattering, respectively. In vitro biocompatibility was assayed via mouse organ of Corti organotypic cultures with and without an external magnetic field gradient. Imaging was performed using immunohistochemical labeling and confocal microscopy. Outer hair cell, inner hair cell, and spiral ganglion neurites were individually quantified. Results: Monocore PEG-MNPs of 45 and 148 nm (mean hydrodynamic diameter) were synthesized. Organ of Corti cultures demonstrated preserved outer hair cell, inner hair cell, and neurite counts across 2 MNP sizes and doses, and irrespective of external magnetic field gradient. Conclusion: MNPs can be custom-synthesized with precise coating, size, and charge properties specific for cochlear drug delivery while also demonstrating biocompatibility in vitro.

Evaluation of Survival, Recurrence Patterns and Adjuvant Therapy in Surgically Staged High-Grade Endometrial Cancer with Retroperitoneal Metastases.

BACKGROUND: We seek to evaluate the difference in recurrence patterns and survival among stage IIIC high-grade endometrial cancer treated with surgery followed by adjuvant chemotherapy alone, radiation therapy alone, or both (chemoradiation). METHODS: A multicenter retrospective analysis of surgically staged IIIC HGEC receiving adjuvant therapy was conducted. HGEC was defined as grade 3 endometrioid adenocarcinoma, serous, clear cell and carcinosarcoma. Differences in the frequency of recurrence sites and treatment delays were identified using Pearson's χ2 test. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier estimates. RESULTS: A total of 155 patients were evaluable: 41.9% carcinosarcoma, 36.8% serous, 17.4% grade 3 and 3.9% clear cell. Of these, 67.1% received chemoradiation, 25.8% received chemotherapy and 7.1% received radiation therapy. There was no difference in the frequency of treatment delays between regimens (p = 0.571). There was a trend towards greater retroperitoneal recurrence with chemotherapy (25.9%) versus chemoradiation (8.4%) and radiation therapy (7.7%) (p = 0.252). Grade 3 tumors had improved progression-free and overall survival (26 and 42 months, respectively) versus serous (17 and 30 months, respectively), carcinosarcoma (14 and 24 months, respectively) and clear cell (24 and 30 months respectively) (p = 0.002, p < 0.001). Overall, chemoradiation was superior to chemotherapy and radiation therapy in PFS (p < 0.001) and OS (p < 0.001). Upon multivariate analysis, only histology and receipt of chemoradiation were independent predictors of survival. CONCLUSION: The majority of stage IIIC high-grade endometrial carcinomas recurred. Chemoradiation was associated with improved survival and less retroperitoneal recurrence. Grade 3 tumors demonstrated improved survival versus other histologies regardless of adjuvant treatment modality.

Preoperative Briefings and Postoperative Debriefings to Increase Resident Operative Autonomy and Performance.

OBJECTIVE: To implement the use of standardized preoperative briefings and postoperative debriefings for surgical cases involving residents in an effort to improve resident autonomy and skill acquisition. DESIGN: Prospective longitudinal study. SETTING: Johns Hopkins Department of Otolaryngology-Head and Neck Surgery. PARTICIPANTS: Resident and attending physicians. RESULTS: Joint Huddles for Improving Resident Education (JHFIRE) tool was created and successfully implemented by 19 residents and 17 faculty members. Over the course of three data collection periods spanning an academic year, overall scores improved though not statistically significantly in the metrics of Zwisch autonomy, Resident Performance, and Objective Structured Assessment of Technical Skills (OSATS) scores. Female residents were scored significantly higher by attendings than their male counterparts in the assessment of baseline Resident Performance. CONCLUSIONS: (1) JHFIRE tool implemented a standardized preoperative briefing and postoperative debriefing to improve communication and resident skill acquisition; (2) The tool was accepted and utilized throughout an academic year; (3) Zwisch, Resident Performance, and OSATS scores improved though not significantly.

The Role of Preoperative Briefing and Postoperative Debriefing in Surgical Education.

OBJECTIVE: To study the impact of a new preoperative briefing and postoperative debriefing tool on the perceived quality of surgical education and to assess attitudes of residents and attendings regarding this tool. DESIGN: Surrounding introduction and use of the tool (JHFIRE: Joint Huddles for Improving Resident Education), perceived quality of surgical education was assessed with pre- and postintervention System for Evaluation of Teaching Qualities (SETQ) surveys. Additionally, a postintervention Likert survey regarding the JHFIRE tool itself was completed by residents and faculty. SETTING: Johns Hopkins University Department of Otolaryngology-Head and Neck Surgery, a tertiary care academic institution. PARTICIPANTS: All residents and attendings who used the tool were invited to participate. 40 participants (13 residents, 27 attendings) completed the preintervention SETQ. 11 participants (3 residents, 7 attendings, 1 unspecified) completed the postintervention SETQ. For postintervention qualitative assessment of the tool itself, 12 participants (3 residents, 7 attendings, 2 unspecified) provided feedback. RESULTS: The tool was well-received with large subjective benefit in improving resident surgical education. A total of 88% thought that the time spent on the debriefings was "just right" and 91% planned to make the debriefings a regular part of operative performance assessments. Despite this overwhelmingly positive feedback, there was no overall difference in pre- and postintervention SETQ scores for climate of surgical education in the Department (4.25 ± 0.55 vs. 4.10 ± 0.88, p = 0.63). CONCLUSIONS: Introduction of 4 item preoperative briefing and 4 item postoperative debriefing checklists was welcomed by both residents and faculty for its ability to shape surgical education in the operating room into a guided discovery model of hands-on education. Overall SETQ scores did not change, but most participants found value in the tool and plan to continue its use.

Evaluation of the optimal sequence of adjuvant chemotherapy and radiation therapy in the treatment of advanced endometrial cancer.

OBJECTIVE: The optimal sequence of adjuvant chemoradiation in the treatment of advanced endometrial carcinoma (EC) remains unclear. We sought to evaluate the outcomes of patients treated with chemoradiation in sandwich fashion (chemotherapy-radiotherapy-chemotherapy; CRC), versus those treated sequentially (chemotherapy-radiotherapy; CR) (radiotherapy-chemotherapy; RC), to determine if there is a survival advantaged associated with a particular treatment sequence. METHODS: A multicenter retrospective analysis of patients with stage III and IV EC from 2000-2018 was conducted. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking; followed by adjuvant chemoradiation. Differences in the frequencies of adverse events were evaluated using Pearson's χ² test. Progression free survival (PFS) and overall survival (OS) rates were calculated using Kaplan-Meier estimates. RESULTS: Final analysis included 152 patients; 36.8% (n=56) CRC, 28.9% (n=44) CR, and 34.2% (n=52) RC. Histology included 44.0% endometrioid, 47.5% serous and 8.5% clear cell tumors. There was no difference in the frequency of histology (p=0.973), stage (p=0.143), cytoreduction status (p=0.932), or treatment delays (p=0.571) between adjuvant therapy sequences. The most frequent location of disease recurrence was abdomen. The median PFS favored CRC versus CR or RC (36-months vs. 22-months and 24-months, respectively) (p=0.038), as did the median OS (48-months vs. 28-months and 34-months, respectively) (p=0.003). CRC demonstrated superiority over CR and RC sequencing in terms 3-year PFS (55% vs. 34% and 37%, respectively) and 3-year OS (71% vs. 50% and 52%, respectively). CONCLUSIONS: Adjuvant chemoradiation delivered in CRC sequence was associated with improvements in both PFS and OS compared to alternant therapy sequencing.

Concomitant nonalcoholic fatty liver disease does not alter the activity, severity or course of primary biliary cholangitis.

BACKGROUND & AIMS: The impact of nonalcoholic fatty liver disease (NAFLD) on the natural history of primary biliary cholangitis (PBC) has yet to be described. The aim of this study was to document the activity, severity and progression of PBC in patients with concomitant NAFLD and compare the findings to those with PBC alone. METHODS: Disease activity was assessed by serum liver enzyme levels; severity, by Fib-4 scores and percent of patients with APRI >1.5; and progression, by changes in Fib-4 and prevalence of APRI >1.5 during follow-up. RESULTS: The study populations consisted of 168 PBC alone and 68 PBC/NAFLD patients. The mean ages and gender distributions of the two cohorts were similar. At presentation, PBC alone patients had greater disease activity (higher serum ALP and GGT values, P = .003 and 0.01, respectively) and advanced disease (higher Fib-4 (P = .04) scores) than PBC/NAFLD patients. Although the prevalence of APRI >1.5 was also higher in PBC alone (11.1%) vs PBC/NAFLD (4.7%) patients, the difference was not significant (P = .16). During mean follow-up of 6.7 ± 5.5 (PBC alone) and 6.4 ± 4.4 (PBC/NAFLD) years (ranges: 0.5-21 years) annual increases in Fib-4 and prevalence of ≥ APRI 1.5 were greater in PBC alone patients but the differences did not reach statistical significance. CONCLUSIONS: The results of this retrospective, single centre study suggest that the activity, severity and progression of PBC are not adversely affected by concomitant NAFLD.

Structural insights of SmKDAC8 inhibitors: Targeting Schistosoma epigenetics through a combined structure-based 3D QSAR, in vitro and synthesis strategy.

A predictive structure-based 3D QSAR (COMBINEr 2.0) model of the Schistosoma mansoni lysine deacetylase 8 enzyme (SmKDAC8) was developed, validated and used to perform virtual screening (VS) of the NCI Diversity Set V database (1593 compounds). Three external datasets (with congeneric structures to those experimentally resolved in complexes by X-ray and previously reported as SmKDAC8 inhibitors) were employed to compose and validate the most predictive model. Two series characterized by 104 benzodiazepine derivatives (BZDs) and 60 simplified largazole analogs (SLAs), recently reported by our group as human KDAC inhibitors, were tested for their inhibition potency against SmKDAC8 to probe the predictive capability of the quantitative models against compounds with diverse structures. The SmKDAC8 biochemical results confirmed: (1) the benzodiazepine moiety as a valuable scaffold to further investigate when pursuing SmKDAC8 inhibition; (2) the predictive capability of the COMBINEr 2.0 model towards non-congeneric series of compounds, highlighting the most influencing ligand-protein interactions and refining the structure-activity relationships. From the VS investigations, the first 40 top-ranked compounds were obtained and biologically tested for their inhibition potency against SmKDAC8 and hKDACs 1, 3, 6 and 8. Among them, a non-hydroxamic acid benzothiadiazine dioxide derivative (code NSC163639), showed interesting activity and selectivity against SmKDAC8. To further elucidate the structure-activity relationships of NSC163639, two analogs (herein reported as compounds 3 and 4) were synthesized and biologically evaluated. Results suggest the benzothiadiazine dioxide moiety as a promising scaffold to be used in a next step to derive selective SmKDAC8 inhibitors.

Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.

A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.

N3-arylmalonamides: a new series of thieno[3,2-b]pyridine based inhibitors of c-Met and VEGFR2 tyrosine kinases.

A family of thieno[3,2-b]pyridine based small molecule inhibitors of c-Met and VEGFR2 were designed based on lead structure 2. These compounds were shown to have IC(50) values in the low nanomolar range in vitro and were efficacious in human tumor xenograft models in mice in vivo.

N-(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.

A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.

N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.

A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.