Resistance mechanisms of EGFR tyrosine kinase inhibitors, in EGFR exon 20 insertion-mutant lung cancer.

BACKGROUND: Mobocertinib, an EGFR exon 20 insertion (Ex20ins)-specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown. METHODS: To investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation. RESULTS: EGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response. CONCLUSIONS: Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.

Comparison of time and cost between conventional surgical planning and virtual surgical planning in orthognathic surgery in Korea.

BACKGROUND: The purpose of this study was to measure the time of the conventional surgical planning (CSP) and virtual surgical planning (VSP) in orthognathic surgery and to compare them in terms of cost. MATERIAL AND METHOD: This is a retrospective study of the patients who underwent orthognathic surgery at the OOOOO University Dental Hospital from December 2017 to August 2018. All the patients were analyzed through both CSP and VSP, and all the surgical stents were fabricated through manual and 3-dimensional (3D) printing. The predictor variables were the planning method (CSP vs. VSP) and the surgery type (group I: Le Fort I osteotomy+bilateral sagittal split osteotomy [LFI+BSSO] or group II: only bilateral sagittal split osteotomy [BSSO]), and the outcomes were the time and cost. The results were analyzed using paired t test. RESULTS: Thirty patients (12 females, 18 males) met the inclusion criteria, and 17 patients were excluded from the study due to missing or incomplete data. There were 20 group I patients (LFI+BSSO regardless of genioplasty) and 10 group II patients (BSSO regardless of genioplasty). The average time of CSP for group I was 385±7.8 min, and that for group II was 195±8.33 min. The time reduction rate of VSP compared with CSP was 62.8% in group I and 41.5% in group II. On the other hand, there was no statistically significant cost reduction. CONCLUSIONS: The time investment in VSP in this study was significantly smaller than that in CSP, and the difference was greater in group I than in group II.

Burden of Nasal Polyps in the United States.

OBJECTIVE: To investigate the clinical and health care burden of chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) in the United States. STUDY DESIGN: Retrospective, cross-sectional design with analyses of patient visits from 2 databases. SETTING: National Ambulatory Medical Care Survey (NAMCS, 2012-2016) and State Ambulatory Surgery and Services Databases (SASD, 2012-2015) in available states. METHODS: In each analysis, we identified patients (≥18 years old) with a diagnosis of CRSwNP (ICD-9-CM: 471.x; ICD-10-CM: J33.x) in the visit record during the study period. CRS patients without polyps (CRSsNP: ICD-9-CM: 473.x, ICD-10-CM: J32.x; without CRSwNP codes) were identified for comparison. In the SASD, we focused on visits involving relevant sinus procedures. Outcomes included comorbidities, diagnostic testing, and prescribed medication (NAMCS) and surgery visit characteristics (SASD). RESULTS: We identified 2272 NAMCS records from physician offices (183 CRSwNP, 2089 CRSsNP). Most visits were for patients aged <65 years (78.8%, 80.6%) and privately insured (67.7%, 61.5%); CRSwNP visits had a male majority (56.3%, 35.4%). CRSwNP vs CRSsNP visits more often reported asthma (40.2%, 10.3%), allergic rhinitis (14.0%, 8.7%), and congestion (22.0%, 21.1%), with the use of glucocorticoids (21.0%, 17.7%) and nasal allergy medication (26.2%, 10.2%). In the SASD, 427,306 surgery visits were identified (71,195 CRSwNP, 356,111 CRSsNP); demographics were similar to NAMCS. CRSwNP surgeries involved more sinus types (59.3%, 41.4%). Surgeries were mostly elective (>99%) and completed quickly (<2 hours), without perioperative complications (>99%), followed by routine discharge (>91%); follow-up visits were common (14.9%, 13.9%). CONCLUSION: CRSwNP compared to CRSsNP patients have a distinct clinical experience, with moderately higher medication need and more extensive surgery.

Combined blockade of polo-like kinase and pan-RAF is effective against NRAS-mutant non-small cell lung cancer cells.

NRAS mutation is rarely observed in non-small cell lung cancer (NSCLC) patients, and there are no approved treatments for NRAS-mutant NSCLC. Here, we evaluated the effect of pan-RAF inhibitors on human NRAS-mutant NSCLC cell lines and performed high-throughput screening using human kinome small interfering (si)RNA or CRISPR/Cas9 libraries to identify new targets for combination NSCLC treatment. Our results indicate that human NRAS-mutant NSCLC cells are moderately sensitive to pan-RAF inhibitors. High-throughput kinome screenings further showed that G2/M arrest, particularly following knockdown of polo-like kinase 1 (PLK1), can inhibit the growth of human NRAS-mutant NSCLC cells and those treated with the type II pan-RAF inhibitor LXH254. In addition, treatment with volasertib plus LXH254, resulting in dual blockade of PLK1 and pan-RAF, was found to be more effective than LXH254 monotherapy for inhibiting long-term cell viability, suggesting that this combination therapeutic strategy may lead to promising results in the clinic.

Complications associated with specific characteristics of supernumerary teeth.

OBJECTIVES: The purpose of this study was to identify the characteristics of supernumerary teeth, analyze the associated complications, and to present new clinical knowledge on surgical interventions for supernumerary teeth. STUDY DESIGN: This retrospective cohort study was based on the medical records and radiographic records of patients who underwent surgical extraction of supernumerary teeth. The relationships among the patient's age, gender, anatomic features of supernumerary teeth, and presence and type of complications (i.e., spacing, rotation, delayed eruption of the adjacent tooth, cyst formation.) were investigated. The groups were compared by using the Mann-Whitney U test, the Kolmogorov-Smirnov test, and multiple logistic regression analysis (P < .05). RESULTS: The study population consisted of 705 participants who underwent extraction for 1036 supernumerary teeth. The mean age of the participants was 11.5 years, and 73.5% of the participants were males. The complication rate was 55.6%. Variables associated with an increased risk of complications were the patient's age, dentition, tuberculate shape, and horizontal direction of eruption (P < .05). CONCLUSIONS: An increase in the patient's age or abnormalities in the shape and direction of eruption of supernumerary teeth was associated with complications. These parameters should be considered while formulating the treatment plan.

Patient Perceptions and Familiarity With Medical Therapy for Heart Failure.

Importance: There are major gaps in use of guideline-directed medical therapy (GDMT) for patients with heart failure (HF). Patient-reported data outlining patient goals and preferences associated with GDMT are not available. Objective: To survey patients with chronic HF to better understand their experiences and perceptions of living with HF, including their familiarity and concerns with important GDMT therapies. Design, Setting, and Participants: Study participants were recruited from the GfK KnowledgePanel, a probability-sampled online panel representative of the US adult population. English-speaking adults who met the following criteria were eligible if they were (1) previously told by a physician that they had HF; (2) currently taking medications for HF; and (3) had no history of left ventricular assist device or cardiac transplant. Data were collected between October and November 2018. Analysis began in December 2018. Main Outcomes and Measures: The survey included 4 primary domains: (1) relative importance of disease-related goals, (2) challenges associated with living with HF, (3) decision-making process associated with HF medication use, and (4) awareness and concerns about available HF medications. Results: Of 30 707 KnowledgePanel members who received the initial survey, 15 091 (49.1%) completed the screening questions, 440 were eligible and began the survey, and 429 completed the survey. The median (interquartile range) age was 68 (60-75) years and most were white (320 [74.6%]), male (304 [70.9%]), and had at least a high school education (409 [95.3%]). Most survey responders reported familiarity with ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics. Overall, 107 (24.9%) reported familiarity with angiotensin receptor-neprilysin inhibitors or mineralocorticoid receptor antagonists. Overall, 136 patients (42.5%) reported have safety concerns regarding angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 133 (38.5%) regarding ß-blockers, 35 (37.9%) regarding mineralocorticoid receptor antagonists, 38 (36.5%) regarding angiotensin receptor-neprilysin inhibitors, and 123 (37.2%) regarding diuretics. Between 27.7% (n = 26) and 38.5% (n = 136) reported concerns regarding the effectiveness of ß-blockers, angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, or diuretics, while 41% (n = 132) were concerned with the effectiveness of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Conclusions and Relevance: In this survey study, many patients were not familiar with GDMT for HF, with familiarity lowest for angiotensin receptor-neprilysin inhibitors and mineralocorticoid receptor antagonists. Among patients not familiar with these therapies, significant proportions questioned their effectiveness and/or safety. Enhanced patient education and shared decision-making support may be effective strategies to improve the uptake of GDMT for HF in US clinical practice.

Changes in Opioid Utilization Following Tumor Necrosis Factor Inhibitor Initiation in Patients with Rheumatoid Arthritis.

INTRODUCTION: Pain control is one of the most important aspects of rheumatoid arthritis (RA) management from the patient's perspective. Newer generations of RA treatment including tumor necrosis factor inhibitor (TNFi) have the potential to alleviate pain and thus reduce opioid utilization. However, patterns of opioid utilization before and after TNFi initiation have not been well characterized. This study aims to examine multiple measures of change in opioid utilization after the initiation of TNFi. METHODS: Patients aged ≥ 18 years with RA and 24 months continuous enrollment between January 2007 and December 2015 who newly initiated a TNFi in IQVIA™ Health Plan Claims Data were included in our study. Opioid utilization at baseline and during follow-up were identified and compared. RESULTS: Of 2330 patients with RA that were included in the study, 38.8% of patients used opioids in both baseline and follow-up periods. From pre-index to post-index, the proportion of patients receiving any opioid decreased from 54.0 to 51.0%. In addition, the proportion of those who received ≥ 50 mg median daily MED decreased from 12.6 to 10.6% during pre-post periods. CONCLUSIONS: This real-world study of commercially insured patients with RA suggests that opioid use among these patients is prevalent. There was a small decrease in overall opioid utilization after TNFi initiation.

Comparison of time and cost between conventional surgical planning and virtual surgical planning in orthognathic surgery in Korea.

BACKGROUND: The purpose of this study was to measure the time of the conventional surgical planning (CSP) and virtual surgical planning (VSP) in orthognathic surgery and to compare them in terms of cost. MATERIAL AND METHOD: This is a retrospective study of the patients who underwent orthognathic surgery at the Pusan National University Dental Hospital from December 2017 to August 2018. All the patients were analyzed through both CSP and VSP, and all the surgical stents were fabricated through manual and three-dimensional (3D) printing. The predictor variables were the planning method (CSP vs. VSP) and the surgery type (group I: Le Fort I osteotomy + bilateral sagittal split osteotomy [LFI+BSSO] or group II: only bilateral sagittal split osteotomy [BSSO]), and the outcomes were the time and cost. The results were analyzed using the paired t test. RESULTS: Thirty patients (12 females, 18 males) met the inclusion criteria, and 17 patients were excluded from the study due to missing or incomplete data. There were 20 group I patients (LFI+BSSO regardless of genioplasty) and 10 group II patients (BSSO regardless of genioplasty). The average time of CSP for group I was 385 ± 7.8 min, and that for group II was 195 ± 8.33 min. The time reduction rate of VSP compared with CSP was 62.8% in group I and 41.5% in group II. On the other hand, there was no statistically significant cost reduction. CONCLUSIONS: The time investment in VSP in this study was significantly smaller than that in CSP, and the difference was greater in group I than in group II.

Comparative effectiveness of early-line nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer: a US community-based real-world analysis.

BACKGROUND: Real-world analyses of treatments for patients with metastatic breast cancer are limited. We evaluated the comparative effectiveness of nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer using data from an electronic medical record database from community practices across the USA. METHODS: We performed a retrospective cohort study using fully de-identified data from an independent US electronic medical record platform of patients with metastatic breast cancer initiating single-agent nab-paclitaxel or paclitaxel as a first- or second-line treatment from December 1, 2010 to October 6, 2014. The clinical efficacy objectives were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Subgroup analyses were performed in patients with 2 types of metastatic breast cancer as follows: 1) hormone receptor-positive and human epidermal growth factor receptor 2 negative, and 2) triple-negative disease. RESULTS: This analysis included 925 patients. Patients receiving nab-paclitaxel vs. paclitaxel had significantly longer TTD (median 4.2 vs. 2.8 months, P<0.0001) and TTNT (median 6.0 vs. 4.2 months, P<0.0001); similar outcomes were observed for patients with hormone receptor-positive/human epidermal growth factor receptor 2 negative disease. Compared with paclitaxel, nab-paclitaxel was associated with significantly longer TTD in patients with triple-negative disease. nab-Paclitaxel was associated with significantly less all-grade neuropathy, anemia, pain, and diarrhea than paclitaxel. Antiemetic and antihistamine use were significantly less frequent with nab-paclitaxel vs. paclitaxel, whereas use of granulocyte colony-stimulating factor, hydrating agents, and bone-directed therapy to decrease skeletal-related events were more frequent. CONCLUSION: nab-Paclitaxel demonstrated improved clinical effectiveness compared with paclitaxel when examining TTD and TTNT in patients with metastatic breast cancer in a real-world setting.

Fatal vocal cord granuloma after orthognathic surgery.

Endotracheal intubation is commonly associated with laryngeal injury that often resolves spontaneously without any complication. However, stenosis or granulomatous lesions are generally found on the tracheal wall or vocal process at the tube cuff level, caused by excessive cuff pressure. We present a case of fatal vocal cord granuloma leading to dyspnea following orthognathic surgery and sustained intubation for 14 hours.

Comparative effectiveness and resource utilization of nab-paclitaxel plus gemcitabine vs FOLFIRINOX or gemcitabine for the first-line treatment of metastatic pancreatic adenocarcinoma in a US community setting.

INTRODUCTION: Despite a clinically relevant, statistically significant survival benefit with nab-paclitaxel plus gemcitabine and FOLFIRINOX vs single-agent gemcitabine for metastatic pancreatic cancer (mPC), little is known regarding their real-world effectiveness. We analyzed patients with mPC using a nationally representative electronic medical records database to address this unmet need. METHODS: This retrospective analysis of the Navigating Cancer database compared outcomes among patients who received first-line nab-paclitaxel plus gemcitabine, FOLFIRINOX, or gemcitabine for mPC. Effectiveness, safety, and supportive care use were examined. nab-Paclitaxel plus gemcitabine was the reference for statistical comparisons. RESULTS: Baseline characteristics were similar except age (oldest patients were in the gemcitabine cohort followed by nab-paclitaxel plus gemcitabine, then FOLFIRINOX). Patients receiving nab-paclitaxel plus gemcitabine (n=122) demonstrated similar time to treatment discontinuation (TTD; median, 3.4 vs 3.8 months; P=0.947) and database persistence (DP; median, 8.6 vs 8.6 months; P=0.534) vs FOLFIRINOX (n=80); however, TTD (median, 3.4 vs 2.2 months; P<0.001) and DP (median, 8.6 vs 5.3 months; P=0.030) were significantly longer with nab-paclitaxel plus gemcitabine vs gemcitabine (n=46). There were more any-grade adverse events with FOLFIRINOX or gemcitabine vs nab-paclitaxel plus gemcitabine (95% or 89% vs 84%, respectively). CONCLUSION: This real-world analysis confirms the phase III MPACT trial findings and demonstrates that nab-paclitaxel plus gemcitabine has effectiveness similar to that of FOLFIRINOX but greater tolerability for treating mPC despite younger patients being in the FOLFIRINOX cohort. These findings support nab-paclitaxel plus gemcitabine as an appropriate first-line treatment option for patients with mPC.

Osteogenesis from human induced pluripotent stem cells: an in vitro and in vivo comparison with mesenchymal stem cells.

The purpose of this study was to examine the in vitro and in vivo osteogenic potential of human induced pluripotent stem cells (hiPSCs) against that of human bone marrow mesenchymal stem cells (hBMMSCs). Embryoid bodies (EBs), which were formed from undifferentiated hiPSCs, were dissociated into single cells and underwent osteogenic differentiation using the same medium as hBMMSCs for 14 days. Osteoinduced hiPSCs were implanted on the critical-size calvarial defects and long bone segmental defects in rats. The healing of defects was evaluated after 8 weeks and 12 weeks of implantation, respectively. Osteoinduced hiPSCs showed relatively lower and delayed in vitro expressions of the osteogenic marker COL1A1 and bone sialoprotein, as well as a weaker osteogenic differentiation through alkaline phosphatase staining and mineralization through Alizarin red staining compared with hBMMSCs. Calvarial defects treated with osteoinduced hiPSCs had comparable quality of new bone formation, including full restoration of bone width and robust formation of trabeculae, to those treated with hBMMSCs. Both osteoinduced hiPSCs and hBMMSCs persisted in regenerated bone after 8 weeks of implantation. In critical-size long bone segmental defects, osteoinduced hiPSC treatment also led to healing of segmental defects comparable to osteoinduced hBMMSC treatment after 12 weeks. In conclusion, despite delayed in vitro osteogenesis, hiPSCs have an in vivo osteogenic potential as good as hBMMSCs.

Osteogenic differentiation and angiogenesis with cocultured adipose-derived stromal cells and bone marrow stromal cells.

The purpose of this study was to determine the influence of cocultured adipose-derived stromal cells (ASCs) in enhancing the osteogenic differentiation and angiogenesis of bone marrow stromal cells (BMSCs) as well as the underlying mechanism and the optimal ratio. Two in vitro coculture models, segregated cocultures using transwell and mixed cocultures, were employed to assess the indirect and direct effects of coculture respectively. Coculture was carried out for 14 days using 1 × 10(5) BMSCs and ASCs of variable number. BMSCs, ASCs, or both were seeded in PLGA scaffold and implanted in the subcutaneous tissue of 25 nude mice for in vivo analysis of angiogenesis. To evaluate the orthotopic bone formation, critical size calvarial defects were created on 20 mice, and implanted with hydroxyapatite/ß-tricalcium phosphate granules plus BMSCs, ASCs, or both. From both transwell and mixed coculture model, 1 × 10(5) BMSCs cocultured with 0.5 × 10(5) ASCs showed significantly greater osteogenic differentiation and mineralization than BMSCs alone. The mixed ASC/BMSC coculture at or above a ratio of 0.5/1 showed increased secretion of vascular endothelial growth factor (VEGF), and induced effective tube formation from human umbilical vein endothelial cells, which were comparable to ASCs. Cytokine profiling assay and gene expression study showed elevated levels of angiogenic factors VEGF and CXCL1, osteogenic factor Wnt5a as well as transforming growth factor (TGF)-ßR1 and SMAD3 from BMSCs when cocultured with ASCs. After 5 weeks of implantation, polylactic-co-glycolic acid (PLGA)-ASCs-BMSCs had a number of vascular structures comparable to PLGA-ASCs and significantly greater than PLGA-BMSCs. Calvarial defects treated with ceramic/BMSCs/ASCs had greater area of repair and better reconstitution of osseous structure than the defects treated with ceramic/ASCs or ceramic/BMSCs after 10 weeks. In conclusion, ASCs added to BMSCs promoted osteogenesis and angiogenesis at the optimal ASC/BMSC ratio of 0.5/1.

In vitro chondrogenesis and in vivo repair of osteochondral defect with human induced pluripotent stem cells.

The purpose of this study was to investigate the chondrogenic features of human induced pluripotent stem cells (hiPSCs) and examine the differences in the chondrogenesis between hiPSCs and human bone marrow-derived MSCs (hBMMSCs). Embryoid bodies (EBs) were formed from undifferentiated hiPSCs. After EBs were dissociated into single cells, chondrogenic culture was performed in pellets and alginate hydrogel. Chondro-induced hiPSCs were implanted in osteochondral defects created on the patellar groove of immunosuppressed rats and evaluated after 12 weeks. The ESC markers NANOG, SSEA4 and OCT3/4 disappeared while the mesodermal marker BMP-4 appeared in chondro-induced hiPSCs. After 21 days of culture, greater glycosaminoglycan contents and better chondrocytic features including lacuna and abundant matrix formation were observed from chondro-induced hiPSCs compared to chondro-induced hBMMSCs. The expression of chondrogenic markers including SOX-9, type II collagen, and aggrecan in chondro-induced hiPSCs was comparable to or greater than chondro-induced hBMMSCs. A remarkably low level of hypertrophic and osteogenic markers including type X collagen, type I collagen and Runx-2 was noted in chondro-induced hiPSCs compared to chondro-induced hBMMSCs. hiPSCs had significantly greater methylation of several CpG sites in COL10A1 promoter than hBMMSCs in either undifferentiated or chondro-induced state, suggesting an epigenetic cause of the difference in hypertrophy. The defects implanted with chondro-induced hiPSCs showed a significantly better quality of cartilage repair than the control defects, and the majority of cells in the regenerated cartilage consisted of implanted hiPSCs.