Epithelial Tight Junction Anomalies in Nasal Inverted Papilloma.

OBJECTIVES: As a critical component of the epithelial barrier, tight junctions (TJs) are essential in nasal mucosa against pathogen invasion. However, the function of TJs has rarely been reported in nasal inverted papilloma (NIP). This study aims to investigate the potential factors of TJs' abnormality in NIP. METHODS: We assessed the expression of ZO-1, occludin, claudin-1, claudin-3, and claudin-7 in healthy controls and NIP by real-time quantitative polymerase chain reaction and immunofluorescent staining. The correlation between TJs expression and neutrophil count, TH 1/TH 2/TH 17 and regulatory T cell biomarkers, and the proportion of nasal epithelial cells was investigated. RESULTS: Upregulation of ZO-1, occludin, claudin-1, and claudin-7, along with downregulation of claudin-3, was found in NIP compared to control (all p < 0.05). An abnormal proportion with a lower number of ciliated cells (control vs. NIP: 37.60 vs. 8.67) and goblet cells (12.52 vs. 0.33) together with a higher number of basal cells (45.58 vs. 124.00) in NIP. Meanwhile, claudin-3 was positively correlated with ciliated and goblet cells (all p < 0.01). Additionally, neutrophils were excessively infiltrated in NIP, negatively correlated with ZO-1, but positively with claudin-3 (all p < 0.05). Furthermore, FOXP3, IL-10, TGF-ß1, IL-5, IL-13, and IL-22 levels were induced in NIP (all p < 0.01). Occludin level was negatively correlated with IL-10, IL-5, IL-13, and IL-22, whereas ZO-1 was positively with TGF-ß1 (all p < 0.05). CONCLUSION: Nasal epithelial barrier dysfunction with TJs anomalies is commonly associated with abnormal proliferation and differentiation of epithelial cells and imbalance of immune and inflammatory patterns in NIP. LEVEL OF EVIDENCE: NA Laryngoscope, 134:552-561, 2024.

Cluster Analysis of DSC MRI, Dynamic Contrast-Enhanced MRI, and DWI Parameters Associated with Prognosis in Patients with Glioblastoma after Removal of the Contrast-Enhancing Component: A Preliminary Study.

BACKGROUND AND PURPOSE: No report has been published on the use of DSC MR imaging, DCE MR imaging, and DWI parameters in combination to create a prognostic prediction model in glioblastoma patients. The aim of this study was to develop a machine learning-based model to find preoperative multiparametric MR imaging parameters associated with prognosis in patients with glioblastoma. Normalized CBV, volume transfer constant, and ADC of the nonenhancing T2 high-signal-intensity lesions were evaluated using K-means clustering. MATERIALS AND METHODS: A total of 142 patients with glioblastoma who underwent preoperative MR imaging and total resection were included in this retrospective study. From the normalized CBV, volume transfer constant, and ADC maps, the parametric data were sorted using the K-means clustering method. Patients were divided into training and test sets (ratio, 1:1), and the optimal number of clusters was determined using receiver operating characteristic analysis. Kaplan-Meier survival analysis and log-rank tests were performed to identify potential parametric predictors. A multivariate Cox proportional hazard model was conducted to adjust for clinical predictors. RESULTS: The nonenhancing T2 high-signal-intensity lesions were divided into 6 clusters. The cluster (class 4) with the relatively low normalized CBV and volume transfer constant value and the lowest ADC values was most associated with predicting glioblastoma prognosis. The optimal cutoff of the class 4 volume fraction of nonenhancing T2 high-signal-intensity lesions predicting 1-year progression-free survival was 9.70%, below which the cutoff was associated with longer progression-free survival. Two Kaplan-Meier curves based on the cutoff value showed a statistically significant difference (P = .037). When we adjusted for all clinical predictors, the cluster with the relatively low normalized CBV and volume transfer constant values and the lowest ADC value was an independent prognostic marker (hazard ratio, 3.04; P = .048). The multivariate Cox proportional hazard model showed a concordance index of 0.699 for progression-free survival. CONCLUSIONS: Our model showed that nonenhancing T2 high-signal-intensity lesions with the relatively low normalized CBV, low volume transfer constant values, and the lowest ADC values could serve as useful prognostic imaging markers for predicting survival outcomes in patients with glioblastoma.

Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study.

BACKGROUND: The phase III FLAURA2 (NCT04035486) study will evaluate efficacy and safety of first-line osimertinib with platinum-pemetrexed chemotherapy versus osimertinib monotherapy in epidermal growth factor receptor mutation-positive (EGFRm) advanced/metastatic non-small-cell lung cancer (NSCLC). The safety run-in, reported here, assessed the safety and tolerability of osimertinib with chemotherapy prior to the randomized phase III evaluation. PATIENTS AND METHODS: Patients (≥18 years; Japan: ≥20 years) with EGFRm locally advanced/metastatic NSCLC received oral osimertinib 80 mg once daily (QD), with either intravenous (IV) cisplatin 75 mg/m2 or IV carboplatin target area under the curve 5, plus pemetrexed 500 mg/m2 every 3 weeks (Q3W) for four cycles. Maintenance was osimertinib 80 mg QD with pemetrexed 500 mg/m2 Q3W until progression/discontinuation. The primary objective was to evaluate safety and tolerability of the osimertinib-chemotherapy combination. RESULTS: Thirty patients (15 per group) received treatment [Asian, 73%; female, 63%; median age (range) 61 (45-84) years]. Adverse events (AEs) were reported by 27 patients (90%): osimertinib-carboplatin-pemetrexed, 100%; osimertinib-cisplatin-pemetrexed, 80%. Most common AEs were constipation (60%) with osimertinib-carboplatin-pemetrexed and nausea (60%) with osimertinib-cisplatin-pemetrexed. In both groups, 20% of patients reported serious AEs. No specific pattern of AEs leading to dose modifications/discontinuations was observed; one patient discontinued all study treatments including osimertinib due to pneumonitis (study-specific discontinuation criterion). Hematologic toxicities were as expected and manageable. CONCLUSIONS: Osimertinib-chemotherapy combination had a manageable safety and tolerability profile in EGFRm advanced/metastatic NSCLC, supporting further assessment in the FLAURA2 randomized phase.

Dynamic trial fitting of the cup in press-fit total hip arthroplasty, a feasibility study.

Trial fitting of the cup during total hip arthroplasty (THA) is done by trial cups, which do not resemble the real press-fit obtained by the definitive implant. Our goal is to judge feasibility of the X-pander® in clinical practice ; a device developed to mimic the real press-fit obtained by the definitive cup, to ensure satisfactory press-fit. In this feasibility study 45 experienced orthopaedic surgeons from 7 European countries filled in a structured survey after 78 primary THA and 31 revision surgeries, using the X-pander instead of traditional trial cups. Primary outcomes were decision change concerning cup size or further reaming and increased confidence regarding cup insertion and size. Additionally, potential association between the primary outcomes and procedure (primary or revi- sion), bone quality and experience of the surgeon were evaluated. In 33.3% of the primary and 32.2% of the revision cases the X-pander measurement changed the deci- sion and further reaming or change of cup size was decided. In 61.5% and 58.1% of respectively the primary and revision THAs the X-pander was judged to give fairly to much more reliable information than traditional trial cups. The X-pander could lead to less additional screw fixation, as stated in 37.2% of the primary and 25.8% of the revision cases and to better cup insertion in respectively 50.0% and 51.6%. This study validates that the X-pander may be a suitable option for accurate sizing and assessment of the reamed acetabulum and could replace traditional trial cups in THA.

Diagnostic accuracy of the jetting sign and a dilatation ratio of left renal vein in CT urography for detecting anterior nutcracker syndrome.

AIM: To investigate the diagnostic value of computed tomography (CT) urography findings of anterior nutcracker syndrome (NCS). MATERIALS AND METHODS: The study included patients with left renal vein (LRV) compression at the aortomesenteric portion at CT urography who underwent renal venography or cystoscopy. Patients with a renocaval pressure gradient of ≥3 mmHg on renal venography or bloody urine jetting from the left ureteral orifice on cystoscopy were defined as the NCS group; the remaining patients comprised the non-NCS group. CT findings were analysed using the jetting of contrast medium flow from the LRV to the inferior vena cava (jetting sign), aortomesenteric distance, presence of collateral veins, and a dilatation ratio of LRV diameter at the aortomesenteric portion (arterial phase/delayed phases). Clinical findings, including age, gender, and body-mass-index, were also analysed. CT features and clinical findings were compared between the NCS and non-NCS groups. Diagnostic performance of CT parameters was assessed using receiver operating characteristic curve analysis. RESULTS: A total of 70 patients (21 men, mean age 44.4 ± 17.2 years) with NCS (n=13) and non-NCS (n=57) were included. Younger age (<40 years), presence of the jetting sign, and a lower dilatation ratio of LRV diameter between the arterial and delayed phases (<1.7) were found to be significant independent factors for predicting the NCS group (OR 24.5, 18.9, 19.4, respectively, p<0.05 for all). The combination of the presence of the jetting sign and a dilatation ratio of LRV diameter of <1.7 obtained the highest AUC of 0.88. CONCLUSION: The jetting sign and the dilatation ratio of LRV diameter between the arterial and delayed phases can both be very useful in the diagnosis of anterior nutcracker syndrome during CT urography.

High patient satisfaction and good long-term functional outcome after endoscopic calcaneoplasty in patients with retrocalcaneal bursitis.

PURPOSE: The primary objective of this study was to determine the degree of patient satisfaction at a minimum of 5 years of follow-up after endoscopic calcaneoplasty. The secondary objectives were to assess functional outcome measures, pain scores, analysis of bone removal, reformation of exostosis at follow-up and correlation of the size of the exostosis and recurrent or persisting complaints. METHODS: This study evaluated patients who underwent endoscopic calcaneoplasty, between January 1st 2000 and December 31st 2010, for the diagnosis of retrocalcaneal bursitis. The evaluation consisted of PROMs (patient-reported outcome measures), a questionnaire and a visit to the outpatient clinic for physical examination and a standard lateral weight-bearing radiograph of the ankle. Patient satisfaction, functional outcomes and pain scores were measured by use of a numeric rating scale (NRS). Size of the posterosuperior calcaneal exostosis was measured on a standard lateral weight-bearing radiograph using parallel pitch lines (PPL) and the Fowler-Philip angle (PFA). RESULTS: The response rate was 28 out of 55 (51%) and the median time to follow-up was 101(IQR 88.5-131.8) months. The median satisfaction score for treatment results was 8.5 out of 10 (IQR 6-10). FAOS symptoms 84.5 (IQR 58.0-96.4), FAOS pain 90.3 (IQR 45.1-100.0), FAOS ADL 94.9 (IQR 58.1-100.0), FAOS sport 90.0 (IQR 36.3-100.0) and FAOS QOL 71.9 (IQR 37.5-93.8) and median AOFAS was 100 (IQR 89-100). The median PLL difference between before operation and 2 weeks after the operation was - 4 mm (IQR-6 and -1) and the median PLL difference between 2 weeks after the operation and at follow-up was 1 mm (0-2). The median PFA was 65 (63-69) at baseline, 66.5 (60.8-70.3) 2 weeks after the operation and 64 (60.8-65.3) at follow-up. CONCLUSION: Despite the limited response rate, this study shows high patient satisfaction and good long-term functional outcome in patients affected by retrocalcaneal bursitis who underwent endoscopic calcaneoplasty. LEVEL OF EVIDENCE: Level IV.

HLA-corrected tumor mutation burden and homologous recombination deficiency for the prediction of response to PD-(L)1 blockade in advanced non-small-cell lung cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited response to ICIs remain unclear. PATIENTS AND METHODS: We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients. RESULTS: Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved. CONCLUSION: HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.

Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial.

BACKGROUND: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. PATIENTS AND METHODS: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. RESULTS: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). CONCLUSIONS: MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).

Dynamic Contrast-Enhanced MR Imaging of Nonenhancing T2 High-Signal-Intensity Lesions in Baseline and Posttreatment Glioblastoma: Temporal Change and Prognostic Value.

BACKGROUND AND PURPOSE: The prognostic value of dynamic contrast-enhanced MR imaging on nonenhancing T2 high-signal-intensity lesions in patients with glioblastoma has not been thoroughly elucidated to date. We evaluated the temporal change and prognostic value for progression-free survival of dynamic contrast-enhanced MR imaging-derived pharmacokinetic parameters on nonenhancing T2 high-signal-intensity lesions in patients with glioblastoma before and after standard treatment, including gross total surgical resection. MATERIALS AND METHODS: This retrospective study included 33 patients who were newly diagnosed with glioblastoma and treated with gross total surgical resection followed by concurrent chemoradiation therapy and adjuvant chemotherapy with temozolomide in a single institution. All patients underwent dynamic contrast-enhanced MR imaging before surgery as a baseline and after completion of maximal surgical resection and concurrent chemoradiation therapy. On the whole nonenhancing T2 high-signal-intensity lesion, dynamic contrast-enhanced MR imaging-derived pharmacokinetic parameters (volume transfer constant [K trans], volume of extravascular extracellular space [v e], and blood plasma volume [vp ]) were calculated. The Cox proportional hazards regression model analysis was performed to determine the histogram features or percentage changes of pharmacokinetic parameters related to progression-free survival. RESULTS: Baseline median K trans, baseline first quartile K trans, and posttreatment median K trans were significant independent variables, as determined by univariate analysis (P < .05). By multivariate Cox regression analysis including methylation status of O6-methylguanine-DNA methyltransferase, baseline median K trans was determined to be the significant independent variable and was negatively related to progression-free survival (hazard ratio = 1.48, P = .003). CONCLUSIONS: Baseline median K trans from nonenhancing T2 high-signal-intensity lesions could be a potential prognostic imaging biomarker in patients undergoing gross total surgical resection followed by standard therapy for glioblastoma.

Prognostic Predictions for Patients with Glioblastoma after Standard Treatment: Application of Contrast Leakage Information from DSC-MRI within Nonenhancing FLAIR High-Signal-Intensity Lesions.

BACKGROUND AND PURPOSE: Attempts have been made to quantify the microvascular leakiness of glioblastomas and use it as an imaging biomarker to predict the prognosis of the tumor. The purpose of our study was to evaluate whether the extraction fraction value from DSC-MR imaging within nonenhancing FLAIR hyperintense lesions was a better prognostic imaging biomarker than dynamic contrast-enhanced MR imaging parameters for patients with glioblastoma. MATERIALS AND METHODS: A total of 102 patients with glioblastoma who received a preoperative dynamic contrast-enhanced MR imaging and DSC-MR imaging were included in this retrospective study. Patients were classified into the progression (n = 87) or nonprogression (n = 15) groups at 24 months after surgery. We extracted the means and 95th percentile values for the contrast leakage information parameters from both modalities within the nonenhancing FLAIR high-signal-intensity lesions. RESULTS: The extraction fraction 95th percentile value was higher in the progression-free survival group of >24 months than at ≤24 months. The median progression-free survival of the group with an extraction fraction 95th percentile value of >13.32 was 17 months, whereas that of the group of ≤13.32 was 12 months. In addition, it was an independent predictor variable for progression-free survival in the patients regardless of their ages and genetic information. CONCLUSIONS: The extraction fraction 95th percentile value was the only independent parameter for prognostic prediction in patients with glioblastoma among the contrast leakage information, which has no statistically significant correlations with the DCE-MR imaging parameters.

Endoscopic Treatment of Mid-Portion Achilles Tendinopathy: A Retrospective Case Series of Patient Satisfaction and Functional Outcome at a 2- to 8-Year Follow-up.

PURPOSE: To evaluate the results of endoscopic treatment in patients affected by mid-portion Achilles tendinopathy, by release of the paratenon combined with a resection of the plantaris tendon, regarding patient satisfaction, functional outcome, and pain scores. METHODS: This retrospective study evaluated patients endoscopically treated for mid-portion Achilles tendinopathy between 2000 and 2013. Patient satisfaction, functional outcome, pain scores, and health-related quality of life were measured by the use of a numeric rating scale, the Foot and Ankle Outcome Score, the Victorian Institute of Sport assessment for the Achilles tendon, the numeric rating scale for pain during running and during sports, and the EuroQol 5D (EQ-5D-3L) standardized questionnaire. Additional questions were asked on the effectiveness of the treatment and sport participation. RESULTS: The response rate was 76.3% (45 of 59). Thirty-five (78%) patients were treated unilaterally and 10 (22%) patients were treated bilaterally. For the unilaterally treated patients, the median time to follow-up was 67 months (interquartile range [IQR] 48-99 months), and for the bilaterally treated patients, it was 89.5 months (IQR 37.5-161.75 months). The median satisfaction score for treatment results was 9 out of 10 (IQR 7-10) and 9.5 (IQR 7-10), respectively. The median Foot and Ankle Outcome Score subscales were scored 75 to 99 and 75 to 97, the median Victorian Institute of Sport assessment for the Achilles tendon scored 81 (IQR 47-90) and 97 (IQR 87-100), and the median numeric rating scale pain scores during both running and sports were 1 (IQR 0-6.5) for the unilaterally treated patients and 0 (IQR 0-4.5) and 0 (IQR 0-1) for the bilaterally treated patients, respectively. The median EQ-5D were 0.81 (IQR 0.71-1) and 1 (IQR 0.64-1), respectively. One reoperation for recurrence of symptoms was necessary. CONCLUSIONS: This study shows high patient satisfaction and good functional outcomes in patients affected by mid-portion Achilles tendinopathy who were endoscopically treated by means of release of the paratenon in combination with transection of the plantaris tendon. LEVEL OF EVIDENCE: Level IV, retrospective case series (therapeutic).

The subchondral bone healing after fixation of an osteochondral talar defect is superior in comparison with microfracture.

PURPOSE: Arthroscopic bone marrow stimulation (BMS) has been considered the primary surgical treatment for osteochondral defects (OCDs) of the talus. However, fixation has been considered as a good alternative. Recently, a new arthroscopic fixation technique was described: the lift, drill, fill and fix procedure (LDFF). The purpose of this study was to evaluate the clinical and radiological results between arthroscopic LDFF and arthroscopic BMS in primary fixable talar OCDs at 1-year follow-up. METHODS: In a prospective comparative study, 14 patients were treated with arthroscopic BMS and 14 patients with arthroscopic LDFF. Pre- and postoperative clinical assessment included the American Orthopaedic Foot and Ankle Society (AOFAS) score and the numeric rating scales (NRSs) of pain at rest and running. Additionally, the level of the subchondral plate (flush or depressed) was analysed on the 1 year postoperative computed tomography scans. RESULTS: No significant differences in the AOFAS and NRS pain at rest and running were found between both groups at 1-year follow-up. After LDFF the level of the subchondral bone plate was flush in 10 patients and after BMS in three patients (p = 0.02). CONCLUSION: No clinical differences were found between arthroscopic LDFF and arthroscopic BMS in the treatment of talar OCDs at 1-year follow-up. However, the subchondral bone plate restores significantly superior after arthroscopic LDFF compared to arthroscopic BMS. It may therefore give less progression of ankle osteoarthritis in the future with a thus potential better long-term outcome. LEVEL OF EVIDENCE: III.

Prevalence of Os Trigonum on CT Imaging.

BACKGROUND: The os trigonum is known as one of the main causes of posterior ankle impingement. In the literature, a wide variation of occurrence has been reported. METHODS: All foot and/or ankle computed tomography (CT) scans made between January 2012 and December 2013 were reviewed. CT images were assessed, blinded for patient characteristics, for the presence of an os trigonum, size of the os trigonum, and type of os trigonum. In addition, the shape of the lateral tubercle of the posterior talar process was assessed. RESULTS: A total of 628 patients (1256 ankles) were included. In 32.5% of the patients of the cohort, an os trigonum was present. In 14.3% of these patients, it was present bilaterally. In a subgroup of patients without posterior ankle impingement the prevalence was 30.3%. Of the nonaffected ankles, an os trigonum was present in 23.7%. Patients with posterior ankle impingement were more likely to have an os trigonum (adjusted odds ratio [OR], 1.86). Afro-Caribbean/Surinamese/Central African origin was associated with a lower rate of occurrence of os trigonum (adjusted OR 0.43). In the ankles without an os trigonum, an enlarged lateral tubercle of the posterior talar process was found in 34.9% and 36.5% of the ankles. CONCLUSION: This study showed that os trigonum is a common accessory bone. With a prevalence of 30.3% in a population of patients with CT imaging of both ankles and 23.7% of the nonaffected ankles, the os trigonum is more common than previously reported. Patients with posterior ankle impingement complaints had a higher prevalence of an os trigonum. In one-third of the patients without an os trigonum, there was an enlarged lateral tubercle of the posterior talar process. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

BACKGROUND: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). METHODS: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. RESULTS: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. CONCLUSIONS: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

Analysis and comparison of the cost-effectiveness of statins according to the baseline low-density lipoprotein cholesterol level in Korea.

WHAT IS KNOWN AND OBJECTIVE: There are a few Korean studies on the economics of statins based on reduction in low-density lipoprotein cholesterol (LDL-C) data from other countries. This study aimed to analyse and compare the cost-effectiveness of statins according to the baseline LDL-C level in Korea. METHODS: Between January 2009 and December 2015, the data of patients who were prescribed statins for the first time were extracted from electronic medical records. We performed a cost-effectiveness analysis (CEA) based on the LDL-C reduction rate (CEA-RR) and target achievement rate. RESULTS AND DISCUSSION: Among high-intensity statins, the CEA-RR value of rosuvastatin (20 mg) was significantly lower than that of atorvastatin (40 mg) at all baseline LDL-C levels, except levels of 160-189 mg/dL. Additionally, at baseline LDL-C levels of 130-159 mg/dL, the CEA-RR value of rosuvastatin (20 mg) was three times lower than that of atorvastatin (40 mg) (9·1 ± 2·5 $/% vs. 31·7 ± 15·0 $/%, P < 0·001). Among moderate-to-low-intensity statins, rosuvastatin (5 mg) showed the lowest CEA-RR value (4·0 ± 0·6 $/%), and the value significantly increased for pitavastatin (2 mg) (8·0 ± 0·6 $/%), atorvastatin (10 mg) (9·5 ± 0·5 $/%), simvastatin (10·8 ± 1·1 $/%) and pravastatin (40 mg) (11·5 ± 0·9 $/%) in order (P < 0·0001). On changing from atorvastatin (10 mg) to atorvastatin (20 mg), the additional yearly cost was 16·0 and additional CEA-RR value was 2·74 $/%. On the other hand, on changing from atorvastatin (10 mg) to rosuvastatin (10 mg), the additional yearly cost was -16·3 and additional CEA-RR value was -1·8 $/%. WHAT IS NEW AND CONCLUSION: We successfully compared the cost-effectiveness of statins according to the baseline LDL-C level in Korea. It is expected that our findings will help clinical decision-making with regard to statin prescription, and this will help reduce national medical expenditure.

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

Complex chromosomal rearrangements by single catastrophic pathogenesis in NUT midline carcinoma.

Background: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare aggressive malignancy often occurring in the tissues of midline anatomical structures. Except for the pathognomonic BRD3/4-NUT rearrangement, the comprehensive landscape of genomic alterations in NMCs has been unexplored. Patients and methods: We investigated three NMC cases, including two newly diagnosed NMC patients in Seoul National University Hospital, and a previously reported cell line (Ty-82). Whole-genome and transcriptome sequencing were carried out for these cases, and findings were validated by multiplex fluorescence in situ hybridization and using individual fluorescence probes. Results: Here, we present the first integrative analysis of whole-genome sequencing, transcriptome sequencing and cytogenetic characterization of NUT midline carcinomas. By whole-genome sequencing, we identified a remarkably similar pattern of highly complex genomic rearrangements (previously denominated as chromoplexy) involving the BRD3/4-NUT oncogenic rearrangements in two newly diagnosed NMC cases. Transcriptome sequencing revealed that these complex rearrangements were transcribed as very simple BRD3/4-NUT fusion transcripts. In Ty-82 cells, we also identified a complex genomic rearrangement involving the BRD4-NUT rearrangement underlying the simple t(15;19) karyotype. Careful inspections of rearrangement breakpoints indicated that these rearrangements were likely attributable to single catastrophic events. Although the NMC genomes had >3000 somatic point mutations, canonical oncogenes or tumor suppressor genes were rarely affected, indicating that they were largely passenger events. Mutational signature analysis showed predominant molecular clock-like signatures in all three cases (accounting for 54%-75% of all base substitutions), suggesting that NMCs may arise from actively proliferating normal cells. Conclusion: Taken together, our findings suggest that a single catastrophic event in proliferating normal cells could be sufficient for neoplastic transformation into NMCs.

Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition.

Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.

Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.

Background: Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and safety of vandetanib 300 mg daily in this patient population. Patients and methods: This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0-2. The primary endpoint was the objective response rate. Results: A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35-71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity. Conclusion: Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.