ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

Topology Optimized Prelithiated SiO Anode Materials for Lithium-Ion Batteries.

Silicon monoxide (SiO)-based materials have great potential as high-capacity anode materials for lithium-ion batteries. However, they suffer from a low initial coulombic efficiency (ICE) and poor cycle stability, which prevent their successful implementation into commercial lithium-ion batteries. Despite considerable efforts in recent decades, their low ICE and poor cycle stability cannot be resolved at the same time. Here, it is demonstrated that the topological optimization of the prelithiated SiO materials is highly effective in improving both ICE and capacity retention. Laser-assisted atom probe tomography combined with thermogravimetry and differential scanning calorimetry reveals that two exothermic reactions related to microstructural evolution are key in optimizing the domain size of the Si active phase and Li2 SiO3 buffer phase, and their topological arrangements in prelithiated SiO materials. The optimized prelithiated SiO, heat-treated at 650 °C, shows higher capacity retention of 73.4% and lower thickness changes of 68% after 300 cycles than those treated at other temperatures, with high ICE of ≈90% and reversible capacity of 1164 mAh g-1 . Such excellent electrochemical properties of the prelithiated SiO electrode originate from its optimized topological arrangement of active Si phase and Li2 SiO3 inactive buffer phase.

Ancient volcanos as species pumps: A case study of freshwater amphipods in Northeast Asia.

Volcano-tectonic processes have been viewed as primary drivers in the formation of present-day diversity. Volcanos associated with mountain uplifts drive allopatric speciation through vicariance and may impact the surrounding areas like species pump or species attractor. However, the application of these hypotheses to aquatic fauna has rarely been tested explicitly. We tested these hypotheses in the Changbai Mountains (Mts), which are one of the most typical, active volcanic ranges in Northeast (NE) Asia with a long and turbulent geological history. The Gammarus nekkensis species complex of amphipod crustaceans, widely distributed throughout NE Asia with poor dispersal abilities and a long evolutionary history, is a suitable model for testing hypotheses of species pump or species attractor. Phylogenetic and ancestral range reconstructions demonstrated that the studied amphipod originated from the Changbai Mts ~27 Ma and diverged into eastern (Clade I) and western (Clade II) clades, which corresponds well with the initial volcanic eruption of the Changbai Mts in the Late Oligocene. The subsequent diversifications of subclades CI-3, CII-1a and CII-2a were probably driven by second and third eruptions of the Changbai Mts during the Miocene. In particular, the Changbai lineages had spread to the Russian Far East multiple times since the Early Miocene, and widely colonized the region during the Pleistocene. Our discoveries suggest that the ancient volcanos of the Changbai Mts act as species pumps in NE Asia, resulted in burst of diversification around the Changbai Mts and subsequent dispersals into adjacent regions.

Determining Which Patients Require Preoperative Pelvic Radiotherapy Before Curative-Intent Surgery and/or Ablation for Metastatic Rectal Cancer.

BACKGROUND: The aim of this study is to determine the optimal indications for preoperative pelvic radiotherapy (RT) in patients with metastatic rectal cancer who underwent curative-intent surgical resection and/or ablation. METHODS: Between January 2000 and October 2019, 246 patients who met our inclusion criteria were enrolled. Preoperative RT was performed in 22 patients (8.9%). Lower margin below the peritoneal reflection (p < 0.001), mesorectal fascia (MRF) invasion (p = 0.02), and lateral pelvic lymph node (LPLN) involvement (p = 0.005) were more frequent in the preoperative RT group. RESULTS: During the median follow-up period of 13.3 months (interquartile range [IQR]: 6.0-36.3 months), local recurrence (LR) was identified in 60 patients (24.4%). It was the first site of recurrence in 45 of them (18.3%). Among them, three patients were in the preoperative RT group. On multivariable analysis, lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, carcinoembryonic antigen (CEA) level ≥ 10 ng/mL before treatment, and preoperative RT were significant prognostic factors for LR-free survival (LRFS). In the patient group without any risk factors, the 2-year LRFS rate was 94.9% without preoperative RT. In the patient group with one or more risk factors, the 2-year LRFS was 64.4% without and 95.2% with preoperative RT. CONCLUSION: LR developed in about 25% of patients within 2 years. Preoperative RT should be considered, especially in patients with a risk factor for LR, including lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, or CEA ≥ 10 ng/mL before treatment.

Prediction of epithelial-to-mesenchymal transition molecular subtype using CT in gastric cancer.

OBJECTIVES: To develop a prediction model with computed tomography (CT) images and to build a nomogram incorporating known clinicopathologic variables for individualized estimation of epithelial-to-mesenchymal transition (EMT) subtype gastric cancer. METHODS: Patients who underwent primary resection of gastric cancer (GC) and molecular subgroup analysis (n = 451) were reviewed. Multivariable analysis using a stepwise variable selection method was performed to build a predictive model for EMT subtype GC. A nomogram using the results of the multivariable analysis was constructed. An optimal cutoff value of total prognostic points of the nomogram for the prediction of EMT subtype was determined. The predictive model for the EMT subtype was internally validated by bootstrap resampling method. RESULTS: There were 88 patients with EMT subtype and 363 patients with non-EMT subtype based on transcriptome analysis. The patient's age, Lauren classification, and mural stratification on CT were variables selected for the predictive model. The area under the curve (AUC) of the model was 0.865, and the validated AUC of the bootstrap sample was 0.860. The optimal cutoff value of total prognostic points for the prediction of EMT subtype was 94.622, with 90.9% sensitivity, 67.2% specificity, and 71.8% accuracy. CONCLUSION: A predictive model using patient's age, Lauren classification, and mural stratification on CT for EMT molecular subtype GC was made. A nomogram was built which would serve as a useful screening tool for an individualized estimate of EMT subtype. KEY POINTS: • A predictive model for epithelial-to-mesenchymal transition (EMT) subtype incorporating patient's age, Lauren classification, and mural stratification on CT was built. • The predictive model had high diagnostic accuracy (area under the curve (AUC) = 0.865) and was validated (bootstrap AUC = 0.860). • Adding CT findings to clinicopathologic variables increases the accuracy of the predictive model than using only.

First-line pembrolizumab versus dabrafenib/trametinib treatment for BRAF V600-mutant advanced melanoma.

BACKGROUND: Limited data are available to assist the selection between immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors as first-line treatment for patients with BRAF-mutant advanced malignant melanoma. OBJECTIVE: To investigate the outcomes associated with first-line pembrolizumab or dabrafenib/trametinib treatment for advanced melanoma with activating BRAF V600 mutation. METHODS: Data of patients with BRAF V600-mutant melanoma who were treated with first-line pembrolizumab (n = 40) or dabrafenib/trametinib (n = 32) were analyzed. Tumor response, progression-free survival, and overall survival were evaluated. Immune evasion accompanied with emerging resistance to BRAF/mitogen-activated protein kinase kinase inhibitors was assessed. RESULTS: A longer overall survival was observed after first-line pembrolizumab treatment than after first-line dabrafenib/trametinib treatment (hazard ratio = 2.910, 95% CI: 1.552-5.459), although there were no significant differences in progression-free survival (P = .375) and response rate (P = .123). Emergence of resistance to dabrafenib/trametinib co-occurred with immune evasion, enabling melanoma cells to escape recognition and killing by Melan-A-specific CD8+ T cells. LIMITATIONS: Analysis was conducted in a retrospective manner. CONCLUSION: Pembrolizumab may be recommended over BRAF/mitogen-activated protein kinase kinase inhibitors as the first-line treatment in patients with advanced BRAF V600-mutant melanoma.

A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer.

Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).

Programmed Death Ligand 1 Expression as a Prognostic Marker in Patients with Advanced Biliary Tract Cancer.

BACKGROUND: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. PATIENTS AND METHODS: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity. RESULTS: Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer. CONCLUSION: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.

Prognostic significance of sarcopenia in microsatellite-stable gastric cancer patients treated with programmed death-1 inhibitors.

BACKGROUND: Sarcopenia has been underscored as a significant predictor of poor prognosis in cancer patients undergoing immunotherapy with programmed death-1 (PD-1) inhibitors. We aimed to investigate the prognostic significance of computed tomography (CT)-determined sarcopenia in patients with microsatellite-stable (MSS) gastric cancer (GC) treated with PD-1 inhibitors. METHODS: We retrospectively assessed patients with MSS GC who had been treated with PD-1 inhibitors from March 2016 to June 2019. Pre-treatment sarcopenic status was determined by analyzing L3 skeletal muscle index with abdominal CT. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and the differences in survival probability according to sarcopenic status were compared using the log-rank test. Cox proportional hazards regression analyses were performed to identify predictors of PFS and OS. RESULTS: Of 149 patients with MSS GC (mean age, 57.0 ± 12.3 years; 93 men), 79 (53.0%) had sarcopenia. Patients with sarcopenia had significantly shorter PFS than patients without sarcopenia (median, 1.4 months vs. 2.6 months; P = 0.026). Sarcopenia was independently associated with shorter PFS (adjusted hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.10-2.93; P = 0.020). Patients with sarcopenia had shorter OS than patients without sarcopenia (median, 3.6 months vs. 4.9 months; P = 0.052), but sarcopenia itself was not a significant prognostic factor for OS (adjusted HR, 1.01; 95% CI, 0.58-1.75; P = 0.974). CONCLUSIONS: CT-determined sarcopenia is an independent prognostic factor for PFS in patients with MSS GC treated with PD-1 inhibitors.

A Deep Learning Approach with Data Augmentation to Predict Novel Spider Neurotoxic Peptides.

As major components of spider venoms, neurotoxic peptides exhibit structural diversity, target specificity, and have great pharmaceutical potential. Deep learning may be an alternative to the laborious and time-consuming methods for identifying these peptides. However, the major hurdle in developing a deep learning model is the limited data on neurotoxic peptides. Here, we present a peptide data augmentation method that improves the recognition of neurotoxic peptides via a convolutional neural network model. The neurotoxic peptides were augmented with the known neurotoxic peptides from UniProt database, and the models were trained using a training set with or without the generated sequences to verify the augmented data. The model trained with the augmented dataset outperformed the one with the unaugmented dataset, achieving accuracy of 0.9953, precision of 0.9922, recall of 0.9984, and F1 score of 0.9953 in simulation dataset. From the set of all RNA transcripts of Callobius koreanus spider, we discovered neurotoxic peptides via the model, resulting in 275 putative peptides of which 252 novel sequences and only 23 sequences showing homology with the known peptides by Basic Local Alignment Search Tool. Among these 275 peptides, four were selected and shown to have neuromodulatory effects on the human neuroblastoma cell line SH-SY5Y. The augmentation method presented here may be applied to the identification of other functional peptides from biological resources with insufficient data.

A Randomized Controlled Trial of Epidermal Growth Factor Ointment for Treating Epidermal Growth Factor Receptor Inhibitor-Induced Skin Toxicities.

BACKGROUND: The efficacy of epidermal growth factor (EGF) receptor (EGFR) inhibitors in patients with non-small cell lung cancer (NSCLC), pancreatic cancer (PC), or colorectal cancer (CRC) has been demonstrated. However, dermatological reactions to these inhibitors can cause significant physical and psychosocial discomfort. The objective of the present study was to evaluate the efficacy of EGF ointment for EGFR inhibitor-related skin adverse events (ERSEs). MATERIALS AND METHODS: This placebo-controlled, double-blind, multicenter, pilot phase III trial enrolled patients with NSCLC, PC, or CRC treated with EGFR inhibitors. Patients with grade ≥2 ERSEs were included. Patients were randomized to three treatment arms: arm 1, placebo; arm 2, 1 ppm of EGF ointment; and arm 3, 20 ppm of EGF ointment. Patients applied ointment to their skin lesions twice daily. RESULTS: Efficacy evaluation was available for 80 patients (9 for PC, 28 for NSCLC, and 43 for CRC). Responses were 44.4% in arm 1, 61.5% in arm 2, and 77.8% in arm 3. There was a linear correlation between EGF concentrations and responses (p = .012). Quality of life (QoL) was assessed for 74 patients. Maximum changes in composite scores by Skindex-16 after treatment were significantly different among arms (mean ± SD: -5.2 ± 8.6 for arm 1, -11.7 ± 14.2 for arm 2, and - 18.6 ± 17.7 for arm 3; p = .008). EGF arms showed significant improvement in emotions (p = .005) and functioning (p = .044) scores over the placebo arm. CONCLUSION: EGF ointment is effective for managing ERSEs. It can also improve patients' QoL compared with placebo. Clinical trial identification number. NCT02284139 IMPLICATIONS FOR PRACTICE: Patients with non-small cell lung cancer, pancreatic cancer, or colorectal cancer who are treated with epidermal growth factor (EGF) receptor (EGFR) inhibitors may experience dermatologic reactions to their treatment. This study investigated the benefit of an EGF ointment in the treatment of these adverse events and observed the ointment to be effective in managing EGFR inhibitor-related skin adverse events.

FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape.

BACKGROUND: With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of FGFR2-altered GEA. We examined FGFR2 alteration frequency and frequency of co-occurring alterations in GEA. SUBJECTS, MATERIALS, AND METHODS: A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups. RESULTS: We identified a total of 269 (4.0%) FGFR2-altered cases consisting of FGFR2-amplified (amp; 193, 72% of FGFR2-altered), FGFR2-mutated (36, 13%), FGFR2-rearranged (re; 23, 8.6%), and cases with multiple FGFR2 alterations (17, 6.3%). Co-occurring alterations in other GEA RTK targets including ERBB2 (10%), EGFR (8%), and MET (3%) were observed across all classes of FGFR2-altered GEA. Co-occurring alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for FGFR2-altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in FGFR2 wild-type samples. CONCLUSION: FGFR2-altered GEA is a heterogenous subgroup with approximately 20% of FGFR2-altered samples harboring concurrent RTK alterations. Putative co-occurring modifiers of FGFR2-directed therapy including oncogenic MYC, KRAS, and PIK3CA alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials. IMPLICATIONS FOR PRACTICE: Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to HER2 amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in FGFR2-altered GEA parallels the heterogeneity findings in HER2-amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas.

Prognostic Impact of Microsatellite Instability in Asian Gastric Cancer Patients Enrolled in the ARTIST Trial.

BACKGROUND: Caucasian patients with microsatellite instability (MSI)-high gastric cancer (GC) may have better prognosis but worse outcomes. OBJECTIVE: Here we explored the prognostic role of MSI in Asian patients. METHODS: This post hoc analysis comprehended radically resected GC patients randomized to XP (capecitabine/cisplatin) or XPRT. MSI status was assessed by combining immunohistochemistry with multiplex polymerase chain reaction. The MSI prognostic effect on disease-free survival (DFS) and overall survival (OS) was evaluated. RESULTS: 393 tissue samples were analyzed and 35 (9%) were MSI-high. This subgroup was characterized by: older age, Borrmann classification 1-2, antral localization, T3-4 stage, and intestinal type. At univariable analysis, the microsatellite-stable subgroup showed a trend toward a worse prognosis as compared to the MSI-high group: 3-year DFS was 76.3 versus 85.4% (p = 0.122); 3-year OS was 81.7 versus 91.4% (p = 0.046). Multivariable analyses confirmed it in both DFS (hazard ratio, HR = 2.32 [95% CI 0.91, 5.88]; p = 0.077) and OS (HR = 3.17 [95% CI 0.97, 10.43]; p = 0.057). CONCLUSIONS: MSI-high status was associated with specific clinical-pathological features and a trend toward better outcomes of Asian GC patients.

Comprehensive molecular and clinical characterization of Asian melanoma patients treated with anti-PD-1 antibody.

BACKGROUND: Clinical features of Asian melanoma patients are distinct from those of Western patients. This study was designed to determine the molecular and clinical characteristics of Asian melanoma patients treated with anti-PD-1 antibody. METHODS: Patients with recurrent or metastatic melanoma who began anti-PD-1 antibody therapy between January 2015 and April 2018 were retrospectively reviewed. Patients who underwent next-generation sequencing were also analyzed. RESULTS: A total of 152 patients were included. The median age was 61 years, and 53% of patients were female. A total of 56 patients (37%) received immunotherapy as second-line or greater chemotherapy. Primary sites were acral (38%), mucosal (31%), cutaneous (24%), uveal (2%), and unknown (5%). The overall response rate was 17% (95% CI, 11-22%), and disease control rate was 60% (95% CI, 52-68%). The median progression-free survival (PFS) was 4.2 months (95% CI, 1.8-6.6 months), and median overall survival (OS) was 32.9 months (95% CI, 20.0-45.7 months). However, BRAFV600 and KIT mutational statuses were not associated with response or survival. High neutrophil-lymphocyte ratio (NLR) was associated with poor PFS (median PFS 6.9 vs. 2.4 months, p = 0.015) and OS (median OS NR vs. 10.4 months, p < 0.001). In multivariate analysis, high NLR independently predicted poor survival. CONCLUSION: This study includes the largest set of integrated genomic data analyzing Asian patients with melanoma treated with immunotherapy. BRAF V600 and KIT mutational statuses were not associated with response or survival, and high NLR was a strong predictor of poor response to and survival with anti-PD-1 therapy.

Asymmetric Synthesis of Enantioenriched 2-Aryl-2,3-Dihydrobenzofurans by a Lewis Acid Catalyzed Cyclopropanation/Intramolecular Rearrangement Sequence.

A cyclopropanation/intramolecular rearrangement initiated by the Michael addition of in situ generated ortho-quinone methides (o-QMs) has been developed for the enantioselective synthesis of 2-aryl-2,3-dihydrobenzofurans containing two consecutive stereogenic centers, including a quaternary carbon atom. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in excellent yields (up to 95 %) with excellent stereoselectivity (up to >99 ee, up to >20:1 d.r.).

Phase I Pharmacokinetic Study of Nivolumab in Korean Patients with Advanced Solid Tumors.

LESSONS LEARNED: This pharmacokinetic study of nivolumab showed that there is little ethnic difference in the handling of nivolumab.Nivolumab was well tolerated in Korean patients. BACKGROUND: This phase I study of nivolumab, an anti-programmed cell death-1 (anti-PD-1) monoclonal antibody, investigated the pharmacokinetics and safety of nivolumab in Korean patients with advanced solid tumors. Findings were compared with results from Japan and the U.S. MATERIALS AND METHODS: In this two-part study, patients received a single dose of nivolumab (1, 3, and 10 mg/kg; ONO-4538-13) and were followed up for 3 weeks. Those who met the required criteria proceeded to the second part (ONO-4538-14), and received the same dose as in part one every 2 weeks. RESULTS: Six patients per dose level were enrolled (n = 18). The mean elimination half-life of nivolumab among the groups ranged from 15.0 to 19.1 days. The maximum serum concentration and area under serum concentration-time curve increased almost dose-proportionally at doses from 1 to 10 mg/kg. Adverse drug reactions (ADRs; mostly grade ≤2) were reported in seven patients (38.9%). ADRs grade ≥3 occurred in one patient (5.6%; pneumonitis). Three patients (16.7%) developed ADRs related to thyroid dysfunction. CONCLUSION: The pharmacokinetic parameters of nivolumab were similar among patients from Korea, Japan, and the U.S. The safety profile was consistent with findings from previous studies.

Triptolide as a novel agent in pancreatic cancer: the validation using patient derived pancreatic tumor cell line.

BACKGROUND: Triptolide induces apoptosis and DNA damage followed by inhibition of DNA repair associated gene expression. However, there is the limited data for biomarker to predict the benefit to triptolide in various cancers including pancreatic cancer. METHODS: We investigated the anti tumor efficacy of triptolide in various pancreatic cancer cell lines (Capan-1, Capan-2, SNU-213, SNU-410, HPAFII, and Hs766T) and patient derived cells (PDCs) from metastatic pancreatic cancer patients. RESULTS: In vitro cell viability assay for triptolide in 6 PC cell lines, the IC50 was 0.01 uM, 0.02 uM, 0.0096 uM for triptolide in Capan-1, Capan-2 and SNU-213. However, the growth of tumor cells was not significantly reduced by triptolide in Hs766T, SNU-410 and HPAFII. The distinct difference of gene expression was also observed between Capan-1, Capan-2 and SNU-213 and Hs766T, SNU-410 and HPAFII. In analysis of pathway using gene expression profiles, the integrin mediated RAS signaling pathway was associated with the sensitivity of the triptolide in PC cell lines. Immunoblot assay showed that Chk2 phosphorylation after triptolide was distinctively observed in SNU-213 sensitive to triptolide but, not in SNU-410 insensitive to triptolide. This finding in immunoblot assay was also reproduced in PDCs originated from pancreatic cancer patients. CONCLUSIONS: Our findings might be helpful to completely capture the subset of patients who may benefit to tripolide (minnelide). More robust biomarkers such as KRAS mutation and Chk2 phosphorylation and careful clinical trial design using triptolide (minnelide) are warranted.

Antiemetic Corticosteroid Rotation from Dexamethasone to Methylprednisolone to Prevent Dexamethasone-Induced Hiccup in Cancer Patients Treated with Chemotherapy: A Randomized, Single-Blind, Crossover Phase III Trial.

BACKGROUND: To assess whether the rotation of dexamethasone to methylprednisolone decreases the intensity of dexamethasone-induced hiccup (DIH) in cancer patients treated with chemotherapy. MATERIALS AND METHODS: Adult patients who experienced DIH within 3 days after the administration of dexamethasone as an antiemetic were screened. Eligible patients were randomly assigned to receive dexamethasone (n = 33) or methylprednisolone (n = 32) as an antiemetic (randomization phase). In the next cycle of chemotherapy, the dexamethasone group received methylprednisolone and vice versa in the methylprednisolone group (crossover phase). The primary endpoint was the difference in hiccup intensity as measured using the numeric rating scale (NRS) between two groups. RESULTS: No female patients were enrolled, although the study did not exclude them. At the randomization phase, hiccup frequency was 28/33 (84.8%) in the dexamethasone group versus 20/32 (62.5%) in the methylprednisolone group (p = .04). Intensity of hiccup was significantly higher in the dexamethasone group than that in the methylprednisolone group (mean NRS, 3.5 vs. 1.4, p < .001). At the crossover phase, hiccup intensity was further decreased after the rotation of dexamethasone to methylprednisolone in the dexamethasone group (mean NRS, 3.5 to 0.9, p < .001), while it was increased by rotating methylprednisolone to dexamethasone in the methylprednisolone group (mean NRS, 1.4 to 3.3, p = .025). There were no differences in emesis intensity between the two groups at either the randomization or crossover phases. Clinicaltrials.gov identifier: NCT01974024. CONCLUSION: Dexamethasone-induced hiccup is a male-predominant phenomenon that can be ameliorated by rotating dexamethasone to methylprednisolone without compromising the antiemetic efficacy. IMPLICATIONS FOR PRACTICE: In this randomized, multicenter, phase III trial, hiccup intensity was significantly lower when the antiemetic corticosteroid was rotated from dexamethasone to methylprednisolone without a change in emesis intensity than that when dexamethasone was maintained. At the crossover phase, hiccup intensity was increased again if dexamethasone was readministered instead of methylprednisolone. The present study demonstrated that dexamethasone-induced hiccup can be improved by rotating from dexamethasone to methylprednisolone without compromising its antiemetic efficacy.

Clinical Application of Targeted Deep Sequencing in Solid-Cancer Patients and Utility for Biomarker-Selected Clinical Trials.

Molecular profiling of actionable mutations in refractory cancer patients has the potential to enable "precision medicine," wherein individualized therapies are guided based on genomic profiling. The molecular-screening program was intended to route participants to different candidate drugs in trials based on clinical-sequencing reports. In this screening program, we used a custom target-enrichment panel consisting of cancer-related genes to interrogate single-nucleotide variants, insertions and deletions, copy number variants, and a subset of gene fusions. From August 2014 through April 2015, 654 patients consented to participate in the program at Samsung Medical Center. Of these patients, 588 passed the quality control process for the 381-gene cancer-panel test, and 418 patients were included in the final analysis as being eligible for any anticancer treatment (127 gastric cancer, 122 colorectal cancer, 62 pancreatic/biliary tract cancer, 67 sarcoma/other cancer, and 40 genitourinary cancer patients). Of the 418 patients, 55 (12%) harbored a biomarker that guided them to a biomarker-selected clinical trial, and 184 (44%) patients harbored at least one genomic alteration that was potentially targetable. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. IMPLICATIONS FOR PRACTICE: This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase.

Prospective phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy.

BACKGROUND: We designed a single-arm, open-label phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy (#NCT02449538). METHODS: Everolimus was administered orally at a daily dose of 10 mg continuously (28-day cycles). Treatment was continued until progression of the disease or intolerable toxicity was observed. Based on Simon's two-stage optimal design, 10 patients were treated with everolimus during the first stage. RESULTS: The median age of the patients was 55.5 years (range, 42-72), and the median Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2 (range, 1-2). Most of the patients (50.0%) had gastric cancer (GC) as the site of their primary tumor followed by colorectal cancer (CRC), pancreatic cancer, and cholangiocarcinoma. Patients received everolimus as a third-line (3 patients), fourth-line (4 patients), fifth-line (1 patient) or sixth-line (2 patients) treatment. Complete or partial responses were not observed in any of the patients. Four patients showed stable disease, resulting in a disease control rate of 40%. The median PFS was 1.6 months (95% CI, 0.8-2.4 months). Grade 3 or greater hematologic/non-hematologic toxicity was not observed. Grade 2 diarrhea and stomatitis were reported in one patient each. There were no treatment-related deaths. There was less than one response out of the 10 initial patients during the first stage, and the study did not progress to the second stage. CONCLUSIONS: The study did not meet its primary objective of demonstrating the anti-tumor activity of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy. Further investigation using other genomic candidates and new-generation mTOR inhibitors is warranted in patients with treatment-refractory cancer. TRIAL REGISTRATION: # NCT02449538 , April 2015.