Publications by authors named "Huanyu Zhao"

52 Publications

Noninvasive papillary urothelial carcinoma with pathological features in between low and high grades: A case report.

Medicine (Baltimore) 2021 Apr;100(17):e25693

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.

Rationale: Urinary bladder urothelial carcinoma is the most common malignant tumor in the urinary system, and noninvasive papillary urothelial carcinoma (NIPUC) comprises most bladder malignancies. NIPUC grading is important for therapeutic and clinical protocol selection. Here, we report a case of NIPUC with pathological features in between low (LG-NIPUC) and high (HG-NIPUC) grades NIPUC.

Patient Concerns: A 72-year-old male, presenting with a 20-year history of hypertension and 5 months of hematuria.

Diagnoses: Computed tomography examination revealed a tumor in the urinary bladder neck. Microscopic investigation revealed that most tumor tissue samples had a branching papillary architecture, with well-developed fibrous-vascular cores. Tumor cells were slightly crowded, with somewhat altered cell polarity and cell adhesion. Immunohistochemistry showed positive Ki67 staining, mostly in the basal layer, while p53 staining was rarely positive. These samples were diagnosed as LG-NIPUC. However, a few tumor tissue samples presented mildly fused papillary architectures without cell polarity or adhesion. Most nuclei stained intensely and were pleomorphic. All epithelial tissue layers were ki67 positive, and the p53 positive rate was higher than that in the LG samples. Therefore, these were classified as HG-NIPUC.

Interventions: The tumor was completely resected during lithotomy postural surgery.

Outcomes: The patient is alive with a good recovery during 3 months after the surgery.

Lessons: We diagnosed this patient as having LG-NIPUC with local HG-NIPUC components. HG- and LG-HIPUC have different outcomes. This case is a new challenge for the pathological grading of NIPUC. An intermediate HIPUC grade might need to be added to the original NIPUC grading system.
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http://dx.doi.org/10.1097/MD.0000000000025693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084004PMC
April 2021

Clinicopathologic features and treatment of thymic lymphoepithelioma-like carcinoma: two case reports and literature review.

Am J Transl Res 2021 15;13(3):1896-1903. Epub 2021 Mar 15.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University No. 155 Nanjing North Street, Heping District, Shenyang 110001, Liaoning, China.

Lymphoepithelioma-like carcinoma (LELC) is rare in the thymus, and easily misdiagnosed. To improve its clinicopathologic knowledge, we describe two cases of thymic LELC, and investigate their microscopic and immunohistochemical features, treatment, and follow-up with a review of previously published cases. Two patients in the First Affiliated Hospital of China Medical University underwent complete surgical resection for thymic LELC. They were treated with chemotherapy or radiotherapy after operation. Histologically, tumor cells exhibited nest patterns or showed stripe-shaped infiltration in fibrous tissue containing lymphocytes. Tumor was diffusely positive for pan-cytokeratin (CK), CK19, cluster of differentiation 5 (CD5), CD117, epithelial membrane antigen (EMA), and p63, and negative for TdT. Recent follow-up showed that the two patients were alive with no signs of recurrence. We report two cases of thymic LELC with a review of previously published cases to summarize knowledge of their clinicopathological characteristics, which is necessary for accurate diagnosis and clinical treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014405PMC
March 2021

WBP2 negatively regulates the Hippo pathway by competitively binding to WWC3 with LATS1 to promote non-small cell lung cancer progression.

Cell Death Dis 2021 Apr 9;12(4):384. Epub 2021 Apr 9.

Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital of China Medical University, Shenyang, China.

WW domain binding protein-2 (WBP2) can function as a Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) co-activator and has a crucial role in promoting breast cancer progression. However, the expression and potential molecular mechanisms of WBP2 in the context of lung cancer are not fully understood. We determined that WBP2 was highly expressed in lung cancer specimens and cell lines and that this expression was closely related to the advanced pTNM stage, lymph node metastasis, and poor prognosis of patients. In addition, gain- and loss-of-function experiments revealed that WBP2 could significantly promote the proliferation and invasion of lung cancer cells both in vivo and in vitro. To elucidate the underlying molecular mechanism, we determined that wild-type WBP2 could competitively bind to the WW domain of WWC3 (WW and C2 domain-containing-3) with LATS1 (Large tumor suppressor-1) through its PPxY motifs, thus inhibiting the formation of the WWC3-LATS1 complex, reducing the phosphorylation level of LATS1, suppressing the activity of the Hippo pathway, and ultimately promoting YAP nuclear translocation. Therefore, from the aspect of upstream molecules of Hippo signaling, WBP2 promotes the malignant phenotype of lung cancer cells in a unique manner that is not directly dependent upon YAP, thus providing a corresponding experimental basis for the development of targeted therapeutic drugs for lung cancer.
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http://dx.doi.org/10.1038/s41419-021-03600-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035140PMC
April 2021

Design and optimization of integrated flexure mounts for unloading lateral gravity of a lightweight mirror for space application.

Appl Opt 2021 Jan;60(2):417-426

This paper presents an integrated flexure mount (IFM) to unload the lateral gravity of a lightweight mirror. The significance of the position relationship between the plane of mirror centroid and the center of flexure pivot is analyzed using the coupling kinematic stiffness model of the flexure mounts derived in this paper. Based on the analysis, an IFM with S-type flexure hinges was designed, and the structure and assembly are described. Then, the optimal position and size parameters of an S-type flexure hinge were obtained by optimization. The optimization results attained by finite element analysis (FEA) indicate that the optimization objectives and constraints were satisfied. Moreover, the degradation of the mirror's optical performance caused by lateral gravity was minimized, and the effects of temperature variation and assembly tolerance were reduced. The IFMs were fabricated based on the optimization results and assembled with a mirror prototype for a pointing precision test and sine-frequency sweep test. A FEA and test results for the IFMs confirm the validity and feasibility of the flexure mounts model and structure design, and we believe the IFM meets the requirements of a lightweight mirror for space application.
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http://dx.doi.org/10.1364/AO.414054DOI Listing
January 2021

Nivolumab in Advanced Hepatocellular Carcinoma: Safety Profile and Select Treatment-Related Adverse Events From the CheckMate 040 Study.

Oncologist 2020 10 24;25(10):e1532-e1540. Epub 2020 Aug 24.

Providence Cancer Center, Providence, Oregon, USA.

Background: CheckMate 040 assessed the efficacy and safety of nivolumab in patients with advanced hepatocellular carcinoma (HCC). Understanding the safety profile of nivolumab is needed to support the management of treatment-related adverse events (TRAEs). This analysis assessed the safety of nivolumab monotherapy in the phase I/II, open-label CheckMate 040 study.

Materials And Methods: Select TRAEs (sTRAEs; TRAEs with potential immunologic etiology requiring more frequent monitoring) occurring between first dose and 30 days after last dose were analyzed in patients in the dose-escalation and -expansion phases. Time to onset (TTO), time to resolution (TTR), and recurrence of sTRAEs were assessed, and the outcome of treatment with immune-modulating medication (IMM) was evaluated.

Results: The analysis included 262 patients. The most common sTRAE was skin (35.5%), followed by gastrointestinal (14.5%) and hepatic (14.1%) events; the majority were grade 1/2, with 10.7% of patients experiencing grade 3/4 events. One patient had grade 5 pneumonitis. Median (range) TTO ranged from 3.6 (0.1-59.9) weeks for skin sTRAEs to 47.6 (47.1-48.0) weeks for renal sTRAEs. Overall, 68% of sTRAEs resolved, with median (range) TTR ranging from 3.7 (0.1-123.3+) weeks for gastrointestinal sTRAEs to 28.4 (0.1-79.1) weeks for endocrine sTRAEs. Most gastrointestinal and all hepatic events resolved with treatment in accordance with established toxicity management algorithms. In 57 patients (40%), sTRAEs were managed with IMM. Reoccurrence of sTRAEs was uncommon following rechallenge with nivolumab.

Conclusion: Nivolumab demonstrated a manageable safety profile in this analysis of patients with advanced HCC. A majority of sTRAEs resolved with treatment.

Implications For Practice: Nivolumab is a viable treatment option for patients with previously treated advanced hepatocellular carcinoma as it has demonstrated durable tumor responses and promising survival. Nivolumab has a manageable safety profile. The most common select treatment-related adverse events (sTRAEs) in this analysis were skin related (35%). Gastrointestinal and hepatic sTRAEs were observed in approximately 14% of patients. The majority of sTRAEs resolved (68%). Safety events are easier to manage if addressed early. Patient education on signs and symptoms to watch out for and the importance of early reporting and consultation should be emphasized.
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http://dx.doi.org/10.1634/theoncologist.2019-0591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543234PMC
October 2020

Signaling in TNFSF15-mediated Suppression of VEGF Production in Endothelial Cells.

Methods Mol Biol 2021 ;2248:1-18

State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.

Vascular endothelial growth factor (VEGF) plays a pivotal role in promoting neovascularization. Tumor necrosis factor superfamily 15 (TNFSF15) is an antiangiogenic cytokine prominently produced by endothelial cells in a normal vasculature. In this study, Western blot, quantitative polymerase chain reaction (qPCR), and dual luciferase reporter gene assay were used to validate the mechanisms of TNFSF15-mediated suppression of VEGF production in endothelial cells. We report that TNFSF15 inhibits VEGF production via microRNA-29b (miR-29b) targeting the 3'-UTR of VEGF transcript in mouse endothelial cell line bEnd.3. Neutralizing antibody against TNFSF15, 4-3H, inhibits the level of miR-29b and reinvigorates VEGF. In addition, TNFSF15 activates the JNK signaling pathway as well as the transcription factor GATA3, resulting in enhanced miR-29b production. SP600125, an inhibitor of JNK, eradicates TNFSF15-induced GATA3 expression. Moreover, GATA3 siRNA suppressed TNFSF15-induced miR-29b expression. Together, this study provides evidence and method of activation of the JNK-GATA3 signaling pathway by TNFSF15 that suppresses VEGF gene expression, which gives rise to upregulation of miR-29b.
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http://dx.doi.org/10.1007/978-1-0716-1130-2_1DOI Listing
April 2021

KIT ligand produced by limbal niche cells under control of SOX10 maintains limbal epithelial stem cell survival by activating the KIT/AKT signalling pathway.

J Cell Mol Med 2020 10 11;24(20):12020-12031. Epub 2020 Sep 11.

Laboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China.

Homeostasis and function of limbal epithelial stem cells (LESCs) rely on the limbal niche, which, if dysfunctional, leads to limbal epithelial stem cell deficiency (LSCD) and impaired vision. Hence, recovery of niche function is a principal therapeutic goal in LSCD, but the molecular mechanisms of limbal niche homeostasis are still largely unknown. Here, we report that the neural crest transcription factor SOX10, which is expressed in neural crest-derived limbal niche cells (LNCs), is required for LNCs to promote survival of LESCs both in vivo and in vitro. In fact, using mice with a Sox10 mutation and in vitro coculture experiments, we show that SOX10 in LNCs stimulates the production of KIT ligand (KITL), which in turn activates in LESCs the KIT-AKT signalling pathway that protects the cells against activated CASPASE 3-associated cell death. These results suggest that SOX10 and the KITL/KIT-AKT pathway play key roles in limbal niche homeostasis and LESC survival. These findings provide molecular insights into limbal niche function and may point to rational approaches for therapeutic interventions in LSCD.
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http://dx.doi.org/10.1111/jcmm.15830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579694PMC
October 2020

Inhibition of p66Shc Oxidative Signaling via CA-Induced Upregulation of miR-203a-3p Alleviates Liver Fibrosis Progression.

Mol Ther Nucleic Acids 2020 Sep 10;21:751-763. Epub 2020 Jul 10.

Department of Pharmacology, Dalian Medical University, Dalian 116044, China. Electronic address:

We previously found that inhibition of p66Shc confers protection against hepatic stellate cell (HSC) activation during liver fibrosis. However, the effect of p66Shc on HSC proliferation, as well as the mechanism by which p66Shc is modulated, remains unknown. Here, we elucidated the effect of p66Shc on HSC proliferation and evaluated microRNA (miRNA)-p66Shc-mediated reactive oxidative species (ROS) generation in liver fibrosis. An in vivo model of carbon tetrachloride (CCl)-induced liver fibrosis in rats and an LX-2 cell model were developed. p66Shc expression was significantly upregulated in rats with CCl-induced liver fibrosis and in human fibrotic livers. Additionally, p66Shc knockdown in vitro attenuated mitochondrial ROS generation and HSC proliferation. Interestingly, p66Shc promoted HSC proliferation via β-catenin dephosphorylation in vitro. MicroRNA (miR)-203a-3p, which was identified by microarray and bioinformatics analyses, directly inhibited p66Shc translation and attenuated HSC proliferation in vitro. Importantly, p66Shc was found to play an indispensable role in the protective effect of miR-203a-3p. Furthermore, carnosic acid (CA), the major antioxidant compound extracted from rosemary leaves, protected against CCl-induced liver fibrosis through the miR-203a-3p/p66Shc axis. Collectively, these results suggest that p66Shc, which is directly suppressed by miR-203a-3p, is a key regulator of liver fibrosis. This finding may lead to the development of therapeutic targets for liver fibrosis.
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http://dx.doi.org/10.1016/j.omtn.2020.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417942PMC
September 2020

Synthesis of Polymer Single-Chain Nanoparticle with High Compactness in Cosolvent Condition: A Computer Simulation Study.

Macromol Rapid Commun 2020 Dec 5;41(24):e1900655. Epub 2020 Mar 5.

State Key Laboratory of Supramolecular Structure and Materials, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun, 130021, China.

Polymeric single-chain nanoparticles (SCNPs) are soft nano-objects synthesized by intramolecular crosslinking of isolated single polymer chains. Syntheses of such SCNPs usually need to be performed in a dilute solution. In such a condition, the bonding probability of the two active crosslinking units at a short contour distance along the chain backbone is much higher than those which are far away from each other. Such a reaction condition often results in local spheroidization and, therefore, the formation of loosely packed structures. How to inhibit the local spheroidization and improve the compactness of SCNPs is thus a major challenge for the syntheses of SCNPs. In this study, computer simulations are performed and the fact that a precollapse of the polymer chain conformation in a cosolvent condition can largely improve the probability of the crosslinking reactions at large contour distances is demonstrated, favoring the formations of closely packed globular structures. As a result, the formed SCNPs can be more spherical and have higher compactness than those fabricated in ultradilute good solvent solution in a conventional way. It is believed this simulation work can provide a insight into the effective syntheses of SCNPs with spherical conformations and high compactness.
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http://dx.doi.org/10.1002/marc.201900655DOI Listing
December 2020

Bioinspired Patterned Bubbles for Broad and Low-Frequency Acoustic Blocking.

ACS Appl Mater Interfaces 2020 Jan 23;12(1):1757-1764. Epub 2019 Dec 23.

Key Laboratory of Green Printing, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry , Chinese Academy of Sciences (ICCAS), Beijing Engineering Research Center of Nanomaterials for Green Printing Technology, Beijing National Laboratory for Molecular Sciences (BNLMS) , Beijing 100190 , P. R. China.

Bubble crystals in water are expected to achieve the broad and low-frequency acoustic band gaps that are crucial for acoustic blocking. However, preparing patterned bubble crystals in water remains a challenge because of the instability of bubbly liquids. Here, inspired by biological superhydrophobic systems, we report a simple and rapid approach to prepare patterned bubble arrays in water and their applications in low-frequency acoustic blocking. Patterned bubbles with the desired size, shape, and position can be prepared. Single-layer bubble arrays can block the sounds at low frequencies because of local resonance. By varying the size and distance of the bubbles without changing the thickness, the operating frequency can change from 9 to 1756 kHz. Besides, by preparing multilayer bubbles, broad and low-frequency acoustic band gaps can be achieved, with the generalized width of γ (ratio of the bandgap width to its start frequency) reaching 1.26. This method provides a feasible strategy to control acoustic waves at low frequencies for applications such as acoustic blocking, focusing, imaging, and detecting.
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http://dx.doi.org/10.1021/acsami.9b15683DOI Listing
January 2020

SIRT3-mediated deacetylation of PRDX3 alleviates mitochondrial oxidative damage and apoptosis induced by intestinal ischemia/reperfusion injury.

Redox Biol 2020 01 12;28:101343. Epub 2019 Oct 12.

Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China. Electronic address:

Background: Hydrogen peroxide (HO)-induced mitochondrial oxidative damage is critical to intestinal ischemia/reperfusion (I/R) injury, and PRDX3 is an efficient HO scavenger that protects cells from mitochondrial oxidative damage and apoptosis. However, the function of PRDX3 in intestinal I/R injury is unclear. The aim of this study was to investigate the precise mechanism underlying the involvement of PRDX3 in intestinal I/R injury.

Methods: An intestinal I/R model was established in mice with superior mesenteric artery occlusion, and Caco-2 cells were subjected to hypoxia/reoxygenation (H/R) for the in vivo simulation of I/R.

Results: PRDX3 expression was decreased during intestinal I/R injury, and PRDX3 overexpression significantly attenuated H/R-induced mitochondrial oxidative damage and apoptosis in Caco-2 cells. The level of acetylated PRDX3 was clearly increased both in vivo and in vitro. The inhibition of SIRTs by nicotinamide (NAM) increased the level of acetylated PRDX3 and impaired the antioxidative activity of PRDX3. Furthermore, NAM did not increase the acetylation of PRDX3 in sirtuin-3 (SIRT3)-knockdown Caco-2 cells. Importantly, PRDX3 acetylation was increased in mice lacking SIRT3, and this effect was accompanied by serious mitochondrial oxidative damage, apoptosis and remote organ damage after intestinal I/R injury. We screened potential sites of PRDX3 acetylation in the previously reported acetylproteome through immunoprecipitation (IP) experiments and found that SIRT3 deacetylates K253 on PRDX3 in Caco-2 cells. Furthermore, PRDX3 with the lysine residue K253 mutated to arginine (K253R) increased its dimerization in Caco-2 cells after subjected to 12 h hypoxia and followed 4 h reoxygenation. Caco-2 cells transfected with the K253R plasmid exhibited notably less mitochondrial damage and apoptosis, and transfection of the K253Q plasmid abolished the protective effect of PRDX3 overexpression. Analysis of ischemic intestines from clinical patients further verified the correlation between SIRT3 and PRDX3.

Conclusions: PRDX3 is a key protective factor for intestinal I/R injury, and SIRT3-mediated PRDX3 deacetylation can alleviate intestinal I/R-induced mitochondrial oxidative damage and apoptosis.
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http://dx.doi.org/10.1016/j.redox.2019.101343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820261PMC
January 2020

Glucose Transporter 1 Promotes the Malignant Phenotype of Non-Small Cell Lung Cancer through Integrin β1/Src/FAK Signaling.

J Cancer 2019 27;10(20):4989-4997. Epub 2019 Aug 27.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, China.

: Glucose transporter 1 (GLUT1) is the main factor of Warburg effect, which is associated with poor prognosis in many tumors. However, the underlying molecular mechanism of GLUT1 in the progression of non-small cell lung cancer (NSCLC) is unclear. : We used quantitative real-time PCR to detect GLUT1 mRNA expression in bronchial brushing samples and performed Western Blot and biological behavior testing to check the effect of GLUT1 on NSCLC cell proliferation, migration, invasion and apoptosis. : We found that the C(t) normalized value of GLUT1 in malignant bronchial brushing samples was significantly higher than that in benign samples (<0.05). GLUT1 significantly increased the expressions of cyclin A, cyclin D1, cyclin E, cyclin dependent kinase 2 (CDK2), CDK4, CDK6 and matrix metalloproteinase 2 (MMP2), but decreased the expressions of p53 and p130 in NSCLC cells. The biological behavior testing indicated that GLUT1 enhanced NSCLC cell proliferation, invasion and migration but inhibited cell apoptosis. In addition, GLUT1 upregulated the expression of integrin β1 and promoted the phosphorylation of focal adhesion kinase (FAK, phosphorylation at Tyr576/577) and Src (Src phosphorylation at Tyr530). siRNA knock down of integrin β1 expression suppressed GLUT1 induced NSCLC cell biological behavior, as well as the phosphorylation of FAK and Src. : Taken together, our data confirms that GLUT1 promotes the malignant phenotype of NSCLC through integrin β1/Src/FAK signaling, which provides a new therapeutic target for the treatment and research of lung cancer.
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http://dx.doi.org/10.7150/jca.30772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775508PMC
August 2019

Medical image enhancement in F-shift transformation domain.

Health Inf Sci Syst 2019 Dec 24;7(1):13. Epub 2019 Jul 24.

4The School of Computer and Data Engineering, Zhejiang University (NIT), Ningbo, China.

Image enhancement technology plays an important role in the diagnosis and treatment of medical diseases. In this paper, we propose a method to automatically enhance medical images. The proposed method could be used to support clinical medical diagnosis, adjuvant therapy and curative effect diagnosis. This scheme uses contrast limited adaptive histogram equalization (CLAHE) method in F-shift transformation domain. Firstly, we adjust the overall brightness of the underexposed or overexposed image. Secondly, we perform CLAHE to enhance the low-frequency components obtained by one-level two-dimensional F-shift transformation (TDFS) on the adjusted images. At this stage, most of the coefficients in the high-frequency component can be changed to zero through properly setting the error bound. We then use inverse transformation to reconstruct image which is further enhanced with CLAHE. Compared to previous work, this approach takes into account not only the image enhancement, but also the data compression. Experimental results and comparison with state-of-the-art methods show that our proposed method has a better enhancement performance. Moreover, it has a certain data compression ability.
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http://dx.doi.org/10.1007/s13755-019-0075-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650515PMC
December 2019

Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis.

J Hepatol 2019 09 7;71(3):543-552. Epub 2019 Jun 7.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.

Background & Aims: Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040.

Methods: CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018.

Results: There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations.

Conclusion: Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients.

Lay Summary: The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878.
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http://dx.doi.org/10.1016/j.jhep.2019.05.014DOI Listing
September 2019

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer.

Oncologist 2019 11 30;24(11):1453-1461. Epub 2019 May 30.

Emory University Winship Cancer Institute, Atlanta, Georgia, USA.

Background: Early detection and management of treatment-related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate [ORR] 55%, median duration of response not reached, 12-month overall survival [OS] rate 85%) and manageable safety for previously treated microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). In-depth safety and additional efficacy outcomes from CheckMate 142 are presented.

Materials And Methods: Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune-mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune-modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs.

Results: Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2-12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5-9.0 weeks). IMMs were used to manage sTRAEs in 22%-56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12-month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%).

Conclusion: The benefit-risk profile of nivolumab plus low-dose ipilimumab provides a promising treatment option for patients with previously treated MSI-H/dMMR mCRC.

Implications For Practice: Nivolumab (NIVO) plus low-dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment-related adverse events (sTRAEs) occurred early, were managed using evidence-based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune-modulating medications. The benefit-risk profile of NIVO + low-dose IPI provides a promising treatment option for MSI-H/dMMR mCRC.
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http://dx.doi.org/10.1634/theoncologist.2019-0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853093PMC
November 2019

p66Shc Contributes to Liver Fibrosis through the Regulation of Mitochondrial Reactive Oxygen Species.

Theranostics 2019 20;9(5):1510-1522. Epub 2019 Feb 20.

Department of Pharmacology, Dalian Medical University, Dalian 116044, China.

p66Shc is a redox enzyme that mediates mitochondrial reactive oxygen species (ROS) generation. p66Shc inhibition confers protection against liver injury, however, its functional contribution to liver fibrosis remains unclear. The aim of this study is to explore the involvement of p66Shc in liver fibrosis and underlying mechanism of p66Shc by focusing on mitochondrial ROS. p66Shc-silenced mice were injected with carbon tetrachloride (CCl). Primary hepatic stellate cells (HSCs) were performed with p66Shc silencing or overexpression prior to TGF-β1 stimulation. p66Shc expression was progressively elevated in mice with CCl-induced liver fibrosis, and p66Shc silencing significantly attenuated fibrosis development, reducing liver damage, oxidative stress and HSC activation, indicated by the decreased α-SMA, CTGF and TIMP1 levels. Furthermore, in primary HSCs, p66Shc-mediated mitochondrial ROS production played a vital role in mitochondrial morphology and cellular metabolism. Knockdown of p66Shc significantly inhibited mitochondrial ROS production and NOD-like receptor protein 3 (NLRP3) inflammasome activation, which were closely associated with HSC activation, indicated by the decreased α-SMA, CTGF and TIMP1 levels. However, p66Shc overexpression exerted the opposite effects, which were suppressed by a specific mitochondrial ROS scavenger (mito-TEMPO). More importantly, p66Shc expression was significantly increased in human with liver fibrosis, accompanied by NLRP3 inflammasome activation. p66Shc is a key regulator of liver fibrosis by mediating mitochondrial ROS production, which triggers NLRP3 inflammasome activation.
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http://dx.doi.org/10.7150/thno.29620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401497PMC
January 2020

Understanding the desulphurization process in an ionic porous aromatic framework.

Chem Sci 2019 Jan 23;10(2):606-613. Epub 2018 Oct 23.

Key Laboratory of Polyoxometalate Science of the Ministry of Education , Faculty of Chemistry , Northeast Normal University , Changchun 130024 , P. R. China . Email:

An ionic porous aromatic framework, iPAF-1, was successfully synthesized from a designed monomer with imidazolium functional groups. The iPAF-1 exhibits the highest dibenzothiophene uptake among all reported adsorptive desulphurization adsorbents. The so-called precursor designed synthetic route provides the stoichiometric and homogeneous introduction of desired functional groups into the framework. Molecular dynamics simulation was performed to understand the structure and the desulphurization process within the amorphous iPAF-1. The insight into the key role of the moderate bonding interaction between the adsorbate and the functional groups of iPAF-1 for improved uptake is highlighted in this work.
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http://dx.doi.org/10.1039/c8sc03727bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334719PMC
January 2019

Inhibition of the ubiquitination of HSF1 by FBXW7 protects the intestine against ischemia-reperfusion injury.

Apoptosis 2018 12;23(11-12):667-678

Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.

Epithelial apoptosis is an important factor in intestinal ischemia-reperfusion (I/R) injury. Heat shock factor 1 (HSF1) is a classical stress response factor that directly regulates the transcription of heat shock proteins (HSPs) under stress conditions. Although HSPs are involved in protecting the intestine against I/R, the mechanism whereby HSF1 is regulated in I/R is poorly understood. Here, we show that the ubiquitin ligase FBXW7 targets HSF1 for ubiquitination and degradation in intestinal I/R. In this study, we found that FBXW7 expression was upregulated at the transcriptional level in intestinal mucosae subjected to I/R. In Caco-2 and IEC-6 cells subjected to hypoxia/reoxygenation (H/R), a high FBXW7 level led to excessive HSF1 ubiquitination and degradation. FBXW7 knockdown attenuated HSF1 ubiquitination and downregulation and accelerated HSPB1 and HSP70 expression. In addition, FBXW7 deletion alleviated the apoptosis of intestinal epithelial cells, as evidenced by decreased activation of caspase-3 and caspase-9. The results suggest that FBXW7 suppression protects against intestinal I/R, at least partly through the HSF1/HSP pathway. These findings indicate that FBXW7 may be a potential therapeutic target for inhibiting intestinal mucosa apoptosis during intestinal I/R.
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http://dx.doi.org/10.1007/s10495-018-1484-5DOI Listing
December 2018

Hint1 expression inhibits proliferation and promotes radiosensitivity of human SGC7901 gastric cancer cells.

Oncol Lett 2018 Aug 5;16(2):2135-2142. Epub 2018 Jun 5.

Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China.

Gastric cancer is a prevalent, malignant tumor that frequently escapes treatment. Histidine triad nucleotide-binding protein 1 (Hint1) is a haploinsufficient tumor suppressor gene which contributes to intercellular communication, helps to regulate cell proliferation and survival, and is frequently underexpressed in gastric cancer. To examine the involvement of Hint1 in gastric cancer, small interfering RNA was used to knock down Hint1 expression in the human gastric cancer cell line SGC-7901. The data revealed that Hint1 inhibited cell proliferation, reduced radiation-induced DNA damage repair and caused G1 phase arrest, which increased the radiosensitivity of gastric cancer cells. Further mechanistic studies revealed a novel function of Hint1, whereby it acted as a negative regulator of extracellular signal-regulated kinase. These results demonstrated the critical function of Hint1 in the biology of human gastric cancer. Acting as a tumor growth suppressor and a radiosensitive agent, this protein is a potential biomarker and may be an attractive target for specific therapeutic interventions against gastric cancer.
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http://dx.doi.org/10.3892/ol.2018.8900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036515PMC
August 2018

Alloreactive cytotoxic T lymphocyte immunotherapy treatment of a patient with metastatic prostate cancer: A case report.

Medicine (Baltimore) 2018 Jun;97(24):e11111

Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing Clinical Research Center, Xuyi People's Hospital, Xuyi Department of Oncology, Nanjing Pukou Central Hospital, Nanjing Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China.

Rationale: Cytotoxic T lymphocyte (CTL) immunotherapy is an autologous cellular immune therapy that has been approved for treating patients with malignant tumors. However, there is still limited information regarding the impact of CTL on metastatic prostate cancer (PC) patients with bone metastatic lesions.

Patient Concerns: An 82-year-old male patient complained of interrupted urination, urination pain, and significant dysuria on November 24, 2014. Transurethral resection of the prostate (TURP) and postoperative pathological examination showed prostatic adenocarcinoma, and a SPECT/CT scan demonstrated multiple bone metastases. In addition, prostate specific antigen (PSA) and free PSA (FPSA) levels were 54.54 μg/mL and 2.63 μg/mL, respectively, at the beginning of treatment.

Diagnoses: The man was diagnosed with prostatic adenocarcinoma and multiple bone metastases.

Interventions: The patient received 30 cycles of alloreactive CTL (ACTL) immunotherapy regularly.

Outcomes: Over the course of the 2-year treatment, the PC patient exhibited diminished bone metastasis accompanied by a marked reduction of serum PSA and FPSA from 54.54 and 2.63 μg/ml to 0.003 and <0.006 μg/ml, respectively.

Lessons: Our clinical observations demonstrate that CTL immunotherapy is a viable treatment option for PC patients, particularly those with bone metastatic lesions and high serum levels of PSA and FPSA.
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http://dx.doi.org/10.1097/MD.0000000000011111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023702PMC
June 2018

Carnosic Acid Alleviates BDL-Induced Liver Fibrosis through miR-29b-3p-Mediated Inhibition of the High-Mobility Group Box 1/Toll-Like Receptor 4 Signaling Pathway in Rats.

Front Pharmacol 2017 19;8:976. Epub 2018 Jan 19.

Department of Pharmacology, Dalian Medical University, Dalian, China.

Fibrosis reflects a progression to liver cancer or cirrhosis of the liver. Recent studies have shown that high-mobility group box-1 (HMGB1) plays a major role in hepatic injury and fibrosis. Carnosic acid (CA), a compound extracted from rosemary, has been reported to alleviate alcoholic and non-alcoholic fatty liver injury. CA can also alleviate renal fibrosis. We hypothesized that CA might exert anti-liver fibrosis properties through an HMGB1-related pathway, and the results of the present study showed that CA treatment significantly protected against hepatic fibrosis in a bile duct ligation (BDL) rat model. CA reduced the liver expression of α-smooth muscle actin (α-SMA) and collagen 1 (Col-1). Importantly, we found that CA ameliorated the increase in HMGB1 and Toll-like receptor 4 (TLR4) caused by BDL, and inhibited NF-κB p65 nuclear translocation in fibrotic livers. , CA inhibited LX2 cell activation by inhibiting HMGB1/TLR4 signaling pathway. Furthermore, miR-29b-3p decreased HMGB1 expression, and a dual-luciferase assay validated these results. Moreover, CA down-regulated HMGB1 and inhibited LX2 cell activation, and these effects were significantly counteracted by antago-miR-29b-3p, indicating that the CA-mediated inhibition of HMGB1 expression might be miR-29b-3p dependent. Collectively, the results demonstrate that a miR-29b-3p/HMGB1/TLR4/NF-κB signaling pathway, which can be modulated by CA, is important in liver fibrosis, and indicate that CA might be a prospective therapeutic drug for liver fibrosis.
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http://dx.doi.org/10.3389/fphar.2017.00976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780338PMC
January 2018

Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties.

J Med Chem 2018 02 30;61(3):946-979. Epub 2018 Jan 30.

Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.

CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4 tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4 immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4 metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4 leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR4 cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off-target liabilities. Herein, we report a series of novel tetrahydroisoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure-activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01420DOI Listing
February 2018

Dact3 inhibits the malignant phenotype of non-small cell lung cancer through downregulation of c-Myb.

Int J Clin Exp Pathol 2017 1;10(12):11580-11587. Epub 2017 Dec 1.

Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University Shenyang, Liaoning, China.

Dact3 is a negative regulator of Wnt/β-catenin signaling. c-Myb promotes tumor cell invasion through Wnt/β-catenin pathway. However, the detailed mechanism by which Dact3 and c-Myb modulate the progression of non-small cell lung cancer (NSCLC) remains unclear. In this study, the expressions of Dact3 and c-Myb in 254 surgically resected NSCLC samples were detected by immunohistochemistry. We transfected Dact3 cDNA to A549 and H157 cells or siRNA-Dact3 to SPC cells and examined above effects on the activity of Wnt/β-catenin signaling by Western blot and luciferase activity assay, in addition to cell biological behavior by Transwell and MTT assay. Dact3 expression was reduced in NSCLC tissue. Reduced Dact3 expression was correlated with lymph node metastasis and poor prognosis of NSCLC (P<0.05). In addition, Dact3 expression was negatively correlated with the c-Myb expression (R = -0.626, P<0.05). Dact3 transfection resulted in c-Myb reduced expression in NSCLC cells, as well as decreased activity of Wnt/β-catenin signaling and reduced cell invasive and proliferative capacity. siRNA-Dact3 transfection had the opposite effect. Our results indicate that Dact3 may inhibit the malignant phenotype of NSCLC through downregulation of c-Myb.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966047PMC
December 2017

Carnosol-mediated Sirtuin 1 activation inhibits Enhancer of Zeste Homolog 2 to attenuate liver fibrosis.

Pharmacol Res 2018 02 26;128:327-337. Epub 2017 Oct 26.

Department of Pharmacology, Dalian Medical University, Dalian, 116044, China. Electronic address:

Quiescent hepatic stellate cell (HSC) activation and subsequent conversion into myofibroblasts is the central event in hepatic fibrosis pathogenesis. Epithelial-mesenchymal transition (EMT), another vital participant in liver fibrosis, has the potential to initiate HSC activation, which promotes abundant myofibroblast production. Previous studies suggest that Enhancer of Zeste Homolog 2 (EZH2) plays a significant role in myofibroblast transdifferentiation; however, the underlying mechanisms remain largely unaddressed. Carnosol (CS), a compound extracted from rosemary, displays multiple pharmacological activities. This study aimed to investigate the signaling mechanisms underlying EZH2 inhibition and the anti-fibrotic effect of CS in liver fibrosis. We found that CS significantly inhibited CCl- and TGFβ1-induced liver fibrosis and reduced both HSC activation and EMT. EZH2 knockdown also prevented these processes induced by TGFβ1 in HSCs and AML-12 cells. Interestingly, the protective effect of CS was positively associated with Sirtuin 1 (SIRT1) activation and accompanied by EZH2 inhibition. SIRT1 knockdown attenuated the EZH2 inhibition induced by CS and increased EZH2 acetylation, which enhanced its stability. Conversely, upon TGFβ1 exposure, SIRT1 activation significantly reduced the level of EZH2 acetylation; however, EZH2 overexpression prevented the SIRT1 activation that primed myofibroblast inhibition, indicating that EZH2 is a target of SIRT1. Thus, SIRT1/EZH2 regulation could be used as a new therapeutic strategy for fibrogenesis. Together, this study provides evidence of activation of the SIRT1/EZH2 pathway by CS that inhibits myofibroblast generation, and thus, CS may represent an attractive candidate for anti-fibrotic clinical therapy.
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http://dx.doi.org/10.1016/j.phrs.2017.10.013DOI Listing
February 2018

p0071 interacts with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of non-small cell lung cancer.

Mol Carcinog 2018 Jan 25;57(1):89-96. Epub 2017 Sep 25.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China.

As a member of the p120-catenin (p120ctn) subfamily, the p0071 study in tumor is very limited. We demonstrated the clinicopathological significance of p0071 in non-small cell lung cancer (NSCLC), as well as E-cadherin. Co-immunoprecipitation was used to detect the interaction of p0071 with E-cadherin in A549 and SPC cells (E-cadherin is mainly expressed in the cytoplasm of these cells). p0071 cytoplasmic expression was knocked down by siRNA in these cells and this effect on the RhoA activity and cell invasion and migration ability were measured. p0071 overexpression in the cytoplasm of tumor cell was correlated with lymphatic metastase and poor prognosis of NSCLC. The patients with both abnormal expression of p0071 and E-cadherin (cytoplasmic expression) had a statistically significant shorter survival than the patients without both abnormal expression (P  < 0.05). There is a significant correlation between cytoplasmic overexpression of p0071 and E-cadherin in NSCLC tissues. p0071 interacted with E-cadherin in the cytoplasm of A549 and SPC cell lines. Treatment with siRNA-p0071 inhibited the invasion and migration ability of NSCLC cells. Above results confirmed that p0071 interacted with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of NSCLC.
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http://dx.doi.org/10.1002/mc.22734DOI Listing
January 2018

An isolated unusual digit metastasis from esophageal carcinoma: a case report.

Onco Targets Ther 2017 9;10:2449-2452. Epub 2017 May 9.

Department of Oncology, Nanjing First Hospital, Nanjing Medical University.

Distant soft tissue tumor metastasis isolated in the digit, presenting as a primary esophageal squamous cell carcinoma is considered extremely rare. Herein, we present a rare case of a 44-year-old male patient with squamous cell carcinoma of the esophagus associated with the clinical symptoms of progressive dysphagia and hoarseness in the course of 2 days. During the second course of chemotherapy, the patient sustained a fall with scald to his right ring finger, while the swelling in the right ring finger was soft, cystic and 2.0×1.8 cm in size. Then, phalangectomy was performed in his right ring finger and pathologic diagnosis was considered metastasis from the esophagus. Unfortunately, the patient succumbed to this disease within 2 months of diagnosis of metastasis. In conclusion, detection of soft tissue metastasis may have prognostic implications, providing more accessible biopsy sites and helping avoid invasive procedures.
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http://dx.doi.org/10.2147/OTT.S132027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431735PMC
May 2017

Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025.

Eur Urol 2017 09 12;72(3):368-376. Epub 2017 Apr 12.

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.

Background: Response patterns to nivolumab differ from those seen with other approved targeted therapies.

Objective: To investigate the efficacy of nivolumab in previously treated patients with advanced renal cell carcinoma who were treated beyond (Response Evaluation Criteria In Solid Tumors) RECIST progression.

Design, Setting, And Participants: This was a subgroup analysis of patients treated with nivolumab in the phase 3 CheckMate 025 study. Patients continuing to tolerate therapy and exhibiting investigator-assessed clinical benefit were eligible to be treated beyond RECIST progression (TBP) and received therapy for ≥4 wk after first progression; patients not treated beyond RECIST progression (NTBP) received 0 wk to <4 wk of therapy after progression.

Interventions: Nivolumab 3mg/kg intravenously every 2 wk.

Results And Limitations: Of 406 nivolumab-treated patients, 316 (78%) progressed by RECIST criteria. Of those who progressed, 48% were TBP, 52% were NTBP. Before being TBP, objective response rate (95% confidence interval) was 20% (14-28) and 14% (9-21) in patients TBP and NTBP, respectively. Differences in clinical characteristics assessed at first progression between patients TBP versus NTBP included better Karnofsky performance status, less deterioration in Karnofsky performance status, shorter time to response, lower incidence of new bone lesions, and improved quality of life. Postprogression, 13% of all patients TBP (20/153) had ≥30% tumor burden reduction including patients with preprogression and postprogression tumor measurements (n=142) and complete/partial response (28%, 8/29), stable disease (6%, 3/47), and progressive disease (14%, 9/66) as their best response before being TBP. Incidence of treatment-related adverse events in patients TBP was lower after (59%) versus before (71%) progression. Limitations included potential bias from the nonrandomized nature of the analysis.

Conclusions: A subset of patients with advanced renal cell carcinoma and RECIST progression experienced tumor reduction postprogression with nivolumab, and had an acceptable safety profile. Clinical judgment remains essential when switching therapy. ClinicalTrials.gov Identifier: NCT01668784.

Patient Summary: A subset of patients with advanced renal cell carcinoma and disease progression may continue to benefit from nivolumab treatment beyond progression as evidenced by tumor reduction postprogression and an acceptable safety profile.
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http://dx.doi.org/10.1016/j.eururo.2017.03.037DOI Listing
September 2017

Cutaneous presentation preceding acute monocytic leukemia: A CARE-compliant article.

Medicine (Baltimore) 2017 Mar;96(10):e6269

Department of Dermatology, The Second Hospital of Jilin University, Changchun, China.

Rationale: Cutaneous presentation preceding acute myeloid leukemia (AML) is rare, and the prognosis is poor.

Patient Concerns: We report 4 cases of AML cutis, where skin infiltration precedes any blood or bone marrow evidence of leukemia. We also reviewed 13 cases reported in English and Chinese literature. The 4 cases all presented typical cutaneous lesions without any systemic evidence of leukemia. Histopathological examination found that dense monomorphous cell infiltration involved the dermis. Some cells surrounded blood vessels and skin appendages in a concentric manner or showed single-row arrangement in the collagen fiber bundles. Uninvolved papillary dermis was found to separate normal epidermis from dermal infiltration. Minor cells had a large kidney-shaped or oval nucleus with nucleoli and slightly eosinophilic cytoplasm. Immunohistochemical analysis was positive for CD4, CD56, while CD123 was negative in all cases.

Diagnoses: AML-M5.

Interventions: 2 patients received chemotherapy ,but others rejected treatment.

Outcomes: Most patients died within 1 year after the onset of skin lesions.

Lessons: These findings suggest that skin infiltration of AML may precede any systemic evidence, and typical cutaneous lesions in elderly individuals may be indicative for AML.
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http://dx.doi.org/10.1097/MD.0000000000006269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348187PMC
March 2017