Publications by authors named "Rene Gonzalez"

128 Publications

Maximizing Patient and Staff Safety During Transesophageal Echocardiography in the COVID-19 Era by Use of a New Oxygen Delivery System: Endoscopy Oxygen Masks with Self-Sealing Endoscope Insertion Ports.

J Am Soc Echocardiogr 2020 Dec 31. Epub 2020 Dec 31.

Department of Anesthesiology, Southern Ocean Medical Center, Manahawkin, New Jersey.

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http://dx.doi.org/10.1016/j.echo.2020.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774456PMC
December 2020

Myeloid arginase-1 controls excessive inflammation and modulates T cell responses in Pseudomonas aeruginosa pneumonia.

Immunobiology 2021 Jan 24;226(1):152034. Epub 2020 Nov 24.

University of Kentucky, Department of Pharmacy Practice and Science, 789 S. Limestone Street, Lexington, KY 40536, USA. Electronic address:

Regulatory properties of macrophages associated with alternative activation serve to limit the exaggerated inflammatory response during pneumonia caused by Pseudomonas aeruginosa infection. Arginase-1 is an important effector of these macrophages believed to play an essential role in decreasing injury and promoting repair. We investigated the role of arginase-1 in the control of inflammatory immune responses to P. aeruginosa pneumonia in mice that exhibit different immunologic phenotypes. C57BL/6 mice with conditional knockout of the arginase-1 (Arg1) gene from myeloid cells (Arg1) or BALB/c mice treated with small molecule inhibitors of arginase were infected intratracheally with P. aeruginosa. Weight loss, mortality, bacterial clearance, and lung injury were assessed and compared, as were the characterization of immune cell populations over time post-infection. Myeloid arginase-1 deletion resulted in greater morbidity along with more severe inflammatory responses compared to littermate control mice. Arg1 mice had greater numbers of neutrophils, macrophages, and lymphocytes in their airways and lymph nodes compared to littermate controls. Additionally, Arg1 mice recovered from inflammatory lung injury at a significantly slower rate. Conversely, treatment of BALB/c mice with the arginase inhibitor S-(2-boronoethyl)-l-cysteine hydrochloride (BEC) did not change morbidity as defined by weight loss, but mice at day 10 post-infection treated with BEC had gained significantly more weight back than controls. Neutrophil and macrophage infiltration were similar between groups in the lung parenchyma, and neutrophil migration into the airways was reduced by BEC treatment. Differences seem to lie in the impact on T cell subset disposition. Arg1 mice had increased total CD4+ T cell expansion in the lymph nodes, and increased T cell activation, IFNγ production, and IL-17 production in the lymph nodes, lung interstitium, and airways, while treatment with BEC had no impact on T cell activation or IL-17 production, but reduced the number of T cells producing IFNγ in the lungs. Lung injury scores were increased in the Arg1 mice, but no differences were observed in the mice treated with pharmacologic arginase inhibitors. Overall, myeloid arginase production was demonstrated to be essential for control of damaging inflammatory responses associated with P. aeruginosa pneumonia in C57BL/6 mice, in contrast to a protective effect in the Th2-dominant BALB/c mice when arginase activity is globally inhibited.
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http://dx.doi.org/10.1016/j.imbio.2020.152034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855574PMC
January 2021

Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).

Melanoma Res 2021 02;31(1):67-75

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79-84] and 70% (95% CI 66-74), respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.
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http://dx.doi.org/10.1097/CMR.0000000000000708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757740PMC
February 2021

Facile preparation of a novel Ga-67-labeled NODAGA-conjugated lactam-cyclized alpha-MSH peptide at room temperature for melanoma targeting.

Bioorg Med Chem Lett 2020 12 24;30(24):127627. Epub 2020 Oct 24.

Department of Radiology, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address:

In this study, the melanoma targeting property of Ga-NODAGA-GGNle-CycMSH {1,4,7-triazacyclononane,1-gluteric acid-4,7-acetic acid-GlyGlyNle-c[Asp-His-D-Phe-Arg-Trp-Lys]-CONH} was determined on B16/F10 melanoma-bearing C57 mice to demonstrate the feasibility of NODAGA as a radiometal chelator for facile room temperature radiolabeling of NODAGA-GGNle-CycMSH. The IC value of NODAGA-GGNle-CycMSH was 0.87 ± 0.12 nM on B16/F10 melanoma cells. Ga-NODAGA-GGNle-CycMSH was readily prepared at room temperature with greater than 98% radiolabeling yield and displayed MC1R-specific binding on B16/F10 melanoma cells. The B16/F10 melanoma uptake of Ga-NODAGA-GGNle-CycMSH was 10.31 ± 0.78, 14.96 ± 1.34, 13.7 ± 3.33 and 10.4 ± 2.2% ID/g at 0.5, 2, 4 and 24 h post-injection, respectively. Approximately 85% of the injected dose was cleared out the body via urinary system at 2 h post-injection. Ga-NODAGA-GGNle-CycMSH showed high tumor/blood, tumor/muscle and tumor/skin uptake ratios after 2 h post-injection. Overall, Ga-NODAGA-GGNle-CycMSH could be easily prepared at room temperature and exhibited favorable melanoma targeting property, suggesting the potential use of NODAGA as a radiometal chelator for facile room temperature radiolabeling of α-MSH peptides.
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http://dx.doi.org/10.1016/j.bmcl.2020.127627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704577PMC
December 2020

Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft.

Mol Cancer Res 2021 Feb 21;19(2):346-357. Epub 2020 Oct 21.

Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood-derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM, and NOD/SCID/IL2rg (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non-HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)-related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated using tumor-derived cell lines. IMPLICATIONS: Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864867PMC
February 2021

Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity.

Nat Commun 2020 10 16;11(1):5259. Epub 2020 Oct 16.

QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.
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http://dx.doi.org/10.1038/s41467-020-18988-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567804PMC
October 2020

[History of child abuse among patients with bipolar disorders].

Rev Med Chil 2020 Feb;148(2):204-210

Facultad de Medicina, Universidad de Chile, Santiago, Chile.

Background: A history of child abuse is common and has a significant impact in the clinical course of patients diagnosed with bipolar disorders (BD).

Aims: To assess the frequency of child abuse experiences in patients BD type I and to evaluate its association with clinical course and cognitive functioning variables.

Material And Methods: 117 patients with BD aged 45 ± 14 years (66% women) answered the Childhood Trauma Questionnaire (CTQ). The clinical course (illness onset, history of suicide attempts and number of hospitalizations) was obtained from medical records. Cognitive functioning was evaluated through social and non-social cognition tasks.

Results: 64% of participants reported some type of child abuse. This variable was associated with an early onset of the disease (Odds ratio (OR) = 3.3; p < 0.02), increased risk of suicide attempts (OR = 2.4; p < 0.04) and specific disturbances in social cognitive tasks.

Conclusions: Our study supports evidence of a common history of child abuse in patients with BD. Although child abuse predicts a worse clinical course, major clinical practice guidelines, as well as research designs, do not highlight this evidence.
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http://dx.doi.org/10.4067/s0034-98872020000200204DOI Listing
February 2020

A Portable Fuzzy Driver Drowsiness Estimation System.

Sensors (Basel) 2020 Jul 23;20(15). Epub 2020 Jul 23.

Research & Development Department, Solinftec, Araçatuba 16013337, Brazil.

The adequate automatic detection of driver fatigue is a very valuable approach for the prevention of traffic accidents. Devices that can determine drowsiness conditions accurately must inherently be portable, adaptable to different vehicles and drivers, and robust to conditions such as illumination changes or visual occlusion. With the advent of a new generation of computationally powerful embedded systems such as the Raspberry Pi, a new category of real-time and low-cost portable drowsiness detection systems could become standard tools. Usually, the proposed solutions using this platform are limited to the definition of thresholds for some defined drowsiness indicator or the application of computationally expensive classification models that limits their use in real-time. In this research, we propose the development of a new portable, low-cost, accurate, and robust drowsiness recognition device. The proposed device combines complementary drowsiness measures derived from a temporal window of eyes (PERCLOS, ECD) and mouth (AOT) states through a fuzzy inference system deployed in a Raspberry Pi with the capability of real-time response. The system provides three degrees of drowsiness (Low-Normal State, Medium-Drowsy State, and High-Severe Drowsiness State), and was assessed in terms of its computational performance and efficiency, resulting in a significant accuracy of 95.5% in state recognition that demonstrates the feasibility of the approach.
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http://dx.doi.org/10.3390/s20154093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435375PMC
July 2020

Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy.

Cancers (Basel) 2020 Jul 17;12(7). Epub 2020 Jul 17.

Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.

Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. However, predicting which patients will respond to immunotherapy remains a significant knowledge gap. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in , a negative regulator of , were found exclusively in the responders. Mutations in -related genes were also enriched in the responder group compared to the non-responders. Patients that harbored -related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subset of tumor samples identified that CD83 was highly expressed in our responder group. Additionally, Gene Set Enrichment Analysis showed that the signaling via pathway was one of the top pathways with differential expression in responders vs. non-responders. In vitro activity assays indicated that the G34E variant caused loss-of-function of , and resulted in activation of signaling. Flow cytometry assays indicated that G34E variant was associated with upregulation of CD83 in human melanoma cell lines. These results suggest that activation and signaling in tumor cells contributes to a favorable anti-PD1 treatment response, and clinical screening to include aberrations in -related genes should be considered.
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http://dx.doi.org/10.3390/cancers12071943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409244PMC
July 2020

Pembrolizumab Monotherapy for Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: A Single-Arm Phase II Trial (KEYNOTE-629).

J Clin Oncol 2020 09 16;38(25):2916-2925. Epub 2020 Jul 16.

Royal Brisbane and Women's Hospital, Herston, QLD, Australia.

Purpose: Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC); mortality rates exceed 70% in patients with distant metastases. Here, we present the first interim analysis of the R/M cSCC cohort from the 2-cohort-locally advanced and R/M-phase II KEYNOTE-629 study.

Patients And Methods: Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety.

Results: At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2%; 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months; '+' refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15; 14.3%), asthenia (n = 14; 13.3%), and fatigue (n = 13; 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy.

Conclusion: Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.
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http://dx.doi.org/10.1200/JCO.19.03054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460151PMC
September 2020

Novel [Tc]-Tricarbonyl-NOTA-Conjugated Lactam-Cyclized Alpha-MSH Peptide with Enhanced Melanoma Uptake and Reduced Renal Uptake.

Mol Pharm 2020 09 28;17(9):3581-3588. Epub 2020 Jul 28.

The purpose of this study was to examine the melanoma targeting and imaging properties of Tc(CO)-NOTA-GGNle-CycMSH {1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-GlyGlyNle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH} and Tc(CO)-NODAGA-GGNle-CycMSH {1,4,7-triazacyclononane,1-gluteric acid-4,7-acetic acid-GlyGlyNle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH} on B16/F10 melanoma-bearing C57 mice to demonstrate the feasibility of NOTA/NODAGA as metal chelators for Tc(CO) radiolabeling. NOTA/NODAGA-GGNle-CycMSH were synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry. The melanocortin-1 (MC1) receptor binding affinities of the peptides were determined on B16/F10 melanoma cells. The biodistribution of Tc(CO)-NOTA-GGNle-CycMSH and Tc(CO)-NODAGA-GGNle-CycMSH were determined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of Tc(CO)-NOTA-GGNle-CycMSH and Tc(CO)-NODAGA-GGNle-CycMSH were determined on B16/F10 melanoma-bearing C57 mice. The IC values of NOTA/NODAGA-GGNle-CycMSH were 0.8 ± 0.1 and 0.9 ± 0.1 nM on B16/F10 cells. Tc(CO)-NOTA-GGNle-CycMSH and Tc(CO)-NODAGA-GGNle-CycMSH were readily prepared via the [Tc(CO)(OH)] intermediate and displayed MC1R-specific binding on B16/F10 cells. Tc(CO)-NOTA-GGNle-CycMSH was further evaluated as a lead peptide because of its higher tumor uptake (19.76 ± 3.62% ID/g) and lower kidney uptake (1.59 ± 0.52% ID/g) at 2 h postinjection than Tc(CO)-NODAGA-GGNle-CycMSH. The B16/F10 melanoma uptake of Tc(CO)-NOTA-GGNle-CycMSH was 16.07 ± 4.47, 19.76 ± 3.62, 11.30 ± 2.81, and 3.16 ± 2.28% ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. Tc(CO)-NOTA-GGNle-CycMSH showed high tumor to normal organ uptake ratios after 2 h postinjection. The B16/F10 melanoma lesions were clearly visualized by SPECT/CT using Tc(CO)-NOTA-GGNle-CycMSH as an imaging probe at 2 h postinjection. High tumor uptake, low kidney uptake, and fast urinary clearance of Tc(CO)-NOTA-GGNle-CycMSH highlighted its potential for melanoma imaging and facilitated the evaluation of Re(CO)-NOTA-GGNle-CycMSH for melanoma therapy.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484323PMC
September 2020

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

Cancer Chemother Pharmacol 2020 04 15;85(4):673-683. Epub 2020 Feb 15.

GlaxoSmithKline, Collegeville, PA, USA.

Purpose: This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.

Methods: This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.

Results: Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses).

Conclusions: Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.
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http://dx.doi.org/10.1007/s00280-020-04038-8DOI Listing
April 2020

IL-6 and IL-8 Are Linked With Myeloid-Derived Suppressor Cell Accumulation and Correlate With Poor Clinical Outcomes in Melanoma Patients.

Front Oncol 2019 8;9:1223. Epub 2019 Nov 8.

Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

We sought to identify tumor-secreted factors that altered the frequency of MDSCs and correlated with clinical outcomes in advanced melanoma patients. We focused our study on several of the many factors involved in the expansion and mobilization of MDSCs. These were identified by measuring circulating concentrations of 13 cytokines and growth factors in stage IV melanoma patients ( = 55) and healthy controls ( = 22). Based on these results, we hypothesized that IL-6 and IL-8 produced by melanoma tumor cells participate in the expansion and recruitment of MDSCs and together would be predictive of overall survival in melanoma patients. We then compared the expression of IL-6 and IL-8 in melanoma tumors to the corresponding plasma concentrations and the frequency of circulating MDSCs. These measures were correlated with clinical outcomes. Patients with high plasma concentrations of either IL-6 (40%) or IL-8 (63%), or both (35%) had worse median overall survival compared to patients with low concentrations. Patients with low peripheral concentrations and low tumoral expression of IL-6 and IL-8 showed decreased frequencies of circulating MDSCs, and patients with low frequencies of MDSCs had better overall survival. We have previously shown that IL-6 is capable of expanding MDSCs, and here we show that MDSCs are chemoattracted to IL-8. Multivariate analysis demonstrated an increased risk of death for subjects with both high IL-6 and IL-8 (HR 3.059) and high MDSCs (HR 4.265). Together these results indicate an important role for IL-6 and IL-8 in melanoma patients in which IL-6 potentially expands peripheral MDSCs and IL-8 recruits these highly immunosuppressive cells to the tumor microenvironment. This study provides further support for identifying potential therapeutics targeting IL-6, IL-8, and MDSCs to improve melanoma treatments.
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http://dx.doi.org/10.3389/fonc.2019.01223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857649PMC
November 2019

Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in -Mutant Melanoma.

Clin Cancer Res 2020 01 15;26(1):46-53. Epub 2019 Nov 15.

Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia, and University of Melbourne, Parkville, Victoria, Australia.

Purpose: To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study.

Patients And Methods: This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced -mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve ( = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy-progressive disease (PD); = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7).

Results: Median OS was 31.8 months [95% confidence interval (CI), 24.5-not estimable] in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy-PD cohort, the median OS was 8.5 months (95% CI, 6.7-11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events.

Conclusions: A subset of patients with advanced -mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942621PMC
January 2020

Melanoma-Targeting Property of Y-90-Labeled Lactam-Cyclized α-Melanocyte-Stimulating Hormone Peptide.

Cancer Biother Radiopharm 2019 Nov 23;34(9):597-603. Epub 2019 Oct 23.

Department of Radiology, University of Colorado Denver, Aurora, Colorado.

The purpose of this study was to evaluate melanoma-targeting property of Y-DOTA-GGNle-CycMSH to facilitate its potential therapeutic application. DOTA-GGNle-CycMSH was synthesized and readily labeled with Y in 0.25 M NHAc-buffered solution to generate Y-DOTA-GGNle-CycMSH. The specific receptor binding, internalization, and efflux of Y-DOTA-GGNle-CycMSH were determined on B16/F10 murine melanoma cells. The biodistribution property of Y-DOTA-GGNle-CycMSH was examined on B16/F10 melanoma-bearing C57 mice. Y-DOTA-GGNle-CycMSH displayed receptor-specific binding, rapid internalization, and prolonged efflux on B16/F10 melanoma cells. Y-DOTA-GGNle-CycMSH exhibited high uptake and prolonged retention in melanoma, and fast urinary clearance on B16/F10 melanoma-bearing C57 mice. The B16/F10 tumor uptake was 20.73% ± 7.99%, 19.93% ± 5.73%, 14.8% ± 4.61%, and 6.69% ± 1.85% ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. Y-DOTA-GGNle-CycMSH displayed melanocortin-1 receptor (MC1R) targeting and specificity on B16/F10 melanoma cells and tumors. The favorable melanoma-targeting property and fast urinary clearance of Y-DOTA-GGNle-CycMSH warranted its evaluation for melanoma therapy in future studies.
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http://dx.doi.org/10.1089/cbr.2019.3049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856944PMC
November 2019

A nomogram to predict node positivity in patients with thin melanomas helps inform shared patient decision making.

J Surg Oncol 2019 Dec 10;120(7):1276-1283. Epub 2019 Oct 10.

Department of Surgery, University of Colorado, Aurora, Colorado.

Objective: To develop a nomogram to estimate the probability of positive sentinel lymph node (+SLN) for patients with thin melanoma and to characterize its potential impact on sentinel lymph node biopsy (SLNB) rates.

Methods: Patients diagnosed with thin (0.5-1.0 mm) melanoma were identified from the National Cancer Database 2012 to 2015. A multivariable logistic regression model was used to examine factors associated with +SLN, and a nomogram to predict +SLN was constructed. Nomogram performance was evaluated and diagnostic test statistics were calculated.

Results: Of the 21 971 patients included 10 108 (46.0%) underwent SLNB, with a 4.0% +SLN rate. On multivariable analysis, age, Breslow thickness, lymphovascular invasion, ulceration, and Clark level were significantly associated with SLN status. The area under the receiver operating curve was 0.67 (95% confidence interval, 0.65-0.70). While 15 249 (69.4%) patients had either T1b tumors or T1a tumors with at least one adverse feature, only 2846 (13.0%) had a nomogram predicted probability of a +SLN ≥5%. Using this cut-off, the indication for a SLNB in these patients would be reduced by 81.3% as compared to the American Joint Committee on Cancer 8th edition staging criteria.

Conclusions: The risk predictions obtained from the nomogram allow for more accurate selection of patients who could benefit from SLNB.
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http://dx.doi.org/10.1002/jso.25720DOI Listing
December 2019

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

N Engl J Med 2019 10 28;381(16):1535-1546. Epub 2019 Sep 28.

From the Royal Marsden NHS Foundation Trust, London (J.L.), and the College of Medicine, Swansea University, Swansea (J.W.) - both in the United Kingdom; the Oncology Institute of Veneto IRCCS, Padua (V.C.-S.), the European Institute of Oncology, IRCCS, Milan (P.F.F.), Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples (P.A.A.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and the Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital, Siena (M.M.) - all in Italy; the University of Colorado Cancer Center, Aurora (R.G.); Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille Hôpital Timone, Marseille (J.-J.G.), and Université de Paris, INSERM Unité 976, Assistance Publique-Hôpitaux de Paris Dermatology and Centres d'Investigation Clinique, Saint Louis Hospital, Paris (C.L.) - both in France; the Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.); the University of Michigan, Ann Arbor (C.D.L.); Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.); the Department of Dermatology, University of Essen, Essen, and the German Cancer Consortium, Heidelberg - both in Germany (D.S.); Universitäts Spital, Zurich, Switzerland (R.D.); Cross Cancer Institute, Edmonton, AB (M.S.), and the Princess Margaret Cancer Centre, Toronto (D.H.) - both in Canada; Tasman Oncology Research, Southport, QLD (A.H.), the Crown Princess Mary Cancer Centre, Melanoma Institute Australia, University of Sydney, Sydney, NSW (M.S.C., G.V.L.), and the Royal North Shore and Mater Hospitals (G.V.L.), Sydney, and the Peter MacCallum Cancer Centre, Melbourne, VIC (G.M.) - all in Australia; General University Hospital Gregorio Marañon and Centro de Investigación Biomédica en Red de Oncología, Madrid (I.M.-R.); the Netherlands Cancer Institute, Amsterdam (J.H.); the Leuven Cancer Institute, Department of General Medical Oncology, University Hospital Leuven, Leuven, Belgium (P.S.); University of California San Diego Health-La Jolla Moores Cancer Center, La Jolla (G.A.D.); the Department of Oncology, Odense University Hospital, Odense, Denmark (L.B.); Bristol-Myers Squibb, Princeton, NJ (J.I.R., A.B., A.M.); Dana-Farber Cancer Institute, Boston (F.S.H.); and the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W.).

Background: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.

Methods: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.

Results: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.

Conclusions: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
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http://dx.doi.org/10.1056/NEJMoa1910836DOI Listing
October 2019

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.

Nat Med 2019 06 6;25(6):929-935. Epub 2019 Jun 6.

MD Anderson Cancer Center, Houston, TX, USA.

Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF mutations. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAF-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4 T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1-85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6-25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.
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http://dx.doi.org/10.1038/s41591-019-0474-7DOI Listing
June 2019

Inflammatory side effects of BRAF and MEK inhibitors.

Melanoma Res 2019 10;29(5):522-526

Department of Ophthalmology.

The aim of this study was to describe inflammatory side effects in patients treated with BRAF and MEK inhibitors at a single tertiary care institution. This was a retrospective chart review of patients prescribed single-agent or combination BRAF and MEK inhibitors from January 2010 until May 2015. The primary outcome was the presence of inflammatory side effects. Among 124 patients, 56.4% were male, the median age was 59 years, and most (91.1%) were treated for metastatic melanoma. Most patients (74.2%) developed inflammatory side effects, some with multiple occurrences, for a total of 211 occurrences. The overall prevalence of inflammatory side effects did not differ across therapies. In a subanalysis, patients treated with both single-agent and combination therapies were more likely to experience an inflammatory side effect on single-agent therapy (P = 0.0126 for BRAF inhibitor, P = 0.0833 for MEK inhibitor). The most common inflammatory side effects for the entire cohort included arthralgias/myalgias (32.9%), nonacneiform rash (28.0%), pyrexia (25.5%), and erythema nodosum (11.2%), although side effects differed across the class of therapy. Corticosteroids were initiated in 73 side effect instances among 47 patients. Drug interruption or dose reduction was reported in 78 side effect instances in 50 patients. Fifteen side effect instances led to treatment termination. There is a high prevalence of inflammatory side effects encompassing all organ systems in patients treated with BRAF and MEK inhibitors. There is no significant difference in the prevalence of inflammatory side effects in patients treated with single-agent versus combination therapies, however, side effect profile differs across agents.
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http://dx.doi.org/10.1097/CMR.0000000000000599DOI Listing
October 2019

Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial.

J Clin Oncol 2019 04 27;37(11):867-875. Epub 2019 Feb 27.

17 Veneto Institute of Oncology-Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy.

Purpose: Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) is approved for first-line treatment of patients with advanced melanoma in several countries. We conducted a phase IIIb/IV study (CheckMate 511) to determine if nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) improves the safety profile of the combination.

Patients And Methods: Patients (N = 360) age 18 years or older with previously untreated, unresectable stage III or IV melanoma were randomly assigned 1:1 to NIVO3+IPI1 or NIVO1+IPI3 once every 3 weeks for four doses. After 6 weeks, all patients received NIVO 480 mg once every 4 weeks until disease progression or unacceptable toxicity. The primary end point was a comparison of the incidence of treatment-related grade 3 to 5 adverse events (AEs) between groups. Secondary end points included descriptive analyses of objective response rate, progression-free survival, and overall survival. The study was not designed to formally demonstrate noninferiority of NIVO3+IPI1 to NIVO1+IPI3 for efficacy end points.

Results: At a minimum follow-up of 12 months, incidence of treatment-related grade 3 to 5 AEs was 34% with NIVO3+IPI1 versus 48% with NIVO1+IPI3 ( P = .006). In descriptive analyses, objective response rate was 45.6% in the NIVO3+IPI1 group and 50.6% in the NIVO1+IPI3 group, with complete responses in 15.0% and 13.5% of patients, respectively. Median progression-free survival was 9.9 months in the NIVO3+IPI1 group and 8.9 months in the NIVO1+IPI3 group. Median overall survival was not reached in either group.

Conclusion: The CheckMate 511 study met its primary end point, demonstrating a significantly lower incidence of treatment-related grade 3-5 AEs with NIVO3+IPI1 versus NIVO1+IPI3. Descriptive analyses showed that there were no meaningful differences between the groups for any efficacy end point, although longer follow up may help to better characterize efficacy outcomes.
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http://dx.doi.org/10.1200/JCO.18.01998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455714PMC
April 2019

Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition.

J Immunother Cancer 2019 02 18;7(1):49. Epub 2019 Feb 18.

Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored.

Methods: Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIM database. Patient characteristics, toxicity and efficacy were analyzed.

Results: A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy.

Conclusion: In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.
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http://dx.doi.org/10.1186/s40425-019-0522-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380045PMC
February 2019

Evaluation of a Novel Pb-203-Labeled Lactam-Cyclized Alpha-Melanocyte-Stimulating Hormone Peptide for Melanoma Targeting.

Mol Pharm 2019 04 25;16(4):1694-1702. Epub 2019 Feb 25.

Versant Medical Physics and Radiation Safety, Richland , Washington 99354 , United States.

The purpose of this study is to examine the melanocortin-1 receptor (MC1R) targeting and specificity of Pb-DOTA-GGNle-CycMSH in melanoma cells and tumors to facilitate its potential therapeutic application when labeled with Pb. The MC1R-specific targeting and imaging properties of Pb-DOTA-GGNle-CycMSH were determined on B16/F1 and B16/F10 murine melanoma cells and in B16/F1 flank melanoma-, B16/F10 flank melanoma-, and B16/F10 pulmonary metastatic melanoma-bearing C57 mice. Pb-DOTA-GGNle-CycMSH displayed MC1R-specific binding on B16/F1 and B16/F10 melanoma cells and tumors. B16/F1 flank melanoma, B16/F10 flank melanoma, and B16/F10 pulmonary metastatic melanoma lesions could be clearly imaged by single photon emission computed tomography (SPECT) using Pb-DOTA-GGNle-CycMSH as an imaging probe. The favorable melanoma targeting and imaging properties highlighted the potential of Pb-DOTA-GGNle-CycMSH as a MC1R-targeting melanoma imaging probe and warranted the evaluation of Pb-DOTA-GGNle-CycMSH for melanoma therapy in future studies.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443429PMC
April 2019

Klotho Gene and Protein in Human Placentas According to Birth Weight and Gestational Age.

Front Endocrinol (Lausanne) 2018 15;9:797. Epub 2019 Jan 15.

School of Medicine, Maternal and Child Research Institute (IDIMI), University of Chile, Santiago, Chile.

Fetal growth restriction may be the consequence of maternal, fetal, or placental factors. The insulin-like growth factors (IGFs) are major determinants of fetal growth, and are expressed in the mother, fetus and placenta in most species. Previously we reported higher placental protein content of IGF-I, IGF-IR, and AKT in small (SGA) compared with those from appropriate for gestational age (AGA) placentas. The protein Klotho, has been reported in placenta and may regulate IGF-I activity. In this study we determined Klotho gene expression and protein immunostaining in term (T-SGA y T-AGA) and preterm (PT-SGA y PT-AGA) human placentas. In addition, we assessed the effect of Klotho on the IGF-IR and AKT activation induced by IGF-I. Placentas ( = 1 17) from 32 T-SGA (birth weight (BW) = -1.74 ± 0.08 SDS), 37 T-AGA (BW = 0.12 ± 0.12 SDS), 20 PT-SGA (BW = -2.08 ± 0.14 SDS), and 28 PT-AGA (BW = -0.43 ± 0.13 SDS) newborns were collected. mRNA expression by RT-PCR in the chorionic (CP) and basal (BP) plates of the placentas, and the presence of Klotho was evaluated by immunohistochemistry (integral optical density, IOD). In addition, we developed placental explants that were incubated with IGF-I in the presence or absence of Klotho. We found a lower mRNA expression and protein immunoreactivity of Klotho in the CP of SGA (term and preterm) compared with AGA placentas. We also observed a significant reduction in IGF-IR tyrosine activation induced by IGF-I 10 nM when preincubated with 2.0 nM of Klotho (2.4 ± 0.5 arbitrary units vs. 1.3 ± 0.3 AU), and similar results we observed on AKT and ERK activation. We describe for the first time that Klotho mRNA and protein varies according to fetal growth and gestational age. In addition, Klotho appears to down-regulate the activation induced by IGF-I on IGF-IR and AKT, suggesting that Klotho may be regulating IGF-I activity in human placentas according to intrauterine fetal growth.
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http://dx.doi.org/10.3389/fendo.2018.00797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340928PMC
January 2019

Ga-DOTA-GGNle-CycMSH targets the melanocortin-1 receptor for melanoma imaging.

Sci Transl Med 2018 11;10(466)

Department of Radiology, University of Colorado Denver, Aurora, CO 80045, USA.

Melanocortin-1 receptor (MC1R) is a molecular target for melanoma imaging and therapy because of its overexpression on rodent and human melanoma cells. Here, we evaluated the MC1R targeting and specificity of Ga-DOTA-GGNle-CycMSH and Cy5.5-GGNle-CycMSH using murine and human melanoma cells, and murine and xenografted tumors. Ga-DOTA-GGNle-CycMSH was used first in human as an imaging probe to evaluate the possibility of radionuclide therapy in patients with advanced-stage melanoma. Ga-DOTA-GGNle-CycMSH and Cy5.5-GGNle-CycMSH displayed MC1R-specific targeting properties in murine and human melanoma cells, as well as in murine melanoma and human melanoma-xenografted tumors. Both B16/F10 and M21 melanoma lesions could be easily imaged by positron emission tomography using Ga-DOTA-GGNle-CycMSH The first-in-human images of melanoma brain metastases in patients demonstrated the clinical relevance of MC1R as a molecular target for melanoma imaging, highlighting the potential of Ga-DOTA-GGNle-CycMSH as an MC1R-targeting melanoma imaging probe and underscoring the need to develop MC1R-targeting therapeutic agents for treating patients with metastatic melanoma.
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http://dx.doi.org/10.1126/scitranslmed.aau4445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383514PMC
November 2018

Strengths based rehabilitation assessment: Adapted Inventory of Virtues and Strengths.

Work 2018 ;61(3):421-435

Virginia Medicaid Enrollment Broker and Education Services, Richmond, VA, USA.

Background: The Values in Action Inventory of Strengths (VIA-IS) operationalizes 24 character strengths that compose the six virtues proposed in Peterson and Seligman's classification theory. Though the utility of the VIA-IS has been demonstrated in the general population, its applicability to the study of psychosocial adaptation in rehabilitation for individuals with disabilities has been controversial.

Objective: The present study was to develop a measure of rehabilitation clients' positive traits, the Adapted Inventory of Virtues and Strengths (AIVS) designed to complement the applicability issues of the VIA-IS.

Method: Step-by-step AIVS development procedures are presented, and the AIVS factor structure identified via factor analysis is interpreted from a psychosocial adaptation perspective and compared to the VIA-IS factor structure.

Results: AIVS subscales include Courage, Integrity, Practical Wisdom, Committed Action, and Emotional Transcendence. Construct validity was assessed by correlating AIVS factors with measures of resilience, life satisfaction, and well-being.

Conclusions: The AIVS offers a reliable framework that has clinical utility for strengths-based rehabilitation practice.
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http://dx.doi.org/10.3233/WOR-182807DOI Listing
March 2019

Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.

Lancet Oncol 2018 11 22;19(11):1480-1492. Epub 2018 Oct 22.

Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.

Background: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.

Methods: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAF mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.

Findings: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9-51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5-51·4) in the nivolumab group, and 18·6 months (7·6-49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2-not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3-not reached) in the nivolumab group, and 19·9 months (16·9-24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44-0·67; p<0·0001) and for nivolumab versus ipilimumab was 0·65 (0·53-0·79; p<0·0001). Median progression-free survival was 11·5 months (95% CI 8·7-19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1-10·2) in the nivolumab group, and 2·9 months (2·8-3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 (95% CI 0·35-0·51; p<0·0001) and for nivolumab versus ipilimumab was 0·53 (0·44-0·64; p<0·0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.

Interpretation: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.

Funding: Bristol-Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(18)30700-9DOI Listing
November 2018

Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab.

Int Immunopharmacol 2018 Oct 16;63:282-291. Epub 2018 Aug 16.

University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Surgical Oncology, Department of Surgery, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address:

Background: Immune checkpoint inhibitors have improved overall survival rates for many cancers, yet the majority of patients do not respond to treatment and succumb to disease progression. One tumor-related mechanism limiting the efficacy of immunotherapies in melanoma is the recruitment and expansion of myeloid-derived suppressor cells (MDSCs). Therefore, targeting MDSCs in combination with immunotherapies is an attractive strategy to improve response rates and effectiveness.

Methods: We tested this strategy by designing a randomized phase II clinical trial treating advanced melanoma patients with either Ipilimumab monotherapy or Ipilimumab plus all-trans retinoic acid (ATRA). Clinicaltrails.gov identifier (NCT02403778). The frequency of circulating MDSCs and the activation of CD8(+) T cells was measured by flow cytometry. Expression of immunosuppressive genes was measured with quantitative real time-PCR. T cell suppressive functions were measured by mixed lymphocyte reaction.

Results: Here we show that in vitro treatment with ATRA decreases immunosuppressive function of MDSCs in mixed lymphocyte reactions. Additionally, ATRA reduces the expression of immunosuppressive genes including PD-L1, IL-10, and indoleamine 2,3‑dioxygenase by MDSCs. Furthermore, the addition of ATRA to standard of care Ipilimumab therapy appears safe, as ATRA did not increase the frequency of grade 3 or 4 adverse events. Finally, ATRA significantly decreased the frequency of circulating MDSCs compared to Ipilimumab treatment alone in advanced-stage melanoma patients.

Conclusions: These results illustrate the importance of MDSCs in immunotherapy resistance and provide evidence that targeting MDSCs in cancer patients may augment immunotherapeutic approaches.
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http://dx.doi.org/10.1016/j.intimp.2018.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134177PMC
October 2018

Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases.

J Neurooncol 2018 Oct 16;140(1):55-62. Epub 2018 Jun 16.

Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, USA.

Introduction: Brain metastases are common in metastatic melanoma and radiosurgery is often utilized for local control. Immune checkpoint inhibitors (CPIs) play a central role in contemporary melanoma management; however, there is limited data exploring outcomes and potential toxicities for patients treated with CPIs and radiosurgery.

Methods: We retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery.

Results: Thirty-eight patients were included with a median follow-up of 31.6 months. Two-year local control was 92%. Median time to out-of-field CNS and extra-CNS progression were 8.4 and 7.9 months, respectively. Median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was not reached (NR). Twenty-five patients (66%) received anti-CTLA4 and 13 patients (34%) received anti-PD-1+/-anti-CTLA4. Compared with anti-CTLA4, patients that received anti-PD-1+/-anti-CTLA4 had significant improvements in time to out-of-field CNS progression (p = 0.049), extra-CNS progression (p = 0.015), and PFS (p = 0.043), with median time to out-of-field CNS progression of NR vs. 3.1 months, median time to extra-CNS progression of NR vs. 4.4 months, and median PFS of 20.3 vs. 2.4 months. Six patients (16%) developed grade ≥ 2 CNS toxicities (grade 2: 3, grade 3: 3, grade 4/5: 0).

Conclusions: Excellent outcomes were observed in patients that initiated CPIs within 8 weeks of undergoing radiosurgery for newly diagnosed MBM. There appears to be an advantage to anti-PD-1 or combination therapy compared to anti-CTLA4.
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http://dx.doi.org/10.1007/s11060-018-2930-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931903PMC
October 2018

Performance of a prognostic 31-gene expression profile in an independent cohort of 523 cutaneous melanoma patients.

BMC Cancer 2018 02 5;18(1):130. Epub 2018 Feb 5.

Skin Cancer Institute, Northwestern University, Lurie Comprehensive Cancer Center, 420 East Superior Street, Chicago, IL, 60611, USA.

Background: The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP's prognostic accuracy in an independent cohort of cutaneous melanoma patients.

Methods: This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence-free (RFS) and distant metastasis-free (DMFS) survival.

Results: The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively (P < 0.001). The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each). GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate (RFS HR = 2.1, 1.2, and 2.5, respectively, P < 0.001 for each; and DMFS HR = 2.7, 1.3 and 3.0, respectively, P < 0.01 for each).

Conclusions: The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual's risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively.
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http://dx.doi.org/10.1186/s12885-018-4016-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800282PMC
February 2018

Vemurafenib treatment for patients with locally advanced, unresectable stage IIIC or metastatic melanoma and activating exon 15 BRAF mutations other than V600E.

Melanoma Res 2017 12;27(6):585-590

aDepartment of Internal Medicine, Advocate Medical Group - Oncology North, Park Ridge, Illinois bMelanoma Research Clinic, University of Colorado Cancer Center, Aurora, Colorado cDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia dDepartment of Hematology and Oncology, The University of Arizona Cancer Center, Tucson, Arizona eDepartment of Medicine, Washington University School of Medicine, St Louis, Missouri fDepartment of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee gDepartment of Surgery, Columbia University Medical Center, New York, New York hDepartment of Medical Oncology, Texas Oncology, Dallas, Texas iDepartment of Medicine, Jonsson Comprehensive Cancer Center at University of California jDepartment of Immuno-Oncology, The Angeles Clinic and Research Institute, Los Angeles kDepartment of Oncology, Moores Cancer Center, University of California, San Diego, La Jolla lGenentech Inc., South San Francisco, California mMid Ohio Oncology and Hematology Inc., Columbus, Ohio nDepartment of Melanoma, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC oDepartment of Pathology, University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania pDepartment of Melanoma, Carol G. Simon Cancer Center, Atlantic Health System, Morristown, New Jersey, USA.

BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10-41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5-54%) versus other mutations (22%; 95% confidence interval=6-48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.
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http://dx.doi.org/10.1097/CMR.0000000000000398DOI Listing
December 2017