bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyanoacrylate Dermal Closure in Spine Surgery: Systematic Review and Pooled Analysis
Authors: Tan Terence , Rutges Joost , Marion Travis , Hunn Martin , Tee Jin
Published: July 2019

Study Design:

Systematic review.

Objectives:

Cyanoacrylate glue closure has been utilized for dermal closure in surgical incisions. Its safety and efficacy in spine surgery are not established. The authors perform a systematic review to determine the rate of surgical site infection (SSI), wound dehiscence, and wound erythema with cyanoacrylate dermal closure in spine surgery.

Methods:

A systematic review adhering to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was performed utilizing the PubMed/MEDLINE, EMBASE, and Cochrane databases on patients undergoing spine surgery with cyanoacrylate dermal closure. Pooled analysis was performed with stratification of patients according to spinal level and the presence/absence of instrumentation. Risk-of-bias and methodological quality was appraised using 17 prespecified criteria.

Results:

Five articles (1 retrospective cohort study, 4 cases series) with a total of 1282 patients were included. A total of 967 patients, all diagnosed with degenerative spine disease, were suitable for pooled analysis. In 290 patients who underwent anterior cervical discectomy and fusion, and in 23 patients with posterior cervical decompression (without instrumentation), there was 0% rate of SSI, wound dehiscence, and erythema. In 489 patients who underwent lumbar microdiscectomy, there was 0.41% rate of SSI, 0.20% rate of wound dehiscence, and 0.20% rate of wound erythema. In 165 lumbar laminectomy patients, there was a 1.82% rate of SSI, 0.61% rate of wound dehiscence, and 0% rate of wound erythema.

Conclusion:

Cyanoacrylate dermal closure for the aforementioned procedures is associated with low rates of wound complications (SSI, dehiscence, and erythema). Further studies should be performed, especially in nondegenerative surgery, instrumented thoracic and lumbar spine surgery.
The Safe Distance to the Popliteal Neurovascular Bundle in Pediatric Knee Arthroscopic Surgery: An Age-Based Magnetic Resonance Imaging Anatomic Study
Authors: Schachne Jonathan M. , Heath Madison R. , Yen Yi-Meng , Shea Kevin G. , Green Daniel W. , Fabricant Peter D.
Published: July 2019

Background:

The close proximity of the popliteal neurovascular bundle to the posterior horn of the lateral meniscus puts it at risk of compromise during lateral meniscal repair. This is particularly important in smaller pediatric patients, who are commonly treated for lateral meniscal abnormalities in isolation (discoid meniscus) or concomitantly with anterior cruciate ligament reconstruction.

Purpose:

To quantify the distance between the posterior horn of the lateral meniscus and the popliteal neurovascular bundle along the path of meniscal repair and to investigate for associations with age, sex, height, weight, body mass index (BMI), and skeletal maturity.

Study Design:

Cross-sectional study; Level of evidence, 3.

Methods:

A total of 144 magnetic resonance imaging scans were evaluated in a cohort of patients aged 10 to 18 years without meniscal or ligament abnormalities. Measurements were made along a line from the anterolateral portal between the popliteal neurovascular bundle and the free edge, midpoint, and meniscocapsular junctions of the posterior horn of the lateral meniscus. In addition to descriptive statistics of these distances by age and sex, analyses of variance and linear regression analyses were performed to investigate for associations with age, sex, height, weight, BMI, and skeletal maturity.

Results:

Male participants had a significantly larger mean free edge distance (14.4 ± 2.5 vs 13.1 ± 2.5 mm, respectively; P = .005) and midpoint distance (9.6 ± 2.2 vs 8.9 ± 1.8 mm, respectively; P = .011) than female participants but not a significantly larger meniscocapsular distance (5.2 ± 1.6 vs 4.6 ± 1.4 mm, respectively; P = .096). Linear regression analyses revealed significant associations between these distances and age, height, weight, and BMI ( P < .001 for all). There were statistically significant pairwise differences for free edge and midpoint distances to the neurovascular bundle between patients with open and closed physes.

Conclusion:

The distance between the posterior horn of the lateral meniscus and the popliteal vasculature along a trajectory from the standard anterolateral arthroscopic portal increases linearly throughout development between the ages of 10 and 18 years. There were also significant associations between height, weight, BMI, and skeletal maturity and these anatomic distances. Knowing the safe distance to the popliteal vasculature will increase the safety of arthroscopic lateral meniscal repair in children, especially with all-inside devices that require setting the penetration depth for the advancement of a sharp delivery device beyond the posterior capsule.
Scheduled Tribes, Reserved Constituencies and Political Reservation in India
Authors: Ambagudia Jagannath
Published: July 2019

Scheduled Tribes (STs, indigenous people) are one of the most marginalised communities in the political sphere. Political marginalisation of STs due to historical injustices has compelled the Indian state to explore alternative means to ensure adequate representation for them by adopting a political reservation system. Political reservation has, therefore, become their primary means of political empowerment, wherein it has ensured the redistribution of political resources in favour of the marginalised communities. Against this backdrop, the article explores the location of tribal communities in the colonial political system and the reasons for their disproportionate representation, the nature and dynamics of ST reserved constituency and the effects of political reservation on these communities. Further, the article concludes by suggesting that the political reservation system has brought both hope and despair among the STs.
Conservation of a Cultural Heritage Incentives Programme in a Malay Village: Assessing Its Effectiveness
Authors: Radzuan Indera Syahrul Mat , Ahmad Yahaya , Zainal Rozlin , Shamsudin Zarina , Wee Seow Ta , Mohamed Sulzakimin
Published: July 2019

This article elaborates on how living heritage can be understood and shows that conservation programmes can be a catalyst for establishing sustainable communities in heritage areas. The authors in this article have examined one typical Malay traditional village, Kampung Morten, in the Melaka state of Malaysia. This village will serve as a prism for exploring community perceptions and as a platform for asking a number of questions, including how the conversation programme works, what impacts urbanization has on traditional villages, how do communities survive, and what limitations does the current incentives policy have in meeting community needs. This research has employed a mixed method study, involving various data generation instruments including surveying, interviewing and observation. From this research, it has been found that the impacts of urbanization have altered community lifestyle and values. The authors have tried to illustrate the residents’ perception of the heritage incentives programme, shedding light on their strengths and weaknesses. This article concludes that that there are constraints on the current incentives policy implementation and related issues due to its rapid development and its impact on local livelihoods.
Noncatalytic Function of a JmjC Domain Protein Disrupts Heterochromatin
Authors: Bao Kehan , Jia Songtao
Published: July 2019

Chromatin-modifying enzymes are frequently overexpressed in cancer cells, and their enzymatic activities play important roles in changing the epigenetic landscape responsible for tumorigenesis. However, many of these proteins also execute noncatalytic functions, which are poorly understood. In fission yeast, overexpression of Epe1, a histone demethylase homolog, causes heterochromatin defects. Interestingly, in our recent work, we discovered that overexpressed Epe1 recruits SAGA, a histone acetyltransferase complex important for transcriptional regulation, to disrupt heterochromatin, independent of its demethylase activity. Our findings suggest that overexpressed chromatin-modifying enzymes can alter the epigenetic landscape through changing their proteomic environments, an area that needs to be further explored in dissecting disease etiology associated with overexpression of chromatin regulators.
Fertility preservation in patients with hematologic malignancies and recipients of hematopoietic cell transplants
Authors: Loren Alison Wakoff , Senapati Suneeta
Published: July 2019

Patients with hematologic malignancies and those undergoing hematopoietic cell transplantation (HCT) face a complex set of challenges when considering options for fertility preservation (FP). There are no standard options for prepubertal children, and women with hematologic malignancies may not be eligible for standard FP options. Fortunately, initial therapies for most blood cancers are not highly gonadotoxic, affording an important opportunity for postremission counseling and referrals to fertility specialists. These patients face a high risk of relapse, and many will be referred for autologous or allogeneic HCT, which carries an extremely high risk of infertility. The expanding indications for HCT to include benign hematologic disorders as well as autoimmune diseases mandate that all hematologists are familiar with these risks. Oncofertility researchers are continually pushing the boundaries of what may be possible for our patients; in the meantime, communication and shared decision-making between hematologists and patients, as well as program-building, education, and outreach are essential to ensure that these patients, many of whom will be cured, maintain all of their options for a fulfilling life after intensive therapy.
Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia
Authors: Giacopelli Brian , Zhao Qiuhong , Ruppert Amy S. , Agyeman Akwasi , Weigel Christoph , Wu Yue-Zhong , Gerber Madelyn M. , Rabe Kari G. , Larson Melissa C. , Lu Junyan , Blachly James S. , Rogers Kerry A. , Wierda William G. , Brown Jennifer R. , Rai Kanti R. , Keating Michael , Rassenti Laura Z. , Kipps Thomas J. , Zenz Thorsten , Shanafelt Tait D. , Kay Neil E. , Abruzzo Lynne V. , Coombes Kevin R. , Woyach Jennifer A. , Byrd John C. , Oakes Christopher C.
Published: July 2019

Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.
Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR
Authors: Dehn Jason , Spellman Stephen , Hurley Carolyn K. , Shaw Bronwen E. , Barker Juliet N. , Burns Linda J. , Confer Dennis L. , Eapen Mary , Fernandez-Vina Marcelo , Hartzman Robert , Maiers Martin , Marino Susana R. , Mueller Carlheinz , Perales Miguel-Angel , Rajalingam Raja , Pidala Joseph
Published: July 2019

This Special Report, this month’s CME article, details evidence-based guidelines for the selection of optimal unrelated donors and cord blood units for allogeneic hematopoietic cell transplantation.
Targeted sequencing of plasma cell-free DNA to predict response to PD1 inhibitors in advanced non-small cell lung cancer.
Authors: Guibert Nicolas , Jones Greg , Beeler John F. , Morris Clive D. , Plagnol Vincent , Mourlanette Jean , Delaunay Myriam , Rouquette Isabelle , Favre Gilles , Pradines Anne , Mazieres Julien
Published: July 2019

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Background: Tumor mutational burden is an emerging biomarker of response to immune checkpoint inhibitors (ICI), whose clinical adoption is challenging, especially in liquid biopsies. We hypothesized that targeting limited but relevant genetic alterations in plasma cell-free DNA with next generation sequencing (NGS) along with early monitoring may represent a non-invasive approach to predict response to ICI. Methods: Plasma samples from responders (PFS > 6 months) and non-responders (progressive disease at first evaluation) patients collected before nivolumab (second line) initiation and at 1 month were tested using tagged amplicon sequencing of hotspots and coding regions from 36 genes, blinded to clinical outcomes and tumor genotype. Molecular profile of ctDNA, and its early kinetics (1 month) were analyzed as potential early indicators of response. Results: 98 patients were analyzed, of which 86 (39 responders, 47 non-responders) were evaluable for response. Alterations in ctDNA were detectable in 67/86 baseline samples (78%). The detection of a targetable oncogenic driver (5 EGFR, 1 ALK) was associated with progressive disease on the first CT-scan The presence of a PTEN and/or STK11 mutations (b-PS(+)) was correlated with poor outcomes (median PFS 1.5 months vs. 8 months in b-PS(-)) patients, p = 0.0007), while the presence of transversion mutations in KRAS and/or TP53 (b-KP-Tv(+)) predicted good outcomes (median PFS 11 months vs. 2 months in b-KP-Tv(-) patients, p = 0.0088). Combining these results, patients with a low “immune score” (driver and/or b-PS(+) and/or b-KP-Tv(-)) derived poor outcomes (PFS 2 months), compared with patients with a high immune score (no driver, b-PS(-) and b-KP-Tv(+), PFS 14 months, p = 0.0001, HR 2.96). Studying early changes in 65 specimens, molecular response was correlated with clinical outcomes (14 months PFS in patients with early ctDNA decrease compared to 2 months in patients with increase, p < 0.0001; HR 2.7). Using cut-off of 30% and 50% of plasma response increased the ability of ctDNA to predict response (HR 4 and 4.17, respectively). Conclusions: Targeted sequencing of plasma ctDNA and its early variations can predict response to anti-PD-1. Clinical trial information: NCT02827344.
Preclinical CAR-T cell target safety, biodistribution, and tumor infiltration analysis using in situ hybridization technology.
Authors: Pimentel Helly , Jarnagin Helen , Zong Hailing , Todorov Courtney , Anderson Courtney M. , Zhang Bingqing , Bunker Christopher , Ma Xiao-Jun
Published: July 2019

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Background: Chimeric antigen receptor (CAR) T cell therapy is highly effective in treating hematologic malignancies, and major efforts are being made to achieve similar efficacy in solid tumors. The greater potency of CAR-T cells compared to antibody therapeutics demands a more stringent CAR-T target safety assessment to avoid adverse events resulting from “on-target/off-tumor” activity. Furthermore, it is critical to track and monitor CAR+ T cells within intact tissue and tumor to understand the mechanisms underlying off-tumor toxicity and efficacy in tumor killing. Methods: We employed the RNAscope in situ hybridization (ISH) technology to assess target expression specificity and to track CAR-T cell distribution and activation in xenograft and host tissues using the RPMI-8226 xenograft mouse model. Results: For the CAR-T target candidates, Target X and Target Y, RNA ISH revealed that Target X was only expressed in the xenograft tumor and in no mouse organs, while Target Y was found to be expressed at low levels in mouse lung and liver, as well as in the xenograft tumor. Duplex RNA ISH assays with probes targeting the CAR 3’ UTR and either IFNG or GZMB allowed for highly sensitive and specific detection of CAR-T cells and their activation state in both tumor and normal tissues from vehicle, Target X CAR-T cell, or Target Y CAR-T cell treated mice. Activated Target X CAR-T cells expressing GZMB and IFNG were found only in the xenograft tumor, where Target X was expressed. In contrast, activated Target Y CAR-T cells were found almost exclusively in mouse lung and liver, with very few Target Y CAR-T cells being found in the xenograft tumor. Lastly, a multiplex ISH-IHC approach confirmed the presence of activated Target X CAR-T cells in the xenograft tumor through simultaneous detection of the Target X CAR 3’ UTR, IFNG, GZMB, and CD3. Conclusions: These data demonstrate how the RNAscope assay can be utilized for CAR-T cell efficacy and safety/toxicity assessment in preclinical models by detecting very low levels of target antigen expression in off-tumor tissues and monitoring CAR-T cell pharmacodynamics and activation in tumor models and can also be applied for assessing TCR-T cell activity in tumors.
Tolerability and antitumor activity of cemiplimab, a human monoclonal anti-PD-1, in patients with non-small cell lung cancer (NSCLC): Interim data from a phase I dose escalation and NSCLC expansion cohort.
Authors: Moreno Victor , Calvo Emiliano , Olmedo Garcia Maria Eugenia , Gil-Martin Marta , Aljumaily Raid , Papadopoulos Kyriakos P. , Rosen Lee S. , Rietschel Petra , Mohan Kosalai Kal , Li Jingjin , Stankevich Elizabeth , Rowlands Tracey , Feng Minjie , Fury Matthew G.
Published: July 2019

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Background: NSCLC accounts for ~85% of lung cancers; most patients (pts) are at an advanced stage at the time of diagnosis. Cemiplimab (REGN2810) is being investigated for the treatment of NSCLC, in addition to other indications (NCT02383212). Methods: In the dose escalation (DE) phase, enrolled pts with advanced malignancies with no alternative standard-of-care therapeutic option received cemiplimab 1, 3 or 10 mg/kg every 2 weeks (Q2W) intravenously (IV) for up to 48 weeks. In the NSCLC expansion cohort (EC 1), enrolled pts with advanced disease who had relapsed after, or were refractory to at least first-line therapy received cemiplimab 200 mg Q2W IV for up to 48 weeks. Tumor biopsies were performed at baseline (EC 1 only), Day 29 and progression, if possible. Tumor measurements were performed every 8 weeks according to RECIST 1.1. Results: As of Sept 1, 2017, 21 pts with NSCLC (1 in DE at 1 mg/kg; 20 in EC 1) were enrolled; median age was 65.0 years (range, 50–82; 14 M/ 7 F); 81.0% had a ECOG performance status of 1, 19.0% of 0; 13/21 (61.9%) had a histology of adenocarcinoma. The most common treatment-related adverse events (TRAEs) were asthenia, pneumonitis, and rash (each n = 3, 14.3%). Each of the following ≥Grade 3 TRAEs occurred once: pneumonitis, diabetic ketoacidosis, and nephritis. By central independent review, 6 pts had partial response (PR), 6 had stable disease (SD) or non-complete response (CR)/non-progressive disease (PD), and 9 had PD. Overall response rate (ORR; CR + PR) was 28.6%. Duration of response exceeded 8 months in 5 of the 6 responders. Disease control rate (ORR + SD) was 57.1%. Disease control has been maintained for 7 pts after a planned treatment completion at 48 weeks. Of the 17 pts who had tissue available for PD-L1 expression evaluation, 11 (64.7%) had a tumor proportion score (TPS) of < 1%, and 3 (17.6) had a TPS of > 50%. Conclusions: Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated pts with NSCLC. Pivotal trials of cemiplimab as monotherapy or in combination with other treatments in pts with advanced NSCLC are currently enrolling (NCT03088540; NCT03409614). Clinical trial information: NCT02383212.
Immune pneumonitis-related treatment discontinuations and outcomes in metastatic non-small cell lung cancer treated with nivolumab: A pooled analysis from a multi-institutional international collaboration.
Authors: Naqash Abdul Rafeh , Owen Dwight Hall , Ricciuti Biagio , Toi Yukihiro , Chiari Rita , Sharma Nitika , Patel Sandip H. , Sugawara Shunichi , Cherry Cynthia R. , Burkart Jarred Thomas , De Giglio Andrea , Sugisaka Jun , Bowling Mark , Otterson Gregory Alan , Walker Paul R.
Published: July 2019

118

Background: Immune-related adverse events (irAEs) due to immune-checkpoint inhibitors (ICI) can lead to significant morbidity. Immune pneumonitis (IP) constitutes one of the common irAEs in non-small cell lung cancer (NSCLC) with a reported incidence of 3-5%. However outside of clinical trials there is a paucity of data regarding incidence/outcomes of IP in nivolumab (N) treated metastatic-NSCLC (m-NSCLC). Methods: We retrospectively pooled data of 381 m-NSCLC patients (pts) from four cohorts treated with N within different treatment time periods: East Carolina University, USA: 4/2015- 2/2018; Ohio State University, USA: 6/2013-6/2016; University of Perugia, Italy: 10/2013-9/2017, and Sendai Kousei Hospital, Japan: 1/2016-1/2018. IP identification was based on clinical diagnosis of treating team. Grade (G) was based on Common Terminology Criteria for Adverse Events (CTCAE v 4.03). Time to immune pneumonitis (TTIP) was the time from starting N to diagnosis of IP. Results: The rate of IP was 13.1% (n=50) with 68% of IP presenting as the index irAE. Median TTIP was 9.75 weeks (range: 0.25-73.7) with G1 (24.0%), G2 (36.0%), G3 (36.0%), G4 (4.0%). 57.9% of IP ≥G2 had TTIP ≤ 3 months (m). For all-G (IP), 22.0% pts had stopped N before IP either due to non-IP irAEs or progression. Excluding these, treatment discontinuations (d/c) attributed to IP ≥ G2 were 66.6%. IP ≥G2 had higher treatment d/c when TTIP was ≤ 3m vs. > 3m (51.8% vs. 14.8%; P=0.09). Median overall survival (OS) by log rank test for pts with any grade IP vs. no IP was not statistically significant (13.7 vs. 7.5m; P =0.14). IP ≥G2 occurring at > 3m had longer median OS vs. IP ≥G2 occurring in ≤3m (16.7 vs. 3.6m, P=0.008), which was not significant at a 3m landmark analysis when accounting for time on N (P= 0.31). Conclusions: Our real-world multi-institutional data shows a higher incidence of IP in m-NSCLC. We also see a trend for frequent ICI d/c in IP ≥ G2 occurring within 3 months that may ultimately influence OS per our landmark analysis. Thus aggressive and early symptom management specifically directed at allowing reinitiation of ICI after IP needs to be considered.
Outcomes of nivolumab (NIVO)-treated patients (pts) with advanced non-small cell lung cancer (aNSCLC) in United States community oncology practice.
Authors: Nadler Eric , Espirito Janet , Wilson Thomas , Gupte-Singh Komal , Rao Sumati , Korytowsky Beata
Published: July 2019

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Background: The phase 3 Checkmate 017 and 057 trials demonstrated improved survival of NIVO vs. chemotherapy in pts who progressed on or after platinum-based chemotherapy for aNSCLC, regardless of histology (squamous [SQ]/non-squamous [NSQ]) and PD-L1 expression. Real-world (RW) long-term effectiveness data with PD-1 inhibitors are limited. This study evaluated RW adoption of I-O and outcomes of NIVO-treated pts with aNSCLC in community practices, overall and by histology. Methods: This retrospective observational study of US Oncology Network electronic health records and supplemental chart abstraction followed a cohort of pts with aNSCLC receiving PD-1 inhibitors for ≥17 months, from initial FDA approval, 03/2015 through 10/2017. Pts in clinical trials or receiving treatment for other malignancies were excluded. Demographic and clinical features were characterized. Duration of therapy (DOT) and overall survival (OS) were assessed by the Kaplan-Meier method. Results: Of 217 included pts, 203 received NIVO; outcomes for 14 receiving pembrolizumab are not presented. NIVO was administered as first-line (1L) therapy in 15 pts, 2L+ therapy in 188 pts (n = 134 LOT2, n = 54 LOT3-4). For all 2L+ pts treated with a PD-1 inhibitor, median age was 70 years, 57% were male, 73% had NSQ histology, and 82% had ECOG performance status of 0-1. All pts with biomarker data were ALK negative and 5% were EGFR positive. Approximately 13% of pts had PD-L1 testing, of whom 6% were positive (expression > 1%). For 2L+, DOT (median months [mos], 95% CI) was 3.5 (3.0, 4.1) in the overall population, 3.3 (1.9, 4.2) with SQ, and 3.6 (2.3, 4.6) with NSQ histology. Of all 2L+ pts, 30.3% (95% CI 23.9%, 37.0%) remained on treatment at 6 mos. For 2L+, OS (median mos, 95% CI) was 8.7 (7.6, 11.0) overall, 7.0 (3.8, 9.1) with SQ, and 10.5 (8.4, 13.3) with NSQ histology; 1-year OS was 35%. Conclusions: RW DOT and OS for 2L+ NIVO treatment of aNSCLC were similar to outcomes reported in the phase 3 Checkmate 017 and 057 trials, with longer DOT and greater OS in patients with NSQ histology. Few RW pts had PD-L1 testing in this 2L+setting. Future analyses are needed to assess the uptake of PD-1 inhibitors for 1L treatment of aNSCLC.
Hematological profile: A prognosis tool in melanoma patients treated with immunotherapy.
Authors: Lobo Martins Soraia , Miguel-Semedo Patrícia , Martins-Branco Diogo Alexandre , Monteiro Ana Maria , Moreira Cecilia Melo Alvim , Pais Helena , Vendrell Ines , Mansinho Andre , Gouveia Emanuel Jose , Passos Maria-Jose Saramago , Costa Luis , Sousa Ana Rita Teixeira
Published: July 2019

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Background: Immunotherapy (IO) has changed the disease course of metastatic malignant melanoma (mMM). Prognostic biomarkers are lacking, but high neutrophil-lymphocyte ratio (NLR) has been correlated with poor outcome. Lymphocyte-monocyte ratio (LMR) and platelet-lymphocyte ratio (PLR) are also readily available. This study aimed to investigate the prognostic value of NLR, LMR and PLR. Methods: Retrospective cohort of mMM patients (pts) treated with anti PD-1 blockade in 2 centers, between Jan ’13-Aug ’18. Baseline and 6-week (6 w) blood counts were collected. Cut-offs for NLR, LMR and PLR were defined based on literature and ROC curve method. Progression free survival (PFS; primary outcome) and overall survival (OS) were calculated using log rank test. Uni and multivariate analysis were performed using cox-regression model. Results: Baseline characteristics: 83 pts with median age 65.5 years (range 21-90), 77% BRAFwt, 98% PS-ECOG 0-1, 51% LDH >ULN, 5% on steroids. Median NLR 2.7 (IQR 2.1-3.8), LMR 3.1 (2.1-4.3) and PLR 160.8 (98.3-216.4). The majority of pts (65%) were treated with pembrolizumab. With a median follow-up of 6.2 months (m), median PFS was 7.3 m (CI 5.5-9.2) and median OS was 15.9 m (13.4-18.4). In the multivariate model, baseline NLRhigh (≥3.0) and PLRhigh (≥180.0) were associated with worse PFS (HR 2.04, CI 1.11-3.77; p=0.02; and HR 2.50, CI 1.37-4.57; p=0.003). Baseline LMRhigh (≤2.1) was associated with worse PFS (HR 1.886, CI 1.019-3.488; p=0.043) only on the univariate analysis. At 6 w, 16 out of 39 pts with baseline NLRhigh presented a decrease in NLR. This was associated with better PFS (HR 0.24, CI 0.09-0.62; p=0.003). Inversely, an increase ≥20% in NLR or PLR was associated with progression (HR 3.65, CI 1.99-6.72, p < 0.001; and HR 3.99, CI 2.01-7.91, p < 0.001). Conclusions: Our data showed that NLR and PLR, as surrogates for systemic inflammation, might be used as prognostic biomarkers for melanoma patients treated with IO. Decreasing NLR in pts with previously high NLR, has a 76% risk reduction of progression. In clinically challenging situations, these biomarkers may help the clinician in an earlier therapeutic orientation.
Healthcare resource utilization in first-line immunotherapies for patients with metastatic melanoma.
Authors: Liu Frank Xiaoqing , Klink Andrew , Feinberg Bruce A. , Ahsan Sama , Nero Damion , Chmielowski Bartosz
Published: July 2019

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Background: Immunotherapies (I/Os) have demonstrated improved overall survival vs. chemotherapy for patients (pts) with metastatic melanoma (MM). However, little is known about the comparative health care resource utilization (HCRU) among different I/Os. This study examined the real world HCRU across different I/Os: PD-1 inhibitors (pembrolizumab (PEM) or nivolumab (NIVO), PD-1), CTLA-4 inhibitor (ipilimumab, IPI), and combination of I/Os (IPI+NIVO). Methods: A retrospective observational study was conducted using a large US payer claims data. Adults with ≥2 claims for MM and ≥1 claim for metastasis were identified between 1/1/2012 and 6/30/2017 and followed through 9/30/2017. All pts had pharmacy and medical claims and ≥6 months pre-index enrollment. HCRU was calculated per pt per month (PPPM) and by percentages across PD-1, IPI, IPI+NIVO from Index date until the first occurrence of: change in regimen, end of continuous enrollment, or end of study period. Adjusted odds ratios (OR) for HCRU were estimated using logistic regressions to control for baseline patient characteristics. Results: On average, pts in the PD-1 cohort (n = 255) were older than those in IPI (n = 555) and IPI+NIVO (n = 88) cohorts (mean 68 vs 63 and 63, both p < 0.05) and had less brain metastasis (22% vs 34% and 31%, p < 0.05 and p = 0.11, respectively). During 1L therapy, fewer PD-1 pts had any hospitalization (HOSP, 25.9% vs 39.8% and 45.5%, both p < 0.05), fewer HOSPs PPPM (mean 0.06 vs 0.10 and 0.14, both p < 0.05), and fewer ER visits PPPM (mean 0.09 vs 0.13 and 0.18, both p < 0.05) compared to IPI and IPI+NIVO, respectively. Any 30-day re-HOSP and ER visits were numerically lower with PD-1 compared with IPI and IPI+NIVO, but not statistically significant (13.7% vs 19.1% and 18.2%; 40.0% vs 47.0% and 50.0% respectively). Adjusting for baseline characteristics, pts treated with IPI and IPI+NIVO were more likely to have a HOSP than PD-1s (OR = 2.10, 95% CI, 1.44-3.07; and 2.35; 95% CI, 1.32-4.12, both p < 0.01). Conclusions: Pts treated with IPI or IPI+NIVO had significantly increased odds of being hospitalized and higher HOSP and ER visits PPPM compared to PD-1s. Further studies are warranted to confirm these findings.
Emerging treatment patterns and checkpoint inhibitor (CPI) use among newly diagnosed Merkel cell carcinoma (MCC) patients in the United States veteran population.
Authors: Zheng Ying , Pandya Shivani , Yu Ting , Kearney Mairead , Shrestha Sulena , Wang Li , Kim Ruth , Phatak Hemant
Published: July 2019

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Background: MCC is a rare and aggressive skin cancer with annual incidence of 2,500 in the U.S. Checkpoint inhibitors (CPIs) demonstrated durable disease response historically not seen with chemotherapy among MCC patients in clinical trials. Avelumab, a PD-L1 antibody, became the first and only approved treatment for metastatic MCC by the U.S. FDA in March 2017. This study evaluated emerging treatment patterns among MCC patients using the US Veterans Health Administration (VHA) database. Methods: This retrospective study identified newly-diagnosed MCC patients who initiated ≥1 systemic therapy from Oct. 2013 to Jan. 2018 and had continuous enrollment from ≥6 months pre-initial MCC diagnosis date until ≥2 months post-index date with follow-up until the earliest of death, disenrollment, or study end. The index date was defined as the start date of first-line (1L) systemic therapy. A subsequent line of therapy (2L) was defined by the earliest of new therapy addition, regimen switch, or a new/existing regimen after a >60-day gap from the prior cycle end. Duration of 1L therapy was evaluated among patients treated with CPIs, National Cancer Comprehensive Network (NCCN)-recommended chemotherapy (recCTs), and other chemotherapy (oCTs). The median duration of therapy was estimated using the Kaplan Meier method. Results: Of the 120 MCC patients (72% pre-2017) with 1L systemic therapy, 17%, 45%, and 38% were treated with CPIs, recCTs and oCTs, respectively. More than 75% were white men aged ≥65 years with mean baseline Charlson comorbidity index scores ≥5. Carboplatin-etoposide (56%) and cisplatin-etoposide (26%) were the most commonly-used recCTs. The median duration of 1L therapy in patients treated with CPI, recCTs and oCTs was 300, 91, and 21 days, respectively. 2L therapy was initiated in 33% of all 1L patients. Conclusions: Among 1L MCC patients, CPIs treated patients appear to be on treatment longer than both recCTs and oCTs patients. These descriptive findings provide important insights into the emerging real-world treatment patterns amongst MCC patients in the VHA population.
Phase Ib/II trial of lenvatinib plus pembrolizumab in advanced melanoma.
Authors: Taylor Matthew H. , Vogelzang Nicholas J. , Cohn Allen Lee , Stepan Daniel E. , Shumaker Robert Charles , Dutcus Corina E. , Guo Matthew , Schmidt Emmett V. , Rasco Drew W.
Published: July 2019

15

Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is approved for first-line treatment of advanced melanoma (objective response rates [ORR], 21–34%). In preclinical studies, LEN decreased tumor-associated macrophage populations, increased CD8+ T cell infiltration, and augmented PD-1 inhibitor activity; thus, LEN is a rational combination partner for PEM. We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in solid tumors, focusing on advanced melanoma. Methods: In this multicenter, open-label study, patients (pts) with measurable, confirmed, metastatic melanoma and ECOG PS ≤1 received oral LEN (20 mg/day) + PEM (200 mg Q3W, IV). Pts were not preselected for PD-L1 status. Tumor assessments were by investigator per immune-related RECIST (irRECIST). Phase 2 primary end point was ORR at 24 weeks (ORRWK24). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 14 (67%) were PD-L1+, 4 (19%) were PD-L1-; 3 (14%) not tested. 38% had ≥1 prior anticancer therapy. ORRWK24 was 47.6% (95% CI, 25.7–70.2). All pts had ≥1 treatment-related adverse event (TRAE). Grade 3 and 4 TRAEs occurred in 13 (62%) and 1 (5%; adrenal insufficiency) pts respectively. There were no fatal TRAEs. Most common any-grade TRAEs were fatigue (52%), decreased appetite (48%), diarrhea (48%), hypertension (48%), dysphonia (43%), and nausea (43%). Dose reduction and interruption due to TRAEs occurred in 13 (62%) and 10 (48%) pts, respectively. Conclusions: LEN + PEM was well-tolerated and had encouraging clinical activity. The combination may potentially improve on the antitumor activity of anti-PD-1 monotherapies, supporting further evaluation in advanced melanoma. Clinical trial information: NCT02501096. [Table: see text]
Infections in patients receiving immune checkpoint inhibitors.
Authors: Sae-Tia Sutthichai , Naidoo Jarushka , Mehta Seema
Published: July 2019

155

Background: Immune checkpoint inhibitors (ICIs) - anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, avelumab), anti-CTLA-4 (ipilimumab) - have improved outcomes for several malignancies. ICIs may cause immune-related adverse events (irAEs), often treated with immunosuppression. The incidence of infections arising de novo during ICI therapy or from immunosuppression for irAEs is not well described. Methods: In- and outpatients receiving ICIs were referred for Infectious Diseases consultation between 6/2011-6/2018. Twenty-five were randomly selected for retrospective summarization of the spectrum of infections. Diagnosis of infection was made by the primary oncologist, based upon clinical/radiographic/laboratory data. Results: Solid tumor (24, 96%) and hematologic malignancies (1, 4%) were represented (Table). All 25 had infections. 15 (60%) were male; median age 58 years (29-97). 17 (68%) had irAEs: pneumonitis (10, 40%), thyroiditis (5, 20%), colitis (5, 20%), hepatitis (4, 16%), dermatitis (4, 16%) and myocarditis (1, 4%). 17 (68%) patients developed +1 irAE. 50% with pneumonitis were concurrently treated for pneumonia. Of the 25, 17 (72%) developed de novo infections on ICIs; whereas others were receiving systemic corticosteroids (7, 28%) or infliximab (1, 4%). Initial infections included pneumonia (13, 52%), bacteremia (3, 12%), sinusitis (2, 8%), wound infection (2, 8%), viral infections (HSV, CMV, HCV; 1, 4% each) and 1 (4%) each of empyema, UTI, peritonitis, osteomyelitis, and meningitis. 44% (11) developed a second infection within 60 days of the first. Conclusions: Patients receiving ICIs for cancer developed a myriad of infections, both de novo during ICI therapy, or consequent to immunosuppression for irAEs. Second infections are common, occurring in nearly half the patients. Awareness of this is vital for early diagnosis and appropriate management. Patients with suspected ICI-related infection. (n=25). [Table: see text]
A phase Ib/II trial of lenvatinib plus pembrolizumab in non-small cell lung cancer.
Authors: Brose Marcia S. , Vogelzang Nicholas J. , DiSimone Christopher , Jain Sharad K. , Richards Donald A. , Encarnacion Carlos A. , Rasco Drew W. , Shumaker Robert Charles , Dutcus Corina E. , Stepan Daniel E. , Guo Matthew , Schmidt Emmett V. , Taylor Matthew H.
Published: July 2019

16

Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is an approved monotherapy for previously treated patients (pts) with PD-L1 (+) (tumor proportion score ≥1%) metastatic non-small cell lung cancer (mNSCLC; objective response rate [ORR] 18%). We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in pts with solid tumors, focusing on the mNSCLC cohort. Methods: In this multicenter, open-label study (NCT02501096), pts with measurable, confirmed mNSCLC, ECOG PS ≤1, ≤ 2 prior systemic therapies (phase 2 only) received oral LEN (20 mg/day) and PEM (200 mg Q3W, IV). Pts were not preselected by PD-L1 status. The phase 2 primary end point was ORR at 24 weeks (ORRWK24) by investigator-assessed immune-related RECIST (irRECIST). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 9 (43%) PD-L1(+), 5 (24%) PD-L1(-), and 7 (33%) not tested. Pts were treatment-naïve (14%); or had 1 (33%), 2 (48%), or ≥3 (5%) prior lines of systemic therapy. ORRWK24 was 33.3% (95% CI, 14.6–57.0); other efficacy outcomes are summarized in the table. Grade 3 and 4 treatment-related adverse events (TRAEs) occurred in 48% and 5% (increased aspartate aminotransferase) of pts. There was 1 fatal TRAE (exsanguination; “possibly related” to study treatment). The most common grade 3 TRAEs were hypertension (24%), fatigue (14%), diarrhea (14%), proteinuria (10%), and arthralgia (10%). Conclusions: LEN + PEM showed promising clinical activity and a manageable safety profile in previously treated pts with mNSCLC who were not preselected for PD-L1 status. Further study is warranted.[Table: see text]
The SAINT: Initial results of a phase I/II study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma.
Authors: Chawla Sant P. , Chua-Alcala Victoria S. , Kim Katherine , Assudani Nupur , Al-Shihabi Ahmad , Moradkhani Ania , Quon Doris , Wong Steven , Tseng William W. , Pollack Seth , Srikureja Amor M. , Jalas John , Jones Robin Lewis , Gordon Erlinda Maria
Published: July 2019

22

Background: Sarcoma cells are most immunogenic at the onset of cancer. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To evaluate the safety of ipilimumab (I), a CTLA4 inhibitor, nivolumab (N), a PD-1 inhibitor, and escalating doses of trabectedin (T), a marine-derived natural alkaloid, in advanced soft tissue sarcomas (STS), (2) To investigate the BORR, DCR, PFS and OS, and (3) to correlate response with immune cell trafficking in the tumor microenvironment. Methods: This is an IRB-approved dose-seeking phase 1/2 study using defined doses of I (1 mg/kg IV q 12 weeks), N (3 mg/kg IV q 2 weeks) and escalating doses of T (1.0, 1.3, 1.5 mg/m2 IV q 3 weeks), employing “cohort of three” design, with a Phase 2 component using the MTD of T. Results: Phase 1 safety analysis: At Dose 1: Grade 3 treatment related adverse events (TRAEs): fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs: thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs: anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). At Phase 2, Grade 4 TRAEs: increased CK (n = 1); Grade 3 TRAEs: increased ALT (n = 4), anemia (n = 3) neutropenia (n = 1), portal cellulitis (n = 1). Efficacy analysis: Phase 1 (n = 9): At Dose 1: DCR 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1, rhabdomyosarcoma), DCR 60%, median PFS, > 42 weeks; median OS, > 47 weeks. Phase 2 (n = 16): PR (n = 3; 1 liposarcoma, 1 leiomyosarcoma, 1UPS); BORR 18.75%, DCR 87.5%, median PFS, > 19 weeks; median OS, > 26 weeks. Surgical resection was undertaken in 1 patient with SD after 4 cycles. The surgical specimen showed 80% necrosis and greater number (30%) of CD8+ killer T cells, 10% PD-L1+ cells in the TME compared to that of archived pre-treatment tumor. Conclusions: Taken together, these data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. The phase 2 part of the study is on-going. Clinical trial information: NCT03138161.
A novel humanized anti-CTLA-4 antibody compared to ipilimumab in preclinical studies.
Authors: Shi Qian , Liu YanLi , Yang Lan , Ma Hongli , Ma Wencui , Sun Ziyong
Published: July 2019

32

Background: The efficacy of ipilimumab as a single agent and in combination for the treatment of melanoma and other malignancies has validated the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) blockade in immunotherapy. Clinical trials that include anti-CTLA-4 in a combination design have gained traction. However, ipilimumab is the only anti-CTLA-4 antibody therapeutic approved worldwide. Therefore, novel anti-CTLA-4 therapeutics that may overcome the shortcomings of ipilimumab to fulfill the unmet medical needs is desperately desired. Methods: Mouse hybridoma cells were screened, cloned, and lead antibodies were humanized to obtain candidates with high activity in blocking CTLA-4/CD80 interaction. The resulting lead antibody was further characterized with in vitro binding and blocking assays, as well as mixed lymphocyte reaction assay. A humanized CTLA-4-B6 mouse model was used to evaluate the in vivo tumor growth inhibition activity of the antibody. Results: CBT-509, a novel IgG1 humanized monoclonal antibody against CTLA-4 was obtained. EC50 of CBT-509 binding with CTLA-4 and IC50 of CBT-509 blocking CTLA4/CD80 interaction were comparable to ipilimumab. CBT-509 binds to a distinct epitope, and has a high affinity with CTLA-4 (KD = 2.73E-10 M), more than 4-fold stronger than ipilimumab (KD = 1.21E-9 M). Compared with ipilimumab, CBT-509 was more active in mixed lymphocyte reaction, suggesting that it is more potent in human T-cell activation. Importantly, the efficacy of CBT-509 in killing tumor cells in vivo is much stronger than that of ipilimumab. In a MC38 murine colorectal cancer model under huCTLA-4 B6 mice background, CBT-509 eradicated tumors in 7 of 8 mice at a dose of 3 mg/kg, while ipilimumab eradicated tumors in 4 of 8 mice at the same dosage. Conclusions: Taken together, CBT-509 demonstrated an improvement over ipilimumab. Future efforts will focus on developing molecules that can further improve the efficacy and safety of anti-CTLA-4 based therapeutics.
Assessment of PD-1 expression in human resting and activated natural killer cells and murine tumor models.
Authors: Judge Sean J. , Dunai Cordelia , Sturgill Ian R. , Stoffel Kevin M. , Murphy William J. , Canter Robert J.
Published: July 2019

36

Background: Blockade of the PD-1/PD-L1/2 axis has revolutionized cancer therapy. Although reinvigorated PD-1+ T cells are the main effectors in the response to checkpoint blockade, the contribution of Natural Killer (NK) cells to PD-1/PD-L1 inhibition is under debate. While PD-1 has been identified on NK cells, this appears to be restricted to small populations under limited conditions. We sought to evaluate the extent of PD-1 expression in mouse and human resting and activated NK cells. Methods: Human NK cells were isolated from healthy donor PBMCs and cancer patients. Ex vivo activation and proliferation techniques included recombinant human cytokine and feeder line co-culture. Murine NK cells were isolated from splenocytes, and PBMCs from wild type and immunodeficient mice. We assessed NK cell surface markers and intracellular cytokine by flow cytometry, and gene expression by quantitative RT-PCR. Results: Over 21-days of ex vivo expansion, expression of PD-1 or PD-L1 on human NK cells was < 1% at all time points, while TIGIT+ expression increased to > 85%. Conversely, ConA stimulation of T cells increased PD-1 expression with no change in TIGIT expression. QRT-PCR demonstrated absent PD-1 expression in purified NK cells compared to a 5-fold increase in PD-1 gene expression in ConA stimulated PBMCs. PD-1/PD-L1 was also < 1% in the NK92 cell line and < 2.5% in peripheral CD56+CD3- NK cells from patients with soft tissue sarcoma (STS). NK cells from digested freshly resected STS show variable PD-1 ( < 10%) and minimal PD-L1 ( < 1%) expression with a small, but measurable population of intra-tumoral NK cells (1% of immune cells). In vivo mouse studies showed < 5% PD-1+ NK cells in spleen and tumor of CT26 tumor-bearing mice, while PD-L1+ NK cells increased in frequency from spleen (5-35%) to tumor (40-95%) in both wild type BALB/C and SCID mice. Conclusions: In contrast to prior studies, we did not observe a substantial PD-1+ population on human or murine NK cells after multiple activation strategies compared to T cells. Contrary to its application in T cells, our data suggest that PD-1 is not a useful marker for NK cell exhaustion/dysfunction. PD-L1 on NK cells may represent an important link between NK and T cell immunotherapy.