bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of safety, efficacy, and other clinical endpoints of delta-9-tetrahydrocannabinol in older patients with hem/onc malignancies.
Authors: Hansra Damien Mikael
Published: September 2018

e21671

Background: Dronabinol, synthetic delta-9-tetrahydrocannabinol (Δ-9-thc), is the active compound & natural occuring component of Cannabis Sativa L(Marijuana). Dronabinol is used as an appetite stimulant & treatment of chemo induced nausea/vomiting in cancer patients (pts). Here we evaluate the efficacy, safety, & other clinical endpoints in older cancer pts. Methods: Survey study administered to cancer pts prescribed Dronabinol w/ 7 questions (yes/no/n/a): Did Dronabinol increase appetitie? decrease nausea/vomiting? improve mood? decrease insomnia? decrease anxiety? have any side effects? improve quality of life (QOL)? Also pts were asked if they preferred sythetic meds vs natural plant based meds (oil, capsule, liquid, etc). Inclusion: age > 60, hem/onc malignancy, prescribed Dronabinol. Exclusion: death, altered mental status, not taking Dronabinol, off label use. Unpaired t-test w/ two sided P value used to compare differences. Results: N = 28 pts enrolled, 12 pts excluded, 16 pts meeting study criteria. Mean age 70 (range 61-78). 100% white pts w/ 94% Latin 6% non-Latin. 50% male 50% female. 81% Onc vs 19% Heme malignancy. Dose given: 2.5 mg QD (25%), 2.5 mg BID (62.5%), 5mg BID (12.5%). Significant improvements in appetite (87.5% vs 12.5% p = < 0.0001), anxiety (75% vs 25% p = 0.0128), QOL (81.3% vs 18.7% p = 0.0001) observed. No side effects seen in 87.5 % vs 12.5% (dizziness) p = < 0.0001 of pts. 100% vs 0%, p = < 0.0001 of pts preferred natural plant based meds vs synthetics. Non significant improvements in mood (61.5% vs 38.5% p = 0.2567), insomnia (61.5% vs 38.5% p = 0.2567), nausea/vomiting (71.4% vs 28.6% p = 0.1263) observed. Conclusions: This unique study shows Dronabinol significantly improved appetite, anxiety, & QOL in older cancer pts w/ most pts having no side effects. Also non significant improvements in mood, nausea/vomiting, insomnia observed. 100% of pts preferred natural plant based meds vs. synthetics. Further investigations examining the clinical benefits & safety of Dronabinol & Cannabis Sativa L are warranted in older cancer patients.
Cardiotoxicity associated with carfilzomib: Systematic review and meta-analysis.
Authors: Shah Chintan , Bishnoi Rohit , Bejjanki Harini , Jain Ankur , Samal Subhankar , Moreb Jan
Published: September 2018

e21674

Background: Carfilzomib (Carf)is a novel proteasome inhibitor (PI) that is approved for patients with relapsed multiple myeloma (RMM) who have failed ≥ 1 prior lines of therapy. The incidence and seriousness of Carf associated cardiotoxicity (CT) is not well defined. We hypothesize that CT is more frequent than that seen with other PIs. We performed systematic review of Carf literature with meta-analysis to determine its incidence and overall risk. Methods: Initial search of literature led to a total of 175 Carf related articles. However, we used 29 publicatons; phase I/II, phase II and phase III (n = 3) clinical trials in which Carf was used as monotherapy or in combination with other chemo agents. We excluded phase I studies and studies without CT data. Incidence rates and odds ratios (OR) were calculated with either fixed effect or random effect model based on the heterogeneity of included studies. Toxicity was reported according to CTCAE v4.0. Results: A total of 4560 patients with various hematological and solid malignancies were included. Incidence of all grades and high grades (≥ 3) CT (including arrhythmias, CHF with LVEF drop, and coronary syndrome) were 7.8% and 4.72%, respectively. When compared to control group taken from phase III clinical trials, the risk of developing CT due to Carf was significantly higher with OR of 1.90 and 2.03 (P < 0.01) for all grades and high grades, respectively. Moreover, incidence of CT was significantly higher in Carf combination therapy (9.85%) compared to Carf monotherapy (5.40%) (P = 0.01). Furthermore, incidence of high grade CT was 7.5% and 5% with and without concomitant immunomodulatory agent (IMiD), respectively (P = 0.004). There was no variation in the incidence of CT among newly diagnosed versus RMM (P = 0.6), and no Carf dose effect. Mortality rate associated with cardiotoxicity was 1.5%. Conclusions: Overall incidence of Carf related CT seems to be higher than that reported with other PIs. Although, the pathophysiology is poorly understood, this trend could potentially be secondary to irreversible nature of proteasome inhibition by Carf. There seems to be a significant increase in CT with combination of Carf and an IMiD. Prior therapies and higher Carf doses have no effect on CT incidence.
Strategies to embed palliative care into a culture of cancer care.
Authors: Taber Angela Marie , Korber Susan F. , Martin Edward , Mega Anthony E.
Published: September 2018

e21678

Background: In 2012, the 3 hospital Lifespan Health System launched a palliative care initiative. The hospitals and medical oncologists knew this was critical for patient centered and value-based cancer care, but recognized many barriers: physician practice patterns, lack of dedicated resources and systems, patient and family education gaps, and limited return on investment in the current environment. A multi-level inpatient and outpatient strategy was implemented and tracked over four years. Methods: External benchmarking data from a Medicare claims analysis of Vizient (academic health system consortium) member organizations and from ASCO QOPI data were used in the analysis. Internal data analysis included a study on symptom management for lung cancer patients, hospital reports on palliative care service utilization, ED visits and hospital admission trends for cancer patients. Multi-level interventions were employed: hospital investment in staff and systems, partnership with a community-based hospice and palliative care provider, a medical oncology physician champion with Board certification in palliative care, a palliative care inpatient consult service and daily ICU rounds, an oncology medical home, medical oncologist Saturday hours, electronic prompts for consults, and a cancer call triage center. Results: A Medicare claims analysis for 2012 to 2014 on cancer decedents with ICU stays in the last 30 days in the Vizient national study of health systems showed that Lifespan was at the 11th percentile, making them the 4th lowest (days in ICU) in performance (pre/post data requested). QOPI data on appropriate referrals to hospice or palliative care prior to death improved from 58% in 2010, which was below the QOPI benchmark of 61%, to 94% in 2016 which is above the QOPI benchmark of 74%. Other QOPI and hospital data will be included in the presentation. Conclusions: Palliative care, a crucial tool for the delivery of future cancer care, is challenging to implement effectively. This study shows that a hospital/medical oncology partnership can drive change to embed palliative care into the culture of cancer care and these strategies offer a roadmap for others to follow as they strive to offer patient centered and value-based cancer care.
Disparities in supportive care needs among minority and non-minority patients with advanced lung cancer.
Authors: Seiden Danielle , Morillo Jose , Wisnivesky Juan P. , Smith Cardinale B.
Published: September 2018

e21690

Background: Significant racial and ethnic disparities exist in lung cancer care. Thus, minorities are diagnosed with late stage cancer and have inferior outcomes likely leading to increased suffering. Little is known, however, about disparities in supportive care needs among patients with advanced lung cancer. Methods: We performed a prospective cohort study of patients newly diagnosed with advanced lung cancer (stage III and IV). At baseline (within 3 months of diagnosis), patients completed a validated survey assessing needs among seven domains: medical communication and information, psychological and emotional support, daily living, financial concerns, physical symptoms, spiritual needs, and social needs. Univariate and multivariate regression analyses compared differences in supportive care needs among minority (Black and Hispanic) and non-minority patients with advanced lung cancer. Results: We have enrolled 95/160 patients (60%). To date, baseline surveys have been completed on 55 patients. Of those, 37 (67%) are minorities and 18 (33%) non-minorities. Minorities were less likely to be married (p = 0.01), had a lower annual income (p < 0.001), lower education attainment (p = .02) and more likely to have Medicaid (p < 0.001). There were no differences in gender (p = 0.35) or performance status (p = 0.13). Overall, 39% of minorities report having higher supportive care needs across all domains compared with 25% of non-minorities (p < 0.001). Similarly, minorities reported having significantly higher needs among each domain except medical communication and information (p = 0.06). Multivariate analysis, controlling for patient characteristics, found minorities had increased odds of overall supportive care needs (odds ratio [OR]: 1.15, 95% confidence interval [CI]: 1.03-1.16). Conclusions: Minority patients with advanced lung cancer are more likely to have increased supportive care needs than non-minority patients. Ensuring minority patients have adequate supportive care evaluation and treatment is necessary to mitigating health disparities among patients with lung cancer. Future studies will be performed to evaluate how these needs change throughout the trajectory of lung cancer.
Self-guided online cognitive behavioral strategies for chemotherapy-induced peripheral neuropathy (CIPN): A multicenter, single blind, randomized, wait-list controlled trial.
Authors: Knoerl Robert , Yang James , Barton Debra L. , Williams David A. , Holden Janean , Krauss John C. , Bridges Celia , Smith Ellen M. Lavoie
Published: September 2018

e21710

Background: Four in 10 individuals receiving neurotoxic chemotherapy develop chronic painful CIPN, symptoms which negatively influence quality of life and physical function, and may require the withdrawal of effective chemotherapy. However, few recommended pharmacological and no effective non-pharmacological treatments for chronic painful CIPN exist. The purpose of the study was to examine the efficacy of an online cognitive behavioral pain management intervention, the PROactive Self-Management Program for Effects of Cancer Treatment ( PROSPECT), to reduce worst pain intensity in individuals with chronic painful CIPN. The secondary outcomes were average pain intensity, non-painful CIPN symptoms, and impaired function. Methods: Sixty patients with chronic painful CIPN were randomized (1:1 ratio) to receive either 8 weeks of PROSPECT or usual care. A 7-day electronic worst CIPN pain intensity diary was completed at the baseline and eight week time points. At the same time points, participants completed electronic standardized measures of functional impairment, non-painful CIPN symptom severity, and average CIPN pain intensity. Mean change scores from baseline and eight week surveys were compared between groups using ANCOVA adjusting for baseline. Results: Individuals who received the PROSPECT intervention had a mean change in worst pain intensity of -0.94 ( SD = 1.36, Range = -3.29 – 1.29). Those in the control group had a mean change score of 0 ( SD = 1.31, Range = -3.43 – 2.86) ( p = 0.046; d = 0.53) ( n = 38). For the secondary outcomes, no significant mean change score differences were found between groups. Conclusions: PROSPECT use significantly improved worst pain intensity, but not secondary outcomes, in individuals with chronic painful CIPN. A larger study testing PROSPECT is needed to determine if improvements in worst pain intensity may be sustained, to evaluate the effect of the intervention on the secondary outcomes, and to identify mediators of pain-related improvement. If shown to be efficacious with further testing, PROSPECT may be added to pharmacological modalities for the treatment of chronic painful CIPN. Clinical trial information: NCT02760654.
Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.
Authors: Stroud Chipman Robert Geoffrey , Cherry Cynthia R. , Naqash Abdul Rafeh , Sharma Nitika , Cherukuri Sulochana Devi , Parent Teresa , Hardin Jessica , Walker Paul R.
Published: September 2018

e21712

Background: Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events (irAEs) is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid-refractory irAEs. Methods:The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4 mg/kg given IV over 1 hour. C-reactive protein was drawn at first nivolumab infusion and at q 2 weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital d/c within 7 days. Results:Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All pts were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, cytokine release syndrome/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). Median CRP at initial tocilizumab dose was 100.5 mg/L (2.0 -350.4). Clinical improvement was noted in 27/34 pts (79.4%). 52.9% of pts required a single dose, while 35.3% required two, 8.8% required three and 1 pt required 4 doses. Twenty seven doses were given in the inpatient setting (49.1%). Median time to discharge was 4 days (range 1-27). Seventy four percent of pts were discharged home. For the 55 doses of tocilizumab that were delivered there was a cost savings of $147,174.94 (WAC) during the 18 month period versus infliximab 5 mg/kg IV dose. Conclusions: Tocilizumab is a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.
Characterizing social worker and chaplain interactions with parents of critically ill children with cancer.
Authors: Lentini Nicole , Martinez Elizabeth , Michelson Kelly
Published: September 2018

e22024

Background: Parents of children with cancer admitted to the pediatric intensive care unit (PICU) often obtain support from social workers and/or chaplains (SWs/Cs). Yet, empirical work describing the roles and activities of SWs/Cs caring for patients in the PICU is lacking. This study examined the roles of SWs/Cs caring for critically ill children with cancer and their families. Methods: Parents of patients with cancer expected to have a PICU stay > 72 hours, ongoing involvement with palliative care, or a pediatric index of mortality score > 4 were invited to participate. These criteria were meant to identify patients with more complicated PICU admissions. The SWs/Cs caring for these families in the PICU were also invited to participate. SWs/Cs audio recorded information about their encounters with parents and patients, specifically, who was present, the kinds of supports provided, and the discussion topics. These recordings were analyzed using content analysis resulting in broad categories describing support provided to the families by SWs/Cs. Results: In total, 3 SWs and 3 Cs submitted recordings about 34 encounters with families of 9 patients. Categories of activities and supports identified from these recordings included: discussing the child’s condition, assessing parent or child coping, assessing the role of faith, discussing communication between parents and the medical team or advocating for the family with the medical team, providing emotional support to patients and families, discussing concerns outside of the hospital (family, financial, work), and providing legal and/or logistical support. SWs/Cs, in general, provided very similar services to families. Conclusions: SWs and Cs caring for PICU patients with cancer and their families have overlapping roles in providing emotional, communication, and logistical support. Future work will identify barriers and facilitators to SWs and Cs providing support to critically ill children with cancer.
Risk factors associated with ifosfamide (IFOS)-induced encephalopathy in patients (pts) with metastatic (Met) sarcoma (Sarc).
Authors: Ogunniyi Adebayo , Desai Anjali Varma , Horvat Troy Z , Qin Li-Xuan , Chi Ping , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Tap William D. , D'Angelo Sandra P.
Published: September 2018

e22518

Background: IFOS is commonly used in the treatment of met sarc. IFOS has been reported to cause encephalopathy in 5 - 30% of pts. Potential risk factors for IFOS-induced encephalopathy (IIE) include female gender, older age, route of administration of IFOS, low serum albumin, existence of pelvic disease and renal failure. Unfortunately, the majority of the data surrounding potential risk factors is from heterogeneous cohorts. Methods: The purpose of this single-center retrospective analysis was to identify risk factors for developing IIE in a homogenous cohort of met sarc pts treated at MSKCC between 1/2010 and 5/2015. Logistic regression was used to examine the univariate effect of baseline and treatment variables. Variables significant at the 0.05 level were entered into a multivariate model. Results: A total of 328 met sarc pts with a median age of 51 years were analyzed. Thirty-four pts (10%) developed IIE. Of those 34 pts, 88% developed encephalopathy with the first or second cycle of IFOS. Age at the time of treatment (p = 0.0037), low serum albumin (p < 0.0001), increased serum alkaline phosphatase (p = 0.0022), liver met disease (p = 0.0011) and more than 3 met sites at time of IFOS dose (p = 0.0008) were all identified as risk factors by univariate analysis. Only low serum albumin (p < 0.0001, odds ratio = 0.33) and more than 3 met sites at time of IFOS dose (p = 0.0068, odds ratio = 2.47) maintained statistical significance after multivariate analysis. Conclusions: To our knowledge, this is the largest retrospective analysis of risk factors for IIE in the met sarc population. This analysis identified low serum albumin and more than 3 met sites at time of IFOS as predictors of IIE. Our data would suggest that clinicians considering the option of IFOS in met sarc pts should give particular attention to these predictive risk factors when making their treatment decisions.
The role of endomyocardial biopsy in cardiac tumors diagnosis.
Authors: Ionescu Dana , Stone Danielle , Stone James , Durand Jean-Bernard , Banchs Jose , Iliescu Cezar
Published: September 2018

e22536

Background: Pathologic examination is essential for definite diagnosis of both primary and secondary (metastatic) cardiac tumors. Limited data exists on the risks and benefits of catheterization with endomyocardial biopsy (EMB) of cardiac tumors. The present study aims to assess the safety of EBM in diagnosing cardiac tumors. Methods: We retrospectively reviewed therecords of cancer patients who presented with cardiac masses at MD Anderson Cancer Center between 2011 and 2016. Clinical presentation, transthoracic/transesophageal echocardiogram and pathology laboratory results for patients who underwent cardiac catheterization & EMB were reviewed. Results: Out of 8 patients with cardiac tumors (4 females, 4 men, average age of 59.7 y.o.), 5 patients had cardiac catheterization with EMB (5.4 French with Jaw Volume of 2.2, specimens are typically 5 to 20 mg per sample). Clinical presentation included shortness of breath and dyspnea (3 patients), syncope and palpitations (1 patient), and fatigue and slurred speech, as result of a hemispheric stroke (1 patient). Diameter of the cardiac tumors ranged between 4 – 6.5 cm, with no wall abnormalities or hemodynamic compromise as identified by echocardiography. Right atrium (RA) was the most common location (4 patients). One patient had extension of bronchus squamous cell tumor extending into a coronary artery bypass graft (LIMA). Review of the pathological specimens obtained from EMB performed under TEE and fluoroscopic guidance identified 2 patients with cardiac sarcomas in the RA, 1 patient with atrial metastatic melanoma (RA) and 1 patient with lymphoma (right ventricle). EMB was performed with minimal blood loss in all patients. During procedure, one patient developed rapid accumulation of fluid in the pericardial space requiring emergent echo-guided pericardiocentesis. Conclusions: EMB is suggested for the diagnosis of selected cardiac tumors, if the potential benefits from the procedure outweighs the risks. A more invasive approach for rapid histological diagnosis allows appropriate therapy to be promptly initiated. To ensure the safety, EMB should be performed by an experienced operator with fluoroscopy and with transthoracic, transesophageal or intra-cardiac echocardiography guidance.
Association between microRNAs expression in primary breast cancer and presence of circulating tumor cells (CTC) in peripheral blood.
Authors: Mego Michal , Hajduk Matus , Karaba Marian , Minarik Gabriel , Benca Juraj , Sedlackova Tatiana , Repiska Gabriela , Krasnicanova Lucia , Manasova Denisa , Jurisova Silvia , Sufliarsky Jozef , Pindak Daniel , Klucar Lubos , Reuben James M. , Mardiak Jozef
Published: September 2018

e23022

Background: CTCs play major role in tumor dissemination and progression and represent one of the key component of metastatic cascade. MicroRNAs (miRs) are involved in regulation in several biological processes in cancer including invasion, epithelial-mesenchymal transition (EMT) and disease progression. The aim of this study was to identify miRs in primary tumor associated with presence of CTCs in peripheral blood (PB) in non-metastatic breast cancer patients. Methods: This translational study included 79 patients with primary breast cancer for whom fresh frozen tumor tissue and status of CTCs in peripheral blood were available. CTCs were detected before surgery by qRT-PCR assay for expression of epithelial (CK19) or epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1). Total RNA was extracted from fresh frozen primary tumor and the expression profiles were obtained using Human microRNA Microarray v21.0 (Agilent Technologies). Results: We analyzed 48 (60.8%) tumor samples from patients with presence of CTCs in PB and 31 (39.2%) tumors with non-detectable CTCs. From CTCs positive patients, in 20 (41.7%) of them epithelial CTCs (EP_CTC) were detected while in 28 (38.3%) CTCs with EMT (CTC_EMT) phenotype were present. We identified 178 miRs that were expressed at significantly different levels (FDR < 0.05) in tumors with presence of any type of CTCs in PB compared to tumors with non-detectable CTCs. We also identified 174 and 137 miRs (33 overlapping) that were expressed at significantly different levels in tumors with EP_CTCs and CTC_EMT, respectively, compared to tumors with non-detectable CTCs. Overlapping miRs with highest different levels in expression (FDR < 0.01) were miR-3137, miR-3138, miR-3168, miR-605-5p, miR-6165 and miR-6790-5p. Conclusions: We identified for the first time miRs expressed in primary tumor associated with CTCs in peripheral blood in breast cancer patients. Moreover, we identified miRs specifically associated with various subpopulations of CTCs. We suppose, that these miRs could be involved in tumor dissemination and might lead to identification of new therapeutic targets. Study was supported by APVV-14-0327.
Concordance of mutations identified using circulating tumor DNA (ctDNA) compared to tissue based next generation sequencing (NGS) in gastrointestinal malignancies: A single institution experience.
Authors: Kamath Suneel Deepak , Kalyan Aparna , Taxter Timothy J. , Wehbe Firas , Kircher Sheetal Mehta , Nimeiri Halla Sayed , Mulcahy Mary Frances , Benson Al Bowen , Cristofanilli Massimo , Giles Francis J.
Published: September 2018

e23023

Background: The role of the ctDNA in the management of solid organ malignancies is an area of active research. A potential application of this technology is for monitoring disease progression in patients who had sequencing of their tumor tissue at time of diagnosis. This approach relies on concordance between tumor tissue NGS and the ctDNA, which can vary due to biology and technology. Biologic variability can be due to tumor heterogeneity, ctDNA concentration fluctuations and genomic alterations in clonal non-malignant hematopoietic cells. Methods: We retrospectively evaluated 41 patients who had NGS with Foundation Medicine’s FM1 panel performed on tumor tissue from diagnosis and follow up ctDNA NGS using the Guardant 360 panel(G360). Only genes shared by both panels with the same level of gene coverage were evaluated. This eliminated several genes and alterations, particularly amplifications and splice site alterations. Results: Patient demographics are in Table 1. 148 alterations were identified by G360, of which 42 (28%) alterations were also seen on FM1 testing. When these alterations were restricted to KRAS, APC and TP53, the most common genes altered in GI cancers, 53 alterations were identified and 32 (60%) were also identified by FM1 testing. These results demonstrate that concordance between ctDNA and tissue NGS can be improved if restricted to driver mutations. This restriction eliminates potential passenger mutations acquired by subclones of the original tumor and controls for clonal hematopoiesis. Conclusions: It is difficult to base treatment decisions on the overall concordance seen here between ctDNA and tissue NGS. However, quantification of driver mutations using ctDNA may offer another monitoring tool for disease progression beyond tumor markers, which sometimes can be non-specific or absent.
Prognostic value of neutrophil-to-lymphocyte ratio in advanced EGFR-mutated non-small cell lung cancer (NSCLC) treated with a tyrosine-kinase inhibitors: A retrospective analysis in a series of western patients.
Authors: Meriggi Fausto , Codignola Claudio , Beretta Giordano D. , Ceresoli Giovanni Luca , Caprioli Alberto , Scartozzi Mario , Fraccon Anna Paola , Prochilo Tiziana , Ogliosi Chiara , Noventa Silvia , Libertini Michela , Zaniboni Alberto
Published: September 2018

e23045

Background: Several studies demonstrated that an elevated neutrophil-to-lymphocyte ratio (NLR) correlate with a poor prognosis both in early and advanced stage of NSCLC. The aim of this retrospective analysis was to investigate the correlation between NLR and prognosis in caucasian patients diagnosed with advanced EGFR-mutated NSCLC and treated with tyrosine kinase inhibitors (TKIs). Methods: A retrospective database was used to identify consecutive patients diagnosed with advanced EGFR-mutated NSCLC and treated with TKIs. From January 2011 to December 2015, 63 patients from five Institutions were enclosed in our series. NLR was derived from the absolute neutrophil and the absolute lymphocyte counts of a full blood count.Survival curves were calculated with Kaplan-Meier method and data were compared by log-rank test. Prognostic significance of NLR were assessed using a Cox regression analysis. Results: Sixty-three eligible patients were stratified according to the mean pretreatment NLR value (3.57 ± 2.42). The chosen cut-off for NLR was 3.5. Forty patients had NLR < 3.5 while 23 patients had a value of NLR > 3.5.A statistical significant difference, both in PFS and OS, was found in the NLR < 3.5 group compared with the higher NLR group (PFS: p < 0.01, OS: p < 0.05). According to univariate analysis, histological type (adenocarcinoma vs non-adenocarcinoma) and NLR value correlate significantly with PFS and OS. In Cox multivariate analysis, only NLR ³ 3.5 resulted significantly associated as independent prognostic factor for worse PFS (HR 2.275, 95% CI 1.257-4.116, p < 0.01) and OS (HR 2.699, 95% CI 1.187-6.137, p < 0.05). Conclusions: Pre-treatment NLR seems to represent a reliable, simple, and easy to reproduce, laboratory tool to predict survival and outcome to therapies in western caucasian EGFR-mutated NSCLC patients. Further prospective trials are needed to definitively confirm its prognostic and predictive role.
Retrospective analysis of the role of CA 15-3 as a biomarker for breast cancer relapse.
Authors: Shaikh Marwan Elahi , Hall Samantha , Wen Sijin , Liu Hui , Miah Abdul , Salkeni Mohamad Adham
Published: September 2018

e23051

Background: The latest ASCO guidelines regarding tumor markers in breast cancer do not recommend routine monitoring of serum CA 15-3 (CA) levels alone as a marker for relapse. They do, however, acknowledge their use in conjunction with a patient’s history, physical exam, and diagnostic imaging. The study objective is to evaluate CA as a marker for relapse and determine its continued use in our patient population. Methods: We performed a retrospective analysis on female stage I-III breast cancer patients with an elevated CA marker treated in our cancer center between 2009-2014. Patients with metachronous or synchronous malignancies were excluded. Patients were categorized into three groups: Group 1 (elevated CA at relapse), Group 2 (normal CA at relapse, with elevation post-relapse), Group 3 (elevated CA without relapse). Categorical variables were collected to fulfill our objectives and the Fisher’s exact test was used to assess the correlation between them. The incidence rate and its 95% confidence interval were estimated based on the binomial distribution. Results: Out of 340 initially screened patients, 92 met our inclusion criteria: Group 1 (n = 25), Group 2 (n = 23), Group 3 (n = 44). The PPV for an elevated CA as a marker for relapse was 36% (95% CI: 26-48%). On routine surveillance, patients with elevated CA levels were more likely to have relapse if they presented with nausea (p = 0.02), myalgia (p = 0.003), or axial bone pain (p = 0.04). At relapse, an elevated CA was associated with fatigue (p = 0.02), myalgia (p = 0.01), liver metastases (p = 0.01), axial bone metastases (p = 0.005), and peripheral bone metastases (p = 0.0002). In patients with an elevated CA, a BMI < 25 had a higher incidence of relapse in comparison to those with a BMI ≥ 25 (p = 0.01). Conclusions: Our study suggests that a patient’s history, physical, and symptom-dictated imaging should be the main way to screen for relapse in stage I-III breast cancer. Based on the higher incidence of relapse in patients with both an elevated CA and symptoms of nausea, myalgia, or axial bone pain, we conclude that serum CA levels may be used as an adjunctive test in symptomatic patients. Our data also suggests that elevated CA levels may be less useful in detecting relapse in patients with BMI ≥ 25.
Pharmacogenetic 3C interaction associated with the PDGFRA gene as a chromatin conformation marker for treatment with tyrosine kinase inhibitors.
Authors: Akoulitchev Alexandre , Ramadass Aroul , Green Jayne , Uzun Ulku , Mellor Jane , Hunter Ewan , Grand Francis
Published: September 2018

e23054

Background: IDH1 mutations detected in glioma cells impair the insulator function between FIPL1L1 and PDGFRA at 4q12 ( Flavahan et al. 2016). We have used a high-resolution chromosome-conformation capture 3C analysis platform, EpiSwitch, and quantitative PCR, to map, evaluate, and quantify the TKI-sensitive conformational juxtaposition between FIP1L1 and PDGFRA. Loss of the insulator function in glioma prompted us to investigate the same interaction in the context of insulator loss with interstitial deletions at 4q12 in eosinophilic leukemias and AML. Methods: We tested a total of 72 primers in temperature gradient PCRs, with concentration matched negative controls, using the AML cell lines EOL-1 and HL-60. Products were sequenced in forward and reverse order. Dual label 5’FAM-BHQ1-3’hydrolysis probe assays, entirely specific for the PCR products, targeted the junction region of the 3C fragments. A reference 3C interaction was used as an internal copy number control for 3C library production. Results: EpiSwitch predicted and identified six 3C FIP1L1-PDGFRA interactions in different sequence orientations, within the 3D organization of the PDGFRA locus. The interaction D7 identified by the EpiSwitch qPCR assay was detected reproducibly in EOL-1 cells and glioblastoma tissue using both single step PCR and qPCR. An imatinib-sensitive AML cell line EOL-1 was used as a positive control for qPCR assays. Both AML and glioma cell lines tested positive using the assay as did glioma patient biopsies. The glioblastoma cell line DBTRG-05MG also tested positive for the D7 interaction at a maximum of 8.92 copies per 20 ng of the template. Conclusions: We confirmed and characterized, at high resolution, the conformational deregulation of FIP1L1 and PDGFRA in glioma. Additionally, our group detected the interaction in TKI-sensitive leukemia cell lines. The analysis of 3C microstructural alterations is consistent with latest insights into epigenetic regulation of PDGFRA. It provides a promising approach to the stratification of patients for tyrosine kinase inhibitor treatment, which could not be provided diagnostically with conventional sequencing approaches.
Characterization of circulating tumor cells in patients with localized high risk prostate cancer, post-prostatectomy.
Authors: Anantharaman Archana , Friedlander Terence W. , Welty Christopher J. , Zejnullahu Kreshnik , Hough Jeffrey , Edwards Matthew , Jendrisak Adam , Lee Jerry , Greene Stephanie , Ontiveros Priscilla , Graf Ryon , Rodriguez Angel , Suraneni Mahipal , Wang Yipeng , Landers Mark Andrew , Cooperberg Matthew R. , Carroll Peter , Dittamore Ryan Vance , Paris Pamela
Published: September 2018

e23055

Background: Approximately 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features, which increase the risk of recurrence. Better predictive biomarkers, such as circulating tumor cells (CTCs), could allow for earlier detection of biochemical recurrence. Here, we aim to evaluate the ability to detect CTCs using an enrichment free, unbiased CTC identification technology from men with high risk, localized PCa after radical prostatectomy (RP) and correlate their presence with prospective clinical data. Methods: Blood samples of 31 patients with high risk, localized PCa obtained 2-4 months post RP were shipped to Epic Sciences on an IRB approved protocol. All nucleated cells were subjected to immunofluorescent (IF) staining for cytokeratin (CK), CD45, and AR N terminus. CTCs were identified by fluorescent scanners using algorithmic analysis. CK expressing (CK+) CTCs were enumerated and analyzed for AR expression and individually sequenced for copy number variation (CNV) and large scale transition (LST, a surrogate of genomic instability). Patients were followed prospectively for biochemical recurrence, defined as detectable PSA. Progression free survival was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 87.1% (27/31) samples with an average of 5.6 CTCs/ml (range: 0 – 22.87) detected per patient. AR expression was detected in 12.9% (4/31) of patients. Ninety-nine CTCs from 14 patients were amenable to LST and CNV sequencing and analyses. 10.1% (10/99) CTCs from 7 patients exhibited higher ( > = 6) LSTs than control WBCs (95% WBCs had LST < 6). Copy number alterations were identified in CTCs in commonly mutated genes in PCa, including AR, MYC, and TP53 amplification and deletions in PTEN and RB1. Patients with higher CTC burdens exhibited a trend toward shorter PFS (hazard ratio: 1.65; 95% CI: 0.7-3.86; p: 0.13). Conclusions: There was a high incidence of CTC detection after RP in patients with high risk, localized PCa. We observed a trend toward shorter PFS in those with higher CTC burden and genomic alterations detectable in CTCs are consistent with established CNAs in PCa. Tissue genomic correlatives are under analysis.
The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: A meta-analysis.
Authors: Zhang Tengfei , Fan Ruitai , Shi Ni , Ma Wang
Published: September 2018

e23075

Background: Immunotherapy based on anti-PD-1 (Programmed death 1)/PD-L1 (PD-1 Ligand 1) antibodies have achieved significant successes from bench to clinic. In this study, we systematically evaluate the overall efficacy and safety of current anti-PD-1/PD-L1 antibodies for treatment of patients with advanced or refractory cancer. Methods: Clinical trials reporting response or safety of anti-PD-1/PD-L1 antibodies for advanced or refractory cancer patients published were searched in PubMed and EMBASE database. Meta-analyses using random effects models were used to calculate the overall estimate. Results: Fifty-one trials including 6,800 patients were included. The overall response rates for melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) were 29% (95% CI: 1.53-2.41), 21% (95% CI: 17%-25%) and 21% (95% CI: 16%-27%) respectively. While the overall adverse effects rate for melanoma, NSCLC, RCC were 16% (95% CI: 6%-28%), 11% (95% CI: 8%-14%) and 20% (95% CI: 11%-32%) respectively. Tumor PD-L1 expression and patient smoking status might serve as biomarkers to predict response of anti-PD-1/PD-L1 antibody treatment. Compared to tumors with negative PD-L1 expression, tumors with positive PD-L1 expression had a significantly higher clinical response rate (41.4% versus 26.5%) with RR = 1.92 (95% CI: 1.53-2.41, P< 0.001). Smoker patients also showed a significantly higher response rate (33.7%) than patients who never smoked (4.2%) with RR = 6.02 (95% CI: 1.22-29.75, P= 0.028). Nivolumab and Pembrolizumab were associated with significantly increased response rate (RR = 2.89, 95% CI: 2.46-3.40, P< 0.001), reduced death risk (HR = 0.53; 95% CI: 0.48-0.57; P< 0.001), and decreased adverse effect rate (RR = 0.49, 95% CI: 0.30-0.80, P= 0.004) compared with other therapies. Conclusions: Anti-PD-1/PD-L1 antibodies have high response rates and low adverse effect rates for advanced or refractory cancers. PD-L1 expression was associated with better clinical response of anti-PD-1/PD-L1 antibody based immunotherapy.
Tumor mutation burden derived from large NGS panel as biomarker for immunotherapy response.
Authors: Vuzman Dana , Powers Winslow , Huang Xiu , Sun Ruobai , Eifert Cheryl , Cingolani Pablo , Bjonnes Andrew , Lyle Stephen , Protopopov Alexei
Published: September 2018

e23077

Background: Tumor mutation burden (TMB) is an informative biomarker for predicting response to immunotherapy in a growing number of malignancies. The TMB clinical applicability is limited due to cost and bioinformatics requirements of sequencing and analyis of whole exome/gemone. Here, we demonstrate that a large next generation sequencing (NGS) panel can accurately identify hypermutation status. Methods: A novel algorithmic approach to derive the predicted total mutation load (PTML) described in J Roszik et al, BMC Med, 2016, was applied to our large NGS panel, CANCERPLEX. Statistical weights were calculated for each of the genes using publically available TCGA database. The algorithm was tested using CANCERPLEX data of stomach adenocarcinoma (199), colorectal cancer (59), and lung cancer (60) cohorts (n = 318). The correlation of PTML status with mismatch repair (MMR) status (n = 11) was also tested. The correlation of PTML status with clinical outcome was assessed using WES data following distinct immunotherapies (n = 16). The actual total mutation load (ATML) was compared to PTML by downsampling the WES data to our region of interest. Results: The mean values of PTML were evaluated for stomach adenocarcinoma (199), colorectal cancer (59), and lung cancer (60) cohorts. The PTML results for these 3 cancer types were statistically similar, and therefore the cohorts were combined into one dataset (n = 318). The hypermutation threshold was calculated from the PTML distribution of the three cancer types. This hypermutation threshold was in high concordance with our MMR validation set (n = 11), and also correlated (0.86) with an independent validation set of clinical outcome data from WES, which had undergone treatment with distinct immunotherapies (n = 16). This threshold predicts response to immunotherapy with 90% accuracy. Conclusions: NGS across a large gene panel captures sufficient information to predict tumor mutation burden with a single threshold for hypermutation status for stomach adenocarcinoma, colorectal, and lung cancers. This threshold highly correlates with MMR status and clinical outcome for immunotherapy response. Additional cancer types are currently being tested for inclusion in this study.
Influence of a STAT3 inhibitor on tumor infiltrating lymphocytes in malignant pleural mesothelioma.
Authors: Matsumoto Seiji , Takuwa Teruhisa , Kondo Nobuyuki , Hasegawa Seiki
Published: September 2018

e23078

Background: Patients with malignant pleural mesothelioma have elevated IL-6 levels in their blood and pleural fluid. IL-6 activates the JAK-STAT pathway and promotes transcriptional activation. Our previous work on a STAT3 inhibitor (BBI-608: napabucasin) as a molecular target drug for malignant pleural mesothelioma confirmed its antitumor effect. In this study, the effect of napabucasin on tumor immunity, specifically on tumor infiltrating lymphocytes, was evaluated. Methods: A mouse-derived malignant pleural mesothelioma cell line (AB22; 1.0 × 105 cells) was subcutaneously injected into BALB/cAJcl mice. When the tumors grew to 250 mm3, the mice were divided into three groups (five mice per group): untreated control, 5 mg/kg napabucasin, and 20 mg/kg napabucasin groups. The drug was orally administered twice daily. Tumor volumes were measured twice weekly, and the subcutaneous tumors were removed 15 days after treatment initiation. Tumor infiltrating lymphocytes were extracted from the tumors, and the CD8+ cell percentage was measured using FACS. Results: The subcutaneous tumors of the mice in the untreated control, 5 mg/kg napabucasin, and 20 mg/kg napabucasin groups grew to 2318 mm3, 1764 mm3, and 1383 mm3, respectively, after 15 days of treatment. Suppression of subcutaneous tumor growth was observed, and the inhibitory effect was greater in the 20 mg/kg than in the 5 mg/kg napabucasin groups. The CD8+ cell percentage of tumor infiltrating lymphocytes for the untreated control, 5 mg/kg napabucasin, and 20 mg/kg napabucasin groups was 8.6%, 6.9%, and 19.0%, respectively. The CD8+ cell percentage increased with the increase in drug dosage. Conclusions: We had previously confirmed the antitumor effect of napabucasin by STAT3 inhibition in malignant pleural mesothelioma. In this study, 20 mg/kg napabucasin increased the CD8+ cell percentage of tumor infiltrating lymphocytes, indicating that the drug appears to enhance tumor immunity and that it may be used in combination with an antitumor immune antibody.
Effect of CA125/MUC16 on complement-dependent cytotoxicity (CDC) of farletuzumab and other CDC-mediating antibodies via inhibition of antibody-C1q binding.
Authors: Kline J Bradford , Fernando Shawn , Harley Stephen , Grasso Luigi , Nicolaides Nicholas C
Published: September 2018

e23082

Background: Human cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of the tumor-shed antigen CA125 on suppressing complement-dependent cellular cytotoxicity (CDC). This finding relates to a prespecified subgroup analysis of an 1100 patient Ph3 clinical trial testing the investigational agent farletuzumab, a monoclonal antibody (mAb) to folate receptor alpha, plus standard-of-care chemotherapy in patients with recurrent ovarian cancer. In this study, patients with low levels of CA125 (no greater than 3X the upper limit of normal) treated with farletuzumab compared to placebo demonstrated improvements in both progression free survival (HR 0.49, p = 0.0028) and overall survival (HR 0.44, p = 0.0108). Farletuzumab’s pharmacologic activity is mediated in part through antibody dependent cellular cytotoxicity (ADCC) and CDC. Here we show that CA125 inhibits IgG1- and IgM-mediated CDC by suppressing antibody interaction with the C1q complement-initiating protein. Methods: Functional assays employing cell lines expressing antibody-specific antigens were used to measure CDC activity. CA125 isolates from various patients and cell lines were used to monitor CA125 effects on complement function. ELISA assays were used to measure the effects of CA125 inhibition on C1q-antibody interaction. Results: Functional assays showed that CA125 suppressed antibody-mediated CDC in a dose dependent fashion. Molecular studies revealed that this suppression is caused by CA125 binding to antibody, leading to suppression of antibody-C1q interaction. Conclusions: Here we demonstrate that CA125 can elicit immunosuppression by perturbing the interaction of tumor targeting antibodies and the C1q complement-initiating protein. This effect is through a direct binding of CA125 to antibody. These findings provide new insights into the potential biological mechanisms by which tumors produce tumor shed antigens like CA125 to suppress host immune responses such as CDC. This finding has important clinical applications for the development of therapeutics utilizing complement-mediated mechanisms.
Anti-PD1 treatment to induce M1 polarization of tumor infiltrating macrophages in a 3D ex vivo system of lung cancer patients.
Authors: Mediavilla-Varela Melanie , Page Melba Marie , Kreahling Jenny , Antonia Scott Joseph , Altiok Soner
Published: September 2018

e23090

Background: Nivolumab and pembrolizumab treatment targeting the PD1/PD-L1 axis has demonstrated increased survival benefit in subpopulations of patients with advanced non-small cell lung cancer (NSCLC). The impact of these therapeutics on tumor immune microenvironment is not fully understood. Classical M1 macrophages are critical components involved in the inflammatory response and antitumor immunity. In this study, we evaluated the effect of PD1/PD-L1 blockade on M1 polarization of tumor-associated macrophages (TAMs) and activation of cytotoxic T-cells in a 3D ex vivo system of NSCLC. Methods: Fresh tumor tissues obtained from consented patients with NSCLC at the time of surgical resection were utilized in a 3D ex vivo tumor miscrosphere assay. 3D tumor microspheres were treated with nivolumab or pembrolizumab at 10 mg/ml for 36 hours within an intact tumor microenvironment. Flow cytometry analysis was performed to evaluate treatment-mediated TAM polarization, activation of T-cells and changes in CD4 and CD8 subpopulations. A multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines. Additionally, a NanoString platform containing probes to quantitate 770 immune function genes was used to determine potential positive or negative associations between expression of immune function genes and TIL activation by ex vivo treatment. Results: Both nivolumab and pembrolizumab treatment increased population of M1 macrophages (CD68+, CD80+, CD163-) and simultaneous release of MIP1b, IFN-ɣ, TNF-a, and GM-CSF cytokines as well as expression of genes related to the M1 phenotype that was accompanied by activation of CD8 cells assessed by Ki67 and CD107a expression and increased expression of genes involved in the IFNg pathway. Conclusions: Our studies showed that anti PD1/PD-L1 treatment leads to M1 macrophage polarization and T-cell activation in subgroups of NSCLC patients emphasizing the importance of comprehensive analysis of tumor immune microenvironment for a better understanding of the mechanism of action of immuno-oncology drugs that may help developing rationale combination treatments in NSCLC.