tbuckley/cabot-search huggingface dataset:
Effect of interleukin-2 on long term infusion treatment regimen of ch14.18/CHO antibody on activity in relapsed/refractory neuroblastoma patients.
Authors: Hans Loibner, Nikolai Siebert, Christin Eger, Evelyne Janzek, Ruth Ladenstein, Holger N. Lode
Journal: Journal of Clinical Oncology (2016)

10563 Background: Long-term infusion (LTI) emerges as a promising new delivery method of ch14.18/CHO for relapsed/refractory neuroblastoma patients. The role of concomitant treatment with scIL2 is unclear in this setting. Methods: Pts (74) were treated with 5 cycles of LTI with 100 mg/m2 ch14.18/CHO (d8-17) combined with 6x106 IU/m2 sc IL-2 (d1-5; 8-12) (53 Pts) and without IL2 (21Pts) in a single center program. Surrogate parameters for activity and pain toxicity were determined using complement dependent cell mediated cytotoxicity (CDC), the whole blood cytotoxicity test (WBT) (d1, 8, 15) and analysis of the intravenous (iv) morphine usage (d8-17). Results: In CDC and WBT assays, GD2 specific killing of neuroblastoma cells was found in all patients and cycles. The cytotoxic activity in base line samples preceding subsequent ch14.18 applications increased over cycles, indicating persistent lytic activity over the entire treatment period of 6 months. This effect was inhibited by anti-idiotypic antibody ganglidiomab demonstrating a GD2 specific effect. Interestingly, there was no difference in GD2 specific cytotoxic activity against neuroblastoma target cells at any time point between patients treated with or without IL2. Analysis of iv morphine usage in cycle 1 of patients treated in combination with scIL2 revealed a cumulative dose of 2.5 mg/kg/cycle in contrast to patients treated with ch14.18/CHO only (1 mg/kg/cycle). This corresponds to a > 60% increase of the ch14.18/CHO associated pain toxicity by additional scIL2 treatment. Reduction of iv morphine usage in subsequent treatment cycles was observed in both cohorts. However, in patients treated without additional scIL2, 0% of patients required iv morphine in cycles 3 or greater in contrast to 29% in the scIL2 combination group. Conclusions: Neither the surrogate WBT activity parameter nor the higher pain toxicity profile support the combined treatment in above pilot studies. Ongoing SIOPEN trials (EudraCT 2009-018077-31; EudraCT2006-001489-17) randomizing LTI ch14.18/CHO ± scIL2 in front line and relapsed/refractory patients will clarify the optimal approach.
Abstract MP31: Left Ventricular Hypertrophy by Electrocardiogram versus Cardiac Magnetic Resonance Imaging as a Predictor for Heart Failure: The MESA Study
Authors: Abdullahi O Oseni, Waqas T Qureshi, Mohammed F Almahmoud, Alain Bertoni, David A Bluemke, William G Hundley, Joao A Lima, David M Herrington, Elsayed Z Soliman
Journal: Circulation (2016)

Background: Left ventricular hypertrophy (LVH) is an established risk factor for heart failure (HF). However, it is unknown whether LVH detected by electrocardiogram (ECG-LVH) is equivalent to LVH ascertained by cardiac magnetic resonance imaging (MRI-LVH) in terms of prediction of incident HF using risk prediction models like the Framingham Heart Failure Risk Score (FHFRS). Methods: This analysis included 4745 (mean age 61+10 years, 53.5% women, 61.7% non-whites) from the Multi-Ethnic Study of Atherosclerosis who were free of cardiovascular disease at the time of enrollment. ECG-LVH was defined using Cornell’s criteria while MRI-LVH was derived from left ventricular (LV) mass measured by cardiac MRI. Cox proportional hazard regression was used to examine the association between ECG-LVH and MRI-LVH with incident HF. Harrell’s concordance C-index was used to estimate the predictive ability of the FHFRS when either ECG-LVH or MRI-LVH were included as one of its components. The added predictive ability of ECG-LVH and MRI-LVH were investigated using integrated discrimination improvement (IDI) index and relative IDI. Results: ECG-LVH was present in 291(6.1%) while MRI-LVH was present in 499 (10.5%) of the participants. Over a median follow up of 10.4 years, 140 participants developed HF. Both ECG-LVH [HR (95% CI): 2.25(1.38-3.69)] and MRI-LVH [HR (95% CI): 3.80(1.56-5.63)] were associated with an increased risk of HF in multivariable adjusted models (Table 1). The ability of FHFRS to predict HF was improved with MRI-LVH (C-index 0.871, 95% CI: 0.842-0.899) when compared with ECG-LVH (C-index 0.860, 95% CI: 0.833-0.888) (p &lt; 0.0001). To assess the potential clinical utility of using LVH-MRI instead of ECG-LVH, we calculated several measures of reclassification (Table 1), which were consistent with the statistically significantly improved C-statistic with MRI-LVH. Conclusion: Both ECG-LVH and MRI-LVH are predictive of HF when used in the FHFRS. Substituting MRI-LVH for ECG-LVH improves the predictive ability of the FHFRS.
P01.165 A prospective study investigating the Impact Of MultidiscipliNarY tumor Board in brain tumor management: the OMNYBuS Project
Authors: S Chiesa, G Sabatino, S Gaudino, G La Rocca, C Mazzarella, F Beghella Bartoli, C Colosimo, V Valentini, A Olivi, M Balducci
Journal: Neuro-Oncology (2018)

Multidisciplinary clinics have become the standard practice for cancer care worldwide. The aim of the OMNYBuS project is to investigate the impact of tumor board in brain tumor management in order to obtain the best personalized treatment plan. In the first phase of the study, we collected data retrospectively obtained from the first year experience of multidisciplinary tumor board. Neurosurgeons, radiation oncologist, radiologist, anatomopathologists and residents were involved in the multidisciplinary discussion. The analysis was conducted in order to arrange a strategy of the prospective phase. The primary endpoint was the management change rate in terms of exchange, addition, or subtraction of treatment modality. The secondary endpoints were the delay considering treatment starting time, extra diagnostic work-up and time needed for academic discussion Between March 2017 and March 2018, 148 consecutive cases were presented and discussed in terms of diagnostic imaging results and interpretation, medical, surgical, and/or radiation treatment planning, and pathology results and interpretation. The discussed cases were: 33,3% high grade gliomas, 10,8% anaplastic astrocytomas, 6,5% oligodendrogliomas, 2,2% low grade gliomas, 14% meningiomas, 14% single metastases, 8,6% multiple metastases, 5,4% other type of lesion. The terapheutic plan change rate was 9.2%, mostly for high grade gliomas. No delay was observed in treatment starting time. A reduction of diagnostic work-up accounted for 65,7%. The median time for case discussion was 10 minutes with a median tumor team members presence of 22 clinicians. This data emphasizes the fact that in a relevant number of cases the initial treatment strategy could be modified after a multidisciplinary discussion. Almost all respondents indicated that these meetings were “very beneficial” to their own practice and this retrospective phase allows us to elaborate a data collection strategy to prospective analyze the adherence to guidelines, the reduction of diagnostic work-up and the patients related outcomes. We are using the new schedule for data collection in our multidisciplinary clinical practice
Use of next-gen sequencing in an integrated companion diagnostics workflow.
Authors: Heather Gustafson, Lorraine Stewart, Noah Theiss, James Hnatyszyn
Journal: Journal of Clinical Oncology (2016)

e23273 Background: The need for a Next-Generation Sequencing (NGS) workflow in a CAP/CLIA accredited laboratory is rapidly increasing as the sequencing technology matures and becomes more feasible as a diagnostic tool. Validating such a workflow for use on formalin-fixed paraffin tissues (FFPE) is very challenging. Determination of tumor status is important to identify patient populations that may be poor responders to standard therapies and would benefit from alternative therapeutic strategies. Driven by tissue context, sequencing joined with immuno-histochemical (IHC) tests for specific markers can provide comprehensive information to inform clinicians on potential treatment pathways. We have developed an integrated workflow solution that combines the use of IHC, digital imaging, micro-dissection, and NGS to capture important information to drive therapeutic opportunities. Methods: Our Integrated Companion Diagnostics (ICDx) workflow involves staining of a FFPE specimen using a validated IHC test for a specific biomarker. A pathologist would annotate regions of interest that are negative for the primary marker on a digital image. The selected area(s) would be excised on subsequent serial sections by micro-dissection. The captured FFPE tissue would then pass through our automated NGS workflow, whereupon additional validated IHC diagnostic tests identified via sequencing could be employed in our CAP/CLIA accredited laboratory to confirm findings and inform clinicians. Results: To demonstrate the workflow, we excised tissue from tumor regions on whole tissue resections and sequenced utilizing our custom and analytically (in-house) validated Ventana Medical Systems Inc (VMSI) targeted cancer panel. We were able to show that samples acquired from micro-dissection are suitable for use in our downstream workflow for NGS library preparation and sequencing. Additionally, we found that the use of tissue dissection in regions of interest can allow for detection of mutations that would otherwise go undetected. Conclusions: This workflow is aimed to provide as much information as possible about clinical samples to aid in treatment decisions.
Reno-vascular toxicities associated with carfilzomib: Systematic review and meta-analysis.
Authors: Chintan Shah, Harini Bejjanki, Rohit Bishnoi, Ankur Jain, Subhankar Samal, Jan Moreb
Journal: Journal of Clinical Oncology (2017)

e21622 Background: Carfilzomib (Carf) is a novel proteasome inhibitor 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 reno-vascular toxicities (RVT) is not well known. 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 a total of 29 publications; phase I/II, phase II and phase III clinical trials (n = 3) which used Carf as monotherapy or in combination. We excluded phase I studies. Incidence rates and odds ratios (OR) were calculated with either fixed effect or random effect model based on the heterogeneity of included studies. Toxicity such as hypertension (HTN), renal failure (RF) and venous thromboembolism (VTE) were reported according to CTCAE v4.0. Results: A total of 4560 patients with various hematological and solid malignancies were included. Incidences of toxicities were: 15.9% and 4.7 % for HTN, 11.2% and 3.44% for RF, 6.47% and 2.22% for VTE, respectively for all grades and high grades in each category. When compared to control group taken from phase III clinical trials, the risk of HTN and RF due to Carf was significantly higher [OR = 2.91 and 3.32 in HTN (P &lt; 0.001)], [OR = 1.71 and 1.79 (P &lt; 0.05) for RF], respectively for all grade and high grade in each category. Moreover, incidence of HTN with higher than standard dose of carf (27 mg/m2 twice weekly) was significantly higher (P &lt; 0.001). RF and VTE did not have the dose effect. Concomitant use of immunomodulator (IMiD) significantly increased, as expected, the incidence of VTE (P &lt; 0.001). There was no variation in the incidence of RVT among newly diagnosed versus RMM (P = 0.4). Conclusions: Overall incidence and risk of hypertension and renal toxicities seems to be high when using Carf. Higher doses of Carf seem to lead to higher incidence of HTN, while the risk of VTE is higher with concomitant IMiD use. The pathophysiology for these complications is poorly understood, however it could be secondary to endothelial effect of carf. Physician should be vigilant about these effects as it can lead to poor overall outcomes.
Circulating cancer associated macrophage-like cells in the detection of invasive breast cancer.
Authors: Daniel L Adams, Diane K Adams, R. Katherine Alpaugh, Massimo Cristofanilli, Stuart S Martin, Saranya Chumsri, Cha-Mei Tang, Jeffrey R Marks
Journal: Journal of Clinical Oncology (2016)

e23055 Background: Circulating cancer associated macrophage-like cells (CAMLs) are a newly-defined cancer responsive immune effector cell found in the blood of cancer patients. In this abstract we sought to compare the specificity and sensitivity of CAMLs in relation to breast cancer at clinical presentation. Our data suggests that this previously unidentified circulating stromal cell is a highly sensitive, and specific, blood biomarker which may be applicable to screen for invasive carcinomas (ICs) of the breast. Methods: CellSieve microfilters were used to isolate CAMLs from 7.5 mL of whole peripheral blood. Collected cells were stained with DAPI, antibodies against cytokeratin (CK) 8, 18 and 19, CD14, and CD45. CAMLs were defined as enlarged, multinuclear cells with diffuse cytoplasmic CK, CD14+, or CD45+. We performed a prospective blinded study to isolate CAMLs from patients with invasive breast carcinomas (n = 58) to age matched healthy women (n = 18) and to patients with benign diseases of the breast (n = 19), not including DCIS, LCIS, ALH or ADH. Results: CAMLs were found in 91% of patients with ICs (n = 53/58), 26% of those with benign disease (n = 5/19), and none of the 18 healthy controls. Using 1 CAML as a positive finding, CAML sensitivity in ICs vs healthy controls was 91% (CI95% 81-97%), specificity = 100% (CI95% 82-100%), PPV = 100% (CI95% 93-100%), NPV = 78% (CI95% 56-93%), and AUC = 0.96. CAML sensitivity in ICs vs benign disease was 91% (CI95% 81-97%), specificity = 74% (CI95% 49-91%), PPV = 91% (CI95% 81-100%), NPV = 78% (CI95% 56-93%), and AUC = 0.86. Conclusions: We present evidence that CAMLs could be used as a non-invasive, sensitive, blood-based tool for the detection of cancer-responsive immune effector cells in women with the anatomical presence of invasive malignancies. These results indicate the benefit for future studies to further validate the utility of this cellular biomarker in screening for a variety of malignancies and other non-malignant conditions.
Hematopoietic cell transplantation (HCT) in older patients with acute myeloid leukemia (AML).
Authors: Vijaya Raj Bhatt, Baojiang Chen, Stephanie Lee
Journal: Journal of Clinical Oncology (2016)

e18026 Background: Timely receipt of HCT can improve overall survival (OS) in AML. This is particularly important in older patients, who otherwise have poor prognosis. Methods: We utilized the National Cancer Database to determine receipt of HCT in older patients (>60 years) with AML reported between 1998-2012. Subjects with complete data for the variables sex, age, race, education, income, distance traveled for health care, hospital type, facility location, Charlson co-morbidity score, chemotherapy use, time to treatment initiation, use of HCT and vital status were included. We included only those patients, who had all of the first course treatment or a decision not to treat made at the reporting facility. Multivariate logistic regression model was used to determine factors associated with receipt of HCT. Results: Only 1.8% of older patients (n=63,463) underwent HCT. Median OS for all patients was 2.9 months (95% CI 2.8-3.0). Factors associated with a lower likelihood of receiving HCT included receipt of care in a non-academic hospital, race other than white, Charlson comorbidity score of ≥1, uninsured status, Medicaid or Medicare insurance, and lower educational status (Table 1). Conclusions: The receipt of HCT in older patients is low at a population level. Discrepancy exists in receipt of HCT based on race, hospital type, insurance, and educational status. Nation-wide efforts to improve access to HCT are necessary. Factors associated with lack of receipt of HCT. Variable Odds ratio 95% confidence interval P value Academic 1 Non-Academic 3.8 3.2-4.6 <.01 White 1 Black 1.5 1.0-2.1 0.04 Others 1.9 1.2-2.8 <.01 Percentage without high school diploma <7% 1 7-12.9% 1.1 0.9-1.4 0.08 13-20% 1.5 1.1-1.9 <.01 >21% 1.4 1.0-1.9 0.02 Private insurance 1 Medicaid 2.5 1.5-4.2 <.01 Medicare 3.1 2.7-3.6 <.01 Uninsured 4.3 1.9-9.9 <.01 Other government 1.6 0.8-3.1 0.1 Unknown 23.2 10.6-50.7 <.01 Charlson comorbidity score 0 1 1 1.4 1.1-1.6 <.01 ≥2 3.1 2.0-4.7 <.01
Pushing the accelerator and releasing the brake: A phase I dose escalation study evaluating a LAG-3 fusion protein (eftilagimod alpha), together with pembrolizumab in unresectable or metastatic melanoma.
Authors: Melissa A. Eastgate, Victoria Atkinson, Muhammad Adnan Khattak, Amitesh Chandra Roy, Andrew Mark Haydon, Christian Mueller, Tina Dunkelmann, Chrystelle Brignone, Frederic Triebel
Journal: Journal of Clinical Oncology (2018)

e15099 Background: Eftilagimod alpha (efti; previously named IMP321) is a recombinant LAG-3Ig fusion protein binding to MHC class II molecules and mediating antigen presenting cell (APC) activation followed by CD8 T-cell activation. The activation of the dendritic cell network and the subsequent T cell recruitment at the tumor site with efti may lead to stronger anti-tumor CD8 T cell responses than observed with pembrolizumab alone. This combination of an APC activator with an immune checkpoint inhibitor (ICI) is aiming to increase efficacy without additional toxicity. We report results of the dose escalation cohorts from a phase I trial (NCT02676869) with pembrolizumab and efti in melanoma patients (pts). Methods: In this study, melanoma pts treated with pembrolizumab and being without a complete response (CR) or symptomatic progression after 3 cycles continued pembrolizumab (2 mg/kg; IV) plus either 1, 6 or 30 mg injections SC of efti (every 2 weeks for 6 months) from cycle 5 onwards. Blood for pharmacokinetic and -dynamic assessments was withdrawn in cycle 1 and 9. Responses were assessed by immune related response criteria (irRC). Results: Between 04/16 and 12/17 18 pts (17 male, 1 female) with a median age of 66 years (range 48-85) were enrolled. The majority (83 %) of pts had visceral disease. Eight SAEs in 6 patients were reported. None of the SAEs was related to the study treatment. No dose limiting toxicities or adverse events (AEs) ≥ grade 4 were reported. No patient discontinued treatment due to an AE. Four pts experienced 4 different AEs grade 3 related to efti or pembrolizumab. PK results showed a dose proportional increase in Cmax. Sixteen (16) patients were eligible for response evaluation. In 8 (50 %) pts a tumor reduction was observed. This includes one patient with a confirmed CR after initial progression on pembrolizumab monotherapy. Conclusions: Thirty (30) mg efti SC every 2 weeks in combination with standard dose of pembrolizumab is safe. This dose is investigated in an extension cohort. The late tumor responses seen after the combination started may point out to the benefit of adding a systemic APC activator to an ICI. Clinical trial information: NCT02676869.
Association of increased somatic mutations in metastatic melanoma patients with clinical outcome.
Authors: Todd Wechter, Natasha Masub, Yesung Lee, Una Moran, Jeffrey S. Weber, Anna C. Pavlick, Judy Zhong, Iman Osman, Melissa Wilson
Journal: Journal of Clinical Oncology (2018)

e21568 Background: Melanomas are frequently classified by somatic mutation status for driver mutations including BRAF, NRAS, and c-KIT. With next-generation sequencing (NGS) as part of routine clinical care, additional mutations have been identified in patient tumor samples, however, impact on patients’ response to treatment and overall survival have not been adequately addressed Methods: We examined a cohort of 108 metastatic melanoma patients enrolled in an IRB approved database with protocol- driven follow up that had their tumors analyzed by next-generation sequencing. Using the Ion Torrent platform, tumors were examined for 52 known actionable cancer somatic mutations. Progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier analysis. A mutation signature was generated as a composite score from genes associated with worse PFS identified from univariate analysis. Results: BRAF V600 (25%), TP53 (19%), NRAS Q61 (18%) and CDKN2A (13%) mutations were identified, as well as other mutations in lower frequencies. All patients received immunotherapy first line treatment and only two patients with BRAF V600 mutant melanoma patients received targeted therapy. Worse PFS was observed with EGFR (HR = 8.22, p = 0.04), PTEN (HR = 1.92, p = 0.04) and non-canonical BRAF (HR = 1.77, p = 0.04) mutations. Using the generated mutation signature, in all tumor samples, those that harbored a higher number of mutations were associated with a worse PFS (mPFS 18.2, 4.9 and 5.2 months for no mutations, one or two mutations respectively; p = 0.004). Similar results were observed in wildtype BRAF and NRAS tumors (mPFS 27.6, 5.2, and 5.7 months for no mutations, one or two mutations respectively; p = 0.003). Conclusions: Increased number of specific somatic mutations, with or without known driver mutations, may provide predictive information on patient survival. Our results are in discordance with the previously reported data supporting that increased overall mutation burden predict for improved response to immunotherapy treatment and suggest that further investigation of the clinical and biological significance of specific mutations revealed in NGS may provide insight into new treatment strategies.
Assessing the clinical feasibility of electronic Rapid Fitness Assessment (eRFA): A novel geriatric assessment tool for the oncology setting.
Authors: Armin Shahrokni, Andrew J. Vickers, Sanam Mahmoudzadeh, Beatriz Korc-Grodzicki
Journal: Journal of Clinical Oncology (2016)

10011 Background: The American College of Surgeons & the American Geriatrics Society recommend the incorporation of geriatric assessment (GA) in the preoperative evaluation of older patients. GA requires patient reported data, such as on activities of daily living (ADL), or history of falls. Obtaining such data systematically in a busy surgical oncology practice poses considerable practical difficulties. We aim to develop an electronic GA, the electronic Rapid Fitness Assessment (eRFA), & determine the feasibility of clinical implementation in routine care. Methods: The eRFA captures data on multiple GA domains: functional activity, social support, emotional wellbeing, weight loss, polypharmacy and cognitive function. Older cancer patients, who present for preoperative evaluation, complete the eRFA by themselves or with the help of caregivers using a tablet. A nurse completes the evaluation performing the 'timed get up and go' test & the MiniCog test. The final report is available for the clinician at the time of the encounter, & the data is saved for future review. The time used by patients to complete eRFA is registered. A subset of 50 patients was randomly selected to assess satisfaction with the process. Results: Since its inception in 2/2015, a total of 595 older cancer patients (median age 80) completed eRFA. Despite the elderly population, patient acceptance of the electronic tool was excellent. The median time to complete was 11 minutes and only 13% of the assessments were completed by caregivers. Patient satisfaction was very high: 87% of the patients strongly or somewhat strongly agreed that the eRFA was easy to use. More importantly, a large number of geriatric syndromes were uncovered: 36% of patients were dependent for ADLs, 22% needed a cane to ambulate, 23% of patients suffered at least one fall in the last year, and 45% of these patients had high level of distress. Conclusions: The eRFA is patient-centered, easy to use and clinically feasible. It aids determination of clinical syndromes in cancer patients undergoing a surgical procedure that should be addressed for more successful outcomes. Further research on the effects of eRFA on process and outcomes is warranted.