tbuckley/cabot-search huggingface dataset:
Immunological and clinical profiles of patients with advanced or metastatic melanoma receiving immune checkpoint inhibitors to investigate potential biomarkers for immune-related adverse events.
Authors: Stephanie A. Berg, Michael Wesolowski, Brianna Burke, Courtney Regan Wagner, Joseph I Clark, Jose Guevara
Journal: Journal of Clinical Oncology (2019)

e14037 Background: Immune-related adverse events (irAEs) related to immune checkpoint inhibitors (ICIs) may target any organ and originate from autoreactive T cells injuring host tissues. There is a need to develop prognostic and predictive biomarkers to distinguish patients (pts) who will benefit from ICIs avoiding irAEs during treatment. We propose that irAEs are the result of many biological variables. We hypothesize that within each pts complex immunological profile, there may be patterns and associations which exist that represent a state of inflammation that is present prior to ICI therapy and hypothesize this could predict irAEs development. Methods: We created individual immunological profiles of 11 pts diagnosed with MM prior to receiving ICIs. Assays included: PBMC composition, circulating chemokines/cytokines, and IκB degradation status. CD4 and CD8 T cells were studied for their phenotype, activation status, proliferative capacity and cytolytic granules. Clinical data was collected on a larger MM pt cohort (n = 41) and descriptive statistics were utilized to characterize reported irAEs . Results: 110 input markers were utilized for immune signature analysis. 6 of the 11 pts reported grade 2+ irAEs after ICI therapy. The pro-inflammatory CCL13, CCL1, FLT-3, IL12p40, TRAIL, and granzyme b expressing CD4 T cells at steady state and after CD3 activation were significantly higher in pts with irAEs. Known inflammatory suspects (i.e., IL-2, IL-15, TNF-a or % CD8 T cells) were not associated with irAE development . A rank correlation test showed significant associations between the levels of these factors. irAEs were reported in 41% (n = 17) for our larger cohort, most frequently skin rash (7%), colitis (7%), hepatitis (7%) and thyroid dysfunction (4%). Conclusions: The immune signatures of pts with irAEs are highly heterogeneous and possess distinctive immunological patterns. Our results introduce possible molecular mechanisms that may aid understanding of irAE development, perhaps providing the basis for a new model prospectively testing these markers to risk stratify pts receiving ICIs.
Performance evaluation of different strategies based on microscopy techniques, rapid diagnostic test and molecular loop-mediated isothermal amplification assay for the diagnosis of imported malaria
Authors: E. Charpentier, E. Benichou, A. Pagès, P. Chauvin, J. Fillaux, A. Valentin, H. Guegan, E. Guemas, A.-S. Salabert, C. Armengol, S. Menard, S. Cassaing, A. Berry, X. Iriart
Journal: Clinical Microbiology and Infection (2019)
Adverse effects of early bilateral oophorectomy on body composition: Results from a nationally representative sample of United States women.
Authors: Pritesh S Karia, Corinne Joshu, Kala Visvanathan
Journal: Journal of Clinical Oncology (2019)

1568 Background: Prior studies suggest that bilateral oophorectomy (BO), a common cancer prevention strategy, may be associated with adiposity. However, the impact of BO on lean mass, a potential marker of healthy aging, and whole-body composition is not known. Declines in lean mass have been linked to physical disability and mortality. We examined the association between BO and total and regional distribution of fat and lean mass in a cross-sectional study. Methods: The study population included women 35-70 years who underwent dual-energy x-ray absorptiometry (DXA) scans at enrollment as part of the National Health and Nutrition Examination Survey 1999-2006 (N = 3,764). Multinomial logistic regression models were used to examine the relationship between prior BO and tertiles of fat and lean mass. Models were adjusted for age, race, education, BMI at age 25, physical activity, smoking, alcohol use, parity, oral contraceptive use and hormone replacement therapy use. Results: Women with prior BO &lt; 45 years (n = 346) had 2.9-times higher odds than women without BO (n = 3,212) of being in the highest compared to the lowest tertile of total fat mass (OR, 2.91; 95% CI, 1.93-4.38) and 2.7-times higher odds of being in the lowest compared to the highest tertile of total lean mass (OR, 2.67; 95% CI, 1.81-3.95). Results were similar when stratified by age at enrollment ( &lt; 45, 45-54, and ≥55). Similarly, among women with normal BMI at enrollment, those with prior BO &lt; 45 years (n = 74) had higher odds of being in the highest tertile of total fat mass (OR, 9.88, 95% CI, 2.21-44.00) and the lowest tertile of total lean mass (OR, 10.09; 95% CI, 2.72-37.46). These differences in body composition were most pronounced in the trunk region. No difference was observed in women with BO ≥45 years compared to women without BO. Conclusions: Women with a history of early BO experience significant changes in body composition, including increased fat mass and decreased lean mass, even while maintaining a normal BMI. If validated in future prospective studies, our results suggest that a comprehensive evaluation of body composition may be warranted in young women who undergo BO.
High incidence of brain metastases (BrM) in patients with metastatic cutaneous melanoma (MCM) and mutations in the APC/β-catenin (CTNNB1).
Authors: Georgia Sofia Karachaliou, Sarah Bass Carroll, Nirali M. Patel, Xiaobei Zhao, Guillaume Joe Pegna, Frances A. Collichio, Carrie B. Lee, David W. Ollila, Stergios J. Moschos
Journal: Journal of Clinical Oncology (2019)

9527 Background: Activation of the WNT/β-catenin pathway is associated with low/absent tumor-infiltrating lymphocytes (TILs) and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. We aimed to investigate if APC/CTNNB1 mutations in melanoma pts are associated with TIL status, prediction of response to immunotherapy (IT), and overall survival (OS). Methods: Pts with CM and APC or CTNNB1 mutations identified in melanoma tumors using the TruSight Tumor 26 Illumina assay were enrolled. Demographics, clinical (stage, treatment response, follow-up), pathologic (TIL status), and molecular (BRAF/NRAS, C→T (i.e. UV signature) nucleotide transition, functional significance by IMPACT, mutant allele frequency (MAF) corrected from the % tumor) characteristics were investigated. Results: We identified a total of 25 pts (13 males; age at original diagnosis (median 61 yrs, range 22-78 yrs). CTNNB1 and APC mutations were mutually exclusive. 48% (12/25) had APC mutations and 52% (13/25) had CTNNB1 mutations; of which (i.e. CTNNB1 mutations) 69% (9/13) had absent TILs. 88% (22/25) of APC/CTNNB1 mutations had moderate functional significance, 64% (16/25) of the mutations had a C→T nucleotide change, 36% (9/25) had BRAFV600, and 20% (5/25) NRASQ61 mutations. 64% (14/22) of pts with stage II-III progressed to stage IV; of these 14 pts, 8 (57%) developed parenchymal BrM. 13 of the stage II-III 22 pts who progressed to stage IV received IT; of these 13 pts, 7 (53%) had absent TILs. APC/CTNNB1 mutations did not influence response to IT, irrespective of the MAF of the mutations. Of the 12 pts with MCM and measurable disease who received IT 9/12 had absent TILs and 7/12 responded. The median OS from the time of diagnosis of distant MCM (N = 17; 14 pts who progressed from initial stage II-III and 3 pts who were originally diagnosed with stage IV) was 18.8 months (range, 2.4-48.0 months). Conclusions: APC &amp; CTNNB1 mutations are mutually exclusive. CTNNB1 mutations are more frequently associated with absent TILs. Pts with MCM had relatively shorter OS (18.8 months) in part due to development of BrM. In this small cohort APC/CTNNB1 mutations did not seem to impair response to immunotherapy.
Pharmacokinetic/pharmacodynamic assessment of a proposed biosimilar MSB11455 versus the currently licensed pegfilgrastim: A randomized, double-blind trial.
Authors: Jason D. Lickliter, Paul Griffin, Emmanuelle Vincent, Armin Schuler, Eleanor Harrison-Moench, Michael Stahl, Samer El Bawab, Radmila Kanceva, Pere Gascón
Journal: Journal of Clinical Oncology (2019)

e14514 Background: MSB11455 is a proposed biosimilar to the currently licensed pegfilgrastim (Neulasta). This phase I study (NCT03251248) assessed the pharmacokinetic (PK)/pharmacodynamic (PD) bioequivalence of MSB11455 to Neulasta. Methods: Healthy volunteers were randomized to one of two crossover sequences, MSB11455/Neulasta or Neulasta/MSB11455. Subjects received a single subcutaneous dose of either MSB11455 or Neulasta (both 6 mg/0.6 mL) on Day 1 of each study period. Samples for PK/PD analysis were taken predose and up to Day 16 postdose. Immunogenicity samples were taken predose and up to Day 84 postdose. Safety was assessed throughout the study. Results: 244 subjects were randomized and received both treatments. For all primary PK/PD parameters 90% repeated confidence intervals of the geometric mean ratio of MSB11455 versus Neulasta were within the pre-defined equivalence range (80.00%–125.00%): AUC 0–∞ (96.59, 112.82), AUC 0–last (97.29, 113.96), C max (97.13, 114.99), E max (98.74, 102.39) and AUE 0–t (97.30, 100.23). Safety and tolerability as well as immunogenicity were comparable between treatment sequences. No filgrastim-specific neutralizing antibodies were detected in either treatment sequence. Conclusions: PK/PD equivalence of MSB11455 and pegfilgrastim was demonstrated with comparable immunogenicity, safety, and tolerability. This study supports the biosimilarity of MSB11455 to Neulasta. Clinical trial information: NCT03251248.
AI platform in mammography to screening breast cancer: A sole-center experience.
Authors: Jie Li, Zhicheng Zhang, Jia Chang, Bo Lin, Weiming Lv
Journal: Journal of Clinical Oncology (2019)

e18052 {\rtf1\ansi\ansicpg936\cocoartf1347\cocoasubrtf570 {\fonttbl\f0\froman\fcharset0 Times-Roman;\f1\fnil\fcharset0 Calibri;\f2\fswiss\fcharset0 Helvetica; \f3\fnil\fcharset134 STHeitiSC-Light;\f4\froman\fcharset0 TimesNewRomanPSMT;} {\colortbl;\red255\green255\blue255;\red0\green0\blue0;} \paperw11900\paperh16840\margl1440\margr1440\vieww25400\viewh13600\viewkind0 \deftab720 \pard\pardeftab720 \f0\fs24 \cf2 \expnd0\expndtw0\kerning0 \outl0\strokewidth0 \strokec2 AI platform in mammagraphy to screening breast cancer: a sole center experence. \f1\fs21 \cf0 \kerning1\expnd0\expndtw0 \outl0\strokewidth0 \ \pard\pardeftab720\ri714\qj \cf0 Background: The aim of this study was to use deep convolutional neural network (DCNN) to relieve radiologists ' burden and to minimize misses and interpretation errors of suspicious lesions at digital mammography. Methods: We developed and trained the DCNN model on the training set, then validated it in an internal validation set. The labeled data were used for training the DCNN model, and the mass detection, calcification detection and benign and malignant diagnosis were interpreted respectively. After verifying the feasibility of the DCNN model in the diagnosis of breast cancer, we gradually increased the number of cases in the training set and established the verification set to test the training results. The latest training sets include 21100 atlas of our hospital between April 2010 and October 2017, among which the malignant case atlas is 1774. Each atlas contains 2 ipsilateral mammography images. The verification set includes 1307 atlas, among which the malignant case atlas is 248. Results: The DCNN model achieved high performance in identifying breast cancer patients in the validation sets tested, with sensitivity of 98.02%, specificity of 91.86% \f3 \'a3\'ac \f2 and area under the curve values of 0.9813. As for mass detection, we reached a recall rate of 89.6% on the premise of lowing the false positive to 0.168%. For the latest clinical data between October 2018 and November 2018 including 1043 atlas from 576 patients, the sensitivity was 78.6% (95%CI 62.8-89.1) versus 90.5% (95%CI 76.5 \f4 - \f2 96.9; p=0.021) and specificity was 93.4% (95%CI 91.6 \f4 - \f2 94.8) versus 82.7% (95%CI 80.2 \f4 - \f2 85 \f4 . \f2 0; p&lt;0.0001). Conclusions: The DCNN model showed improved specificity in diagnosis breast cancer compared with a group of skilled radiologists. As the number of cases in the training set increases, the capacity of DCNN model will be further improved.
Chronobiological assessment of triple-negative breast cancer.
Authors: Pati Revazishvili, Alexandre Tavartkiladze, Levan Tavartkiladze, Teimuraz Sordia, Ani Gvajaia
Journal: Journal of Clinical Oncology (2019)

e12564 Background: Triple Negative Breast Cancer (ER-, PR-, Her2/neu-., TNBC) constitutes 15-18 per cent of all malignant breast cancers. It is characterized by aggressive course and high lethality. Methods: We assessed chronobiological features of 19 patients with TNBC (medium age group 34-71). We used data of Melatonin and Cortisol circadian secretions for assessment parameters. During the month, we took blood from patients on every third day, from 02:00-04:00 pm to 02:00-04:00 a.m time intervals. The control group was composed of 14 patients with breast cancer, histological type: ER/PR+ and Her2/neu-. Results: As the result of the research, meaningful differences have been revealed between the investigated and control group. In patients with TNBC, the medium day-time concentration of Melatonin during the day was 1.1 pg/ml (normal range - up to 20 pg/ml), while at night its level increased by 4.2 pg/ml. In the control group, the average day-time level was 5.7 pg/ml, and at night - 12.5 pg/ml. Regarding Cortisol, in the investigated group, in day-time hours its average concentration in blood was 2.1 μg/dl (normal tange - 2.5 - 11.9 μg/dl, at afternoon), while at night - 0.7 μg/dl (normal range &lt; 1.8 μg/dl, at night). In the control group, at day-time, the average cortisol concentration was 4.095 μg/dl (normal range - 2.5 - 11.9 μg/dl, at afternoon), at night - 0.94 μg/dl (normal nange &lt; 1.8 μg/dl, Night). Conclusions: The study results have showed significant biochemical differences between ER/PR+/ Her2/neu- and TNBC- patients. Reduction of circadian secretion of Melatonin, as a major biochemical marker, directly correlates with the degree of cancer aggression, as it is seen fom the study. Furthermore, in patients whose Melatonin concentration was critically low, ductal (CK5/6+ and/or EGFR+) and metaplastic (epidermal: CK5/6+, EGFR+, Ck14+, p63+) forms were histochemically detected, which are extremely aggressive subtypes of TNBC. Regarding Cortisol levels in patients with critically Melatonin level, the Cortisol concentration was at critically low margin as well, that is considered to be the additional chronobiological marker for the aggressive course and rapid progression of cancer.
Adherence and cumulative bisphosphonate dose in relation to risk of skeletal-related events among older patients with multiple myeloma.
Authors: Jifang Zhou, Karen Sweiss, Pritesh Rajni Patel, Edith Nutescu, Naomi Ko, Brian C-H Chiu, Gregory Sampang Calip
Journal: Journal of Clinical Oncology (2019)

e18250 Background: Adjuvant intravenous bisphosphonates (IV BP) reduce the risk of skeletal-related events (SRE) in patients with multiple myeloma (MM). We examined the effects of bisphosphonate utilization patterns (adherence, cumulative dose and frequency) on risk of SRE. Methods: Patients aged 65 years or older and diagnosed with first primary MM between 2001 and 2011 were identified using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. Patients receiving at least one dose of IV BP after MM diagnosis were identified and 5-year SRE-free survival was estimated using the Kaplan-Meier method stratified by demographic groups and compared with the log rank test. Cox proportional hazards models were fit to determine the association between IV BP utilization patterns and SRE after propensity score matching. We investigated the outcome of multiple recurrent SRE using the approach of Andersen-Gill, and estimated subdistribution hazard ratios (SHR) and 95% confidence intervals for risk of first SRE, accounting for death as competing risk. Results: The final cohort included 9176 MM patients with a median age of 76 years. The adjusted 5-year competing-risk SRE model showed a 48% reduction in risk of SRE (95% CI 0.49-0.55) with use of IV BP. In multivariable analyses taking into account competing risks, greater adherence to IV BP, higher cumulative IV BP dose and more frequent administration were all associated with a statistically significant reduction in SRE risks (See Table). Conclusions: Use of IV BP in patients with MM was associated with significant reduction in SRE risk over the 5-year period after MM diagnosis. The effectiveness of IV BP therapy was greater with increasing cumulative dose, adherence to and greater frequency of IV BP administration. [Table: see text]
Assessment of treatment patterns of nonmuscle invasive bladder cancer patients in privately insured patients.
Authors: Mark Tyson, Amy Guo, David Rotter, Eros Papademetriou, Samuel Spigelman, Ravi C. Potluri
Journal: Journal of Clinical Oncology (2019)

e16012 Background: 75–85% of bladder cancer patients present with non-muscle invasive disease (NMIBC). While transurethral resection of bladder tumors (TURBT) is the initial standard treatment for visible lesions, there is variation in the utilization of adjuvant intravesical treatments in the real world. This study aims to assess current treatment patterns in privately insured NMIBC patients. Methods: Bladder cancer patients were identified from Truven MarketScan Commercial and Medicare Supplemental databases using ICD-9/ICD-10 codes. In the absence of tumor staging information, patients were considered to have NMIBC based on diagnosis of CIS or an algorithm centered on the use of TURBT, intravesical treatments and absence of immediate progression to muscle invasive disease. Patients were included in the final cohort if they had one year of continuous insurance coverage prior to index diagnosis, and were without any bladder cancer treatment during this period. Results: 18,683 patients met the eligibility criteria and had a median follow-up of 23 months; the mean age was 68.6 years and 75% were male. The median time from diagnosis to TURBT was 8 days. 54% of the cohort had an intravesical treatment (35% specifically with Bacillus Calmette–Guérin (BCG), with median time from TURBT of 69 days). 77% of BCG-treated patients received 5 or more administrations during induction. However, only 22% of patients received maintenance BCG after induction. 16% of the total cohort developed a recurrence or progression during the available follow-up; five percent underwent a cystectomy, while seven percent were diagnosed with metastatic disease. Only 4% of patients with 5 or more BCG administrations during induction met the definition for being BCG-unresponsive; this is influenced by the low adherence to BCG maintenance protocol. Conclusions: Only a third of NMIBC patients are given intravesical BCG treatment. Adherence to BCG maintenance protocols is suboptimal. Rates of cystectomy/ exenteration are low, suggesting patients’ preference of bladder preservation and the unmet need for new bladder-sparing alternatives.
A phase II clinical trial of ipilimumab/nivolumab combination immunotherapy in patients with rare upper gastrointestinal, neuroendocrine, and gynecological malignancies.
Authors: Oliver Klein, Damien Kee, Ben Markman, Rachael Chang Lee, Michael Michael, Linda R. Mileshkin, Clare L. Scott, Richelle Linklater, Sid Menon, Niall C. Tebbutt, Jodie Palmer, Andreas Behren, Jonathan S. Cebon
Journal: Journal of Clinical Oncology (2019)

2570 Background: Patients (pts) with rare cancers represent an unmet medical need and have an inferior overall survival compared to patients with more common malignancies. Due to their low frequency, no therapies, including immunotherapies, have systematically been investigated in this population. Ipilimumab (ipi)/Nivolumab (nivo) combination treatment has demonstrated significant clinical activity in pts with advanced melanoma and renal cell carcinoma and response rates with this regimen are higher compared to single agent anti-PD-1 therapy. This phase II study assessed the efficacy and safety of ipi/nivo in rare cancer pts. Methods: 60 pts with advanced rare upper gastrointestinal (GI), neuroendocrine (NE) and gynaecological (GY) malignancies were enrolled in 3 cohorts. Patients received nivo 3mg/kg and ipi 1mg/kg every 3 weeks for four doses, followed by nivo 3mg/kg every 2 weeks. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR), CR, PR and SD. Exploratory endpoints include correlation of efficacy with relevant biomarkers including PDL1 status and tumour mutation burden. Results: 42 pts have so far undergone restaging, 11 pts clinically progressed prior to their first restaging scan. 50 pts have received prior therapy (1-5 lines). Objective responses have been observed in a range of different malignancies. Clinical trial information: NCT02923934. Grade 3/4 immune related adverse events were detected in 31% of pts. The results of correlative biomarker studies will be presented at the meeting. Conclusions: Ipi/Nivo combination treatment has efficacy in a wide range of advanced rare malignancies. Immune related toxicity is in keeping with previously reported clinical trials using the same dosing regimen. # pts 53 GI (16) NE (20) GY (17) ORR 32% 31% 25% 41% 3 pts Cholangioca 3 pts Atypical bronchial carcinoid 1 pt Ovarian clear cell ca 2 pts Gallbladder ca 1 pt Pancreatic NET 1 pt Ovarian germ cell tumor 1 pt Adrenocortical ca 1 pt Uterine clear cell ca 1 pt Uterine carcinosarcoma 1 pt Uterine leiomyosarcoma 1 pt Vaginal SCC 1 pt low grade serous ovarian ca SD 36% 19% 55% 29% CBR 68% 50% 80% 70% PD 32% 50% 20% 30%