tbuckley/cabot-search huggingface dataset:
Immune landscape of neoadjuvant/preoperative chemoradiotherapy in pancreatic cancer.
Authors: Kosei Nakajima, Yoshinori Ino, Nobuyosh Hiraoka
Journal: Journal of Clinical Oncology (2019)

e15709 Background: Neoadjuvant/preoperative chemoradiotherapy in pancreatic cancer has been implicated to induce a local anti-tumor immunity, however the molecular mechanism remains a conundrum. Methods: Two patients’ cohort samples with/without preoperative chemoradiotherapy were used (n = 26 and n = 20, respectively). The treatment-driven immune microenvironment changes were analyzed by stratified bioinformatic approaches i.e. heat map analysis of immune-related genes selected by Gene Ontology, GSEA with Immunologic Signature data base, and Ingenuity Pathway Analysis (IPA). The results were further validated by immunohistochemical approaches. Results: Preoperative treatment induced 212 genes including DC-SIGN (CD209) and 13 immune-associated pathways such as TCR signaling, with an increasing shift of CD8 T-cell population by upregulation of MAL (T-cell differentiation protein). Consistently, immunohistochemical findings showed that the accumulation of DC-SIGN (+) dendritic cells and MAL (+) lymphocytes were significantly increased in patients with preoperative therapy. Conclusions: Preoperative chemoradiotherapy induces a shift toward CD8 T-cell generation mediated by DC-SIGN (+) dendritic cells and MAL (+) lymphocytes, leading to enhance anti-tumor immunity.
Proteomic profile of high-risk luminal A early breast cancers.
Authors: Nawale Hajjaji, Soulaimane Aboulouard, Yves-Marie Robin, Delphine Bertin, Isabelle Fournier, Jacques Bonneterre, Michel Salzet
Journal: Journal of Clinical Oncology (2019)

3077 Background: Breast cancer is a heterogeneous disease with a wide range of outcomes. Among the intrinsic breast cancer subtypes, luminal A tumors are considered to have a favorable prognosis. However, molecular studies characterizing the genomic landscape of luminal A tumors revealed a molecular heterogeneity within this subtype, which also translated to variability in survival. A better understanding of the biology of this tumor subgroup is therefore needed to determine the appropriate therapeutic strategy. The aims of the study were to determine the frequency of high-risk luminal A tumors in a real life cohort of early breast cancers and provide a proteomic characterization of this subgroup using a mass spectrometry approach. Methods: 222 early breast cancer patients with hormone receptor positive and HER2 negative tumors treated at our institution had a PAM50-based genomic assay Prosigna to estimate their risk of recurrence. This assay assigned each tumor sample to an intrinsic molecular subtype of breast cancer. Luminal A and B tumors were analyzed with MALDI mass spectrometry imaging combined with microproteomics, a spatially-resolved on-tissue shotgun proteomic technology, to determine the proteomic profiles of both cancer cells and stroma. Results: Among the 129 luminal A breast cancers identified in our cohort, 67 (51%) had a risk of distant recurrence of 10% or more (32% had a 10% to 15% risk, and 19% a risk greater than 15%). High-risk luminal A tumors had a distinctive proteomic profile compared to low-risk luminal A or to luminal B tumors. Overexpression of the methionine biosynthesis pathway was the main differential protein expression observed in cancer cells and stroma of high-risk luminal A. Inflammation mediated by chemokine and cytokine signaling pathway and integrin signaling were also overexpressed in high risk luminal A compared to luminal B. In the stroma of luminal B tumors, EGR signaling, Ras and FGF pathways and angiogenesis were overexpressed compared to high-risk luminal A tumors. Conclusions: Real life data showed a significant proportion of high-risk luminal A breast cancers. MALDI mass spectrometry proteomics revealed distinctive tumor and microenvironment profiles in this breast cancer subgroup.
Highly sensitive quantification of Alzheimer's disease biomarkers by aptamer-assisted amplification
Authors: Hei-Nga Chan, Di Xu, See-Lok Ho, Dinggeng He, Man Shing Wong, Hung-Wing Li
Journal: Theranostics (2019)

Alzheimer's disease (AD), a chronic neurodegenerative disease associated with the loss of neurons in the brain, is the most pervasive type of dementia; 47 million people are affected, and the number is expected to increase to more than 131 million by 2050, according to Alzheimer's Disease International.Both early diagnosis and continuous monitoring are crucial for early intervention, symptomatic treatment, monitoring of the efficacy of intervention and improved patient function.Beta-amyloid peptide, tau, and phosphorylated tau are useful for screening and diagnosis; meanwhile, simultaneous assessment of multiple biomarkers is of paramount importance for accurate disease diagnosis.Methods: Herein, we report a direct, inexpensive and ultrasensitive aptamer-based multiplex assay for the quantification of trace amounts of AD biomarkers in both human serum and cerebrospinal fluid (CSF) samples.In this newly developed assay, molecular recognition of an antibody-aptamer pair provides high specificity in target detection, and the use of a DNA amplification strategy affords high sensitivity, allowing quantification of AD biomarkers in both biological fluids in 1.5 h with only a diminutive amount of the sample consumed.A tailor-made turn-on fluorophore, namely, SPOH, was employed to label the antibody-aptamer hybrids and provide a strong fluorescence signal, which was then detected with a total internal reflection fluorescence microscopy electron-multiplying charge-coupled device (TIRFM-EMCCD) imaging system.The simultaneous detection of biomarkers was achieved by a direct shape-coded method in which the nanoplatforms can be distinguished from one another by their morphologies.Results: This assay demonstrated a lower detection limit (in the femtomolar range) for AD biomarkers than the previously reported antibody-antibody method. Conclusion:The developed assay holds tremendous clinical potential for early diagnosis of AD and monitoring of its progression.
Case 46-1985
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Roger L. Jenkins, Austin L. Vickery
Journal: New England Journal of Medicine (1985)

Presentation of CaseA 32-year-old woman was admitted to the hospital because of a cystic mass in the liver.She was well until five months earlier, when diarrhea and fever developed and subsided after three days. Three months before admission she began to experience a "pressure" sensation in the epigastrium, which occurred between meals and was partially relieved by eating, and noticed a mass in the same area. A physician obtained laboratory studies that included a blood count, an erythrocyte sedimentation rate, and an automated scan of multiple biochemical tests, all of which were normal. Several stool examinations for ova . . .
Hypertension and use of bevacizumab among patients treated in community settings.
Authors: Heidi D. Klepin, Elizabeth Garrett-Mayer, Melinda Kaltenbaugh, Suanna S. Bruinooge, Wendy S. Rubinstein, Stephen C. Meersman, Robert S. Miller, Gary H. Lyman, Stacy W. Gray, Larissa Nekhlyudov, Travis John Osterman, Ramya Thota, Apostolia Maria Tsimberidou, Kala Visvanathan, Richard L. Schilsky, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2019)

e18279 Background: CancerLinQ Discovery (CLQD) is a real-world dataset (RWD) derived from electronic health records across the US. This analysis builds on the prior observation of cautioned use of bevacizumab (Bev) among older adults using Medicare claims data. The goals of this study are to estimate the prevalence and incidence of hypertension (HT) and blood pressure (BP) patterns among patients (pts) with breast cancer (BC) or lung cancer (LC) treated with Bev. Methods: The cohort consists of all BC and LC pts in the platform at the time of CLQD dataset creation. At least one administration of Bev was required for inclusion as was diagnosis date and date of first Bev use. Elevated BP was defined as &gt; 140 mmHg for systolic and &gt; 90 mmHg for diastolic BP; elevated and max BP within 90 days of first Bev and 120 after were calculated for each pt. Summary statistics and proportions were calculated within these subgroups: baseline HT, race, age, and ECOG performance status (PS). Results: Overall, 1941 pts with BC and 4590 pts with LC treated from 2005 to 2017 were included. Baseline characteristics included % female (99 BC, 48 LC); % white (71 BC, 81 LC); % age &gt; 65 years (34 BC, 52 LC). PS was available for N = 2118; most pts were PS 0-1 (88% BC, 82% LC). At baseline, more than half of pts were hypertensive (57% BC, 52% LC). An increase of at least 10mmHg in systolic BP within 120 days of treatment occurred in over half of pts with a normal baseline BP (54% BC, 56% LC) and in one-third of those with baseline HT (34% BC, 32% LC.) A significant proportion experienced at least a 20mmHg increase in systolic BP among those normotensive (29% BC, 32% LC) or hypertensive at baseline (16% BC, 16% LC). A majority of pts &gt; 65 years had at least one elevated BP prior to Bev treatment (81% BC, 72% LC) although there were no clinically significant differences in rates of post treatment HT by age, race or PS. Conclusions: RWD provides important insights regarding the use and safety of medications outside the clinical trial population. Bev administration among pts with baseline (or pre-existent) HT is common in these practices. BP elevation post Bev exposure is also common, particularly among those with normal BP at baseline.
A phase I study of ALX148, a CD47 blocker, in combination with established anticancer antibodies in patients with advanced malignancy.
Authors: Laura Quan Man Chow, Justin F. Gainor, Nehal J. Lakhani, Hyun Cheol Chung, Keun-Wook Lee, Jeeyun Lee, Patricia LoRusso, Yung-Jue Bang, F. Stephen Hodi, Philip Fanning, Yonggang Zhao, Feng Jin, Hong Wan, Jaume Pons, Sophia Randolph, Wells A. Messersmith
Journal: Journal of Clinical Oncology (2019)

2514 Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host’s immune response. ALX148 (A) is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. ALX148 is well tolerated in combination with pembrolizumab (P) or trastuzumab (T) with no maximum tolerated dose (MTD) identified (ASCO 2018 #3068, SITC 2018 #P335). Safety and antitumor activity of ALX148 (10 mg/kg QW) in combination with T or P are reported in patients (pts) including those with anti-HER2 or checkpoint inhibitor (CPI) relapsed/refractory diseases. Methods: Patients with malignancy including non-small cell lung cancer (NSCLC: CPI resistant/refractory or PD-L1 tumor proportion score &lt;50%) and head and neck squamous cell carcinoma (HNSCC: progressed on platinum therapy) received A+P. Patients with HER2 malignancy including gastric/gastroesophageal junction (GEJ) cancer (progressed on T + fluoropyrimidine-based therapy) received A+T. Safety, response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed. Preliminary data from fully enrolled cohorts are reported as of 20 Jan 2019 (safety)/28 Jan 2019 (efficacy). Results: Seventy-nine pts received A+P (All, n=50; NSCLC, n=23; HNSCC, n=20) or A+T (All, n=29; Gastric/GEJ, n=23) as of data cutoff. Forty-seven pts reported mostly low grade treatment related adverse events. The most common were fatigue (11%), AST increase (9%), ALT increase (8%), anemia (8%), and platelets decreased (6%). In select tumor histologies, anticancer activity was observed in initial response-evaluable pts [NSCLC (n=23) 1PR, 8SD; HNSCC (n=17) 3PR, 4SD; and Gastric/GEJ (n=21) 4PR, 6SD]. Preliminary results indicate favorable ALX148 PK and CD47 target occupancy profiles, and positive effects on tumor infiltrating immune cells. Results will be updated at presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics to date. Objective responses were observed in patients with late line NSCLC, HNSCC, and Gastric/GEJ, including disease relapsed/refractory to prior CPI and HER2-targeted therapies. Clinical trial information: NCT03013218.
Genetic characterization of early renal changes in a novel mouse model of diabetic kidney disease
Authors: Lois A. Balmer, Rhiannon Whiting, Caroline Rudnicka, Linda A. Gallo, Karin A. Jandeleit, Yan Chow, Zenia Chow, Kirsty L. Richardson, Josephine M. Forbes, Grant Morahan
Journal: Kidney International (2019)
A preliminary comprehensive molecular-based nomogram for individualized estimation of survival in patients with newly diagnosed glioblastoma utilizing global microRNA expression data.
Authors: Denise Fabian, Erica Hlavin Bell, Joseph P. McElroy, Tiantian Cui, Jessica L. Fleming, Aline P. Becker, Marjolein Geurts, Jahar Haque, Pierre A. Robe, Arnab Chakravarti
Journal: Journal of Clinical Oncology (2019)

2044 Background: Glioblastoma (GBM) is the most aggressive and common primary brain tumor. Nomograms are prediction models that help form individualized risk scores for cancer patients, which are valuable for treatment decision-making. The aim of this study is to create a refined nomogram by including novel molecular variables beyond MGMT promoter methylation. Methods: Clinical data and miRNA expression data were obtained from 226 newly diagnosed GBM patients. Clinical data included age at diagnosis, sex, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase ( MGMT) promoter methylation status, IDH mutation status and overall survival. Due to low representation of less than 13 cases each, IDH mutant glioblastomas and patients submitted to biopsy-only were excluded. Total RNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissues; miRNA expression was subsequently measured using the NanoString human miRNA v3a assay. A Cox regression model was developed using glmnet R package with the elastic net penalty while adjusting for known prognostic factors. A dichotomized genomic score was created by finding the optimal cutpoint (maximum association with survival) of the linear combination of the selected. A nomogram was generated using known clinical prognostic factors, specifically age, sex, KPS, and MGMT status along with the dichotomized genomic score. Results: Four novel miRNAs were found to significantly correlate with overall survival and were used to create the dichotomized miRNA genomic score (GS). This score split the cohort into a poor performing group (GS_high) and a better performing group (GS_low) (p = 0.0031). A final nomogram was created using the Cox proportional hazards model (Figure 1). Factors that correlated with improved survival included younger age, KPS &gt; 70, MGMT methylation and a low genomic score. Conclusions: This study is a proof of concept demonstrating that integration of molecular variables beyond MGMT methylation improve existing nomograms to provide individualized information about patient prognosis. Future directions include a more comprehensive analysis, including proteomic and methylation data, and subsequent validation in an external cohort. Finally, network analysis integrating molecular signatures of poor performers will help identify therapeutic targets.
Online advertising and marketing claims by providers of proton beam therapy: Are they guideline based?
Authors: Mark Thomas Corkum, Wei Liu, David A. Palma, Robert Edward Dinniwell, Glenn Bauman, Andrew Warner, Mark Vikas Mishra, Alexander V. Louie
Journal: Journal of Clinical Oncology (2019)

6599 Background: Proton beam therapy (PBT) is a radiotherapy platform that purports an improved therapeutic ratio by way of a rapid radiation dose fall-off. Despite this technology being hindered by significant capital and patient costs, the number of centres offering PBT is increasing exponentially. Consensus guidelines support PBT use in a limited number of disease sites or on clinical trials. As patients frequently obtain information about PBT from hospital or cancer centre websites, the purpose of this study was to evaluate direct to consumer advertising (DTCA) content and claims made by proton therapy centre (PTC) websites. Methods: English PTC websites worldwide were identified using the Particle Therapy Co-Operative Group website. Data abstraction of website content was performed independently by two investigators. Eight international guidelines were consulted to determine indications for PBT. Univariate and multivariate logistic regression models were used to identify website characteristics that were associated with a higher likelihood to make non-evidence-based claims of PBT such as improved disease control or cure. Results: From the 48 PTCs with 46 English websites, most (58%) did not provide any references for claims made regarding PBT. These included: improved disease control or cure (61%), fewer side effects (85%), or was the standard of care (13%). Prostate (87%), head and neck (87%) and pediatric (83%) cancers were the most frequently listed PBT-indicated disease sites, consistent with international guidelines. However, pancreatobiliary (52%), breast (50%) and esophageal (44%) cancers were frequently advertised despite not being endorsed in any consensus guidelines. On multivariate analysis, an increasing number of listed disease sites and claims of being a regional PTC leader were associated with indicating that PBT offers greater disease control or cure. The availability of PBT through a clinical trial was mentioned on 57% of websites. Conclusions: PTC websites often contain information and DTCA claims inconsistent with international consensus guidelines. As online marketing information may have significant influence on patient decision-making, alignment of such information with accepted guidelines and consensus opinion should be adopted by PBT providers.
tRNA-derived small RNA fragments (tRFs) as potential biomarkers for doxorubicin resistance in breast cancer.
Authors: Xiaowei Wu, Ziyi Fu, Han Ge, Xiaoan Liu, Yiqin Xia, Minghui Li, Yue Huang, Jinhui Peng, Shui Wang, Hui Xie
Journal: Journal of Clinical Oncology (2019)

e12000 Background: It has been confirmed that tRNA-derived small RNA fragments (tRFs) participate in various kinds of biological activities. However, the function of tRFs in chemotherapy resistance in breast cancer still remains unclear. The purpose of this study is to elucidate the relation between tRFs expression character and chemotherapy resistance in breast cancer. Methods: Drug sensitivity was validated by using Cell Counting Kit-8 in ADR-sensitive breast cancer cells (MCF-7) and ADR-resistant cells (MCF-7/ADR). Next-generation sequencing technology was conducted to identify differentially expressed tRFs between MCF-7 and MCF-7/ADR breast cancer cell lines; quantitative RT-PCR (qRT-PCR) were used to validate the differentially expressed tRFs in MCF-7 and MCF-7/ADR cell lines and the serums of chemotherapy sensitive and resistant patients. Then the dysregulated tRFs were identified through Gene ontology (GO), Pathway analysis and network analysis. Finally, receiver operated-characteristic curve (ROC) analysis was carried out to assess the predictive power of the dysregulated tRFs as biomarkers for chemotherapy resistance.The growth and sensitivity of breast tumor to Adriamycin were assessed by micro-CT in vivo. Results: There were 588 differentially expressed tRFs between MCF-7 and MCF-7/ADR cell lines (fold change &gt; 2).tRF-2023, which was significantly downregulated in chemotherapeutic resistance breast cancer tissues and cells, could induce the sensitivity of breast cancer cells to Adriamycin both in vivo and in vitro. Bio-informatic analysis showed that tRF-2023 was mainly involved in flavonoid glucuronidation and cellular gluuronidation, and the target genes of tRF-2023 were involved in RNA polymerase, purine and pyrimidine metabolism, and p53 signaling pathway, which might illuminate the function of tRF-2023 in chemotherapy resistance of breast cancer. The result of ROC also showed that tRF-2023 was involved in breast cancer resistance. Conclusions: Our study provides a comprehensive analysis of tRFs in breast cancer resistance. It is helpful in revealing the significance of tRFs during the development of chemotherapy resistance in breast cancer. We also identified that tRF-2023 could be a new potential biomarker and therapeutic target for chemotherapy-resistant breast cancer.
Dynamic changes of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) during treatment with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC).
Authors: Alessandro Russo, Tindara Franchina, Giuseppina Ricciardi, Alessandra Battaglia, Silvia Schifano, Maurizio Schifilliti, Antonino Scimone, Giuseppe Toscano, Mariangela Zanghì, Vincenzo Adamo
Journal: Journal of Clinical Oncology (2019)

2596 Background: ICIs have revolutionized the therapeutic landscape of NSCLC. However, with the exception of PD-L1 expression, predictive biomarkers are lacking. The aim of this study was to evaluate the dynamic changes of some markers of inflammation over time and the outcome of NSCLC patients (pts) treated with nivolumab (N) or pembrolizumab (P). Methods: All consecutive NSCLC pts treated with N or P between Aug. 2015-Dec. 2018 were analyzed. Laboratory results were collected at baseline, 6 weeks (6-wk), and 12 weeks (12-wk) and correlated with the outcome. NLR and PLR were defined as absolute neutrophil and platelet count divided by lymphocyte count, respectively. NLR ≥5, PLR ≥200, and LDH levels ≥ upper normal limit were considered high. Overall survival (OS) was defined as time from ICI start to death and Progression Free Survival (PFS) as time from treatment start to progression disease or death for any cause. OS and PFS curves were estimated using the Kaplan–Meier method and compared with the log-rank test. Results: We included 71 consecutive NSCLC pts treated with either N (75%) or P (25%). Baseline characteristics: median age 69 years (range 46-80), sex male 76%, squamous histology in 39%. PD-L1 expression (39/71): &lt; 1% in 20%, 1-49% in 45%, and ≥50% in 35%. NLR ≥5 was associated with lower PFS and OS, with an increased predictive value over time ( p =0.01 and p =0.009 at baseline; p =0.007 and p &lt;0.001 at 6-wk; p &lt;0.001 and p &lt;0.001 at 12-wk, respectively). PLR ≥200 at baseline and 12-wk was significantly associated with shorter OS ( p =0.05 and p =0.004, respectively), but no in terms of PFS at all the three time points. Finally, LDH ≥UNL at baseline was associated with shorter PFS and OS ( p =0.02 and p =0.03), as well as a reduction of LDH levels at 12-wk compared with baseline values ( p =0.006 and p =0.004). Conclusions: Baseline evaluation of NLR, PLR and LDH levels is significantly associated with outcome in NSCLC treated with single agent ICIs. Moreover, dynamic changes of LDH levels at 12 weeks significantly predicted outcome. These easy to determine parameters may have a place in the selection process of pts candidate for immunotherapy.