tbuckley/cabot-search huggingface dataset:
Abstract 43: Could Serum Lactate Level Predict Neurological Outcome in Patients Undergoing Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest?
Authors: Francesca Verginella, Alice Scamperle, Perla Rossini, Michele Zuliani, Vincenzo Campanile, Alberto Peratoner, Fabio Salvatore Alongi
Journal: Circulation (2014)

Until November 2013 and the printing of TTM trial, TH was a standard of treatment in OHCA. In Italy 55.000 events of CA occur every year. Early Prognostication in neurological outcome is still difficult and controversial. We decided to investigate the influence of lactacidemia at the time of start(T0) TH and after 24 hours(T24) on neurological outcome at 6 months. After the ischemic injury, microcirculation is dysfunctional. Lactacidemia explains how the microcirculation is going to restore itself 1,2 . Methods: We did a retrospective analysis of 88 patients admitted to several Italian ICUs. Patients underwent TH trough endovascular or surface cooling. We tested lactate in mmol/L at ICU admission and after 24 hours. Neurological outcome was measured using the Pittsburgh Cerebral Performance Category Scale (CPC) by phone-interview. We analysed the data using the ROC curve. Results: The mean value of Lactate at T0 was 5,7 mmol/L and and at T24 was 3,6 mmol/L. 47 patients had a good neurological outcome (CPC score of 1-2). 41 patients had a bad neurological outcome (CPC score 3-5). Discussion and Conclusion: At T0 the AUC is 0,69, P value is 0,001. At T24 the AUC is 0,56, P value is 0,288. Lower serum lactate at T0 is weakly associated with CPC 1-2 at 6 months. On the contrary there is no correlation between lower serum lactate at T24 and good neurological outcome. This conclusion is in contrast with current evidence based in literature 3 . Despite Lactacidemia being a sign of microcirculatory damage, our study explains that Lactate at T24 can not be used to predict the neurological outcome. More studies are needed to explain if Lactates Level could be a strong prognostication index. 1 “Post-cardiac arrest syndrome” Nolan et al. Resuscitation 2008;79 2 “Microcirculation during CA and resuscitation” Fries M, et al. Crit Care Med 2006;34 3 “Association of serum lactate and survival outcomes in patients undergoing TH after CA” Starodub et al; Resuscitation 2013;84
Simultaneous extraction of DNA and total RNA from varying specimen types to enhance tissue utilization for molecular analysis.
Authors: Vanessa Spotlow, Kevin Kelly, Aleksandra Ras, Samantha Helm, Joan Malcolm, Gregory J. Tsongalis
Journal: Journal of Clinical Oncology (2016)

e23209 Background: The isolation of both genomic DNA (gDNA) and total RNA (RNA) from tissues of various types is critical for comprehensive molecular profiling, especially as submitted specimens become more limited in size. Simultaneous extraction of both gDNA and RNA from the same specimen would prove invaluable by saving time and sample. The Qiagen Universal All-Prep extraction kit allows for the extraction of both gDNA and RNA from the same sample and is also robust enough to allow for extraction from multiple sample types with this same kit that require only minor modifications. Methods: In this study, subsets of samples from fresh frozen tissue, whole blood, cultured cells, and bone marrow mononuclear cells were extracted using the Qiagen Universal All-Prep kit. The isolated gDNA and RNA were assessed for both quality and quantity using the NanoDrop 2000 and the Qubit fluorometer. These samples were then processed through the CLIA licensed and CAP accredited JAX DiscoverSeq and FusionSeq assays and sequenced on the Illumina NextSeq 500 or MiSeq, respectively. Post-sequencing analysis was performed using an internal Clinical Genomics Analytical (CGA) pipeline as well as fusion detection software. These results were compared to current analytical metrics. Results: Simultaneous extraction of both gDNA and RNA from these various specimen types yielded high quality gDNA and RNA that surpassed all input cutoffs for the JAX DiscoverSeq and FusionSeq assays. The samples were processed through both assays and subsequently run through the internal CGA pipeline and the fusion detection software. All specimen types undergoing validation met the set metrics for sequencing depth and mean target coverage. These metrics showed that this extraction process yielded samples free from analytical interferences. Conclusions: The Qiagen Universal All-Prep extraction process could be used to simultaneously extract gDNA and RNA from multiple sample types using the same amount of input material. By validating and implementing this extraction method, we were able to broaden our acceptable specimen criteria as well as optimize our current extraction process to yield higher quality and quantity of both DNA and RNA.
Increased autophagy is cytoprotective against podocyte injury induced by antibody and interferon-α in lupus nephritis
Authors: Yuan-yuan Qi, Xu-jie Zhou, Fa-juan Cheng, Ping Hou, Ya-li Ren, Su-xia Wang, Ming-hui Zhao, Li Yang, Jennifer Martinez, Hong Zhang
Journal: Annals of the Rheumatic Diseases (2018)

Objective More recent studies suggested that defects in autophagy contribute to the pathogenesis of SLE, especially in adaptive immunity. Occurrence and progression of lupus nephritis (LN) is the end result of complex interactions between regulation of immune responses and pathological process by renal resident cells, but there is still a lot of missing information for an establishment on the role of autophagy in pathogenesis of LN and as a therapy target. Methods Systemic and organ-specific aetiologies of autophagy were first evaluated by autophagy protein quantification in tissue homogenates in MRL lpr/lpr lupus prone and female C57BL mice. Analysis of gene expression was also adopted in human blood and urine sediments. Then, some key mediators of the disease, including complement inactivated serum, IgG from patients with LN (IgG-LN) and interferon (IFN)-α were chosen to induce podocyte autophagy. Podocyte injuries including apoptosis, podocin derangement, albumin filtration and wound healing were monitored simultaneously with autophagy steady-state and flux. Results Elevated LC3B in kidney homogenates and increased autophagosomes in podocyte from MRL lpr/lpr were observed. In humans, mRNA levels of some key autophagy genes were increased in blood and urinary sediments, and podocyte autophagosomes were observed in renal biopsies from patients with LN. Complement inactivated serum, IgG-LN and IFN-α could induce podocyte autophagy in a time-dependent and dosage-dependent manner, and by reactive oxygen species production and mTORC1 inhibition, respectively. Autophagy inhibition aggravated podocyte damage whereas its inducer relieved the injury. Conclusion Podocyte autophagy is activated in lupus-prone mice and patients with lupus nephritis. Increased autophagy is cytoprotective against antibody and interferon-α induced podocyte injury.
Multimodality risk adapted therapy with induction carboplatin/paclitaxel/lapatinib for SCCHN amenable to transoral surgery.
Authors: Jared Weiss, David N. Hayes, Allison Mary Deal, Jose Zevallos, Bhishamjit S. Chera, Jennifer Paul, Mary Knowles, Dmitriy Usenko, Mark Christian Weissler, Samip Patel, Juneko E. Grilley-Olson, Trevor Hackman
Journal: Journal of Clinical Oncology (2017)

6064 Background: Induction chemotherapy in SCCHN has mostly been studied prior to XRT where proof of improved survival is lacking. Regimens using weekly platinum, taxane and targeted therapy have resulted in high RR. Attempts are frequently made to intensify or de-intensify, but few have adapted therapy by response. Methods: Patients with transorally resectable, treatment naïve SCCHN and node positivity or T &gt; 3 were treated weekly 6 times with Carboplatin AUC 2, paclitaxel 135mg/m2 and daily lapatinib 1000mg followed by transoral resection. Subjects with pN0/1 received no radiation; those with close margins, ECE, pN2a-b, PNI/LVSI were treated with weekly cisplatin 30mg/m2 and XRT with involved-field XRT allowed while those with pN2c/3 were treated with cisplatin 100mg/m2 Q3W and standard XRT. Primary endpoint was clinical RR (cRR) following induction chemotherapy. Results: Primary sites: oropharynx (OP) (30), supraglottic larynx (5), oral cavity (4) and hypophyarnx (1). Of OP patients, 17 were HPV low risk. Grade 3/4 toxicity during induction: decreased WBC (7), fatigue (3), diarrhea (2), febrile neutropenia (2), neuropathy (2), rash (2) and 1 each of ALT and AST increased, hyperglycemia, hypotension, nausea, PPDE. 39/40 proceeded to surgical resection (1 patient refused for non-study reasons). 29/39 subjects who were projected to require XRT were able to avoid it. 8/10 subjects with study-defined indication for adjuvant XRT received it. cRR 37/40, pRR 14/40. Clinical and pathologic responses correlated poorly (see table). With median FU of 1.7 years, there has been no recurrence or death. Mean VRQOL was 91.7 before induction, 92.3 before surgery and 92.3 1 year post surgery. Mean MDADI was 82.8 before induction, 85.9 before surgery and 84.5 1 year post surgery. Conclusions: The regimen led to excellent feasibility of surgical resection, high cRR and a real pCR. cR predicted poorly for pR. Most patients were able to avoid XRT. Speech and swallowing function were preserved. NCT01612351. Clinical trial information: NCT01612351. [Table: see text]
SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade
Authors: Mingxia Zhao, Wenjie Guo, Yuanyuan Wu, Chenxi Yang, Liang Zhong, Guoliang Deng, Yuyu Zhu, Wen Liu, Yanhong Gu, Yin Lu, Lingdong Kong, Xiangbao Meng, Qiang Xu, Yang Sun
Journal: Acta Pharmaceutica Sinica B (2018)

Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8+IFN-γ+ T cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.
The demand for psycho-oncological support in 820 melanoma patients: What are the determinants for the development of distress?
Authors: Andrea Forschner, Petra Riedel, Maximilian Gassenmaier, Alexander Scheu, Lukas Kofler, Claus Garbe, Norbert Schäffeler, Simone Mayer, Thomas K. Eigentler
Journal: Journal of Clinical Oncology (2017)

9514 Background: There is limited data about the impact of melanoma on the psychological burden of patients. Despite some known predictors for distress like female gender or younger age, melanoma stages have not been found being related to distress in melanoma patients and there is no data concerning distress in melanoma patients under systemic treatment for metastases. Methods: Between July and September 2016, 820 melanoma patients at the outpatient clinic at the Department of Dermatology at the University of Tuebingen underwent psycho-oncological screening. The patients routinely completed the distress thermometer (DT), supplemented by a problem list, before consulting the physician. DT scores ≥ 5 are above-threshold, indicating the need for psycho-oncological support. We matched psycho-oncological data with tumor and patient specific data to examine tumor or patient specific influence on distress using logistic regression. Results: 406 (49.5%) men and 414 (50.5%) women were included, mean age was 62.35 years (IQR 52-75), mean time since primary diagnosis of melanoma was 54.84 months (IQR 15-76). 359 (44%) of the patients suffered from advanced melanoma (stage III n = 182, stage IV n = 177). 120 patients (14.6%) received systemic treatment for metastases: 90/120 (75%) checkpoint inhibitors, 27/120 (22.5%) targeted therapy and 3/120 (2.5%) chemotherapy. 338/820 (41.2%) of the patients met the cut-off score for distress. Significant influencing factors (p &lt; 0.05) for DT values of ≥ 5 were: female gender, younger age, melanoma stage III and IV. Interestingly we found a lower risk for values above-threshold for patients under systemic treatment, although this was not significant (p = 0.252). Conclusions: This is the first analysis to demonstrate the impact of advanced melanoma stages on DT scores above-threshold. Our study is also the first to indicate a lower risk for distress in patients under systemic treatment. This might be due to the closer contact between these patients and their physicians. Nevertheless, more than 40% of our patients needed psycho-oncological support. Departments that care for melanoma patients should therefore be fitted by a sufficient number of psycho-oncologists.
Detection of ctDNA biomarkers post resection and relationship to recurrent disease in colorectal cancer patients.
Authors: David Murray, Erin L. Symonds, Susanne Kartin Pedersen, Graeme P. Young
Journal: Journal of Clinical Oncology (2018)

e15616 Background: BCAT1 and IKZF1 are aberrantly methylated in almost all neoplastic colorectal tissue specimens. These biomarkers are detected in blood as circulating tumor DNA (ctDNA) in most patients with recurrent colorectal cancer (CRC) [1]. This study investigated the relationship between post-surgery levels of methylated ctDNA and risk of recurrence. Methods: ctDNA levels were determined within 12 months (mo) of initial CRC surgery. Blood samples (4.5mL) with no signal were deemed negative. Samples with 45pg ctDNA (BCAT1+IKZF1, equivalent to 13 DNA copies), or more, were reliably quantifiable. Cox proportional hazard analysis was performed to determine the association between ctDNA and recurrence-free survival during follow-up. The multivariate model was adjusted for treatment status at time of venesection. Results: 138 CRC patients were followed for a median of 23mo (IQR, 12-34). Twenty-three were diagnosed with recurrence (median 23mo, IQR 14-30) and 9 had CRC related death (median 16mo, IQR 9-27). Twenty-three (17%) cases were ctDNA positive post resection: 7 had recurrence (median 17mo, 9-27) and 16 had no indication of disease recurrence at study completion(median 12mo, 7-31). There was an increased risk of recurrence (HR 3.8, 1.5-9.5, univariate analysis, p = 0.004) regardless of the actual level of biomarker(s). Eight cases had ctDNA levels above 13 DNA copies (median 207 DNA copies per sample, IQR 69-2177) and estimated to have 19.3 times the risk of recurrence (6.4-58.4) compared to those who were ctDNA negative (multivariate modeling, p < 0.001). Conclusions: Detection of methylated BCAT1/IKZF1 post primary surgery is a strong and significant risk factor for recurrence. Further studies are justified to evaluate whether these ctDNA markers inform further medical treatment decisions to improve patient survival rates. [1] Young et al. Cancer Medicine 2016. Clinical trial information: 12611000318987.
Prospective validation of gene expression profiling in primary cutaneous melanoma.
Authors: Eddy C. Hsueh, Theresa Lynn Schwartz, Jason Michael Lizalek, Pamela Sue Hunborg, M Yadira Hurley, Leslie J. Hinyard
Journal: Journal of Clinical Oncology (2016)

9565 Background: Gene expression profiling (GEP) is becoming an integral part of treatment decision making in cancer. A GEP test (DecisionDx-Melanoma) has been in commercial use based on data from multicenter archival tumor samples and patient outcome databases. We prospectively evaluated its prognostic utility in primary melanoma patients undergoing sentinel node biopsy (SNB). Methods: From 11/2013 to 9/2015, 174 melanoma patients (age 22–88) undergoing SNB also underwent GEP test of primary tumor at time of initial evaluation. GEP test was reported as Class 1 (low risk), Class 2 (high risk), or insufficient sample (INS). AJCC stage I / II patients after SNB were followed Q 6 months with complete physical exam (PE) and chest X-ray. Stage III patient after SNB underwent baseline brain MRI and PET/CT or CT of chest/abdomen/pelvis (CT/CAP) followed by completion node dissection for SNB(+) patients and subsequently followed with PE, brain MRI, and CT/CAP Q3 months x 1 year then Q4 months x 1 year. Statistical analysis was performed with chi-square analysis, t-test, and log rank test. Disease-free survival (DFS) was estimated using Kaplan-Meier method. Results: Fifteen patients had INS for GEP classification. Final analytic cohort was 159 (62% male). Median Breslow thickness was 1.325 mm (0.17–15 mm). Distribution of primary site was 25 (16%) head/neck, 68 (43%) trunk, and 66 (41%) extremity. Ulceration of primary was noted in 38 patients (24%). SNB was positive for metastases in 20 patients (13%). There were 116 Class 1 and 42 Class 2 patients. Gender, Breslow thickness, ulceration, SNB positivity and DFS were significantly associated with GEP classification (P = 0.008, < 0.0001, < 0.0001, 0.01, < 0.0001 respectively). There was no association between GEP class and age or site of tumor. Median follow-up was 12 months. One of 117 Class 1 ( < 1%) and 13 of 42 Class 2 (31%) patients recurred within 2 years. Seven of 139 (5%) SNB negative and 7 of 20 (35%) SNB positive patients recurred. Of the 10 patients with Class 2 and SNB positivity, 7 recurred. Conclusions: GEP classification significantly associated with early recurrence in patients with primary melanoma. Results of GEP test should be considered in adjuvant treatment trial for primary melanoma patients.
P04.71 LRIG2 promotes the proliferation of glioblastoma cells in vitro and in vivo through enhancing the PDGFRβ signaling pathways
Authors: Q Xiao, M Dong, F Cheng, F Mao, W Zong, K Wu, R Xie, B Wang, T Lei, D Guo
Journal: Neuro-Oncology (2018)

The leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family, comprising of LRIG1, 2 and 3, encodes integral membrane proteins. It is now well established that LRIG1 negatively regulates multiple growth factor signaling and is a proposed tumor suppressor, however the biological functions of LRIG2 remain largely unexplored. Previously, we demonstrated that LRIG2 promoted the growth of glioblastoma by positively regulating the EGFR signaling, the most common aberrant receptor tyrosine kinase (RTK) signaling in glioblastoma. Here, we further addressed the effects of LRIG2 on the proliferation of glioblastoma and the possible mechanisms underlying the regulation of LRIG2 on PDGFRβ signaling, another common oncogenic RTK signal in glioblastoma. A total of 40 glioblastoma samples were surgically obtained and subjected to immunohistochemical staining for LRIG2 and PDGFRβ. U87 glioblastoma cells were stably transduced with retroviral vectors to upregulate or downregulate the expression of LRIG2. CCK-8 assay and soft agar colony formation assay were used to detect the PDGF-BB-induced proliferation of glioblastoma cells, respectively. Flow cytometric analysis was used to investigate the cell cycle progression. Subcutaneous tumor formation in nude mice was performed to investigate the tumor growth in vivo. Immunofluorescence and Co-IP were used to detect the protein interaction, and western blot was used to examine the signaling pathway proteins. First, we found that the expression levels of endogenous LRIG2 and PDGFRβ varied notably in human glioblastoma and the LRIG2 expression level was positively correlated with the expression level of PDGFRβ. Further, to the best of our knowledge, we demonstrated for the first time that LRIG2 promoted the PDGF-BB-induced proliferation of glioblastoma cells in vitro and in vivo through regulating the PDGFRβ signaling mediated cell cycle progression. Mechanistically, LRIG2 has the ability to physically interact with PDGFRβ, promoting the total expression level and the activation of PDGFRβ, and enhancing its downstream pathways of Akt and signal transducer and activator of transcription 3 (stat3) and the effectors of key regulators of cell cycle progression, resulting in the promotion of glioblastoma proliferation. These data indicated that LRIG2 may serve as a tumor promoter gene in gliomagenesis by positively regulating PDGFRβ signaling, another important oncogenic RTK signal besides our previously reported EGFR signaling in glioblastoma modulated by LRIG2, and validated LRIG2 as a promising potential therapeutic target for the treatment of glioblastoma characterized by multiple aberrant RTK signaling. Supported by grants from the National Natural Science Foundation of China (grant nos. 81702480 and 81472364).
Immunologically relevant gene expression as prognostic biomarker in squamous cell carcinoma of the head and neck.
Authors: Andrew Pierce, Maria Secrier, Emma V Jones, Michael Stokes, Norah Shire, Craig Barker, Elizabeth A. Harrington, J Carl Barrett, Helen Angell
Journal: Journal of Clinical Oncology (2017)

e17542 Background: Expression of genes known to be integral to anti-tumour activity may be prognostic for patient outcomes in SCCHN. We hypothesized that broad categories of immune function would be responsible for anti-tumor activity. Methods: A study was conducted using data from patient medical records and analysis of archival tumour samples. Patients were ≥18 years old, diagnosed with SCCHN between 1989 and 2015 (n = 119). We quantified the expression of an annotated list of 71 aggregated genes selected to represent a variety of immunological activities: chemokines and receptors, interferon gamma stimulated genes, immunological checkpoints, HLA class I and II molecules, T cell activation, T cell surface markers, adhesion molecules, cytotoxic granules, immune suppression, inflammation, NK cell associated genes and ‘other functionality’. Results: Using a Cox proportional hazards model starting from consideration of the initial 71 genes and performing 10-fold cross-validation with 100 repetitions, several prognostic gene signatures were derived with overall survival hazard ratios &gt; 2.8 and concordance indexes &gt; 0.7, 95% confidence intervals ranging between [0.709, 0.805]. The signatures remained significantly predictive of outcome when accounting for tumour stage, sex and age of patients, HPV status and smoking habits. A cumulative score per sample taking into account the directionality of association of each gene with outcome and its corresponding expression was derived and this score outperformed tumour staging in distinguishing survival outcomes. The genes CD274 (PD-L1; checkpoints), CD8A (T cell surface markers), CCL11 (chemokines and receptors), GNLY (cytotoxic granules), TNFRSF10A (immune suppression), and EDN1 (other) appeared in all signatures, validating our approach of considering broad categories of functionality to represent the anti-tumor immune system response as an integrated whole. Conclusions: Identification of a prognostic gene signature may have additional utility for evaluating early response to therapy by assessing whether therapy has converted a patient tumour from a prognostically unfavourable to prognostically favourable gene signature status.