tbuckley/cabot-search huggingface dataset:
Germline and somatic SNVS calling in NGS panel tumor samples: Approaches to optimize tumor only genomic analysis for cancer precision medicine.
Authors: Ruobai Sun, Pablo Cingolani, Angeliki Pantazi, Cheryl Eifert, Xiu Huang, Andrew Bjonnes, Stephen Lyle, Alexei Protopopov, Dana Vuzman
Journal: Journal of Clinical Oncology (2017)

e13011 Background: Clinical NGS is often limited by tumor only profiling. Discrimination between somatic and likely germline mutations when calling from tumor patient samples is a critical step for clinical genotyping. Many algorithms have been developed for somatic single nucleotide variant (SNV) detection in matched tumor-normal whole genome and whole exome sequencing. Here, we demonstrate approaches of how a cost-effective large gene panel sequencing can be used to call somatic and germline SNVs for tumor only samples. Methods: Tumor, adjacent normal, and matched normal samples are collected from five patients. The somatic mutations were called with GATK Mutect2 in tumor only and adjacent normal. The germline mutations were called individually for all 15 samples with GATK Haplotype caller. To remove germline mutations from tumor only somatic calls, the filters ExAc pop freq, 1000G pop freq, COSMIC were applied on the tumor only somatic calls. PPV (Positive predictive value) for each filter was calculated by dividing the number of somatic mutations in the post-filtering mutation data by the total number of unfiltered mutations. TPR (True Positive Rate, representing sensitivity) was calculated by dividing the number of true somatic mutations in the tumor-only post-filter. Results: Compared with germline mutations called from matched normal, 70% germline mutations were called in RAWE somatic calls. A PPV of 0.71 and a TPR of 0.95 were optimally provided when the filter ExAc pop freq &gt; 0.01 and COSMIC ( &gt; 5 occurrence) applied. For germline mutations called in tumor samples, when compared with those in blood samples and in adjacent normal samples, PPV is 0.99 and TPR is 0.97. For somatic mutations called with tumor-adjacent normal pair mode in Mutect2, PPV is 0.5 and TPR is 0.99. Conclusions: Optimization of tools and parameters in NGS large panels could detect somatic and germline variants with high specificity, sensitivity and accuracy, without matched or adjacent normal. For the germline variants, when adjacent normal is available, it could replace matched normal with high accuracy.
In vivo hematopoietic effects of recombinant interleukin-1 alpha in mice: stimulation of granulocytic, monocytic, megakaryocytic, and early erythroid progenitors, suppression of late-stage erythropoiesis, and reversal of erythroid suppression with erythropoietin
Authors: CS Johnson, DJ Keckler, MI Topper, PG Braunschweiger, P Furmanski
Journal: Blood (1989)
Predictive value of intratumoral signaling and immune infiltrate for response to preoperative (PO) trastuzumab (T) vs trastuzumab + everolimus (T+E) in patients (pts) with primary breast cancer (PBC): UNICANCER RADHER trial results.
Authors: Mario Campone, Isabelle Treilleux, Julia Salleron, Monica Arnedos, Qing Wang, Suzette Delaloge, Delphine Loussouarn, Jacques Bonneterre, Maeva Lion, Celine Mahier - Ait Oukhatar, Xavier Paoletti, Maria Rios, Veronique Dieras, Marta Jimenez, Jean-Louis Merlin, Thomas Denis Bachelot
Journal: Journal of Clinical Oncology (2016)

606 Background: Blockade of PI3K/AKT/mTOR pathway by E combined with T in HER2+ BC pts shows promising results. It has also been reported that T acted differently when used in PO setting with a lower implication of signaling blockade and a higher induction of ADCC when used alone in chemotherapy naive pts. Additionally, mTOR blockade has been experimentally reported to activate MAPK pathway through a feed-back loop effect. We present the results of a biological integrated approach including markers of PI3K/AKT/mTOR and MAPK pathways, proliferation and immune environment in HER-2 + PBC treated with T +/- E in PO setting. Methods: Eligible pts with HER2+ PBC (IHC 3+ or FISH/SISH+) amenable to surgery were randomized to receive T (loading dose 4 mg/kg, then 2 mg/kg/W), or T+E (10 mg/d) for a 6W PO treatment. All pts had baseline core needle biopsies, tissue collected at surgery and blood samples for biomarkers and pharmacokinetic analyses. FFPE samples were used for PIK3CA mutation status and IHC (pAKT, pS6K, eIF4E, LKB1, p4EBP1, Ki67, caspase 3, PTEN, CD8, CD68). Frozen samples were used for multiplex immunoanalyses of phosphorylated PI3K/AKT/mTOR and MAPKinase signaling proteins (p-AKT, p-GSK3, p-P70S6K, p-MEK1, p-ERK1/2, p-P90RSK). Results: FFPE and frozen tumor samples (n = 80), were obtained from 82 pts randomized from July 2008 to April 2012 (41 per arm). At baseline, only PIK3CA mutation status was predictive of clinical response, whatever the arm. No difference in the expression of phosphorylated signaling kinases was induced by exposure to T while T+E induced a significant activation of MAPKinase pathway. Between baseline and surgery we observed a down regulation of pAKT pS6K, LKB1, Ki67, a lower expression of PTEN and an increase in lymphocytes (CD8+) and macrophages (CD68+) infiltrates in both arms. Conclusions: These results confirm that in PO setting, T +/- E should mostly act via the activation immune response through tumor-associated lymphocytes and macrophages infiltrates. Rapid decrease in PTEN and LKB1 may be related to early cellular mechanism of resistance to HER2 inhibition. Clinical trial information: NCT00674414.
Neutrophilia and lymphopenia as prognostic factors in non-small cell lung cancer.
Authors: Jaeheon Jeong, Sun Kyung Baek, Chi Hoon Maeng, Jaejoon Han, Hwi Joong Yoon, Si-Young Kim, Ji-Hoon Lee
Journal: Journal of Clinical Oncology (2016)

e20587 Abstract Background: Neutrophil count is associated with prognosis in some cancers. Direct cell-cell interactions between neutrophils and tumor cells enhance tumor growth in Non-small cell lung cancer (NSCLC). Methods: We retrospectively reviewed 205 patients with advanced or recurrent NSCLC from 2006 to 2013. We performed univariate and multivariate stepwise Cox regression analyses to identify prognostic factors. Results: Median age was 64 years old. Sixty six patients (32.2%) were current smokers, fifty seven patients (27.8%) were ex-smokers and eighty two patients (40%) were non-smokers. One hundred seventy six patients' ECOG PS was 0 or 1, twenty six patients' ECOG PS was 2 and three patients' ECOG PS was 3. Number of metastatic sites was less than three in the ninety seven patients and remaining one hundred eight patients have more than three metastatic sites. In univariate analysis, twelve factors were identified: Age (HR = 0.754, 95% CI: 0.555-1.024; p= 0.070), number of metastasis (HR = 0.712, 95% CI: 0.506–1.002, p= 0.051), neutrophil count (HR = 0.523, 95% CI: 0.384–0.712, p= 0.000), lymphocyte count (HR = 1.628, 95% CI: 1.196–2.214, p= 0.002), Ca level (HR = 0.667, 95% CI: 0.481–0.926, p= 0.016), CEA level (HR = 0.645, 95% CI: 0.452–0.920; p= 0.016), number of chemotherapy (HR = 0.547, 95% CI: 0.393–0.761; p= 0.000), ECOG PS (HR = 6.879, 95% CI: 1.119–42.269, p= 0.037), loss of appetite (HR = 0.692, 95% CI: 0.461–1.041; p= 0.077), measurable lesion (HR = 0.445, 95% CI: 0.209–0.949, p= 0.036), liver metastasis (HR = 1.642, 95% CI: 1.003–2.687, p= 0.049) and bone metastasis (HR = 1.512, 95% CI: 1.100–2.078; p= 0.011). In multivariate analysis, three independent prognostic factors were identified: neutrophil count (HR = 0.556, 95% CI: 0.324–0.954; p= 0.033), number of chemotherapy (HR = 0.614, 95% CI: 0.383–0.984, p= 0.043) and ECOG PS (HR = 7.478, 95% CI: 1.555–35.965; p= 0.012). Another two factor (lymphocyte count, CEA level) showed trend as prognostic factor (p= 0.085 and 0.076) respectively. Conclusions: Neutrophil count, lymphocyte count, CEA level, number of chemotherapy and ECOG PS can be used to predict survival in advanced or recurrent non-small cell lung cancer patients.
The Salicylamide Derivative, Niclosamide, Inhibits CREB Function in Acute Myeloid Leukemia Cells In Vitro and In Vivo
Authors: Hee-Don Chae, Nick Cox, Xiaohua Zhang, Jae Wook Lee, David Morgens, Michael C Bassik, Mark Smith, Kathleen M. Sakamoto
Journal: Blood (2016)
Randomized, double-blind, phase III trial of a personalized peptide vaccination for human leukocyte antigen-A24-positive glioblastoma multiforme patients refractory to temozolomide-based therapy.
Authors: Mizuhiko Terasaki, Yoshitaka Narita, Yoshiki Arakawa, Kazuhiko Sugiyama, Tomokazu Aoki, Masayuki Kanamori, Motoo Nagane, Toshihiro Kumabe, Yuichi Hirose, Tomotsugu Ichikawa, Takamitsu Fujimaki, Hiroyuki Kobayashi, Hisaharu Goto, Hideo Takeshima, Tetsuya Ueba, Hiroshi Abe, Takashi Tamiya, Yukihiko Sonoda, Tatsuyuki Kakuma, Ryo Nishikawa
Journal: Journal of Clinical Oncology (2017)

2000 Background: To establish whether personalized peptide vaccination (PPV) is clinically beneficial for human leukocyte antigen (HLA)-A24-positive glioblastoma multiforme (GBM) patients refractory to temozolomide (TMZ)-based therapy. Methods: From January 2012 to March 2016, 88 HLA-A24-positive GBM patients refractory to TMZ-based therapy from 20 Japanese hospitals were randomly assigned to receive PPV treatment (n = 58) or best supportive care (BSC) (n= 30) at a 2 to 1 ratio. Four peptides chosen from 12 peptide candidates based on pre-vaccination IgG levels specific to each peptide or 4 corresponding placebos were injected subcutaneously once weekly for 12 times at the first course followed by biweekly vaccinations until disease progression. The primary endpoint was overall survival (OS). Results: The primary endpoint was not met in this clinical trial. Unfavorable prognostic factors were performance status (PS) 3, higher plasma levels of pre-vaccination granulocyte macrophage-colony stimulating factor (GM-CFS), and PPV containing SART2-derived peptides. Therefore, 78 patients with PS of 0 to 2 (50 with PPV and 28 with BSC) were provided for the subgroup analysis. Among them, the median OS of 39 PPV patients (10.4 months, 95% CI, 7.8-12.0 months) who had either lower levels of GM-CSF ( &lt; 0.9 pg/mL) or 4 peptide vaccinations that did not include SART2-derived peptides was significantly (p = 0.03) longer than that of the corresponding 19 BSC patients (6.8, 4.6-12.7). In contrast, the median OS of 10 PPV patients (4.1, 1.1-8.3) who had both higher levels of GM-CSF ( &gt; 0.9 pg/mL) and 4 peptide vaccinations containing SART2-derived peptides was significantly (p = 0.01) shorter than that of the corresponding 9 BSC patients (not reached, 1.6-not reached). A single grade 3 adverse event was the only PPV-related adverse event of grade &gt; 3 in this study. Conclusions: PPV monotherapy could be a new treatment modality for HLA-A24-positive GBM patients refractory to TMZ-based therapy, since this approach showed clinical benefit and safety under precision medicine-based pre-vaccination selection of appropriate patients. Clinical trial information: UMIN000006970.
The islet-resident macrophage is in an inflammatory state and senses microbial products in blood
Authors: Stephen T. Ferris, Pavel N. Zakharov, Xiaoxiao Wan, Boris Calderon, Maxim N. Artyomov, Emil R. Unanue, Javier A. Carrero
Journal: The Journal of Experimental Medicine (2017)

We examined the transcriptional profiles of macrophages that reside in the islets of Langerhans of 3-wk-old non-obese diabetic (NOD), NOD.Rag1-/-, and B6.g7 mice. Islet macrophages expressed an activation signature with high expression of Tnf, Il1b, and MHC-II at both the transcript and protein levels. These features are common with barrier macrophages of the lung and gastrointestinal tract. Moreover, injection of lipopolysaccharide induced rapid inflammatory gene expression, indicating that blood stimulants are accessible to the macrophages and that these macrophages can sense them. In NOD mice, the autoimmune process imparted an increased inflammatory signature, including elevated expression of chemokines and chemokine receptors and an oxidative response. The elevated inflammatory signature indicates that the autoimmune program was active at the time of weaning. Thus, the macrophages of the islets of Langerhans are poised to mount an immune response even at steady state, while the presence of the adaptive immune system elevates their activation state.
Abstract 030: Aspirin Use and Myocardial Infarction in HIV versus Non-HIV Patients
Authors: Sujit Suchindran, Susan Regan, James B Meigs, Steven K Grinspoon, Virginia A Triant
Journal: Circulation (2013)

Introduction: Myocardial infarction (MI) risk is increased among HIV populations, but the use of aspirin (ASA) for primary prevention of MI has not been investigated in this group. Hypothesis: We hypothesized that ASA use would be associated with a decreased risk of incident MI in both HIV and matched control patients. Methods: Patients who received care from the Partners HealthCare System in Boston between 2000 and 2009 without baseline coronary heart disease (CHD) were included. Non-HIV patients were matched to HIV patients by demographic factors, with 33,348 control and 3,698 HIV patients. To ascertain non-episodic ASA use, we developed an algorithm combining medication data and electronic health record free text search and validated it using medical record review. We used a definition of at least two ASA prescriptions, two text strings, or one of each, all occurring more than 30 days prior to MI (sensitivity 73%, specificity 83%, AUC 78%). We used Cox proportional hazard modeling to assess the association between ASA use and first MI within the HIV and control groups. We further assessed the effect of ASA in models stratified by cardiovascular risk (low CHD risk = 0-1 traditional risk factors, high CHD risk = 2 or more risk factors), to minimize potential confounding by indication. Results: ASA use was significantly lower in HIV compared to non-HIV patients in the overall groups (12.4% vs. 15.3%, p&lt;0.001) and among men (13.1% vs. 17.3%, p&lt;0.001) but not among women. The relative difference in the rates of ASA use between HIV and non-HIV was greater among patients at high CHD risk (22.1% vs. 42.4%, p&lt;0.001) compared to patients at low CHD risk (5.5% vs. 6.7%, p=.037). Similar patterns were seen within each gender. In multivariate models adjusting for CHD and HIV-related factors, ASA use was not associated with decreased MI risk among HIV patients overall (HR 0.97, 95% confidence interval [CI] 0.64-1.49, p=0.90), by CHD risk category or by gender. In contrast, ASA use was associated with significantly decreased MI risk in the non-HIV group in models adjusted for traditional CHD risk factors, with a reduced hazard of 71% (95% CI: 66%-76%). Relative risk reduction for MI in the non-HIV group was more pronounced among patients with high underlying CHD risk (71% vs. 57% in low CHD risk) and among males (76% vs. 50% in females). Conclusions: ASA use was relatively lower in HIV compared to matched control patients, particularly among those with high underlying CHD risk. In contrast to non-HIV patients for whom ASA was significantly associated with decreased MI risk, ASA did not show this effect among HIV patients. Further studies will help to establish whether patients with HIV disease may represent a subgroup in which ASA is less effective for primary prevention of MI.
Implications of attention deficit and hyperactivity disorders on neurocognitive performance and recovery in collegiate student–athletes
Authors: Caroline Ketcham, Kirtida Patel, Eric Hall
Journal: British Journal of Sports Medicine (2017)

Background Approximately 3–13% of college-aged students have a diagnosis of Attention Deficit/Hyperactivity Disorder (ADD/ADHD) which is characterised by impulsivity, inattention, and cognitive speed deficits which affects academic, athletic, and occupational performance even when treated. Objective The purpose of this study was to examine baseline neurocognitive differences in collegiate student-athletes with diagnosis of ADD/ADHD as well as recovery time from concussion. Design Cross-sectional. Setting Collegiate campus in North Carolina Participants Participants of this study included 1161 student-athletes (varsity, n=272 and club, n=889). 89 participants were followed post-concussion with 8 having diagnosis of ADD/ADHD. Assessment of risk factors Diagnosis of ADD/ADHD and days of recovery following concussion. Outcome measures Participants completed the Immediate Post-Concussion Assessment and Cognitive Testing which generated composite scores on Verbal Memory, Visual Memory, Visuomotor Speed, and Reaction Time as well as Total Symptom Scores. Main results There were no significant differences between groups for Visual Memory, Reaction Time and Total Symptom Scores (p&gt;0.05). Those with diagnosis of ADD/ADHD (n=146) had lower verbal memory(m no =85.3, %95 CI: [84.6, 86] vs. m add =82.5, %95 CI:[80.7, 84.3], F(1, 1145)=8.6, p=0.003) and slower visuomotor speed (mno=41.7, %95 CI: [41.3, 42.7] vs. madd=40.5, %95: CI:[39.5,41.5],F (1,1145) =8.6,p=0.027) compared to those without a diagnosis. Those with ADD/ADHD took almost two times longer to recover than those without (m no =7.3 days, %95 CI: [6.2, 8.4] vs. m add =13.3 days, %95 CI:[9.4, 17.2], F (1, 89) =9.8, p=0.002). Conclusions Student-athletes with diagnosis of ADD/ADHD may benefit from targeted interventions as part of return to play/learn protocols. Previous research has shown that practice may help rehabilitate those with cognitive and visuomotor processing speed deficits following a concussion. Competing interests None.
Breast cancer risk assessment and chemoprevention use among VA primary care.
Authors: Joseph Merriman, Balmatee Bidassie, Amanda Kovach, Marissa Vallette, Yeun-Hee Anna Park, Anita Aggarwal, Sarah Violet Colonna
Journal: Journal of Clinical Oncology (2017)

1543 Background: Despite recommended guidelines and available medicationsto reduce breast cancer risk by up to 50-65%, &lt;5% of the 10 million eligible women are offered chemoprevention in the U.S. The comfort level, practice patterns, and barriers to breast cancer risk assessment and chemoprevention use within the VA have not been reported. Methods: We assessed VA primary care providers using a REDcap survey. We obtained provider demographics, use and comfort level with breast cancer risk models and chemoprevention and knowledge about chemoprevention. Data was analyzed with Fishers exact or chi-square tests. Results: Of the 200 survey respondents, 167 were included for analysis. Overall, 30% used the Gail model monthly or more often, and 1.5 % prescribed chemoprevention in the last 2 years. Fewer than 30% correctly answered chemoprevention knowledge questions. Designated women's health providers were more comfortable with risk assessment and chemoprevention (p&lt;.046, p&lt;.004) and used risk models more often (p&lt;.045). 63% expressed interest in education about breast cancer prevention. Conclusions: Breast cancer risk assessment and chemoprevention use by VA primary care is limited by lack of comfort and familiarity. Women's health providers are more comfortable and knowledgeable about breast cancer risk models and chemoprevention, offering an opportunity for partnership with high-risk oncologists to improve breast cancer risk assessment and chemoprevention use among female Veterans.[Table: see text]
The upregulation of FOXA2 transcription factor in RET rearranged lung adenocarcinoma.
Authors: Jeong-Oh Kim, Jung-Young Shin, Min Young Kim, Kyoung Hwa Son, Chan-Kwon Jung, Sang-Ju Bae, Hyun-Jung Min, Jin-Hyoung Kang
Journal: Journal of Clinical Oncology (2016)

e20014 Background: KIF5B-RET gene rearrangement occurs in about 1% of lung adenocarcinomas. In recent, the targeted agents to inhibit RET phosphorylation have been examined in several clinical studies. However, little was known about how this fusion gene drive lung cancer. Methods: We established transformed HEK293T cells with KIF5B-RET fusion gene using Lenti virus system. In transformed HEK293T cells, we identified transcription factors which are activated using qRT-PCR array and then, checked mRNA, protein, expressions of FOXA2. We performed immunohistochemistry to evaluate the expressions of FOXA2 protein in tumor tissues obtained from 38 lung adenocarcinoma patients who were screened by FISH, RT-PCR, and Nanostring analysis. Results: In the qRT-PCR array, the transcription factors of which the relative expression increased more than 1.5 in KIF5B-RET transformed HEK293T cells were MYF5, STAT5A, ESR1 and FOXA2. We confirmed the increased expressions of FOXA2 mRNA and protein in transformed HEK293T cells. Interestingly, we found that FOXA2 was strongly expressed in nucleus of transformed cells compared to cytoplasm. Of 38 adenocarcinoma pts, 18 cases had RET rearrangement, but 20 with no RET rearrangement. Immunohistochemical staining, FOXA2 was strongly expressed in most of all RET-positive cases (17/18). In contrast, the intensity of its expression was various in 20 RET-negative cases. Conclusions: Taken together, our data suggest that FOXA2 may have an important role in tumor progression in RET rearranged lung adenocarcinoma. Now, we are undergoing further investigations about biological function of FOXA2 as a transcription factor.
Effect of bariatric surgery on breast tissue and biomarkers in obese women at increased risk for breast cancer.
Authors: Tarah Jean Ballinger, Kathy Miller, Kandice Ludwig, Sunil S. Badve, Don Selzer, Ying Zhang, Anna Maria Storniolo, Lida A. Mina
Journal: Journal of Clinical Oncology (2017)

TPS1592 Background: Obesity represents a challenging epidemic associated with increased risk of several malignancies, including breast cancer in post-menopausal women. Proposed mechanisms for the association between obesity and breast cancer risk include increased insulin resistance, elevated levels of circulating estrogens, and chronic inflammation. Intentional weight loss from bariatric surgery has been associated with decreased risk of breast cancer. While rapid improvements in serologic markers of metabolism and inflammation are seen following bariatric surgery, short- and long- term changes in breast tissue remain less clear. This study investigates the effect of bariatric surgery on breast density and biomarkers of increased risk in breast tissue. Methods: This pilot, single institution, observational study (NCT02681120) is recruiting pre- and post-menopausal women with BMI ≥30 from a University bariatric surgery clinic using the Hughes risk application as a screening tool. Eligible patients must have a lifetime risk for breast cancer of ≥20%. Participants are evaluated by imaging, breast biopsy, and blood samples at baseline, 14 days post-operatively to determine the effects of rapid metabolic changes, and 1 year post-operatively to determine the effects of significant weight loss. The impact of bariatric surgery on known imaging parameters of breast cancer risk is assessed by background parenchymal enhancement on MRI and breast density on mammogram. Breast tissue is evaluated for changes in immune infiltrates, aromatase expression, and the presence of crown-like structures, a marker of inflammation seen in the breast tissue of obese women. Tissue samples at each time point are also compared to samples from lean women in the Susan G. Komen Tissue Bank at the IU Simon Cancer Center. Blood is collected for correlative studies evaluating markers of inflammation, insulin resistance, metabolism, and hormone synthesis. Enrollment is currently ongoing with a planned accrual of 40 patients, and data collection is estimated to complete by the end of 2018. Clinical trial information: NCT02681120.