tbuckley/cabot-search huggingface dataset:
Genomic feature differences in <i>APC</i>-mutant and wild-type colorectal cancer patients.
Authors: Jing Hu, Yun Guo, Jie Lin, Xiaojian Liu, Honglin Guo, Ruobing Ma, Yuan Zhang, Yu-An Dong, Weiwei Shi, Ming Yao
Journal: Journal of Clinical Oncology (2018)

e15609 Background: Adenomatous polyposis coli (APC) is a tumor suppressor gene whose inactivating mutation leads to inherited familial adenomatous polyposis and subsequently almost definitive early onset of colorectal cancer (CRC). Therefore, it is important to characterize the difference of genomic features in Chinese CRC patients (pts) with or without APC mutations. Methods: FFPE tumor tissues and matched blood samples of 127 Chinese CRC pts including 79 males and 48 females with a median age of 58 years were collected for NGS based 450-gene panel assay. Genomic alterations including single base substitutions, short and long insertions/deletions, copy number variations, gene rearrangements and fusions were assessed. Tumor mutational burden (TMB) was determined by an in-house developed algorithm and microsatellite instability (MSI) status were assessed either by NGS based algorithm or PCR. Results: APC mutations were detected in 68.5% (87/127) of the Chinese CRC pts including 1.6% (2/127) germline mutations. In the APC mutated (APCmt) cohort, the top mutated genes were TP53 (73.2%), KRAS (52.0%), PIK3CA (18.9%), and SMAD4 (16.5%). The rate of CTNNB1 mutation (2.3%) in the APCmt cohort is significantly lower than it (22.5%) in the APC wild type cohort (APCwt) (p < 0.001). Eight out of eleven patients with CTNNB1 mutations in the APCwt cohort were MSI-H. The other 3 patients were MSS with long deletions of 174bp, 0.6kb and whole exon 3 in CTNNB1. MSI were significantly more frequently found in pts with APCwt than APCmt (22.5% vs 8.0%, p = 0.046). No significant differences of TMB was found between APCmt and APCwt groups (p = 0.52). Conclusions: Our study revealed that Chinese CRC patients with APC mutation possessed distinct genomic features particularly in CTNNB1 from the APC wild type ones. MSI-H and CTNNB1 mutations were more common in APCwt pts, which indicated different mechanism in pathogenesis from wild type ones. Hence therapeutic strategy including CTNNB1 as potential targeted therapy options to mTOR or gamma-secretase inhibitors should be selectively applied.
Abstract 11375: Hyperventilation Induced Coronary Vasospasm in a Man With Left Main Atresia With a Single Coronary Artery
Authors: M Umer Tariq, Samad Zaheeruddin, Amy Celarier, Susan Odonoghue, Michael Gaglia, Michael Lipinski
Journal: Circulation (2016)

Introduction: Coronary anomaly accounts for about a 3rd of sudden deaths in young individuals and coronary vasospasm in an anomalous coronary artery is very rare. Case: A 66 year old male with history of hypertension, diabetes &amp; hyperlipidemia presented with syncope. He reported 2 months of episodic dyspnea, near-syncope, and epigastric pain. Stress cardiac magnetic resonance imaging demonstrated normal myocardial perfusion. While awaiting an electrophysiology study, he was observed to hyperventilate with associated epigastric pain, numbness and tingling followed by syncope with pulseless electrical activity arrest, receiving 2 minutes of cardiopulmonary resuscitation. Post-arrest electrocardiogram demonstrated posterior ST elevation MI so the patient was taken for coronary angiography which revealed congenital left main atresia with a single coronary artery taking the course of the right coronary artery giving rise to the left circumflex via the posterior lateral branch and then the left anterior descending artery (LAD) with mild to moderate disease (Fig 1). During the case, the patient had evidence of dynamic vasospasm in multiple segments that resolved with intracoronary nitroglycerin. All episodes of syncope/pre-syncope occurred after an episode of anxiety and hyperventilation, raising concern for hyperventilation-induced coronary vasospasm. Despite a trial with nifedipine, lorazepam and nitrates, he had another syncopal episode &amp; was referred for coronary artery bypass surgery with left internal mammary artery to the LAD and saphenous vein graft to the obtuse marginal artery. Discussion: In this rare case, cardiac arrest was a result of coronary vasospasm which would result in global ischemia as the patient only had a single coronary artery, resulting in cardiovascular collapse with drop in cardiac output and pulseless arrest. This is the first case of vasospasm in a single coronary artery.
Universal genetic screening for Chinese colorectal cancer patients with higher hereditary susceptibility.
Authors: Shiyong Li, Wu Jiang, Fengming Guo, Yun Xiong, Han Liu, Yihong Ling, Jun Luo, Yuhang Cai, Yuying Yuan, Dingxin Liu, Weirong Li, Jinghua Tang, Mao Mao, Pei-Rong Ding, Mingzhi Ye
Journal: Journal of Clinical Oncology (2018)

e13620 Background: The incidence and death rates of colorectal cancer (CRC) in China have increased dramatically in recent decades. It is estimated that there were almost 376,000 new diagnoses of CRC in 2015 in China. Family cancer history was the mainly high-risk for hereditary CRC. Genetic screening is critical for CRC effective prevention, early detection, and therapy. Methods: 162 patients with family CRC or gastric cancer history, which were newly diagnosed CRC (exclude familial adenomatous polyposis) at Sun Yat-sen University Cancer Center in China, enrolled in this study. DNA was extracted from patients' peripheral blood samples, then construct library and sequence by HiSeq platform. GATK was used for SNP/InDel detection. In-house developed software was used for exonic deletion/duplication detection. All the pathogenic SNP/InDel and CNV were confirmed by Sanger sequencing or qPCR. Results: Among 162 CRC patients with family history, 38(23.4%) patients have detected one or two pathogenic/likely pathogenic mutations. However, only 18.5% Lynch syndrome (LS) patients could be screened according to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment (Colorectal, 2015). After Comprehensive hereditary gene screening, 4 patients with proficient MMR status by IHC test, also identified mutations in mismatch repair (MMR) genes. 3.7% patients carried non-LS genetic pathogenic mutations, which included 2 high-penetrance genes: 1 in APC from FAP syndrome, and 1 for PALB2 from hereditary breast/ovarian cancer syndrome, and 4 patients found moderate-penetrance CRC risk gene mutations (two BLM, one ATM, one BRIP1). Conclusions: This is the first comprehensive genetic screening study on the Chinese CRC patients with family history. 23.6% patients carried pathogenic mutations. However, 24.4% pathogenic mutations would be missed if we used traditional screening strategy according to NCCN guideline (Colorectal, 2015). 21.0 % patients with family cancer history have detected MMR genetic mutations, which could benefit from immunotherapy.
Electron microscopy of urinary sediments in Fabry disease
Authors: Yoshiki Murayama, Mayu Uchida, Akihiro Tojo, Toshihiko Ishimitsu
Journal: Kidney International (2018)

A 60-year-old woman on peritoneal dialysis was found to have fatty bodies with whorl-like structures (called Mulberry bodies) in her urine, suggesting Fabry disease. Fabry disease is an X-linked hereditary disease, and the phenotypes of female patients are often mild with a normal range of α-galactosidase activity. Her plasma globotriaosylceramide was increased, but renal biopsy samples showed a few ceramide deposits in the glomerular podocytes, renal tubular cells, and interstitial macrophages. Immunofluorescence-labeled antibody against podocalyxin, a marker of podocytes, was positive in the Mulberry bodies (Figure 1, insert). Electron microscopic observation of urinary sediments showed zebra bodies in the cytoplasmic vesicles of urinary cells (Figure 1). The urinary podocyte excretion normally increases in cases of Fabry disease, and Katz and Lyons1Katz S.M. Lyons P.J. Urinary ultrastructural findings in Fabry disease.JAMA. 1977; 237: 1121-1122Crossref PubMed Scopus (8) Google Scholar previously reported the presence of urinary myelin-like structures in 1977. The electron microscopic observation of urinary sediments is therefore useful for the diagnosis of Fabry nephropathy. We are grateful to Mr. Kinichi Matsuyama at the Department of Pathology, Dokkyo Medical University, for his excellent technical support with regard to our electron microscopy observations.
Development of HOPE-Genomics: An IT platform for patient-directed cancer genome sequencing education and return of results.
Authors: Ilana Solomon, Jenny Shen, Adem Albayrak, Gil Alterovitz, Ethan Cerami, Catherine Del Vecchio Fitz, Rachel A. Freedman, Lisa Lopez, Lynette M. Sholl, Eliezer VanAllen, Sarah A McGraw, Stacy W. Gray
Journal: Journal of Clinical Oncology (2018)

1532 Background: Profiling of somatic/germline tissue has the potential to improve outcomes for patients with cancer. However, the realization of precision medicine is hindered by patients’ limited understanding of genetics and their own tumor/germline results. Innovations to improve patient education and care engagement are urgently needed. Methods: We recruited patients at a comprehensive cancer center to help develop a web-based, patient-directed cancer genomic sequencing education and reporting tool: HOPE-Genomics. We obtained clinical data through patient surveys and chart reviews. We obtained feedback on the tool from patients, family members, and clinicians via focus groups. Results: 40 patients (mean age 40, 92% White, 8% Asian, 15% Hispanic, 15% ≤ high school) completed the survey; 93% had advanced disease and 30% had lung, 25% breast, 10% ovarian, 18% colon, and 17% other cancers. Although 98% had tumor and/or germline profiling on chart review, 33% of patients were unaware this tested occurred. All breast and gastric cancer patients knew they had HER2 testing whereas only 20% of CRC patients knew they had KRAS testing. The majority of participants wanted to see, or their patients to see, “patient-friendly” reports. When presented with HOPE-Genomics, themes identified in patient/family focus groups included the opinion that the tool could help patients prepare questions, a desire for all types of information (e.g., prognostic, uncertain), and favorable attitudes about including genetic counseling information. Themes identified in clinician focus groups included the opinion that the tool could help patients share information with family and decrease patient confusion. Clinicians had mixed feelings about tool implementation (e.g., provider control vs. time-dependent release of report, concern over disclosure of some types of information). Conclusions: Many patients do not recall having molecular/genomic testing but are interested in learning their results. Early development of a web-based education and reporting tool appears to be acceptable to patients, family members and clinicians. We plan to refine the tool and develop processes for optimal clinical integration.
Myeloid derived suppressor cells (MDSC) and inflammatory biomarkers in metastatic urothelial carcinoma (mUC).
Authors: Moshe Chaim Ornstein, C. Marcela Diaz-Montero, Patricia A. Rayman, Paul Elson, Samuel Haywood, Jin Sub Kim, Paul G Pavicic, James Finke, Brian I. Rini, Andrew J. Stephenson, Marcelo Lamenza, Priscilla Dann, Kim Schach, Sarah Devonshire, Jennifer S Ko, Amr Farouk Fergany, Marc S. Ernstoff, Christopher J. Hoimes, Jorge A. Garcia, Petros Grivas
Journal: Journal of Clinical Oncology (2017)

4548 Background: MDSC are potent immunosuppressive cells with prognostic implications in many solid tumors. We previously reported significant correlations between MDSC and clinicopathologic features in localized UC. We hypothesized that different MDSC populations may correlate with inflammatory biomarkers and clinicopathologic features in mUC. Methods: Peripheral blood samples were collected from 46 mUC pts. MDSCs were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations &amp; clinicopathologic factors. Results: Of 46 pts:78% men, median age at diagnosis 69 (31-83), 33% never smokers, 76% pure UC, 76% bladder primary, 28% prior intravesical therapy, 35% prior neoadjuvant chemotherapy, 56% prior cystectomy, 83% overweight/obese. G-MDSC was the predominant subset in WB (43%) and PBMC (39%), although M-MDSC were almost equally predominant in PBMC (35%). There was a correlation between the WB and PBMC values of T-, I-, and M- MDSC (p≤0.05). Higher % WB I-MDSC correlated with lower blood neutrophil/lymphocyte ratio (NLR) (p = 0.009), while higher WB G-MDSC and %PBMC G-MDSC were associated with higher NLR (p = 0.03 and p = 0.02, respectively). Higher I-MDSC / G-MDSC ratio was associated with lower NLR (r = -0.35, p = .02) and with various clinicopathologic parameters. Conclusions: HigherI-MDSC / G-MDSC ratio correlates inversely with NLR, which is considered an inflammatory biomarker and had prognostic value in other studies. The mechanism of MDSC interaction with inflammatory response in mUC pts merits evaluation and is being investigated in a larger cohort of UC pts on chemotherapy or immunotherapy (with longer follow up).
PD-L1 mRNA expression in patients with resectable gastric cancer and adenocarcinoma of the oesophago-gastric junction undergoing perioperative chemotherapy: Results from the FLOT4 phase III trial of the AIO.
Authors: Lisa Waberer, Nils Homann, Ralph M Wirtz, Harald Schmalenberg, Georg Martin Haag, Martin H. Schuler, Stefan Kasper, Thorsten Oliver Goetze, Claudia Pauligk, Ralf Hofheinz, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2018)

e24277 Background: The objective of the present study was to assess the prognostic role of PD-L1 mRNA expression in patients (pts) with gastric cancer and adenocarcinoma of the oesophago-gastric junction undergoing perioperative FLOT or ECF/ECX chemotherapy. Furthermore, the association of PD1 and PD-L1 with immuncell infiltrates and HER1-4 expression was analyzed. Methods: For this pilot study paraffin fixed pretreatment tissue samples from the first 100 pts participating in the FLOT4 trial were prospectively collected and analyzed. RNA was extracted by commercial kits and relative RNA expression of PD-L1, PD1, HER1-4, MMP9, CXCL9, CXCL13, CD3, CD8, FOXP3, IGKC, CD68 and MMP9 was assessed by qRT-PCR. Intergene correlation and Kaplan Meier analysis of PFS and OS were performed by JMP 9.0.0 (SAS software). Pathological response and PDL1 mRNA expression were correlated by Kruskal Wallis test. Results: PD-L1 expression was significantly associated with MMP9 and PD1 (Spearman r = 0.45 & r = 0.39), whereas PD1 was significantly associated with expression of T- and B-cell markers and related chemokines. High PD-L1 mRNA expression (defined as expression above median) was associated with significantly inferior PFS (median 14.4 vs. 53.9 months in pts with low PD-L1; p = 0.0345) and OS (median 24.8 vs. 68.1 months in pts with low PD-L1; p = 0,0296). High PD-L1 expression significantly associated with signet cell morphology (p = 0.0109), gastric rather than GEJ tumors (p = 0.0056). There was a trend for an association with more advanced primaries (cT3/cT4, p = 0.0933). None of these associations emerged as an independent risk parameter at multivariate cox regression analysis. Furthermore, high PDL1 above median was trended to be associated with non response (i.e no CR, SR or PR according to Becker; p = 0.0796). Conclusions: High PD-L1 RNA expression strongly associates with inferior outcomes in patients with resectable esophagogastric cancer. Validation of these findings in an independent cohort is ongoing. The addition of anti-PD-1/PD-L1 antibodies may improve current perioperative therapy in these patients.
Therapy-related myeloid neoplasms (t-MN) in 84 patients (pts) following radiation therapy (RT) only.
Authors: Niloufer Khan, Richard Jirui Lin, Michelle M. Le Beau, Howard Weiner, Margaret Green, Theodore Karrison, Richard A. Larson
Journal: Journal of Clinical Oncology (2016)

e18534 Background: Exposure to ionizing radiation is associated with the development of secondary malignancies including t-MNs, a clinically defined subset of myeloid leukemia with characteristic features. Methods: We reviewed the clinical, epidemiologic, and cytogenetic characteristics of 84 consecutive cases of t-MN presenting to the University of Chicago between 1972-2015 in pts who had received RT alone for a prior disease; 23 (27%) since 2000. Results: There were 40 females and 44 males. The majority (61; 73%) were Caucasian. 76 (90%) pts had had a primary solid tumor, 5 had had a primary hematologic malignancy (4 Hodgkin lymphoma), and 3 had received RT for non-malignant disorders. Prostate and testicular cancers were the predominant primary tumors (n = 35; 42%). Breast (n = 17; 20%) and gynecological cancers (n = 15; 18%, including ovarian, cervical, endometrial, vaginal) were also common. Median age at primary diagnosis was 64 yrs (range, 0-83). Median latency from RT to diagnosis of t-MN was 68 months (interquartile range (IQR), 30-120 mos). Pts with a heme malignancy had shorter latency intervals (median, 25 mos; IQR, 18-50) compared to pts with solid tumors (median, 68 mos; IQR, 33-116). Younger age at primary diagnosis correlated with longer latency. 44 pts had clonal abnormalities of chromosomes 5 and/or 7, 11 had a recurring translocation, 14 had other clonal abnormalities, and 15 had a normal karyotype. 41 pts first presented with t-MDS, while 43 pts had > 20% blasts at diagnosis. Treatments were individualized and variable, ranging from supportive care only to intensive chemotherapy and subsequent hematopoietic cell transplantation. Only 9 pts currently remain alive: 3 with inv(16), 1 with t(16;16), 1 with t(15;17), 1 with del(20q), and 3 with a normal karyotype. Median survival was 280 days from diagnosis (IQR, 121 - 573 days). Conclusions: t-MN following RT alone bears striking clinical and cytogenetic similarities to alkylator-associated t-MN with frequent clonal abnormalities of chromosomes 5 and 7, relatively long latency, and poor outcomes even with intensive therapy. However, some pts with recurring translocations or normal karyotypes have a better response to treatment and longer survival.
Changes in the sleep-wake rhythm, sleep quality, mood, and quality of life of patients receiving treatment for lung cancer: A longitudinal study.
Authors: Chia-Chin Lin, Wen-Pei Chang
Journal: Journal of Clinical Oncology (2017)

e21657 Background: Studies on the diurnal sleep–wake rhythm of patients with lung cancer have mostly examined patients cross-sectionally, whereas the effects of lung cancer treatment over time have rarely been considered. Through long-term longitudinal tracking of patients with lung cancer, this study examined changes in their sleep–wake rhythm, sleep quality, anxiety, depressive symptoms, fatigue, and quality of life (QoL) at various treatment stages. In addition, factors affecting their QoL were explored. Methods: Hierarchical linear modelling was adopted to analyze a convenience sample of 82 patients with lung cancer. The changes in their sleep–wake rhythm, sleep, mood (anxiety, depressive symptoms, and fatigue), and QoL were observed at five time points: prior to treatment and at weeks 6, 12, 24, and 48 after the start of the treatment. The effects of sex, age, cancer stage, treatment type, comorbidities, and time were controlled to determine the predictors of patients’ QoL. Results: The results showed that patients’ sleep–wake rhythms were poor before treatments. Compared with baseline, the sleep–wake rhythms of the patients significantly improved at week 48, and anxiety significantly improved at weeks 6, 12, 24, and 48. By contrast, their fatigue became exacerbated at weeks 8 and 48. Moreover, QoL improved significantly from week 6 until the end of the treatment period. QoL was negatively affected by poor sleep quality ( β = −0.69, p = 0.00) and depressive symptoms ( β = −2.59, p &lt; 0.001) and positively affected by regular sleep–wake rhythms ( β = 0.23, p = 0.001). Conclusions: Therefore, clinical healthcare professionals should focus more attention to the fatigue levels of patients with lung cancer before, during, and after treatment. Healthcare professionals may also need to provide such patients with health education regarding sleep hygiene and with emotional support to assist them in maintaining regular sleep–wake rhythms in order to improve their QoL.
Strategies associated with enhanced inclusion of racial and ethnic minorities in clinical cancer research: US Centers of Excellence current practices.
Authors: Jeanne Regnante, Nicole Richie, Lola Fashoyin-Aje, Laura Lee Hall, Luther Clark, Julie Dang, Nestor F. Esnaola, Marvella Elizabeth Ford, Evelyn Gonzalez, Quita Highsmith, Spencer C. Hoover, Gail Larkins, Simon Craddock Lee, J’Aimee Louis, Lorna H McNeill, Daniel Petereit, Michelle Vichnin, Erin Fenske Williams, Coleman K. Obasaju
Journal: Journal of Clinical Oncology (2018)

e18643 Background: By 2050, racial and ethnic minorities (REMs) will constitute > 50% of the US population. Despite a high prevalence of certain cancers in REM populations, < 10% REMs diagnosed with cancer in the US, engage in cancer clinical research (CCR). Participation in CCR may ensure REMs benefit from the improved outcomes achieved with newer cancer therapies, and advance understanding of disease heterogeneity. We describe a project to identify and characterize strategies that facilitated participation of REMs in CCR at leading cancer centers in the US. Methods: The National Minority Quality Forum and Sustainable Healthy Communities Diverse Cancer Communities working group, identified a sample of US cancer centers, using criteria including: reported accrual of 10–50% of REMs in CCR in the past year; REM constitute ≥10% of catchment area; presence of CCR and quality data capture infrastructure; existing diversity enrollment and community outreach programs. We conducted phone interviews (Nov 2017– Feb 2018) with leaders of centers meeting the criteria covering 5 themes: leadership/commitment; operational capabilities; patient and community engagement; investigator training and research standards; and recommended sponsor practices for enhanced REM recruitment. We used pre-/post-interview questionnaires to confirm participation eligibility, align on key definitions and explore emergent themes. Results: We selected 7 representative CCR centers and conducted 12 in-depth interviews. Notable strategies for REM participation in CCR were identified in all 5 themes. In preliminary analysis, seeking dedicated input into CCR programs (i.e., choice of disease conditions, protocol design and feasibility of implementation) from REMs patients and caregivers was cited by all centers as a key driver of REM accrual success. Full analysis of drivers across themes and centers will be presented. Conclusions: We identified specific notable practices and successful strategies that correlated with increased accrual of REMs in CCR, to reflect the diversity of the US population and enhance opportunities for REMs to receive novel cancer therapies.