tbuckley/cabot-search huggingface dataset:
Occurrence of other cancers in patients with chronic lymphocytic leukemia and mutations in protection of telomeres 1 (POT1) gene.
Authors: Matteo Molica, Courtney Denton Dinardo, Keyur P. Patel, Michael J. Keating, William G. Wierda, Philip A. Thompson, Nitin Jain, Koichi Takahashi, Rashmi Kanagal-Shamanna, Mark Routbort, Guilin Tang, Zhenya Tang, Alessandra Ferrajoli
Journal: Journal of Clinical Oncology (2019)

7529 Background: Mutations in POT1 gene in CLL lead to uncapping of the telomeric ends, causing fusion events and chromosomal aberrations. POT1 is mutated in approximately 4% of pts with CLL. Recent studies reported germline variants in POT1 in pts with familial CLL and in familial melanoma, cardiac angiosarcoma and glioma. We evaluated pts characteristics and the presence of other cancers (OC) in pts with CLL with POT1 mutation seen at our institution. Methods: We performed next generation sequencing (NGS)-based analysis for the detection of mutations in 29 genes frequently mutated in pts with CLL using blood and/or bone marrow samples containing a minimum of 10% clonal B-cells from 1467 pts diagnosed with CLL. Clinical characteristics, prognostic factors (FISH and IGHV status), personal and familial history of OC were collected in pts with POT1 mutations. Results: Mutations in POT1 were found in 52 of the 1467 pts studied (3.5%). Pts with POT1 mutation were young (median age 59 years), commonly presented with early stage disease (Binet stage A 69% vs B/C 31%: p=0.0046 and Rai stage 0-I 65% vs II-IV 35%; p=0.043) and predominantly male (37 male vs 15 female). According to FISH, the more frequent abnormalities were del13q (33%), no abnormalities (25%) and del11q (21%). IGHV status was more commonly unmutated (69%). The most frequent DNA mutations associated with POT1 were NOTCH1 (44%), TP53 (27%) and SF3B1 (23%). Other cancers (excluding non-melanoma skin cancer) were reported in 19 of the 52 pts with POT1 mutation (37%). The most common types were prostate cancer (12%), malignant melanoma (10%) and kidney cancer (8%). Twelve (23%) pts were diagnosed with OC before and 7 pts (13%) after the diagnosis CLL (Table). Four (8%) pts had more than one other cancer diagnoses. Twenty-eight (54%) pts had one of more first degree relatives with history of cancer. Conclusions: POT1 mutations were observed in 3.5% of pts with CLL. These pts are young and often have unmutated IGHV. We observed a high occurrence of OC, particularly malignant melanoma and kidney cancer in these pts. Additional studies are ongoing to determine the proportion of pts with germline POT1 mutation, the distribution of variant allelic frequencies and additional chromosomal abnormalities in pts with OC. Other Cancers in 52 CLL pts with POT1. [Table: see text]
Abstract 77: Association of Sodium and Coronary Arteriopathy in Acute Phase of Kawasaki Disease
Authors: Lucy Y Eun, Sora Park, Mindong Sung, Se Yong Jung, Jo Won Jung, Jae Young Choi
Journal: Circulation (2015)

Background: Kawasaki disease(KD) is an immune related multisystemic inflammatory vasculitis in children, especially ensues coronary artery lesions. Several cardiovascular diseases are known to be correlated with sodium level. In this study, we examined the association between serum sodium levels and the severity of coronary artery lesion in acute phase of Kawasaki disease. Objective: The purpose of this study was to determine the association of serum sodium level for predicting cardiac events in Kawasaki disease (KD) patients especially in coronary artery lesions (CALs). Methods: We conducted a retrospective review of the medical records of 158 Kawasaki disease patients from June 2013 to August 2014. We devided the subjects into two groups regarding to the serum sodium level. Various laboratory tests and echocardiographic data were analyzed. Student t-tests were carried out to analyze the significance of the difference in each group. Results: ESR, CRP, BNP, and liver enzymes were significantly greater in lower sodium group. Echocardiographic diastolic marker of mitral E and E/E’ measurement were statistically different. Coronary arterial changes were significant in lower sodium group as well. Conclusions: The lower sodium group demonstrated significant increase of various inflammatory markers and coronary arterial lesions. The sodium level might be associated with the severity of coronary vessel and cardiac inflammation in acute phase of Kawasaki disease.
5-HT<sub>3</sub>Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface
Authors: Gohar Fakhfouri, Reza Rahimian, Jonas Dyhrfjeld-Johnsen, Mohammad Reza Zirak, Jean-Martin Beaulieu
Journal: Pharmacological Reviews (2019)

5-HT<sub>3</sub> receptor antagonists, first introduced to the market in the mid-1980s, are proven efficient agents to counteract chemotherapy-induced emesis. Nonetheless, recent investigations have shed light on unappreciated dimensions of this class of compounds in conditions with an immunoinflammatory component as well as in neurologic and psychiatric disorders. The promising findings from multiple studies have unveiled several beneficial effects of these compounds in multiple sclerosis, stroke, Alzheimer disease, and Parkinson disease. Reports continue to uncover important roles for 5-HT<sub>3</sub> receptors in the physiopathology of neuropsychiatric disorders, including depression, anxiety, drug abuse, and schizophrenia. This review addresses the potential of 5-HT<sub>3</sub> receptor antagonists in neurology- and neuropsychiatry-related disorders. The broad therapeutic window and high compliance observed with these agents position them as suitable prototypes for the development of novel pharmacotherapeutics with higher efficacy and fewer adverse effects.
Abstract 2655: Oxygen tension regulates lysosomal activation and receptor tyrosine kinase degradation
Authors: Jaewoo Hong, P. Charles Lin, Todd Wuest, Yongfen Min
Journal: Cancer Research (2019)

Abstract Oxygen sensing is crucial for adaptation to variable habitats and physiological conditions. Low oxygen tension, or hypoxia, is a common feature of solid tumors and hypoxic tumors are often more aggressive and resistant to therapy. Here we show that, in mammalian tissue culture cells, hypoxia suppressed lysosomal acidification/activation and receptor tyrosine kinase (RTK) degradation. Hypoxia down-regulated mTORc1, reducing its ability to activate transcription factor EB (TFEB), a master regulator of v-ATPase, the lysosomal proton pump. Hypoxia prevented epidermal growth factor receptor (EGFR) degradation in tumor tissues, whereas activation of lysosomes enhanced tumor cell response to anti-EGFR treatment. Our results linkoxygen tension and lysosomal activity, provide a molecular explanation of the malignant phenotype associated with hypoxic tumors, and suggest activation of lysosomes may provide therapeutic benefit in RTK-targeted cancer therapy. Citation Format: Jaewoo Hong, P. Charles Lin, Todd Wuest, Yongfen Min. Oxygen tension regulates lysosomal activation and receptor tyrosine kinase degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2655.
Abstract 4099: Intrinsic Tumor Cell Consequences of Acquired Resistance to PD-L1 Blockade
Authors: Yuhao Shi, Michalis Mastri, Melissa Dolan, Michael Oberst, John Ebos
Journal: Cancer Research (2019)

Abstract The use of immune checkpoint inhibitors (ICIs) that block programmed cell death protein ligand 1 (PD-L1) binding to PD-1 have led to durable responses in multiple cancer types; however, a subset of patients eventually stop responding. Currently, few preclinical models faithfully recapitulate clinically-relevant acquired ICI resistance that could help identify second-line treatments. Here we describe the in vivo derivation of cells from orthotopically implanted mouse mammary EMT-6 primary tumors in mice that were initially responsive to PD-L1 inhibition but eventually developed resistance. Transcriptomic comparisons of in vivo-derived parental (EMT6P) and anti-PD-L1 resistant (EMT6PDR) cells revealed alterations in multiple signaling pathways controlling secretory profiles that govern metastasis and angiogenesis. Using a small molecule screen of ~1500 FDA approved cancer drugs, we found that anti-proliferative activity in EMT6PDR cells was decreased for ~120 compounds, including numerous receptor tyrosine kinase inhibitors (RTKIs) currently being tested in ICI-refractory patient populations. Molecular analysis indicated resistance-mediated secretory changes may be linked to intrinsic functions of PD-L1 on the resistant tumor cell which, in turn, may explain differential RTKI sensitivity. Subsequent studies show that EMT6PDR secretory changes can be interferon (IFN) mediated. Together, these results reveal that acquired resistance to PD-L1 blockade can result in PD-L1-regulated intrinsic tumor cell changes involving secretory proteins and controlled, at least in part, by IFN signaling. Current studies seek to assess the impact of these cellular changes on RTKI responsiveness to identify secondary treatments after ICI failure. Citation Format: Yuhao Shi, Michalis Mastri, Melissa Dolan, Michael Oberst, John Ebos. Intrinsic Tumor Cell Consequences of Acquired Resistance to PD-L1 Blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4099.
KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer: a double-blind, randomized, placebo-controlled phase 3 study
Authors: H. Chung, Y. Bang, C. Fuchs, S. Qin, T. Satoh, K. Shitara, J. Tabernero, E. Van Cutsem, Z. Cao, X. Chen, S. Kang, C. Shih, Y. Janjigian
Journal: Annals of Oncology (2019)
Poor induction and lack of honest feedback is blamed for higher rate of GMC referrals among BAME doctors
Authors: Jacqui Wise
Journal: BMJ (2019)

The fact that disproportionate numbers of black, Asian, and minority ethnic (BAME) doctors are referred to the General Medical Council for fitness to practise concerns may be because of poor induction, support, and feedback, a report has found.

Between 2012 and 2017, 1.1% of BAME doctors were referred to the GMC compared with 0.5% of white doctors. Doctors who qualified outside the UK have a two and a half times higher rate of being referred to the regulator compared with UK graduates (1.2% compared with 0.5%).

The Fair to Refer report,1 is based on interviews and focus groups with 262 people including GPs, locums, specialty and associate specialist doctors, and consultants from different ethnic backgrounds, some from overseas and some from the UK. …
North Japan multicenter phase II study of oxaliplatin-containing regimen as adjuvant chemotherapy for stage III colon cancer: final analysis (NORTH/HGCSG1003)
Authors: A. Ishiguro, S. Yuki, N. Takahashi, T. Shichinohe, H. Nakatsumi, Y. Kawamoto, T. Kusumi, K. Harada, I. Iwanaga, K. Hatanaka, K. Oomori, M. Nakamura, N. Senmaru, K. Iwai, M. Koike, N. Sakamoto, A. Taketomi, S. Hirano, Y.M. Ito, Y. Komatsu
Journal: Annals of Oncology (2019)
Abstract 2188: Comparing effects of small molecular weight compounds on proliferation and chemotaxis of pancreatic cancer cells
Authors: Masahiro Yamamura, Akira Yamauchi, Naoki Katase, Masakiyo Sakaguchi, Yosuke Katata, Hiroaki Tanioka, Makoto Okawaki, Takeshi Nagasaka, Yoshiyuki Yamaguchi
Journal: Cancer Research (2019)

Abstract Background &amp; Aims: The new therapy for pancreatic cancer which has the poorest prognosis among malignant tumors is high demand nowadays. The overall 5-year survival rate in all stages of this type of cancer is less than 5%, even with the multimodality therapy, including surgery, chemotherapy and radiotherapy. Although gemcitabine (GEM) is a key drug in the treatment of advanced pancreatic cancer, the therapeutic effect is limited because of drug resistance. Heat shock protein 90 (HSP90) is known to be overexpressed in several types of cancer cells, and its inhibition has shown promise in the treatment of solid malignancies. Src kinases work as a signal switch for multiple molecular signal transduction pathways. The objective of this study is to evaluate an antitumor effect of three kinds of small molecular weight compounds (antimetabolite Gemcitabine, HSP90 inhibitor NVP-AUY922, and Src kinase inhibitor Dasatinib) on tumor growth and chemotaxis in pancreatic cancer cell lines. Methods: Pancreatic cancer cell lines were treated with each of the 3 compounds to examine the effect on proliferation assay, apoptosis assay, Western blotting, and chemotaxis assay. Results: Of these compounds, HSP90 inhibitor inhibited cell proliferation in pancreatic cancer cells best in a dose- and time-dependent manner. Growth inhibitory effect of HSP90 inhibitor for pancreatic cancer cells were highest of the three. Further, HSP90 inhibitor inhibited the growth of gemcitabine sensitive and resistant pancreatic cancer cell lines. With flowcytometry and immunostaining, HSP90 inhibitor had higher apoptosis-inducing effect than gemcitabine. In the chemotaxis assay, HSP90 inhibitor inhibited the migration of pancreatic cancer cell best in the three compounds. In western blotting, HSP90 inhibitor suppressed the expression of multiple receptor tyrosine kinase proteins as well as the signal transduction in PI3K-Akt and RAS-MAPK pathways. Conclusion: In this study, HSP90 inhibitor was the best of 3 small molecular compounds and has proven effective in gemcitabine sensitive and resistant pancreatic cancer. The HSP90 inhibitor is useful as an antitumor drug by inhibiting proliferation and chemotaxis of pancreatic cancer cells through multiple kinase pathways. Citation Format: Masahiro Yamamura, Akira Yamauchi, Naoki Katase, Masakiyo Sakaguchi, Yosuke Katata, Hiroaki Tanioka, Makoto Okawaki, Takeshi Nagasaka, Yoshiyuki Yamaguchi. Comparing effects of small molecular weight compounds on proliferation and chemotaxis of pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2188.
Abstract 1748: RAD51 has an anti-recombinase activity that is countered by BRCA2 - <i>In vitro</i>
Authors: Charles Wang, Judit Jimenez-Sainz, Ryan B. Jensen, Alexander A. Mazin
Journal: Cancer Research (2019)

Abstract Homologous Recombination (HR) is a high-fidelity process with a range of biologic functions from generation of genetic diversity to repair of DNA double-strand breaks (DSBs). In mammalian cells, BRCA2 facilitates the polymerization of RAD51 onto ssDNA to form a presynaptic nucleoprotein filament. This filament can then strand invade a homologous dsDNA to form the displacement loop (D-loop) structure leading to the eventual DSB repair. This pro-recombinatory feature of RAD51-BRCA2 is well documented. Here, we present biochemical evidence that RAD51 can cause D-loop disassembly. Furthermore, we show that this RAD51 anti-recombinatory activity is countered by BRCA2. These results demonstrate that BRCA2 may have a previously unexpected role: regulation of HR at a post-synaptic stage by modulating RAD51-mediated D-loop dissociation. Our results provide a biochemical mechanistic understanding of homeostasis between RAD51 and BRCA2, which has been suggested to be an important factor of HR based on previously published cellular data. Citation Format: Charles Wang, Judit Jimenez-Sainz, Ryan B. Jensen, Alexander A. Mazin. RAD51 has an anti-recombinase activity that is countered by BRCA2 - In vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1748.
Phase 2, open-label study of pembrolizumab in children and young adults with newly diagnosed classical Hodgkin lymphoma (cHL) with slow early response (SER) to frontline chemotherapy: KEYNOTE-667.
Authors: Christine Mauz-Körholz, Kara M. Kelly, Frank G. Keller, Rod Ramchandren, Akash Nahar, Lisa Giulino-Roth
Journal: Journal of Clinical Oncology (2019)

TPS7567 Background: High risk for relapse is observed in cHL patients (pts) with SER to initial chemotherapy and organ toxicities may be higher following dose intensification. Methods: The phase 2 KEYNOTE-667 study will enroll 440 pts aged 3 to 17 (children) or 18 to 25 years (young adults) with newly diagnosed, confirmed stage IA, IB, or IIA cHL without bulky disease (Group 1 [low-risk]) or stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL (Group 2 [high-risk]); measurable disease; and performance status per Lansky Play-Performance Scale ≥50 (age ≤16 years) or Karnofsky score ≥50 (age &gt;16 years). Pts will receive induction with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD; Group 1) or vincristine, etoposide/etoposide phosphate, prednisone/prednisolone, doxorubicin (OEPA; Group 2) for 2 cycles, then early response assessment by PET/CT/MRI. Pts with rapid early response (Deauville score 1-3) will receive standard therapy. Pts with SER (Deauville score 4-5) will receive consolidation with pembro 2 mg/kg Q3W up to 200 mg (children) or 200 mg Q3W (young adults) plus 2 cycles AVD (Group 1) or 4 cycles cyclophosphamide, vincristine, prednisone/prednisolone, dacarbazine (COPDAC-28; Group 2). PET/CT for late response assessment (LRA) will be performed after consolidation. After LRA, Group 1 pts with SER and Group 2 pts with Deauville score 4-5 will receive radiotherapy (RT). All pts will receive maintenance with pembro Q3W concomitantly with RT. Pembro will continue up to 17 administrations, with an option to stop after 24 weeks due to CR, or until progression, unacceptable toxicity, or withdrawal. The primary endpoint is ORR per Cheson 2007 IWG criteria by group in SER pts. Secondary endpoints are SERs with PET negativity after consolidation, 2-yr event-free survival (EFS), OS, and RT frequency and details by group, RERs with PET negativity after ABVD induction, 3-yr EFS by investigator, and OS by risk group, and serum TARC levels at screening in SERs by risk group. ORR with 95% CI will be estimated by Clopper-Pearson method. EFS and OS will be estimated by Kaplan-Meier method. Safety will be assessed in all treated pts. Clinical trial information: NCT03407144.
Abstract 15919: Incidence, Trends, and Characteristics of Hospitals Reporting Perfect Door-to-Balloon Time Performance in Patients With ST Elevation Myocardial Infarction
Authors: Chetan Huded, Kathleen Kravitz, Venu Menon, Travis Gullett, Samir Kapadia, Scott Hantz, Stephen Ellis, Damon Kralovic, Seth Podolsky, Steve Meldon, Deborah Brosovich, Elizabeth Smith, Umesh Khot
Journal: Circulation (2017)

Introduction: No registry of consecutive patients with ST elevation myocardial infarction (STEMI) has ever reported 100% of patients treated with door to balloon time (D2BT) < 90 minutes. The incid...
Whole-exome sequencing of non-metastatic anal squamous cell carcinoma: a prognostic genetic variants analysis
Authors: I. Ghanem, L. Trilla, A. Gámez, M. Mendiola, J. Maurel, à. Campos-Barros, C. Peña, M. Cuatrecasas, L. G-Pastrián, P. García Alfonso, J. Feliu, J. Fresno
Journal: Annals of Oncology (2019)
Abstract CT148: Small molecule immune-modulator icaritin: Safety, durable survival and inflammation-immune biomarkers in advanced hepatocellular carcinoma
Authors: Shu-Kui Qin, Qing Li, Jianmin Xu, Jun Liang, Ying Cheng, Shu Li, Limin Zheng, Bin Ye, Kun Meng, Yan Sun
Journal: Cancer Research (2019)

Abstract Objectives: Hepatocellular carcinoma (HCC) was characterized with high heterogeneity and immune “tolerogenic”. Despite of immune checkpoint inhibitors have demonstrated promising results with improved overall survival. Novel small molecule-based immune therapies with high safety profiles might be particularly needed for advanced HCC patients. The purpose of this Phase II study is to explore the safety, clinical activities and treatment associated inflammation-immune biomarkers of icaritin in advanced HCC. Methods: Major eligibility criteria include histologically confirmed unresectable, HCC patients with Child-Pugh Class A or B liver function. Total of 70 advanced HCC patients were enrolled and administrated with 600 mg b.i.d. Primary endpoints were TTP, and secondary endpoints were safety, OS, and DCR. Local disease control was defined as no progressive disease (PD) by RECIST. Kaplan-Meier analysis was utilized for OS assessment. Inflammation-Immune biomarkers NLR, PLR, cytokines, baseline expression of checkpoint/immune gene panel including PD-L1/L2, TIM3, IDO, HLA were evaluated by Nanostring and NGS technologies, retrospectively. Results: There was no ≥ grade III drug related AE observed in all enrolled 70 advanced HCC patients. Objective response evaluation in per-protocol population showed PR (1.6%), SD (32.8%) and PD (59.0%) and median overall survival (OS) 254day (95% CI, 172-296). DCR was achieved 34.4% (95% CI, 22.7-47.7%); Median OS for the PD-L1-positive (n=9) and negative (n=24) subgroups were 389 (95% CI, 80-522) vs. 286.5days (95%CI, 135-482), for IL-6-advantage (n=28) and disadvantage (n=16) subgroups were 328.5 (95% CI, 277-566) vs. 168 days (95% CI, 135-482), for IL-8 low (n=22) and high (n=22) subgroups were 475.5(95% CI, 309-NA) vs. 175days (95% CI, 135-295), respectively. Overall survival was significantly associated with patient genetic profiles such as neo-antigen, bacterial and viral DNA inserts. Conclusion: Icaritin has demonstrated its favorable clinical safety and preliminary immune-modulation efficacy. Potential baseline immune biomarkers to predict the improved OS were suggested including immune cell PD-L1 expression, low level peripheral IL-8, PLR, neoantigen and infection-associated genetic variations. Both safety and immune-response efficacy are warranted for the further Phase III validation. Citation Format: Shu-Kui Qin, Qing Li, Jianmin Xu, Jun Liang, Ying Cheng, Shu Li, Limin Zheng, Bin Ye, Kun Meng, Yan Sun. Small molecule immune-modulator icaritin: Safety, durable survival and inflammation-immune biomarkers in advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT148.
FOLFIRI plus panitumumab as second-line treatment in mutated RAS metastatic colorectal cancer patients who converted to wild type RAS after receiving first-line FOLFOX/CAPOX plus bevacizumab-based treatment: Phase II CONVERTIX trial
Authors: A. Fernández Montes, N. Martinez Lago, J. De la Cámara Gómez, M. Covela Rúa, A. Cousillas Castiñeiras, P. Gonzalez Villarroel, J. Méndez Méndez
Journal: Annals of Oncology (2019)