tbuckley/cabot-search huggingface dataset:
Leptin-Aldosterone-Neprilysin Axis
Authors: Milton Packer
Journal: Circulation (2018)

Obesity (especially visceral adiposity) can be associated with 3 different phenotypes of heart failure: heart failure with a reduced ejection fraction, heart failure with a preserved ejection fraction, and high-output heart failure. All 3 phenotypes are characterized by an excessive secretion of aldosterone and sodium retention. In addition, obesity is accompanied by increased signaling through the leptin receptor, which can promote activation of both the sympathetic nervous system and the renin-angiotensin system and can directly stimulate the secretion of aldosterone. The deleterious interaction of leptin and aldosterone is potentiated by the simultaneous action of adiposity and the renal sympathetic nerves to cause overactivity of neprilysin; the loss of the counterbalancing effects of natriuretic peptides is exacerbated by an additional effect of both obesity and heart failure to interfere with adiponectin signaling. This intricate neurohormonal interplay leads to plasma volume expansion as well as to adverse ventricular remodeling and cardiac fibrosis. Furthermore, the activity of aldosterone and neprilysin is not only enhanced by obesity, but these mechanisms can also promote adipogenesis and adipocyte dysfunction, thereby enhancing the positive feedback loop. Last, in elderly obese women, changes in quantity and biology of epicardial adipose tissue further enhances the release of leptin and other proinflammatory adipokines, thereby leading to cardiac and systemic inflammation, end-organ fibrosis, and multiple comorbidities. Regardless of the phenotypic expression, activation of the leptin-aldosterone-neprilysin axis appears to contribute importantly to the evolution and progression of heart failure in people with obesity. Efforts to interfere with the detrimental interactions of this distinctive neurohormonal ecosystem with existing or novel therapeutic agents are likely to yield unique clinical benefits.
GNMT negatively regulates MAPK pathway and suppresses the growth and metastasis of hepatocellular cancer cells
Authors: S. Jiang, L. Jiang, J. Fang
Journal: Annals of Oncology (2018)

Background: Hepatocellular Carcinoma (HCC) has a generally poor prognosis, and molecular markers to improve early detection and predict outcomes are greatly needed. The aim of this study is to identify the recurrent genetic changes, elucidate their roles and discover new biomarkers for improving clinical management of HCC. Methods: Western blotting and immunohistochemistry were performed to detect the expression level of GNMT. The tumor-suppressive effect of GNMT was determined by both in-vitro and in-vivo assays. Affymetrix cDNA microarray was used to identify the underlying molecular mechanism. Results: We find that the Glycine N-methyltransferase GNMT is less expressed in HCC, where it correlates with well overall survival. Elevating GNMT levels by various means was sufficient to inhibit HCC cell proliferation, clonogenicity, migration and invasion in vitro and tumorigenicity and distant metastasis in vivo Conversely, GNMT attenuation by siRNA elicited the opposite effects in HCC cells. RNA-sequence profiling analyses suggested that GNMT inhibits HCC oncogenesis and metastasis through various pathways, with deregulation of MAPK signaling figuring prominently. Conclusions: Our results establish the significance of GNMT in inhibiting oncogenesis and metastasis in HCC by coordinating MAPK pathway control, with implications for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in this disease setting. Legal entity responsible for the study: Renji Hospital, School of Medicine, Shanghai Jiao Tong University. Funding: National Natural Science Foundation of China. Disclosure: All authors have declared no conflicts of interest.
Abstract 16415: The Consequent Morbidity of Acute Stress-Induced (Takotsubo) Cardiomyopathy
Authors: Caroline Scally, Amelia Rudd, Mezincescu Alice, Heather Wilsom, Janaki Srinivasan, Graham Horgan, Paul Broadhurst, Anke Henning, Dana K Dawson
Journal: Circulation (2017)

Background: Takotsubo cardiomyopathy (TC) is an increasingly recognised acute heart failure syndrome following intense stress. Despite rapid and spontaneous recovery of left ventricular ejection fr...
Ischemia-induced tumor progression after portal triad clamping in a murine model of colorectal liver metastases: Roles of TNF-a and HO-1.
Authors: Desislava Germanova, Jiri Keirsse, Pieter Demetter, Laurine Verset, Arnaud Kohler, Sandrine Delbauve, Nicolas Preyat, Oberdan Leo, Vincent Donckier, Jo Van Ginderachter, Veronique Flamand
Journal: Journal of Clinical Oncology (2018)

e15539 Background: Liver ischemia and reperfusion (I/R) was shown to cause an inflammatory response that can result in metastatic progression. A better understanding of this innate immune cell-dependent inflammatory response would be helpful to develop new surgical and pharmacological strategies aiming to reduce the risk for postoperative recurrence in patients with colorectal liver metastases (CRLM). We assessed the effect of transitory liver ischemia on tumor growth in a mice model of CRLM and evaluated the role of tumor necrosis factor alpha (TNF-a) and heme oxygenase-1 (HO-1) produced by innate immune cells. Methods: C57BL/6, TNF-aflox/flox LysM cre/wt, HO-1 flox/flox LysM cre/wt and RIPK3 KO were submitted to an intrasplenic injection of 1 million MC38 cells. 2d later, liver ischemia was induced by 60min transitory partial portal trial clamping. SHAM-operated mice undergo the same procedure except the clamping. Results: 10d post-ischemia, the tumor load was significantly higher in the ischemic liver lobe compared to the liver of SHAM-operated C57BL/6 mice. This phenomenon is accompanied by a local TNF-a and Heme oxygenase-1 (HO-1). Significant increase of monocytes and neutrophils infiltrations was observed at day two in ischemic (monocytes became the predominant source of HO-1 and TNF-a). We further observed that TNF-aflox/floxLysMcre/wt I/R mice had a higher tumor burden whereas the pro-tumor effect of ischemia was not observed in RIPK3 KO and in HO-1flox/floxLysMcre/wt mice, that was confirmed by a pre-ischemia pharmacological blockage of HO-1 with ZnPPIX. Conclusions: Transitory partial liver ischemia increases CRLM progression. RIP3-dependent Ischemia-induced cell damage is crucial for tumor cells implantation and tumor growth. Ischemia-induced intrahepatic myeloid HO-1 production appears to play a key role in this phenomenon, suggesting that HO-1 blockage could represent a new therapeutic strategy to reduce the risk for tumor recurrence in patients operated for CRLM whereas anti-TNF-a treatment would not be recommended.
Myelomatous effusions in multiple myeloma: 5 year experience from a tertiary medical centre in north India.
Authors: Kamal Kant Sahu, Uday Yanamandra, Nalini Gupta, Subhash Varma, Pankaj Malhotra
Journal: Journal of Clinical Oncology (2016)

e19503 Background: Extra osseous involvement in MM clinically presents only in less than 5% patients. Rarely, MM can involve kidneys, skin, pleura, thyroid, pancreas central nervous system, testes and serous cavities. Methods: Retrospective study of all MM visiting our centre form Jan 2010 to December 2015 was done. In total, 351 MM patients were enrolled under adult haematology clinic. We included all cases who had proven malignant cells in body cavities (namely in pleural fluid, pericardial fluid, ascetic fluid, CSF etc.). Results: Out of 351 patients, we found eleven patients having malignant effusion. There were seven males and four females with average age being 56 years. Bone pain and fatigability were the most common presenting complaints in our cohort (7/11 patients). Interestingly, rest four patients presented with atypical features of abdominal pain (acute pancreatitis), blurring of vision (CNS myeloma related), chronic diarrhoea (gut amyloidosis) and chest wall mass (sternal wall plasmacytoma). MC type of MM was IgG, Kappa (5/10). All patients belonged to either ISS-II (2/8) or III (6/8) category. 55% (6/11), 36% (4/11) and 10% (1/11) patients developed myelomatous effusions on follow up, at diagnosis and during both time periods respectively. All patients had pleural effusions (6/11- right sided, 3/11-left sided and 2/11- bilateral). 27% cases also had ascetic fluid positive for myeloma cells while one case had spinal fluid positivity for myeloma. Four out of eleven patients were found to have cytopathologically/biopsy proven myeloma infiltration of organs namely paraspinal, pancreas, chest wall and gut. Another patient had imaging study suggesting brain parenchyma involvement.7 patients died within average duration of 3.22 months from time of effusion development, 3 lost to follow up and 1 is surviving. Conclusions: The mean survival time is less than four months in MPE which remains very meagre. The median OS can be prolonged with HSCT in MM patients. But this mode of management is not generally applicable for patients with MPE who usually have fulminant course and poor performance status.
Mikie: A randomized, double-blinded, regimen-controlled, phase 2 study to assess the efficacy and safety of two different vismodegib (VISMO) regimens in patients (pts) with multiple basal cell carcinomas (BCCs).
Authors: Gary Rogers, Rainer Kunstfeld, Dirk Schadendorf, Axel Hauschild, Ian Maher, David Zloty, Bruno Labeille, Jean Jacques Grob, Susana Puig, Daniel Bergstrom, Frank Gilberg, Brigitte Dréno
Journal: Journal of Clinical Oncology (2016)

9509 Background: VISMO, a first-in-class Hedgehog pathway inhibitor, is approved for use in adult pts with advanced BCC. Pts with multiple BCCs, including BCC nevus syndrome (BCCNS), require VISMO treatment for extended periods of time. MIKIE (NCT01815840) was designed to assess the efficacy and safety of 2 long-term intermittent VISMO dosing regimens in pts with multiple BCCs. Methods: Adult pts with multiple BCCs (including BCCNS) with ≥ 1 histopathologically confirmed BCC and ≥ 6 clinically evident BCCs were randomized 1:1 to Regimen A (VISMO 150 mg/d × 12 wks, then 3 alternating courses of placebo (P) × 8 wks followed by VISMO × 12 wks) or B (VISMO 150 mg/d × 24 wks, then 3 alternating courses of P × 8 wks followed by VISMO × 8 wks). Primary objective was % reduction from baseline (BL) in number of BCCs at wk 73 (end of treatment). Results: At primary analysis cut-off (Aug 27, 2015), 229 pts were randomized (A: n = 116; B: n = 113). Mean % reduction in number of BCC lesions at wk 73 (ITT population) was 62.1% (Regimen A) vs 54.0% (Regimen B). Mean % reduction from BL in total size of 3 target lesions was 82.9% (Regimen A) vs 68.8% (Regimen B), with a higher proportion of pts in Regimen A (65.5%) experiencing ≥ 50% reduction in total number of BCCs (target and nontarget) vs pts in Regimen B (50.4%). Majority of pts in both regimens (A: 98.3%; B: 97.3%) reported a treatment-emergent adverse event (AE); most common were muscle spasms (A: 71.3%; B: 82.3%), dysgeusia (A: 65.2%; B: 66.4%), and alopecia (A: 62.6%; B: 64.6%). Majority of AEs in both regimens were grade 1-2. Treatment discontinuation rate was 44.0% (A) vs 50.4% (B), with AEs the main reason for discontinuation (A: 19.8%; B: 26.5%). Clinically meaningful improvement ( ≥ 10-point change from BL) in all Skindex-16 QoL domains was noted for both regimens. Conclusions: Both treatment regimens were efficacious, with treatment interruptions not appearing to affect efficacy in either regimen. Regimen A was associated with numerically better outcomes in terms of efficacy and discontinuation rate. The safety profiles of both regimens were similar and consistent with previous clinical experience. Clinical trial information: NCT01815840.
Comprehensive mutation profiling and treatment choices of 111 Chinese advanced lung cancer patients in the real world setting.
Authors: Xiaorong Dong, Gang Wu, Lingjuan Chen, Ruiguang Zhang, Pengcheng Li, Fan Tong, Jihua Dong, Rongrong Chen, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2018)

e21201 Background: NCCN guidelines have advocated broad molecular profiling as a part of the standard diagnostic assessment for advanced non–small cell lung cancer (NSCLC), for identifying driver mutations that may guide effective therapies. However, adherence to genomic testing guidelines and treatment choice may present challenges in the real world setting. Methods: A total of 111 advanced lung cancer patients were consecutively enrolled in this prospective real world study from June 2017 to January 2018. Tissue biopsy was the first choice for mutation profiling, and ctDNA testing was used as an alternative. All samples were analyzed by next-generation sequencing (NGS) across 1021 genes based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations. Results: Among the 111 patients, 75 (67.6%) patients were treatment naïve and 36 (32.4%) were progressed after first line systemic treatment. For the treatment naïve patients, 63 (84.0%) had tissue biopsy sufficient for NGS sequencing, whereas only 20 (55.6%) treated patients had qualified tissue samples for mutation profiling. The most frequently mutated genes in the two groups were different. For the treatment naïve group, most frequently mutated genes were TP53 (46), EGFR (37), SMARCA4 (17), FAT1 (9), MLL3 (9), KRAS (7). However, for the treated group, the most frequently mutated genes were EGFR (26), TP53 (20), ALK (4), GNAS (4) and MTOR (4). In terms of treatment choice, for the 34 patients with EGFR driver mutation, 20 (58.8%) took EGFR-TKI as the first line therapy. However, for the 4 patients with ALK fusion, only 1 (25%) took ALK-TKI as the first line therapy. Further follow-up were undergoing for the assessment of therapeutic efficacy. Conclusions: Insufficient tissue, and patients’ reluctance for repeat biopsies might be of major challenges for comprehensive mutation profiling. ctDNA based “liquid biopsies,” may obviate the need of tissue biopsy samples in select settings. Moreover, access to and acceptance of targeted therapies need improvements in order to increase guideline adherence.
Evolution of radiomic features on serial CT scans as an imaging based biomarker for evaluating response in patients with non-small cell lung cancer treated with nivolumab.
Authors: Yuanqi Xie, Monica Khunger, Rajat Thawani, Vamsidhar Velcheti, Anant Madabhushi
Journal: Journal of Clinical Oncology (2017)

e14534 Background: Nivolumab is a PD-1 inhibitor that is FDA approved for treatment of chemotherapy refractory advanced NSCLC. The current standard clinical approach to evaluating tumor response is sub-optimal in evaluating clinical benefit from immunotherapy drugs. Our study aims to explore whether changes in radiomic features of the tumor between baseline and 2-week post-treatment CT scans can predict treatment response. Methods: 41 NSCLC patients treated with nivolumab were included in this study. 22 patients with pre- and post-nivolumab CT scans were used as a learning set and the remaining 19 for independent testing. Patients who did not receive nivolumab after 2 cycles due to lack of response or progression as per RECIST were classified as ‘non-responders’, and patients who had radiological response as per RECIST, or stable disease as per RECIST and clinical improvement were classified as ‘responders’. Lung nodules on pre-treatment CT scans were annotated with 3D SLICER software by a radiologist. 312 texture features of lung nodules were extracted and investigated in the study. The percent difference of each extracted feature was calculated based on the baseline and 2 week post-therapy CT scan. In the learning set, the six features that most significantly changed between baseline and post-treatment scans and also maximally differentially expressed between responders and non-responders were identified. Unsupervised clustering was applied on the set of 6 features for the 19 patients in the test set to predict which patients did and did not respond. Results: The top 6 features predictive of response corresponded to the Haralick, Gabor and Laws texture families. Unsupervised clustering yielded an accuracy of 78.95%. Conclusions: Our results suggest that changes in certain radiomic texture features between baseline and post-treatment CT scans following nivolumab could identify early clinical response to treatment. Additional validation of these novel quantitative imaging based approaches is warranted to accurately define clinical benefit from immunotherapy.
Phase I results of CAM-H2: Safety profile and tumor targeting in patients.
Authors: Marleen Keyaerts, Jens De Vos, Francois P. Duhoux, Vicky Caveliers, Christel Fontaine, Marjan Vanhoeij, Matthias D'Huyvetter, Hendrik Everaert, Pieterjan Ghykiere, Nick Devoogdt, Geert Raes, Tony Lahoutte
Journal: Journal of Clinical Oncology (2018)

e13017 Background: CAM-H2 is a targeted radionuclide therapeutic drug (TRNT) directed at HER2 expressing cancers. The drug is a single domain antibody fragment (sdAb) covalently linked to the toxic radio-iodine (131I) via the linker SGMIB. The Phase I study was aimed to evaluate the safety, biodistribution, radiation dosimetry and tumor imaging potential of CAM-H2 in healthy volunteers and breast cancer patients. Methods: In a 1st cohort, we included 6 healthy volunteers for the assessment of safety, biodistribution and radiation dosimetry. CAM-H2 was administered intravenously at a low radioactivity level (38MBq +- 9MBq) allowing total body gamma camera imaging of the distribution of CAM-H2. Images were acquired at 40 min, 2, 4, 24 and 72 h post-injection. Blood and urine samples were obtained for safety and PK analysis. Images were analyzed by drawing region of interest around major organs to measure the radioactivity accumulation. Data were processed using OLINDA to obtain the dosimetry of healthy tissues. In the 2nd cohort, we included 3 patients with advanced HER2 positive breast cancer. Whole body gamma camera imaging and SPECT imaging of cancer lesions was performed at 2h and 24h post-injection. Results: No drug related adverse events were measured throughout the study. CAM-H2 showed a rapid tissue distribution after intravenous administration and a blood elimination half-life of 2.5 h. The biological half-life in healthy subjects was 12h. The drug is primarily eliminated via the kidneys. Thyroid and stomach show no specific accumulation. Dosimetry analysis showed very low exposure towards bone marrow (0,03 mGy/MBq +-0,01 mGy/MBq) while kidney has a dose level of 1,54 mGy/MBq (+- 0,25 mGy/MBq) in female subjects. SPECT imaging in patients with advanced breast showed focal uptake of CAM-H2 in metastatic lesions. Conclusions: CAM-H2 is safe and concentrated in cancer lesions of advanced HER positive breast cancer patients while unbound drug is rapidly eliminated via the kidneys. The dosimetry of CAM-H2 will allow administration of high radioactivity therapeutic doses with a minimum risk of toxicity. Clinical trial information: NCT02683083.
Efficacy of milciclib (PHA-848125AC), a pan-cyclin d-dependent kinase inhibitor, in two phase II studies with thymic carcinoma (TC) and B3 thymoma (B3T) patients.
Authors: Benjamin Besse, Marina Chiara Garassino, Arun Rajan, Silvia Novello, Julien Mazieres, Glen J. Weiss, Darren M. Kocs, John Mark Barnett, Cristina Davite, Patrizia Crivori, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2018)

8519 Background: Thymic carcinoma (TC) and B3 thymoma (B3T) are rare malignant tumors of the thymus. While TC, a highly aggressive and easily metastasizing cancer, has a very poor prognosis, B3T is a slow-growing cancer. Milciclib, a pan inhibitor of cyclin D-dependent kinases, Src and other kinases, exhibits antitumor activity against a number of solid tumors. Objectives of these studies were to evaluate efficacy and safety of oral treatment with milciclib in TC/B3T patients (pts). Methods: Two separate phase 2 multi-centered clinical trials (CDKO-125A-006: 72 pts, previously treated with one chemotherapy and CDKO-125A-007: 30 pts, previously treated with multiple chemotherapies) were conducted in the USA, France, and Italy. The proportion of patients with B3T and TC were 27.8% and 72.2% (CDKO-125a-006) and 56.7% and 43.3% (CDKO-125a-007), respectively. Milciclib was orally administered (150 mg daily; 1 cycle is 7d on/7d off) for multiple cycles. Progression-Free Survival rate at 3 months (PFS-3) was the primary endpoint. Results: Oral treatment with milciclib met PFS-3 as primary endpoint and OS as a secondary endpoint in both phase 2 trials. Five pts in CDKO-125A-006 and 2 in CDKO-125A-007 continued with treatment over 2 years and 2 of them over 5 years. 46.1% of pts in both studies experienced at least one AE. Common Grade 3-4 hematological and other toxicities were neutropenia (8.4%), creatinine, amylase, lipase increase (5.6%), nausea and asthenia (8.3%). The AEs leading to discontinuation were 12.7% for both studies. Clinical trial information: NCT01011439 and NCT01301391. Conclusions: Oral treatment with milciclib was safe and well-tolerated and met primary and secondary endpoints, achieving disease stabilization in a majority of TC/B3T patients. Treatment Efficacy CDKO-125a-006 CDKO-125a-007 Primary endpoint: PFS-3 > 17% evaluable pts Primary endpoint: PFS-3 > 40% evaluable pts Evaluable (n = 54) Treated (N = 72) Evaluable (N = 24) Treated (N = 30) PFS-3 (%) 44.4 41.7 54.2 46.7 Median PFS (mos) 6.83 5.78 9.76 5.65 Median OS (mos) 24.18 24.44 Not reached 21.03 Stable Disease (SD) ((%) 72.2 68.1 79.2 66.7 DCR (CR+PR+SD) (%) 75.9 72.2 83.3 70.0 ORR (%) 3.7 4.2 4.2 3.3
Comprehensive genomic profiling of brain tumors to provide targeted therapy options and diagnostic certainty for oligodendrogliomas.
Authors: Lee A. Albacker, Dean Pavlick, Jeffrey S. Ross, Glenn Jay Lesser, Robert John Corona, Howard Colman, Morris D. Groves, Sigmund H. Hsu, Andrew S. Chi, Vincent A. Miller, Garrett Michael Frampton, Shakti Ramkissoon
Journal: Journal of Clinical Oncology (2018)

2039 Background: Genomic profiling of gliomas is vital to ensure diagnostic accuracy, inform prognosis, and identify therapeutic options for primary and recurrent tumors. The integration of genomic biomarkers into brain tumor classification has advanced the development of molecularly stratified clinical trials and the need to characterize tumors by genomic signature. Methods: Comprehensive genomic profiling (CGP) was performed on FFPE material from 6304 consecutive cases of pediatric and adult brain tumors initially diagnosed by submitting institutions based on histology. We analyzed tumors via CGP in 395 cancer-associated genes (including IDH1/2) and for 1p/19q codeletion using a validated algorithm. Results: Of 6304 brain tumor samples, known IDH point mutations included 1182 IDH1 R132, 50 IDH2 R172, and 1 IDH2 R140 variants. In the IDH-mutant cohort, 1p/19q codeletion was detected in 72% (260/363) of histologically defined oligodendrogliomas (ODGs), 21% (17/82) of oligoastrocytomas (OAs), 6% (22/360) of glioma (NOS, not otherwise specified), 4% (2/50) of gliosarcomas, 3% (26/859) of astrocytomas (NOS), and 1% (32/3200) of glioblastomas. ODG with 1p/19q loss were enriched for TERT, CIC, and FUBP1 alterations, whereas 1p/19q intact tumors were enriched for TP53 and ATRX alterations. Actionable alterations in ODG included 8% (29/363) with high tumor mutational burden (potential immunotherapy responsiveness) and 15% (56/363) with PIK3CA mutation. Analysis of OA (mixed glioma) revealed genomic subtypes similar to well-defined gliomas including ODGs (IDH-mutant, 1p/19q loss, TERT, CIC, FUBP1), diffuse astrocytomas (IDH-mutant, TP53, ATRX), and high-grade gliomas (IDH-wild-type, EGFR, NF1). Conclusions: Using co-occurring IDH mutation and 1p/19q codeletion as the diagnostic signature of ODG, we show that as many as 25% may be misclassified on morphologic criteria alone. OAs exhibit genomic features of defined glioma subtypes, suggesting CGP may provide diagnostic clarity in this setting. This study highlights how CGP can improve diagnostic accuracy and provide additional treatment options for patients.