tbuckley/cabot-search huggingface dataset:
Molecular-based classification algorithm for endometrial carcinoma to categorize ovarian endometrioid carcinoma into prognostically significant groups.
Authors: Carlos Parra-Herran, Jordan Lerner-Ellis, Bin Xu, Dina Bassiouny, Matthew Cesari, Nadia Ismiil, Sharon Nofech-Mozes
Journal: Journal of Clinical Oncology (2017)

e17081 Background: The Cancer Genome Atlas classification divides endometrial carcinoma in biologically distinct groups, and testing for p53, mismatch repair proteins (MMR) and polymerase ɛ (POLE) exonuclease domain mutations has been shown to predict the molecular subgroup and clinical outcome. While abnormalities in these markers have been described in ovarian endometrioid carcinoma (OEC), their role in predicting its molecular profile and prognosis is still not fully explored. Methods: OECs resected in a 14 year period were retrieved. Only tumors with confirmed endometrioid histology and negative WT1 were included. POLE mutational analysis and immunohistochemistry for p53, MLH1, MSH2, MSH6 and PMS2 was performed in formalin-fixed, paraffin-embedded tissue. Following the molecular classifier proposed for endometrial carcinoma ( B J Cancer 2015;113:299-310), cases were classified as: POLE mutated, MMR abnormal, p53 abnormal and p53 wild type. Clinicopathologic information was recorded including patient outcome. Results: 73 tumors were successfully reviewed and tested. Of these, 8 (11%) were POLE mutated, 6 (8%) were MMR abnormal and 17 (23%) were p53 abnormal; the remaining 42 cases (58%) were p53 wild type (no POLE, p53 or MMR abnormalities). Mean follow-up period was 69 months (median 62, range 1-179). The molecular classification was an independent predictor for disease free and overall survival on multivariate analysis (p = 0.005 and 0.045 respectively, Cox proportional hazard model). POLE mutated and MMR abnormal groups had 100% 5 year DFS and OS. p53 wild type cases had intermediate survival rates (86% DFS and OS). Conversely, the p53 abnormal group had worse outcomes with 42% DFS and 76% OS at 5 years. Conclusions: OEC can be classified into prognostically distinct subgroups by testing for molecular surrogates, akin to endometrial cancer. MMR and POLE alterations seem to identify a subset of ovarian endometrioid carcinomas with excellent outcome; conversely, abnormal p53 expression carries a worse prognosis. In the era of personalized medicine, the use of these markers in the routine evaluation of ovarian endometrioid tumors should be considered.
Liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) or gemcitabine plus cisplatin in advanced cholangiocarcinoma: The AIO-NIFE-trial, an open label, randomized, multicenter phase II trial.
Authors: Thomas Jens Ettrich, Andreas Wolfgang Berger, Thomas Seufferlein, Lukas Perkhofer
Journal: Journal of Clinical Oncology (2018)

TPS4145 Background: Biliary tract cancer (CCC) is associated with a poor prognosis due to mostly advanced stages at diagnosis. Overall survival does not exceed 6 months and the 5-year overall survival rate is less than 5% for patients with advanced or metastatic disease. Advanced CCC shows response to chemotherapy resulting in an improved disease control, improved survival and quality of life (QoL). In the ABC-02 phase III trial, gemcitabine combined with cisplatin compared with gemcitabine alone prolonged PFS (8.0 vs. 5.0 mo) and OS (11.7 vs. 8.1 mo) and is considered as standard of care. So far this regimen has not been compared with other active combination regimen. Irinotecan in combination with 5-FU showed promising results in 1st- and 2nd-line therapy in many GI cancers. In pancreatic adenocarcinomas, the combination of liposomal irinotecan (nal-IRI) plus 5-FU/LV improves survival in a post gemcitabine-based treatment setting. Our research hypothesis is that this regimen compares well with respect to clinical endpoints with the standard of care gemcitabine plus cisplatin in patients with advanced CCC. Methods: NIFE is a randomized study for patients (to be enrolled n = 92) with locally advanced or metastatic, non-resectable, intra- or extrahepatic cholangiocarcinoma): Arm A (experimental): Nal-IRI 80 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2, on day 1, cycle q2w), Arm B (standard): Cisplatin 25 mg/m2 and Gemcitabine 1000 mg/m2 on day 1 and 8, cycle q3w. NIFE is an open label, non-comparative, multicenter, two-sided phase II study with an unconnected analysis of the results in both arms against a fixed PFS rate ( < 40% at 6months). The randomization (1:1) is eminent to achieve two comparable patient groups. Primary objective is PFS at 6 months. Key secondary objectives are 3-year OS, PFS, ORR, DCR and QoL/TUDD. There will be a retrospective surgical and radiological review. Tissue and blood sample collection will be mandatory for biomarker analyses (microdissection and exome sequencing of tumor tissue, ctDNA exome sequencing, transcriptome, miRNA-arrays). Start was in Q I/2018 in 25 centers in Germany. Clinical trial information: NCT03044587.
Senescent fibroblasts drive ageing pigmentation: ​A potential therapeutic target for senile lentigo
Authors: Jung Eun Yoon, Yeongeun Kim, Soohyun Kwon, Misun Kim, Young Hwa Kim, Jang-Hee Kim, Tae Jun Park, Hee Young Kang
Journal: Theranostics (2018)

Cutaneous ageing is an important extrinsic process that modifies the pigmentary system.Because cellular senescence is a fundamental ageing mechanism, we examined the role of senescent cells in ageing pigmentation.Methods: Biopsies obtained from senile lentigo and perilesional normal skin were assayed for a marker of cellular senescence, p16 INK4A .To determine the secretory phenotypes of senescent fibroblasts, we performed microarray, RNA sequencing and methylation array analyses in senile lentigo and senescent fibroblasts.To further investigate the impact of senescent cells on ageing-related pigmentation, an intervention that targeted senescent cells using radiofrequency was performed.Results: In vivo, senescent fibroblasts accumulated at the sites of age-related pigmentation.Phenotype switching of the cells resulted in the repression of stromal-derived factor 1 (SDF1) by promoter methylation.SDF1 induced melanocyte differentiation via stromal-epithelial interactions, ultimately driving skin pigmentation.Furthermore, the elimination of senescent fibroblasts from pigmented skin using radiofrequency was accompanied by skin lightening, rendering it a potential target for treatment.Conclusion: Aged pigmented skin contains an increasing proportion of senescent fibroblasts.Cells with phenotype switching exhibited a loss of SDF1, which stimulates the melanogenic process and thereby contributes to aging pigmentation.These data may promote the development of new therapeutic paradigms, such as a stroma-targeting therapy for pigmentary disorders.
Three-field versus two-field lymphadenectomy for carcinoma of the middle and lower esophagus: Short-term results of a randomized controlled trial.
Authors: Bin Li, Haiquan Chen
Journal: Journal of Clinical Oncology (2017)

4036 Background: The safety and efficacy of esophagectomy with 3-field lymphadenectomy remain controversial. Methods: We did this randomized trial in Fudan University Shanghai Cancer Center in China. Between March 2013 and November 2016, 400 patients with cancer located in the middle and lower esophagus were recruited and randomly assigned to receive 3-field or 2-field lymphadenectomy at a 1:1 ratio. Postoperative complications between the 3-field group (n = 200) and 2-field group (n = 200) were compared on the basis of the intention-to-treatment principle. Results: There was no significant difference between the two arms in terms of gender, age, BMI, FEV1, and tumor location. Median operative time was 183 minutes (range 125 to 331) in 3-field group versus 168 minutes (range 116 to 375) in 2-field group, P&lt; 0.001. Overall morbidity was 28% (56/200) in the 3-field group and 30.5% (61/200) in the 2-field group, P= 0.583. The mortality rate was 0% (0/200) for the 3-field group and 0.5% (1/200) for the 2-field group, P= 1.000. Although more reintubation occurred in the 3-field group than in the 2-field group (3% [6/200] vs. 0% [0/200], P= 0.030), the distribution of severity (stratified according to the Clavien-Dindo classification) and hospital stay were similar between the two groups. A significantly higher number of lymph nodes were retrieved in the 3-field group (median 37, range 3 to 85) compared to those in the 2-field group (median 24, range 7 to 61) ( P&lt; 0.001). 44 patients (22%) had positive cervical nodes in the 3-field group. Conclusions: Morbidity after esophagectomy with 3-field lymphadenectomy is comparable with that after 2-field lymphadenectomy. Cervical lymphatic involvement is common in patients with middle and lower esophageal cancer. 3-field lymphadenectomy may offer more accurate tumor staging related to cervical lymphatic metastasis. TABLE. Regions of lymph nodes metastases Clinical trial information: NCT01807936. [Table: see text]
N-myristoyltransferase 2: A novel marker for colorectal cancer screening.
Authors: Jenny Rathinagopal, Shiby Kuriakose, Shiv Bhanot, Jordan Min, Nan Hu, Charles N Bernstein, John Fang, Tom H Greene, Shailly Varma Shrivastav, Harminder Singh, Anuraag Shrivastav
Journal: Journal of Clinical Oncology (2017)

e15114 Background: Colorectal cancer (CRC) is the second most common cause of cancer related deaths in North America. Most CRCs arise from pre-malignant adenomatous polyps with some of these polyps developing into cancer over years providing an ideal opportunity for detection and intervention. However, the unpleasant nature of the current screening methods often leads to non-compliance. N-Myristoyltransferase (NMT) has been reported to be overexpressed in CRC tissues. In this study we show that NMT2, an isoform of NMT, is overexpressed in peripheral blood mononuclear cells (PBMC) of individuals with colorectal adenomatous polyps or cancers compared to healthy controls. Methods: PBMC’s were isolated from blood samples of CRC patients (n = 14), individuals with - non-adenomatous polyps (n = 8); adenomatous polyps (n = 18) and healthy controls (n = 24). Immunohistochemistry (IHC) was used to determine the NMT2 expression in these samples. IHC-scores were derived from assessment of both staining intensity (scale 0-3) and percentage of positive cells (0-100%), which were multiplied to generate an IHC -score between 0-300. Observers calculating the IHC scores were unaware of the polyp/CRC status. A receiver operating characteristic (ROC) analysis was performed to assess the overall performance of the NMT2 test via the area under the curve (AUC). Results: NMT2 was significantly overexpressed in PBMC of CRC patients (median IHC score- 196) compared to control subjects (median IHC score- 50). In addition, IHC scores were significantly higher for adenomatous polyps (median IHC score- 165) compared to those with non-adenomatous polyps (median IHC score- 54.8). We included non-adenomatous polyps and healthy subjects in “controls” and adenomatous polyps in “cases” along with CRC in the ROC analysis. The ROC curve of NMT2 expression displayed substantial separation between controls/non adenomatous polyps compared to CRC/adenomatous polyps [AUC = 0.913 (95% CI: 0.830-0.994)]. Conclusions: Our results show an increase in NMT2 expression in PBMC of CRC patients and individuals with adenomatous polyps suggesting that NMT2 could be used as a novel blood based biomarker for the screening and early detection of CRC. Validation studies are the next step.
Cabozantinib in metastatic renal cell carcinoma (mRCC): Real world experience from the UK.
Authors: Alfonso Gomez de Liano, Balaji Venugopal, Kate Fife, Luma Khasti, Stefan N. Symeonides, Claire Pettinger, Thomas Powles, Sarah Maria Rudman, Naveen Vasudev, Ekaterini Boleti
Journal: Journal of Clinical Oncology (2018)

e16578 Background: The randomised phase III METEOR trial showed survival benefit of cabozantinib over everolimus in patients with mRCC who progressed after VEGF targeted therapy. We report real world experience in using Cabozantinib from 7 centres across the UK. Methods: From September 2016 to September 2017 patients received Cabozantinib, mainly within an EAP. The aim was to evaluate its use in real world clinical practice. Patients had PS ECOG 0-2, adequate organ function, and had relapsed after at least 1 prior systemic treatment. Dose reductions were allowed. Adverse events (AEs) were monitored and graded using the National Cancer Institute CTCAE v.4.0.3. Data was retrospectively collected. Results: 128 patients with mRCC were treated with Cabozantinib. Median age was 57 years (range 14-78), 87 (68%) were male, 93 (73%) had prior nephrectomy. Heng score at metastatic diagnosis was good for 35 (27%), intermediate for 62 (48%), poor for 27 (21%) and unknown in 4 cases. 107 (84%) had clear cell histology, 13 papillary, 2 translocation RCC, 1 sarcomatoid and was unknown for 5. 66 (52%) had metastatic disease at initial presentation. At the time of starting Cabozantinib, 92 (72%) had lung, 66 (52%) bone, 42 (33%) liver and 14 (11%) had brain metastases while 55 (43%) had nodal involvement. Patients received a median of 3 previous lines (2-6) of therapy. Cabozantinib was used as 2nd line in 56 (44%), 3rd line in 38 (30%), 4th line in 24 (19%), 5th in 6 (5%) and 6th line in 4 (3%) patients. 1 patient received Cabozantinib rechallenge as 5th line after 3rd line use in the METEOR trial. 71 patients (55%) had dose reductions, G3/G4 AEs were reported in 46 cases (36%), mainly fatigue (10%), diarrhoea (9%), mucositis (5%) and hand-foot syndrome (5%). 9 (7%) discontinued Cabozantinib due to toxicity. 99 patients were assessed for radiological response: 31.3% achieved partial response, 31.3% stable disease and 37.4% progressive disease. After a median follow-up of 6.0 months, and 42 events (33%), median OS was 7.7 months (7.0-8.4). Median PFS was 6.7 months (4.8-8.6). Conclusions: In real world practice, Cabozantinib appears safe with clinical activity, inmultiply treated patients outside a study setting. Survival outcomes are limited by the short follow up time
TAK-659 in combination with NKTR-214 and anti-PD-1 therapy leads to complete and sustained tumor regression and immune memory in pre-clinical syngeneic models.
Authors: Jie Yu, Jessica Huck Sappal, Mengkun Zhang, Karuppiah Kannan, Jonathan Zalevsky
Journal: Journal of Clinical Oncology (2018)

2567 Background: TAK-659 is a highly potent, reversible inhibitor of spleen tyrosine kinase (SYK) and fms related tyrosine kinase 3 (FLT3) that is being tested in combination with nivolumab in patients with advanced solid tumors (NCT02834247). NKTR-214, a CD-122-biased agonist that targets the IL-2 pathway, provides sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over T-regulatory cells in the tumor microenvironment, and is currently in multiple Phase I and II clinical trials in combination with checkpoint inhibitors (NCT02983045, NCT03138889). Treatment with TAK-659 in pre-clinical models resulted in a decrease in MDSCs and B220+ B-cells suggesting an immunomodulatory response, and the combination with anti-PD-1 therapy in pre-clinical in vivo models resulted in increased anti-tumor activity and durable complete responses. NKTR-214 monotherapy increases newly proliferative CD8+ T cells in tumors, increases cell surface PD-1 on immune cells and PD-L1 on tumor cells, and the combination with anti-PD-1 therapy shows marked efficacy in mouse syngeneic models. Methods: Here we explored the pre-clinical combination of TAK-659 with NKTR-214 in the presence or absence of anti-PD-1 therapy in multiple syngeneic tumor models. Results: TAK-659 in combination with NKTR-214 with or without anti-PD-1 therapy resulted in significant antitumor activity and durable complete tumor regressions. In the CT-26 murine colon cancer model, the TAK-659 + NKTR-214 or the triple combination with anti-PD-1 therapy resulted in 9 out of 10 mice having a maintained complete response (CR) 55 days post the end of treatment, versus 1 CR for TAK-659 or anti-PD-1 single agents, and none for NKTR-214 single agent. Complete responders, left untreated and re-challenged with another inoculation of tumor cells, did not form tumors, suggesting a potential immune memory. Conclusions: NKTR-214, TAK-659 and anti-PD-1 therapy bring together complementary non-overlapping mechanisms that create a promising potential therapy, supporting the rationale for examining the clinical combination.
TCT-122 Acute Kidney Recovery After Transcatheter Aortic Valve Replacement: A Report from the Northern New England Cardiovascular Disease Study Group
Authors: Amir Azarbal, David Malenka, Yi-Ling Huang, Cathy Ross, Richard Solomon, James DeVries, James Flynn, David Butzel, Matthew Mckay, Harold Dauerman
Journal: Journal of the American College of Cardiology (2018)
Geriatric oncology - lung adenocarcinoma in elderly patients undergoing systemic palliative treatment: Prospective analysis of clinical characteristics and survival outcomes.
Authors: Mauro Daniel Spina Donadio, Audrey Oliveira, Luciana Moura, Tiago Felismino, Victor Hugo Fonseca Jesus, Aldo A. Dettino
Journal: Journal of Clinical Oncology (2018)

e22027 Background: Elderly population requires special attention to chemotherapy risks and comorbidities, which may limit the capacity to deliver optimal cancer care. We aimed to describe the features and survival outcome of elderly patients (pts) with lung adenocarcinoma treated with non-curative intent at AC Camargo Cancer Center. Methods: We evaluated all pts aged 70+ with lung adenocarcinoma treated with chemotherapy or target therapy in 1st or 2nd-line from 2007 to 2015 who underwent a comprehensive geriatric assessment (CGA). We used summary statistics to describe the population. Overall survival (OS) was calculated according to Kaplan-Meier method. We performed univariate and multivariate analysis to look for potential prognostics factors for OS. Results: 54 pts aged ≥70y with lung adenocarcinoma submitted to CGA. The median age was 76y and 22% had ECOG ≥ 2. Half of pts were male. 51% had polypharmacy (≥5 drugs). Pts were functionally classified according to activities of daily living (ADL): 76% as Katz A and 50% as Lawton ≤27. 68.5% were at risk for malnutrition or malnourished. The median age-adjusted Charlson Comorbidity score was 10. 61.1% had ≥2 comorbidities and 26 patients had at least 2 metastatic sites. CNS was affected in 7.5% of the cases and liver in 9.2%. 79.6% of the patients underwent chemotherapy and the others received target therapy. After follow-up of 29m, median OS was 17.1 months (13.5-27.8m). In univariate analysis, significantly worse survival outcomes were observed for patients with ECOG 2-4 (HR 10.6; p < 0.001), increasing number of sites of metastases (HR 2.2; p = 0.04) and hepatic metastasis (HR 6.03; p < 0.001). In the multivariate analysis, male gender, ECOG 2-4 and liver metastasis were associated with higher risk of death. Conclusions: ADL showed little prognostic value in our small population. Patients with ECOG 2-4 or hepatic metastasis were those that presented the highest risk of death.
Real-world prescribing patterns in acute myeloid leukemia in the United States.
Authors: Bruno C. Medeiros, Bhavik J. Pandya, Anna Hadfield, Samuel Wilson, Cynthia Mueller, Tom Bailey, Scott Flanders, Laura E. Horvath, Alex Rider
Journal: Journal of Clinical Oncology (2017)

e18524 Background: The effective treatment of patients with acute myeloid leukemia (AML) remains a challenge in clinical practice. This analysis describes the patient characteristics and real-world use of AML treatments in the United States for patients on high- and low-intensity treatment. Methods: Data from the Adelphi AML Disease-Specific Programme, a real-world, cross-sectional survey conducted between February–May 2015, were analysed. A total of 61 hematologist/hem-oncologists, across academic, non-academic and office-based practice locations, provided data on 457 AML patients. Patient characteristics were derived from physician-completed patient record forms where each physician was asked to provide treatment details, including the treatment intensity, for each line of therapy. Results: A total of 91% (n = 415) of patients included in this analysis were previously untreated for AML. Patients had a mean age of 60 years and been diagnosed with AML for a median of 5.0 months. At first-line induction therapy, over half (53%; n = 241) of the patients were initiated on a high-intensity treatment, the most common regimen being cytarabine plus anthracycline (61%; n = 147). The remaining 47% (n = 216) of patients received a low-intensity induction therapy such as low dose cytarabine monotherapy (28%, n = 61), azacitidine monotherapy (25%, n = 54), or decitabine monotherapy (21%, n = 45). Over half (55%, n = 62) of patients suited to high intensity treatment went on to receive cytarabine monotherapy during the consolidation phase of their first-line treatment. Conclusions: According to treating physicians, the large majority of patients receive traditional, well-established therapies at first-line induction for AML. Whilst cytarabine combinations dominate the high-intensity treatment setting, the hypomethylating agents, azacitidine and decitabine, are frequently used for those more suited to low-intensity treatment.
Abstract 16831: β-Arrestin-Biased β2-Adrenergic Receptor Activation Confers Cardioprotection in Ischemia/Reperfusion Injury
Authors: Laurel Grisanti, Claudio A de Lucia, Erhe Gao, Walter J Koch, Jeffrey L Benovic, Douglas G Tilley
Journal: Circulation (2017)

Introduction: β-Adrenergic receptors (βAR) are regulate cardiac function in the normal and failing heart. The β1AR subtype increases contractility and cardiomyocyte death whereas the β2AR promotes survival. Catecholamines increase in cardiac injury and downregulate β1AR thus, β-adrenergic receptor antagonists or β-blockers are commonly used to restore β1AR expression and preserve contractility. However, promoting the pro-survival effects of β2AR, which are known to occur in part through β-arrestin (ARR)-dependent signaling, may be a beneficial therapeutic strategy. Pepducins have been developed based on the intracellular loop (ICL) domains of β2AR to activate either Gαs- or βARR-dependent β2AR signaling pathways. Hypothesis: Pepducin-mediated engagement of βARR-dependent β2AR signaling in the heart would be therapeutically advantageous following ischemia/reperfusion (I/R) injury. Methods/Results: Wild-type (WT) mice received intracardiac injections of a βARR-biased pepducin (ICL1-9) or a scrambled control...