tbuckley/cabot-search huggingface dataset:
Sustained Gas6/AXL signaling network in the mes subtype of ovarian cancer as a molecular subtype specific therapeutic target.
Authors: Ruby Yun-Ju Huang, Jane Antony, Tuan Zea Tan, Zoe Kelly, Hani Gabra, Chiara Recchi, Jean Paul Thiery
Journal: Journal of Clinical Oncology (2016)

e17084 Background: Ovarian cancer (OC) is a complex disease demonstrated by the heterogeneity in gene expression molecular subtypes (GEMS). To address the GEMS-specific lethality in OC, we highlight the relevance of how a receptor tyrosine kinase (RTK) differs in the signaling pattern, functional consequences, and therapeutic implications in the context of GEMS. Methods: An enrichment analysis of the human kinome among the OC GEMS was performed to identify top ranking RTKs in each GEMS. A top-ranking RTK for the Mes subtype, AXL, was selected for further studies. AXL activation in GEMS-matched OC cells were analyzed for the downstream signaling cascade by western blotting and Reverse Phase Protein Analysis (RPPA), and in vitro functions. A selective inhibitor to AXL was tested for the attenuation of downstream signaling and functional aggressiveness. Results: AXL is the top-ranking RTK for the poor prognosis Mes subtype. Interestingly, AXL is also expressed, at a lower rank, in the better prognosis Epi-A subtype. Upon ligand stimulation with Gas6, specific to Mes, there is recurrent temporal activation of the extracellular regulated kinase (ERK) signaling downstream of AXL observed by Western blotting. RPPA and proximity ligation assays further show that Gas6/AXL signaling transactivates other RTKs such as cMET, EGFR, and HER2 in Mes, exclusively. This signal amplification downstream to the Gas6/AXL axis alludes to pathway addiction in Mes. Functionally, the recurrent ERK activation results in a motile and invasive phenotype. This further sensitizes Mes to a selective AXL inhibitor, R428, by attenuating the RTK-ERK activation, reducing the in vitro motility and invasion, and inhibiting the in ovo tumor growth in the chick chorio-allantoic membrane (CAM) assay at a lower IC-50 dose compared to Epi-A. Conclusions: Our results imply that the Mes subtype is more sensitive to AXL inhibition, and the RTK crosstalk rewires the system, drastically sensitizing it to RTK node inhibition. The Epi-A subtype retain a linear signaling axis and shows less therapeutic advantage to targeting AXL. Stratifying OC patients based on the GEMS followed by targeting AXL is promising in a prospective clinical setting.
Escape of gastric cancer cell from metabolic stress via DLC3/MACC1 axis.
Authors: Li Lin, Changqie Pan, Xiaoyin Li, Yantan Liu, Chunlin Wang, Yang Zhao, Min Shi, Wangjun Liao
Journal: Journal of Clinical Oncology (2017)

e15550 Background: Metabolic stress usually occurs in rapidly proliferating cells when energy demand exceeds supply. Interestingly, cancer cells can somehow sustain the stress and get rid of it. The mechanisms remain unclear. Previously we discovered that MACC1 is an oncogene promoting gastric cancer (GC) growth and metastasis. Besides, it is upregulated by metabolic stress and promotes glycolysis [2014 ASCO annual meeting abstract e15054 &amp; Oncogene 2015;34(21)]. In current study, we aim to further discover how it helps GC cell metabolize and metastasis. Methods: MACC1 and its correlated gene expression were analyzed via immunohistochemistry staining in GC patients. The mRNA and protein expressions were evaluated under glucose deprivation-induced metabolic stress in human GC cell lines. Cell metabolism, motility, invasiveness and viability were analyzed in GC cells. Promoter luciferase assay and Electrophoretic mobility shift assay (EMSA) were performed to confirm the transcriptional regulatory signals. Results: MACC1 expression is found to be negatively correlated with DLC3 in GC patients and DLC3 low expression indicates an adverse prognosis. Silencing DLC3 significantly promotes MACC1 expression, while silencing MACC1 showed no influence on DLC3, indicating that DLC3 is an upstream regulator of MACC1. Intriguingly, DLC3 is found significantly downregulated under metabolic stress in GC. Silencing DLC3 promotes GC migration and invasion via epithelial to mesenchymal transition (EMT), whereas overexpressing DLC3 demonstrates opposite functions. Moreover, DLC3 suppresses GC cell glycolysis but increases reactive oxygen species production and the mitochondrial membrane potential, which lead to more apoptosis. These DLC3 suppressive effects on GC are reversed by MACC1. Promoter luciferase assay and EMSA show that DLC3 inhibits MACC1 expression in a transcriptional manner, which is regulated via RhoA/JNK/c-JUN signaling. Conclusions: Metabolic stress transcriptionally upregulates MACC1 expression by suppressing DLC3, which facilitates GC glycolysis and metastasis. DLC3/MACC1 axis is one of the mechanisms that help GC cell escape from metabolic stress.
Management of breast cancer with leptomeningeal disease: Is there a role for high dose intravenous methotrexate? The Medical College of Wisconsin’s single institution experience.
Authors: Jonathan Thomas Kapke, Robert John Schneidewend, Zeeshan Ali Jawa, Chiang-Ching Huang, Jennifer Marie Connelly, Christopher R. Chitambar
Journal: Journal of Clinical Oncology (2018)

e14018 Background: Leptomeningeal metastasis (LM) in breast cancer is associated with significant morbidity and mortality. While there is currently no standard therapy, treatment options include craniospinal radiotherapy, intrathecal chemotherapy and systemic chemotherapy. Craniospinal radiotherapy has not demonstrated improved survival and intrathecal chemotherapy is often poorly tolerated due to associated neurotoxicity. The use of systemic chemotherapy can be limited by inadequate central nervous system (CNS) penetration. High-dose systemic methotrexate (HD-MTX) achieves adequate CNS penetration, and it has been reported to both improve quality of life and provide durable remissions for LM in breast cancer. Methods: Breast cancer patients with LM were identified using clinical databases. Patient and disease characteristics were collected. Results: Seventeen patients with breast cancer and clinical diagnosis of LM were identified. Univariate analysis of patient characteristics revealed that hormone receptor type and treatment received were associated with overall survival, p-value 0.04 and 0.03 respectively. The median overall survival from LM diagnosis to date of death or last follow up (OS) for all patients was 8.4 months. For those who received HD-MTX (8g/m2every 2-3 weeks for up to five cycles, n = 7), craniospinal radiotherapy (n = 4) or other therapies (n = 6), the OS was 20.7, 3.6 and 12.7 months respectively. The median OS for HD-MTX trended towards statistical significance when compared to craniospinal radiotherapy or other therapies. Four patients were alive with stable disease at the time of data extraction. Three of the four patients received HD-MTX, and of these three patients, the OS was 13, 24 and 27 months. Conclusions: HD-MTX is a viable treatment option for LM in breast cancer. When compared to craniospinal radiotherapy or other therapies, treatment with HD-MTX trends towards an improved OS, and in certain patients, HD-MTX can achieve long-term survival.
Abstract 18061: Predictors of Hospitalization or Death Due to Heart Failure in Diabetic Patients by Gender in the ACCORD Trial Using Random Survival Forests
Authors: Tejas Patel, Shamsuzzaman, Colin Wu, Eileen Navarro Almario, Bereket Tesfaldet, Jerome Fleg, Gyorgy Csako, Charu Gandotra, George Sopko, Helena Sviglin, Sean Coady, Keith Burkhart, Karim Calis, Lawton Cooper, Neha Amin, Avantika Banerjee, Nashwan Farooque, Austin Taylor, Shivani Gupta, Andrew Dodge, Gauri Dandi, Laboni Hoque, Michelle Fennessy, Subha Raman, Ruth Kirby, Jue Chen, Ye Yan, Lijuan Liu, Eric Leifer, Henry Chang, Carlos Cure, Patrice Desvigne-Nickens, Ana Szarfman, Michael Domanski, Frank Pucino, Yves Rosenberg, Ahmed Hasan
Journal: Circulation (2017)

Background: Heart failure is an important cause of hospitalization and mortality in patients with type 2 diabetes (T2D). In a prior secondary analysis of publicly available ACCORD trial (NC062...
Cost‐savings of adalimumab in hidradenitis suppurativa: a retrospective analysis of a real‐world cohort
Authors: M. Argyropoulou, T. Kanni, M. Kyprianou, N. Melachroinopoulos, E.J. Giamarellos‐Bourboulis
Journal: British Journal of Dermatology (2018)

The introduction of adalimumab in the management of hidradenitis suppurativa (HS) raises questions regarding the cost‐efficacy of treatment. To explore cost‐efficacy of treatment with anti‐tumour necrosis factor (TNF) agents in a real‐world cohort. Patients with Hurley stage II and III HS with ≥ 1 year of follow‐up and at least three visits per year from September 2003 to December 2016 were analysed. Patient visits were divided into two categories – visits for treatment with agents blocking TNF or visits for other therapies. The cost of exacerbations was calculated based on the cost of items provided in current price lists or by the national health insurance agency in cases of hospitalization. Effectiveness of anti‐TNF agents was calculated by assessing containment of exacerbations. The primary study end point was the cost‐savings achieved using anti‐TNF agents. Overall, 1211 patient visits for 250 patients were analysed. Total containment of exacerbations was found in 25·1% of visits involving other therapies and in 63·4% of visits involving anti‐TNF agents. The cost‐savings per patient visit for patients receiving anti‐TNF agents vs. other therapies was €178·92. The odds ratio for the total containment of exacerbations among patients with Hurley stage II and III was 4·86 and 6·03, respectively (P =0·466). Treatment with anti‐TNF agents was an independent variable affecting annual cost as shown by two‐way analysis of variance. In Hurley stage III HS, mean annual cost was €8309·60 under other therapies compared with €3264·20 using anti‐TNF agents (P =0·004). Treatment with anti‐TNF agents achieves significant cost–benefit through containment of HS exacerbations. The efficacy of anti‐TNF agents was similar for both disease stages.
GP at Hand: NHS England upholds CCG’s objection to planned Birmingham expansion
Authors: Gareth Iacobucci
Journal: BMJ (2018)

NHS England has upheld an objection by clinical commissioners to a request from GP at Hand to subcontract its digital service from London to Birmingham, citing concerns about how patients will access screening services.

GP at Hand, run by an NHS general practice in Hammersmith in partnership with the technology company Babylon, offers patients GP consultations 24/7 on their smartphone or in person at five clinics in London. But it is keen to expand beyond the capital and submitted a request on 22 June to vary its subcontracting arrangements with Hammersmith and Fulham Clinical Commissioning Group (CCG) by adding a …
Phase I clinical trials evaluating olaparib in combination with radiotherapy (RT) and/or temozolomide (TMZ) in glioblastoma patients: Results of OPARATIC and PARADIGM phase I and early results of PARADIGM-2.
Authors: Anthony J. Chalmers, Susan Short, Colin Watts, Christopher Herbert, Anna Morris, Jamie Stobo, Garth Cruickshank, Laurence Dunn, Sara Erridge, Lisa Godfrey, Sarah Jefferies, Juanita Suzanne Lopez, Catherine McBain, Marc Pittman, Susan Dillon, Allan James, Stefan A Nowicki, Aiofe Williamson, Caroline Kelly, Sarah E. R. Halford
Journal: Journal of Clinical Oncology (2018)

2018 Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (O) has radio and chemosensitizing properties in GBM models. Clinical development of PARP inhibitor combinations has been restricted by exacerbation of hematological toxicity and acute radiation toxicity. We studied pharmacokinetics (PK), safety and toxicity of O with RT and/or TMZ in three phase I studies. Methods: OPARATIC determined PK of O (AZ tablet formulation) in core and margins of recurrent GBM and maximum tolerated dose (MTD) of O with 42 day cycles of daily TMZ. PARADIGM determined recommended phase II dose (RP2D) of O with 40 Gy 15 fractions of radiotherapy in newly diagnosed patients aged > 70. PARADIGM-2 comprises two phase I studies of O+RT (60 Gy 30#, MGMT unmethylated) or O+RT+TMZ (MGMT methylated) in newly diagnosed patients aged < 70. Results: OPARATIC: 48 patients recruited; 27 underwent surgery, 36 receiving O/TMZ were evaluable. O detected in 71/75 tumor core specimens (27 patients); mean conc. 588nM (97-1374nM), and 27/28 tumor margin specimens (10 patients); mean conc. 500nM (97-1237 nM). Myelosuppression necessitated intermittent O dosing. MTD defined as O 150 mg (OD) days 1-3 weekly plus TMZ 75 mg/m2 daily. For 36 evaluable patients receiving 0/TMZ, progression-free survival at 6 months was 39%. PARADIGM: 16 patients (median age 72) treated in four O dose cohorts. One DLT (agitation grade 3) recorded (cohort 3, 100 mg BID). RP2D of O +40Gy 5# in elderly GBM was 200 mg BID daily. Median overall survival 10.3 months (80% CI: 6.3 – 11.7 months) at 12.9 months median follow up. PARADIGM-2: 29 patients screened, 14 commenced study treatment. Three MGMT unmethylated patients completed cohort 1 (50 mg QID) with no DLTs and 4 recruited to cohort 2 (100 mg QID) with no DLTs to date. Seven MGMT methylated patients recruited to cohort 1 (100 mg x1 per week); 1 DLT reported to date (low platelets). Conclusions: O penetrates core and margins of recurrent GBM. Combination with TMZ requires intermittent dosing but is safe and well tolerated. Combination with radiotherapy is extremely well tolerated and randomized phase II evaluation is underway. Clinical trial information: NCT01390571.
Comparative effectiveness of FOLFIRINOX or nab-paclitaxel plus gemcitabine in locally advanced or metastatic pancreatic cancer: A population-based analysis.
Authors: Ying Wang, Leo Chen, Pierre Camateros, Sharlene Gill, Daniel John Renouf, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2016)

6561 Background: FOLFIRINOX (FFN), nab-paclitaxel plus gemcitabine (NG), and gemcitabine (gem) are 3 systemic therapies that provide clinically meaningful benefit to patients (pts) with unresectable pancreatic cancer (UPC). However, there are no clinical trials that directly compare the efficacy of all 3 regimens. Our aim was to examine and compare the real world effectiveness of these treatments. Methods: Pts diagnosed with UPC who initiated palliative first line chemotherapy from August 2014 to August 2015 at any 1 of 5 cancer centers in British Columbia were identified from the provincial pharmacy. Clinical, pathological, treatment, and outcome characteristics were compared. Results: A total of 150 pts were included: 53% men, 78% ECOG 0/1, 71% metastatic disease, and 41% alive at time of analysis with a median follow-up of 1 year. Pts who received FFN were younger (p < 0.001), in better performance status (p < 0.001), and had less disease burden at presentation (p = 0.049). Pts treated with FFN or NG experienced significantly longer median overall survival (OS) when compared to those treated with gem (7.8 vs 8.5 vs 3.1 months, respectively, p < 0.001). This observation persisted after adjusting for confounders such as age and ECOG (Table). Likewise, progression-free survival (PFS) was also longer among pts on FFN or NG in comparison to gem (Table). Pts on FFN and gem required dose modification earlier on treatment than NG (14, 21, and 44 days respectively, p = 0.0407). Treatment discontinuation due to toxicities was common and occurred in 36%, 17%, 23% of cases on FFN, NG, and gem, respectively (p = 0.119). Conclusions: Delivery of FFN required early dose modification in the majority of pts. Receipt of modified FFN and NG portends a better prognosis than gem alone. In the absence of a randomized comparison of all 3 regimens, our population-based study reveals that the introduction of modified FFN and NG confers real world effectiveness for UPC pts. Treatment N Median Age HR OS P HR PFS P Gem 32 74 ref ref NG 59 69 0.156 (0.076 – 0.331) <0.001 0.327 (0.180 – 0.595) <0.001 FFN 59 63 0.224 (0.100 – 0.500) <0.001 0.420 (0.219 – 0.803) 0.009
Real life data of 601 patients from the QoliXane pancreatic cancer study.
Authors: Caroline Schoenherr, Thorsten Oliver Goetze, Gerrit zur Hausen, Alexander Reichart, Claudia Pauligk, Rudolf Schlag, Gabriele Margareta Siegler, Steffen Doerfel, Ali Aldaoud, Lars Hahn, Joerg Ernst Albert Schubert, Mark-Oliver Zahn, Heinz-Gert Hoeffkes, Marcel Reiser, Michael Koenigsmann, Wolfgang Blau, Jens Uhlig, Nils Homann, Jorg Trojan, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2018)

e16248 Background: Nab-paclitaxel/gemcitabine (NPG) is standard first-line therapy for metastatic pancreatic cancer. Based on this, our study group has established the observational QoliXane study that transitioned into the prospective PARAGON registry for a whole life observation of the clinical course and QoL in metastatic pancreatic cancer patients. The aim is to deliver real life outcome data, quality of life (QoL) data and build a platform for translational research (TR). This is an interim analysis of our data focused on efficacy outcome. Methods: In this prospective, observational study, eligible patients were recruited after written informed consent from 95 German cancer centers. The course of therapy, efficacy-, QoL data (prior to and during therapy) and archival tumor material were prospectively collected. In the present analysis, efficacy endpoints were analyzed in the intention-to-treat population (ITT), defined as all patients who were enrolled. Results: 601 patients fulfilled the criteria of the ITT. Mean age was 69 y (39-86). At the time of analysis, 293 (48.8%) pts of the ITT were alive. Mean no. of metastatic sites involved was 2. Median no. of cycles administered was 4 (range 0-21). 270 (45%) pts needed any dose modification and 236 (39%) received further therapies beyond progression. 165 (28%) pts developed polyneuropathy of any grade. Median progression-free survival was 6 months (95% CI [5.16, 6.28]). Median overall survival (OS) was 10 months (95% CI [8.38, 10.36]). 1-year OS was 42%. Median survivals by ECOG PS of 0, 1, 2, and 3 were 11.2 months, 8.9 months, 5.2 months, and 2.1 months, respectively (p < .0001). Conclusions: The QoliXane/PARAGON study shows good real-life efficacy data for 1st line therapy with NPG that is at least as favorable as in the controlled pivotal study. In the expansion phase, QoliXane transitioned into “PARAGON”, covering the whole life clinical course of the patients and all treatments. Clinical trial information: NCT02691052.
Impact of individual comorbidities on post-transplant outcomes for elderly patients with non-Hodgkin lymphoma (NHL).
Authors: Andrew Ip, Jeffrey M. Switchenko, Michael Graiser, Jean Louise Koff, Vikas Anand Gupta, Mary Jo Lechowicz, Ajay K. Nooka, Jonathan L. Kaufman, Sagar Lonial, Edmund K. Waller, Amelia A. Langston, Zaid S. Al-Kadhimi, Vamsi Kota, William G. Blum, Rebecca B. Klisovic, Kristie A. Blum, Craig C. Hofmeister, Pamela Blair Allen, Christopher Flowers, Jonathon Brett Cohen
Journal: Journal of Clinical Oncology (2018)

e19509 Background: The Hematopoietic cell transplantation-comorbidity index (HCT-CI) predicts non-relapse mortality (NRM) and overall survival (OS) in NHL patients (pts) treated with autologous stem cell transplant (ASCT). It is not known which individual HCT-CI factors impact elderly NHL pts undergoing ASCT. Methods: We evaluated NHL pts age ≥ 60 years who received ASCT at Emory from 2010-2017. Outcomes included hospital readmission up to 30 and 100 days after ASCT, and complicated hospitalization (CH), defined as ICU stay or significant organ dysfunction. Obesity was defined as BMI > 35 in HCT-CI; BMI > 30 was also included as a predictor. OS and relapse-free survival (RFS) were examined using Kaplan-Meier and Cox hazards methods. Competing risk analysis assessed NRM rate. Categorical and numerical variables were compared using chi-squared or Fisher’s exact tests, as well as ANOVA. Results: We included 162 pts (48% diffuse large B-cell, 27% mantle cell, and 26% other). Median age was 66 (38% age 65-70, 17% age > 70). 94% pts had KPS ≥ 80. Common conditioning included BEAM (68%) and Bu/Cy/VP-16 (25%). 42% pts were high-risk by HCT-CI (score ≥3), with 30% low-risk (score 0). Pulmonary (34%), cardiac (27%), diabetes (16%), psychiatric (11%), and obesity (9%) comorbidities were common; 29% had BMI > 30. Overall 12 month NRM rate was 11%. Psychiatric comorbidity was associated with increased 30-day readmission rate (35% vs 10% for pts with no psychiatric comorbidity, p = 0.01) and BMI > 30 with increased 100-day readmission rate (8.5% vs 0.8% p = 0.03). Increased CH occurred with diabetes (73% vs 39%, p = 0.001), psychiatric (71% vs 41%, p = 0.02), and overall HCT-CI risk (50% vs 29% high vs low, p = 0.04). Individual comorbidities associated with increased NRM were BMI > 30 (HR 2.47, 95% CI 1.06-5.73) and > 35 (HR 3.41, 95% CI 1.12-10.35), and diabetes (HR 2.45, 95% CI 1.05-5.74). No individual comorbidities predicted worse RFS or OS. Conclusions: Within the HCT-CI, diabetes and psychiatric comorbidity predicted CH and early readmission. Obesity predicted 100-day readmission and NRM. Further study is required to improve in- and post-hospital care of these pt populations.
Treatment monitoring of metastatic colorectal cancer by quantification and genotyping of mutated KRAS in circulating cell-free DNA.
Authors: Thomas Seufferlein, Daniel Schwerdel, Hanna Welz, Ralf Marienfeld, Stefan A. Schmidt, Alexander Kleger, Thomas Jens Ettrich, Andreas W. Berger
Journal: Journal of Clinical Oncology (2017)

e15037 Background: Treatment of stage IV colorectal cancer (mCRC) has made substantial progress over the last years but therapy monitoring still is in its early stage. A facile, non-invasive, repeatable assessment of the mutational state of a given tumor even during treatment could constitute a desirable biomarker for therapy stratification and disease monitoring. "Liquid biopsies" analyzing circulating free and circulating tumor DNA (cfDNA/ctDNA) from patients’ blood have been proposed as a a simple, non-invasive method that could fulfil this requirement. Methods: 27 patients with histologically confirmed mCRC were enrolled into a treatment surveillance cohort. For the analysis of concordance between tumor tissue DNA and cfDNA we analyzed 40 tissue and blood pairs from therapy naïve patients regarding their KRAS mutation status. The course of cfDNA values combined with targeted genotyping of KRAS mutations were assessed during several palliative chemotherapeutic regimens. cfDNA data were correlated with clinical parameters to establish its prognostic and predictive value. Results: Baseline cfDNA levels allow to significantly differentiate mCRC from healthy controls (14.23 ± 6.33 ng/ml vs. 2.60 ± 1.59 ng/ml; p &lt; 0.0001). cfDNA values at baseline in therapy naïve patients correlate well with tumor burden (p &lt; 0.05) and CEA levels (p &lt; 0.05). cfDNA values significantly increased upon disease progression during 1 st (p &lt; 0.01) and 2 nd line (p &lt; 0.05) treatment, enabling a non-invasive disease monitoring approach. Moreover, there was a significant correlation between the cfDNA levels upon treatment and progression-free survival (p &lt; 0.05). In addition, our data show that KRAS genotyping of cfDNA under therapy is feasible (80% blood-tissue concordance) and might benefit the patient due to early detection of therapy resistance. Conclusions: Repetitive quantitative and mutational analysis of cfDNA is likely to complement current diagnostic standards in stage IV CRC over the whole continuum of treatment.