tbuckley/cabot-search huggingface dataset:
Gemcitabine re-challenge in metastatic soft tissue sarcoma: A therapeutic option for selected patients.
Authors: Ana Sebio, Georgios Antoniou, Khin Thway, Aisha Miah, Shane Zaidi, Charlotte Benson, Winette TA van der Graaf, Robin Lewis Jones
Journal: Journal of Clinical Oncology (2018)

11559 Background: Treatment options for patients with metastatic sarcoma are limited. Gemcitabine-based schedules have shown activity and in selected patients, re-challenge with a previously successful gemcitabine-based regimen is common practice. There are no published data to support this practice. This study evaluates the efficacy and safety of gemcitabine re-challenge in advanced soft tissue sarcoma. Methods: A retrospective search of a prospectively maintained database was performed to identify patients re-challenged with gemcitabine-based chemotherapy (GBC) from 2003 to 2015. Baseline clinical characteristics, progression-free and overall survival were obtained from clinical records and response evaluation was performed by RECIST 1.1 criteria. Results: 29 patients were identified. The most frequent histology was leiomyosarcoma (n = 25, 86%). In the first GBC treatment, 86% (n = 25) of patients received gemcitabine-docetaxel and the others gemcitabine monotherapy. 38% (n = 11) of the patients received the first GBC as 1st treatment line, 45% (n = 13) as 2nd line and 17% (n = 5) as 3rd or further. The re-challenge GBC consisted of gemcitabine-docetaxel in 66% (n = 19) of the patients, gemcitabine monotherapy in 31% (n = 9) and gemcitabine-DTIC in 3% (n = 1) of the cases. Re-challenge GBC was administered as 2nd treatment line in 21% (n = 6) of the patients, as 3rd line in 34% (n = 10) and 45% (n = 13) of the patients received it in 4th or further line. In the evaluable patients (n = 28) the first GBC yielded a 55% response rate and after re-challenge GBC 26% (n = 6) of the evaluable patients (n = 23) responded. Progression-free survival was 11.1 months (95% CI, 7.2-11.9) for the first GBC and 5.3 months (95% CI, 2.0-7.5) in the re-challenge setting. Overall survival following gemcitabine re-challenge was 12.2 months (95% CI, 7.0-18.2). Regarding toxicity, 46 % of the patients (n = 12 of 26 evaluable) treated with re-challenge GBC presented grade 3-4 adverse events (CTCAE 4.03) and 31% of the patients needed a dose reduction. Conclusions: In selected sarcoma patients, re-challenge with a gemcitabine-based regimen can be considered as a treatment option in advanced disease at the expense of increased toxicity.
Comparative molecular analyses of <i>BRAF</i>-V600E mutant tumors: Colorectal cancers (CRC) vs. melanomas.
Authors: Shelly Ann Christiansen, Rebecca Feldman, Michael B. Atkins, Wafik S. El-Deiry, Ari M. Vanderwalde, Michael J. Pishvaian, Jimmy J. Hwang, Lawrence E. Flaherty, Crystal Shereen Denlinger, Sandeep K. Reddy, John Marshall, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2016)

3598 Background: Little is known about the molecular characteristics of BRAF mutant (mt) CRC. It is unknown whether BRAF mt CRC have molecular and biological profiles similar to BRAF mutant melanomas (Mel). Methods: A total of 5139 tumor samples (CRC, 4007 and Mel, 1132) submitted to Caris Life Sciences for IHC (protein expression), ISH (gene amplification), and NGS sequencing between 2009 and 2015 were retrospectively studied. Chi-square tests determined differences. Results: The rate of BRAF-V600E mutation was 7% in CRC (n = 270), and 30% in Mel (n = 334). Most frequently co-mutated genes in BRAF mt CRC were TP53 (56%), APC (26%), and PIK3CA (19%), and most frequently overexpressed proteins were TOP2A (90%), EGFR (77%), and cMET (57%). Most frequently co-mutated genes in BRAF mt Mel were CDKN2A (28%), ROS1 (19%), and TP53 (13%), and most frequently overexpressed proteins were PD1+ TILs (75%), and TS (71%). When compared with BRAF mt Mel, BRAF mt CRCs had a greater frequency of TP53 (56% vs. 13%), APC (26% vs. 3%), PIK3CA (19% vs. 1%), and SMAD4 (18% vs. 0%) mutations (all p-values < 0.01); however, mutations in CDKN2A (28% vs. 19%) and ROS1 (19% vs. 12%) appeared at higher rates in mt Mel (statistical significance not reached). BRAF mt CRC had a higher frequency of P-glycoprotein (PGP) (52% vs. 9%), cMET (57% vs. 13%), EGFR (77% vs. 6%), and HER2 (4% vs. 0%) overexpression (all p-values < 0.001), but lower PD1+ TILs (61% vs. 75%; p = 0.012) and ERCC1 (17% vs. 41%; p = 0.004) when compared with mt Mel. Co-occurring RAS mutations were rare, seen in 3 CRC and 2 Mel pts. MEK1 (1/31) and MEK2 (1/31) mutations were detected only in Mel. Mismatch repair deficiency and MSI were seen in 34% of BRAF mt CRC. On examining PD1+ TILs and PDL1 tumor expression in MSI-high (H) and MSI–stable (S) CRC, and comparing with Mel, PD1+ TILs were found in 75% of Mel, 80% of MSI-H CRC, and 56% of MSI-S CRC (Mel or MSI-H CRC vs. MSI-S CRC; p < 0.01). PDL1 was positive in 10% of MSI-H and 15.8% of MSI-S CRC and 15% of Mel. Conclusions: BRAF mt CRCmay carry molecular alterations that are distinct from BRAF mt Mel, suggesting different carcinogenic pathways, and potential resistance mechanisms. Drug combinations that target these alterations (e.g., cMET, EGFR) may warrant further investigation.
Optimal cut points for Ki-67 proliferative index in predicting survival in high grade neuroendocrine tumors.
Authors: Robert A. Ramirez, Brianne Voros, Katharine Thomas, Dipen Chandrakant Patel, J Philip Boudreaux, Ramcharan Thiagarajan, Eugene Woltering
Journal: Journal of Clinical Oncology (2018)

4103 Background: High grade (HG) neuroendocrine tumors (NETs) are rare neoplasms with limited literature regarding their prognostic course. HG-NETs generally demonstrate aggressive behavior. We hypothesized that patients diagnosed with HG-NETs with a Ki-67 proliferative index of ≥55% will have a worse prognosis. Methods: Records of patients with HG-NETs seen at our clinic between June 1, 2012 and June 1, 2017 were retrospectively reviewed. Demographics, pathologic characteristics, primary site and treatment data were collected. Overall survival (OS) was measured from date of high-grade diagnosis to either the date of death or the study cutoff date (December 31, 2017). Subset analysis was performed based on Ki-67 at initial HG-NET diagnosis ( < 55% or ≥55%) as well as Ki-67 at initial NET diagnosis ( < 20%, > 20-54%, or ≥55%). Results: Fifty-five patients were included in our study. Eleven patients were initially diagnosed with low/intermediate grade NETs (Ki-67 < 20%) and subsequently transformed to HG-NETs (Ki-67 > 20%) after progression. Median OS for the entire group was 18 months (m). The 6, 12 and 24m survival rate was 89%, 62%, and 40% respectively. A significant survival advantage was shown in patients with Ki-67 < 55% as shown in the table (p < 0.05) Survival did not vary significantly between primary tumor site. Low/intermediate (L/I) grade patients who transformed to HG-NETs had a median OS from HG diagnosis of 43m with 6, 12 and 24m survival rate of 100%, 82% and 64% respectively which was a significant compared to the entire cohort (p < 0.05). Conclusions: Using a Ki-67 value of 55% is useful in conferring prognosis in patients with HG-NETs. Interestingly, patients who were initially diagnosed with L/I grade NETs and transformed to HG survived longer than those with an initial HG diagnosis. Treatment options for HG-NETs should take into account Ki-67 values. Ki-67 Proliferative Index N Median OS (months) 6-month OS 12-month OS 24-month OS Ki67 < 55% 27 35 96% 74% 53% Ki-67≥55% 28 12 82% 50% 29%
Loss of placental growth factor ameliorates maternal hypertension and preeclampsia in mice
Authors: Jacqueline G. Parchem, Keizo Kanasaki, Megumi Kanasaki, Hikaru Sugimoto, Liang Xie, Yuki Hamano, Soo Bong Lee, Vincent H. Gattone, Samuel Parry, Jerome F. Strauss, Vesna D. Garovic, Thomas F. McElrath, Karen H. Lu, Baha M. Sibai, Valerie S. LeBleu, Peter Carmeliet, Raghu Kalluri
Journal: Journal of Clinical Investigation (2018)

Preeclampsia remains a clinical challenge due to its poorly understood pathogenesis. A prevailing notion is that increased placental production of soluble fms-like tyrosine kinase-1 (sFlt-1) causes the maternal syndrome by inhibiting proangiogenic placental growth factor (PlGF) and VEGF. However, the significance of PlGF suppression in preeclampsia is uncertain. To test whether preeclampsia results from the imbalance of angiogenic factors reflected by an abnormal sFlt-1/PlGF ratio, we studied PlGF KO (Pgf-/-) mice and noted that the mice did not develop signs or sequelae of preeclampsia despite a marked elevation in circulating sFLT-1. Notably, PlGF KO mice had morphologically distinct placentas, showing an accumulation of junctional zone glycogen. We next considered the role of placental PlGF in an established model of preeclampsia (pregnant catechol-O-methyltransferase-deficient [COMT-deficient] mice) by generating mice with deletions in both the Pgf and Comt genes. Deletion of placental PlGF in the context of COMT loss resulted in a reduction in maternal blood pressure and increased placental glycogen, indicating that loss of PlGF might be protective against the development of preeclampsia. These results identify a role for PlGF in placental development and support a complex model for the pathogenesis of preeclampsia beyond an angiogenic factor imbalance.
Prognostic role of saliva mass spectrometry in the development of suppurative-septic complications after surgical treatment of oral mucosa cancer.
Authors: Aleksey Yurievich Maksimov, Oleg Ivanovich Kit, Vladimir Kononenko, Ekaterina Komarova, Aleksandra Demidova
Journal: Journal of Clinical Oncology (2016)

e17527 Background: A high percentage of suppurative-septic complications in the postoperative period in patients with oral mucosa cancer makes it essential to search readily available diagnostic markers for their prediction. Methods: Saliva protein molecules were identified in 17 patients with oral mucosa cancer (T2N0-2M0) using MALDI TOF mass spectrometry. Patients were divided into two groups: the main group (n = 8) - patients with postoperative suppurative-septic complications. There were no infectious complications in the postoperative period of patients in the control group (n = 9). Statistical analysis of the results was carried out using Mann-Whitney criterion. Results: Molecular weight of most saliva peptides of patients in the groups under consideration ranged from 1000 to 7000 Da. Significant differences between the two groups were expressed by the intensity of 10 peaks attributable to 1062,104 Da (p = 0,004), 1454,178 Da (p < 0,0001), 2212,978 Da (p = 0,02), 2350,701 Da (p < 0,0001), 2621,386 Da (p = 0,004), 3016,108 Da (p = 0,001), 3154,378 Da (p = 0,02), 3163,407 Da (p < 0,0001), 5378,508 Da (p = 0,005), 5435,197 Da (p = 0,002), most expressed for proteins with molecular weight of 1454,178 Da, 2350,701 Da and 3163,407 Da. In the main group, for peptides 2212,978 Da, 2350,701 Da, 2621,386 Da, 3016,108 Da, 3154,378 Da, 3163,407 Da, 5378,508 Da, 5435,197 Da, there was a decrease in peaks (p < 0,05), and for proteins with molecular weight of 1062,104 Da, 1454,178 Da — an increase in peaks (p < 0,05) as compared to the control group. Identification of saliva peptides with mass spectra most distinctive in the intensity enabled to reveal that protein with molecular weight of 1454,178 Da protein was represented by SERPINA1 protein, with weight of 3163,407 Da - F2 Prothrombin precursor protein and weight of 2350,701 Da - Hypoxia Inductor Factors. Conclusions: Reduction in the intensity of the saliva mass spectrum for 2350,701 Da (p < 0,0001) and 3163,407 Da (p < 0,0001) proteins and increase in the spectrum amplitude for 1454,178 Da (p < 0,0001) peptide was a protein pattern associated with the development of suppurative-septic complications after surgical treatment of oral mucosa cancer.
Symptom burden and employment status in breast cancer (BC) survivors.
Authors: Ines Maria Vaz Duarte Luis, Anne M. O'Neill, Karen Sepucha, Kathy D. Miller, Chau T. Dang, Donald W. Northfelt, Eric P. Winer, George W. Sledge, Bryan P. Schneider, Ann Partridge
Journal: Journal of Clinical Oncology (2018)

10073 Background: At time of BC diagnosis, a large proportion of patients (pts) work. However, long term effects of BC and BC treatment are likely to impact employment status in follow up. Methods: The ECOG ACRIN protocol E5103 was a phase III trial that randomized BC pts to receive adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab or placebo. Telephone based surveys were administered to all pts enrolled between 01/Jan/10 and 08/Jun/10 as part of a Decision-Making/QOL component. Symptom burden was evaluated using the Memorial symptom assessment scale's (MSAS) global distress index (GDI), psychological and physical scores. Employment status was defined as 1) full time, 2) unemployed, disabled, medical leave 3) other (part time, homemaker, retired and other/unk). Results presented here are part of the 18 months (m) post enrollment follow up. Results: Of 519 pts who had not withdrawn at a time point prior to 18 m, pt reported outcomes (PRO) were available from 460 (88.6%). At enrollment (at least 1 m from primary surgery), 38% of pts were working full time and 19% were unemployed, disabled or on medical leave. At 18 m, 42% of pts were working full time, but 13% were unemployed, disabled or on medical leave. Pts who were unemployed, disabled or on medical leave reported significantly worse symptom burden -Table. Conclusions: Among pts enrolled in a randomized controlled trial and treated with contemporary adjuvant BC chemotherapy, persistent symptomatology was associated with negative employment outcome. Future strategies are needed to support BC survivors at risk of difficulties in job reintegration. Clinical trial information: NCT00433511.Employment by MSAS symptom burden* at 18 m. N Median Min Max P** GDI score Overall 460 0.6 0 3.3 No symptoms 74 Full time 193 0.5 0 3.1 < 0.01 Unemployed, disabled, medical leave 62 1.4 0 3.3 Others 205 0.6 0 3.3 Psychological score Overall 460 0.8 0 4.0 No symptoms 109 Full time 193 0.7 0 3.7 < 0.01 Unemployed, disabled, medical leave 62 1.7 0 4.0 Others 205 0.6 0 3.7 Physical score Overall 460 0.4 0 3.1 No symptoms 87 Full time 193 0.3 0 3.1 < 0.01 Unemployed, disabled, medical leave 62 0.9 0 2.8 Others 205 0.4 0 2.1 *PRO of how pt feels in past 7 days; score range 0-4; higher: worse QOL.**Wilcoxon rank sum test: full time vs unemployed, disabled, medical leave.
Immune microenvironment profiling of gastrointestinal stromal tumors (GIST).
Authors: Maria A. Pantaleo, Valentina Indio, Giuseppe Tarantino, Claudio Agostinelli, Milena Urbini, Margherita Nannini, Maristella Saponara, Chiara Castelli, Silvia Stacchiotti, Lidia Gatto, Donatella Santini, Antonio De Leo, Andrea Pession, Annalisa Astolfi
Journal: Journal of Clinical Oncology (2018)

11534 Background: GIST benefit from TK inhibitors but unfortunately can develop resistance or intolerance. Patients prolonged life expectancy associated with the complex biology involved in progressive disease led to a growing urgency and interest in developing new therapeutic strategies. Recently, few preclinical studies were conducted investigating the immunological profile in GIST. In the present study we analyzed GIST by whole transcriptome sequencing to estimate the gene expression signature, the presence of immune-infiltrate through in silico analysis, and to define the immunological profile of GIST as basis for immunotherapy . Methods: 18 fresh frozen GIST tumors (14 primary and 4 metastases) were analyzed. RNA-seq was performed with Illumina technology. Gene expression data was used to estimate the relative and absolute presence of 22 hematopoietic cell types in tumor microenvironment adopting CIBERSORT, an analytical tool suited to perform a deconvolution of neoplastic and tumor-infiltrating cells. The data were further processed to evaluate the enrichment of immune cell types, the correlation between cell subpopulations and to compare GIST microenvironment with other tumors. IHC tests for CD163, CD20, CD8 and TIA1 were performed and scored on FFPE samples. Results: A significant presence of immune-infiltrate in all GIST samples was confirmed, with a dominance of macrophages (M2 and M1), immediately followed by CD3+ T cells, both CD4+ and CD8+. Compared to other solid tumors, the immune profile of GIST appears similar to that of melanoma. The most relevant result is the high amount of CD8+ T-cells, suggesting that the adaptive immune response could be an immunotherapeutic target. The presence of CD8+ was confirmed by IHC that also showed the expression of citolytic markers (TIA1). Moreover the abundance of CD8+ T-cells correlated with the expression of IFN-gamma signature genes. Interestingly, the abundance of macrophages negatively correlates with T-cells presence (CD4+ and CD8+) supporting the dynamic balance between the immunosuppressive and active components of the immune-infiltrate. Conclusions: These findings represent a potential rationale to plan an immunotherapy approach along with TK inhibitors in GIST.
PIP5 Kinases Regulate Membrane Phosphoinositide and Actin Composition for Targeted Granule Secretion by Cytotoxic Lymphocytes
Authors: Christian M. Gawden-Bone, Gordon L. Frazer, Arianne C. Richard, Claire Y. Ma, Katharina Strege, Gillian M. Griffiths
Journal: Immunity (2018)

How cytotoxic T lymphocytes (CTLs) sense T cell receptor (TCR) signaling in order to specialize an area of plasma membrane for granule secretion is not understood. Here, we demonstrate that immune synapse formation led to rapid localized changes in the phosphoinositide composition of the plasma membrane, both reducing phosphoinositide-4-phosphate (PI(4)P), PI(4,5)P2, and PI(3,4,5)P3 and increasing diacylglycerol (DAG) and PI(3,4)P2 within the first 2 min of synapse formation. These changes reduced negative charge across the synapse, triggering the release of electrostatically bound PIP5 kinases that are required to replenish PI(4,5)P2. As PI(4,5)P2 decreased, actin was depleted from the membrane, allowing secretion. Forced localization of PIP5Kβ across the synapse prevented actin depletion, blocking both centrosome docking and secretion. Thus, PIP5Ks act as molecular sensors of TCR activation, controlling actin recruitment across the synapse, ensuring exquisite co-ordination between TCR signaling and CTL secretion.
Review: In hypertension, intensive BP goals reduce CV events; self vs office BP measures do not improve BP at 12 mo
Authors: James Brophy
Journal: Annals of Internal Medicine (2018)

Source Citation Reboussin DM, Allen NB, Griswold ME, et al. Systematic review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:2176-98. 29146534
A novel multi-functional KDM1A chemoprobe as a tool for clinical cancer research.
Authors: Filippo Ciceri, Serena Lunardi, Cristina Mascaró, Raquel Ruiz Rodriguez, Elena Carceller, Alberto Ortega, Tamara Maes
Journal: Journal of Clinical Oncology (2018)

e24242 Background: It is crucial for clinical studies to correlate the effects in patients with the degree of target inhibition. If biomarkers under the immediate control of the pharmacological target have been identified, transcriptomic and proteomic analyses are used, to indirectly evaluate enzymatic activity. However, during transcription and translation, multiple signals regulate mRNA and protein levels or modifications. For this reason, direct measurement of target inhibition is a preferable approach to detect target engagement. In oncology, targeted therapies are rarely administrated as single agents and their efficacy often depend on accurate patient selection. Chemoproteomics can provide a rationale for patient stratification and identification of novel potential combinatorial therapies. Methods: For the lysine demethylase 1A (KDM1A), a selective chemoprobe and a sensitive immunoassay were developed to measure the ratio between the free and inhibitor-bound enzyme. Free non-inhibited KDM1A was immobilized in an indirect sandwich ELISA using an ORY-1001-derived warhead linked to a biotin molecule by a polyethyleneglycol chain via a suitable linker. Similarly, total KDM1A was measured using a selective antibody. In human AML cells, the KDM1A chemoprobe was also used to purify protein complexes, for characterization by Mass Spectrometry analyses. Results: The luminescent readouts of the ELISA assays allow to calculate the fraction of inhibitor-bound KDM1A and the ratio of target engagement. This system was successfully applied for pharmacokinetic/pharmacodynamics modeling in both pre-clinical and clinical settings. Chemoproteomics studies showed that the list of KDM1A interactors includes a number of ZNF proteins, together with several members of the CoREST complex. Interestingly, the absence of GFI1 and other SNAG domain transcription factors suggest that the interaction between this class of proteins and KDM1A is compromised by irreversible tranylcypromine-derived KDM1A inhibitors. Conclusions: The ORY-1001-derived chemoprobe is a valid tool for investigating KDM1A target engagement and protein interactions.
Quality of care for metastatic breast cancer (MBC).
Authors: Ines Vaz Luis, Nancy U. Lin, Rachel A. Freedman, William Thomas Barry, Eric P. Winer, Michael J. Hassett
Journal: Journal of Clinical Oncology (2016)

e18031 Background: Many studies have identified shortcomings with the quality of care for early stage breast cancer, but there is minimal research examining the quality of care for MBC. Methods: We used Surveillance, Epidemiology and End Results Medicare data to identify patients (pts) aged ≥66 diagnosed 2010-2011 with de novo MBC with continuous Part D enrollment. We described initial care defined as therapy within 6 months of diagnosis for: hormone receptor (HR+)/human epidermal receptor-2 (HER2)-; HER2+; and triple negative (TN) tumors. Logistic regression examined the odds of receiving no initial systemic treatment. Results: Among 446 pts, 65% were age <80, 57% had a comorbidity score=0. Most had HR+ BC (65%), followed by HER2+ (21%) and TN (14%). Most pts (77%) received initial systemic treatment. Among treated HR+ pts, 15% received upfront chemotherapy, rather than an endocrine agent, as an initial treatment; among treated HER2+ pts, 34% did not receive HER2-targeted initial therapy. Factors associated with receiving no initial systemic therapy included older age (33% if ≥80 vs. 15% if 66-70), not being married, and subtype (46% if TN; 29% if HER2+; and 19% if HR+); all remained significant on multivariable analysis (Table). Of pts who did not receive initial systemic therapy, 84% were hospitalized and 59% received hospice services over that time period. Conclusions: In a population based cohort of pts with MBC, almost one quarter did not receive any systemic therapy within 6 months of diagnosis, and a substantial proportion of treated pts did not receive the most commonly recommended first line therapy. Although some of this care may be appropriate, more research should explore the potential for underuse of relatively less toxic HR and HER2 targeted therapies, and investigate the extent to which current care is consistent with pts preferences. The rates of hospitalization and hospice service use among pts who did not receive any systemic therapy raise concern and may offer areas for intervention as well. Odds of non-receipt of initial systemic treatment. OR 95% CI Age (year) 1.1 1.0-1.1 Marital Status Married ref Other 2.9 1.4-5.8 Subtype HR+ ref HER2+ 1.0 0.5-2.0 TN 5.0 2.5-9.7 Adjusted by comorbidity, race, region, location, income, education, grade, Medicaid.