tbuckley/cabot-search huggingface dataset:
Evaluation of the effect of CXCL13 mRNA expression in early breast cancer outcome: A confirmatory study.
Authors: Evangelia Razis, Ioannis Kotsantis, Kyriaki Manousou, Ralph M Wirtz, Flora Zagouri, George Lazaridis, Helen Gogas, Elke Veltrup, Angelos Koutras, George E. Pentheroudakis, Christos Christodoulou, Dimitris Bafaloukos, Pavlos Papakostas, Ioannis Xanthakis, Konstantine T. Kalogeras, Meletios A. Dimopoulos, George Fountzilas
Journal: Journal of Clinical Oncology (2018)

e24286 Background: CXCL13 mRNA expression has been associated with subtype specific outcome in breast cancer and its prognostic markers. Methods: Early breast cancer patients with T1-4, N1-2, M0 were included in a prospective randomized trial (ACTRN12609001036202) and treated with anthracyclines and taxanes, concurrently or sequentially followed by cyclophosphamide/methotrexate/5 fluorouracil (CMF) from 2000 to 2005. Formalin fixed paraffin embedded tissue samples from the original surgery were tested for CXCL13 mRNA expression by qRT-PCR. All clinical and molecular parameters, including immunohistochemically defined breast cancer subtypes, were tested for their association with CXCL13 (high vs. low; predefined cut off of 32.9), as was its association with disease free (DFS) and overall survival (OS). The association with relapse/mortality rate was evaluated with Cox proportional hazards model. Results: A total of 557 patients were included. Of them, 50.8% had high-grade disease, 79.1% were ER/PgR positive and 22.8% were HER2-positive. CXCL13 was significantly associated with tumor size (p = 0.016), histological grade (p < 0.001), ER/PgR status (p = 0.034), HER2 status (p = 0.006) and breast cancer subtypes (p < 0.001). With a median follow-up of 124.2 months, 188 (33.8%) patients progressed and 149 (26.8%) died, with a 5-year DFS rate of 78.6% and OS of 88.2%. In multivariate analysis, high CXCL13 was marginally associated with improved DFS (p = 0.051) but not OS (p = 0.22) when adjusted for number of positive lymph nodes, tumor size, radiotherapy and subtypes. However, CXCL13 was found to have a significant impact on both DFS and OS in the luminal HER2 subgroup [DFS: HR 0.29, 95% CI 0.13-0.68, p = 0.004; HR 0.32, 95% CI 0.14-0.75, p = 0.009]. Of note high CXCL13 was significantly associated with the presence of tumor infiltrating lymphocytes(TILs) as indicated by its association with CD3, CD8 and FOXP3 (p-values < 0.001). Conclusions: High CXCL13 mRNA expression was significantly associated with poor prognostic parameters, but specifically in the luminal HER2 subgroup, it was found to have a significant positive impact on both DFS and OS, possibly due to its association with the tumor immune microenvironment and TILs.
Disrupting end-of-life cancer care delivery: Results from the engagment of patients with advanced cancer trial.
Authors: Manali I. Patel, Vandana Sundaram, Manisha Desai, VJ Periyakoil, James Kahn, Steven M Asch, Arnold Milstein, Kate Bundorf
Journal: Journal of Clinical Oncology (2017)

6525 Background: Sustainable approaches to improve quality and safety of care of patients with advanced cancer while concurrently reducing costs is a growing national need. As part of the Veterans Administration Engagement of Patients with Advanced Cancer (EPAC) trial, we trained a lay health worker (LHW) to engage patients with stage 3 and 4 cancer in early advance care planning (ACP). The goal of this follow-up study was to examine the effect of the LHW intervention on patient-reported care experiences, healthcare utilization, and costs in the last 30 days of life for patients who died within 15 months of enrollment. Methods: We evaluated patient-reported experiences with decision-making, healthcare utilization, and total healthcare costs 30 days prior to death. A T-test was used to compare patient experiences with decision-making. To compare ED use and hospitalizations, we utilized an exact Poisson regression. A generalized linear model with gamma link-log function was used to compare total costs. The latter methods adjusted for length of follow-up. Results: In the 30 days prior to death, 60 patients died in each arm within 15 months of enrollment (difference not statistically significant). Patients in the intervention had significantly improved rates of ACP documentation (98% versus 18% p &lt; 0.001), improved experiences with decision-making as measured by an index ranging from 0-5 with higher values representing more favorable experience (4.73 (SD 0.61) vs 4.15 (SD 1.02)) p &lt; 0.001), higher utilization of hospice (77% vs 52%, p &lt; 0.005), lower rates of any emergency department use (5% versus 45% p &lt; 0.001) and any hospitalization (5% versus 43% p &lt; 0.001), and significantly lower total costs of care ($1,048 versus $23,482 p &lt; 0.001) compared to the patients randomized to the usual care arm. Conclusions: Integrating a LHW into oncology care to engage patients in early advance care planning resulted in significantly improved patient experience, decreased utilization and decreased total costs in the last month of life. LHWs may represent a sustainable resource to facilitate optimal patient-centered cancer care at the end-of-life. Clinical trial information: NCT02966509.
Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies.
Authors: John M Burke, Anna Katharina Wilkins, Andrew Matteson, Lore Gruenbaum, Josh F Apgar
Journal: Journal of Clinical Oncology (2017)

e14000 Background: The pharmacokinetics of antibody drug conjugate (ADC) therapeutics typically show a discrepancy between the PK of total antibody (conjugated and unconjugated antibody) and that of conjugated antibody, carrying one or more payload molecules This discrepancy is often attributed to deconjugation (Kamath, 2014), however recent evidence suggests that the underlying mechanisms may be more complex. Methods: This work employs a computational quantitative systems pharmacology (QSP) approach to understand the impact of drug antibody ratio (DAR) and the resulting changes in molecular properties on overall PK and relative payload disposition as observed in preclinical and clinical studies. Results: Using QSP approaches, the model (1) describes the kinetics of individual DAR species and agrees well with typical ADC PK, individual DAR PK, and average DAR measurements in vivo; (2), quantitatively describes the trade-off between higher DAR and lower exposure; consequently, we predict that ADC2 is half as potent as ADC4 and ADC8, which are equipotent; (3) longer mAb half-life reduces payload delivery after multiple doses; and (4) ADC half-life affects the percent of payload delivered through different mechanisms. Conclusions: A QSP model describing mechanism is a useful tool to translate and understand PK from preclinical species to human, by acting as a central repository of data, knowledge, and hypotheses. It provided a rational basis to generate testable hypotheses and provide early insights into complex ADC PK data and established the benefit of using computational models to design novel ADCs and to optimize the discovery and development of existing ADCs.
Value based healthcare and patient reported outcome measures (PROMS) in clinical practice: pilot trial in lung cancer.
Authors: Ingel Demedts, Ulrike Himpe, Philippe Bertrand, Geert Anthoons, Jelle Bossuyt, Kristof Baetens, Svin Deneckere
Journal: Journal of Clinical Oncology (2018)

e21107 Background: Value based healthcare aims to increase value of patient care by optimizing health outcomes. It is critical to include measurement of patient/disease/treatment variables and outcome indicators, including PROMS. We developed a digital care pathway for lung cancer, integrating health outcome measurements and collection of PROMS in clinical practice. Methods: Stage IV lung cancer patients who started systemic treatment between April 2017 and January 2018 were included in this pilot project. Baseline patient and disease variables were registered by patients and care team respectively, based on the International Consortium of Health Outcomes Measurement (ICHOM) standard set. Patients weekly digitally reported a limited set of PROMS , while every 6 weeks EORTC QLQ-C30 and QLQ-LC13 were collected. Results: 51 patients (40 Male/11 Female) were included, median age 63 years. Patients received 70 treatments: 48 chemo-, 18 immuno- and 4 targeted therapy. Compliance with weekly symptom reporting was 93%, 100% after a reminder email. Compliance with 6-weekly QOL questionnaires was 100%. Baseline case mix variables were collected in 100% of patients. Most frequently reported complaints were fatigue (87%), dyspnea (61%) and pain (53%). In the TKI arm, rash and diarrhea were also prominent (82% and 52% respectively). A subset analysis in 34 patients showed that physicians systematically underestimated patient symptoms when compared to PROMS. In particular, ‘fear’ and ‘cough’ were reported at least once by the patient in 28/34 and 30/34 of cases respectively, compared to physician reporting in 3/34 and 6/34 of patients respectively. Global health status was on average slightly higher (+3%) than historical reference values. Compared to baseline levels, global health status slightly dropped over time during treatment (-5%). These observations were dependent on the treatment type. There was a strong correlation of global health with physical functioning (R² = 0.4458), role functioning (R² = 0.387) and fatigue (R² = 0.159). Conclusions: In stage IV lung cancer patients, systematic measurement of health outcomes (including PROMS), is feasible in clinical practice, using an digital care pathway.
miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels
Authors: Katerina Musilova, Jan Devan, Katerina Cerna, Vaclav Seda, Gabriela Pavlasova, Sonali Sharma, Jan Oppelt, Robert Pytlik, Vit Prochazka, Zuzana Prouzova, Martin Trbusek, Lenka Zlamalikova, Kvetoslava Liskova, Lenka Kruzova, Marie Jarosova, Andrea Mareckova, Christoph Kornauth, Ingrid Simonitsch-Klupp, Ana-Iris Schiefer, Olaf Merkel, Heidi Mocikova, Pavel Burda, Katerina Machova Polakova, Leos Kren, Jiri Mayer, Clive S. Zent, Marek Trneny, Andrew G. Evans, Andrea Janikova, Marek Mraz
Journal: Blood (2018)
A technical feasibility report on correlative studies from the investigator-initiated phase II study of pembrolizumab (Pembro) immunological response evaluation (INSPIRE).
Authors: Derek L. Clouthier, Cindy Yang, Scott Lien, Diana Gray, Ilaria Colombo, Stephanie Lheureux, Jeremy Howard Lewin, Albiruni Ryan Abdul Razak, Anna Spreafico, Philippe L. Bedard, Marcus O. Butler, Daphne Day, Aaron Richard Hansen, Trevor John Pugh, Helen Chow, Sawako Kobori, Amanda Giesler, Pamela S Ohashi, Lillian L. Siu
Journal: Journal of Clinical Oncology (2017)

11607 Background: Validated biomarkers of response to immune checkpoint inhibitors are needed. Methods: INSPIRE (NCT02644369) is a biomarker-driven study to comprehensively evaluate changes in genomic and immune landscapes in tumors and blood of patients (pts) treated with pembro at 200 mg IV Q3W. It consists of 5 histological cohorts of 20 evaluable pts each: head and neck squamous cell cancer (SCCHN), triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC), melanoma (MM) and mixed solid tumors (MST). All pts undergo pre- and on-treatment (week 6-9) fresh tumor biopsies (bx), and at progression for responders. The first core bx is for immunohistochemistry and subsequent cores are pooled to create single cell suspension for 5 prioritized biomarker assay groups: (1) whole exome/RNA-/TCR-sequencing; (2) T/B/NK, APCs, and/or Treg phenotyping; (3) patient-derived xenografts; (4) RNA-seq on viably sorted immune populations; (5) TIL expansion and characterization. Serial blood samples for immunophenotyping, chemokines/cytokines and ctDNA are collected. Results: 53 pts were enrolled from March 21, 2016-January 16, 2017 (5 SCCHN, 8 TNBC, 17 HGSOC, 7 MM, 16 MST). 84 tumor bx (53 pre-, 30 on-treatment, 1 progression) and 244 blood-based biomarker samples have been collected. The most common sites of tumor bx were: lymph nodes (27%), liver (22%) and skin (14%) (see table). For the 5 cohorts, the % of tumor bx with sufficient cellularity for biomarker assay groups 1 and 2 are: SCCHN (33%), TNBC (9%), HGSOC (52%), MM (55%), MST (55%). Conclusions: This report provides robust technical feasibility data to plan immune and molecular characterization of tumor and blood-based biomarkers in pts receiving ICI. Clinical trial information: NCT02644369. [Table: see text]
Cutaneous angioimmunoblastic T-cell lymphoma: Epstein-Barr virus positivity and its effects on clinicopathologic features
Authors: Woo Jin Lee, Kwang Hee Won, Jae Won Choi, Chong Hyun Won, Sung Eun Chang, Jee Ho Choi, Mi Woo Lee
Journal: Journal of the American Academy of Dermatology (2018)
Utility of a novel biopsy instrument with long side-notch needle in the selection of patients for active surveillance.
Authors: Kent Kanao, Keishi Kajikawa, Ikuo Kobayashi, Hiroyuki Muramatsu, Shingo Morinaga, Genya Nishikawa, Yoshiharu Kato, Masahito Watanabe, Kogenta Nakamura, Makoto Sumitomo
Journal: Journal of Clinical Oncology (2017)

e16581 Background: Active surveillance (AS) is now an accepted strategy for men with low-risk prostate cancer (PCa). A critical factor for successful AS is the best possible patient selection. We recently develop a novel 18-G biopsy instrument based on an existing instrument, by extending the side-notch length from 19 to 25 mm and the stroke length from 22 to 28 mm, to take a longer tissue core and to reach the anterior portion of the prostate.In this study, we evaluated utility of the novel biopsy instrument in the selection of patients for AS. Methods: A total of 167 PCa patients diagnosed with the long-notch needle (n = 62; long-notch group) or normal-notch needle (n = 105; normal-notch group), who subsequently underwent prostatectomy, were retrospectively analyzed. All patients were diagnosed with 12 transrectal ultrasound-guided standard cores.The sampled core length, correlation between total tumor length in biopsy specimens, and total tumor volume in prostatectomy specimens were compared between the two groups. Gleason score (GS) upgrading was also compared. Prostatectomy specimens of patients who met the criteria of the PRIAS study were compared for the two groups. Results: The mean length of tissue taken with the long-notch needle was significantly longer than that taken with the normal-notch needle (16.3 vs. 22.4 mm, p &lt; 0.001). The correlation coefficient between total tumor length in biopsy specimens and total tumor volume in prostatectomy specimens of the long-notch group was higher (r = 0.701) than that in the normal-notch group (r = 0.611). GS upgrading in the long-notch group was significantly lower than that in the normal-notch group (25.8 vs. 41.0%, p = 0.0479).Only 1 patient with tumor volume &gt; 0.5 cc and GS 4+3 or more was included among the 5 who met the criteria of the PRIAS study in the long-notch group, while 6 patients were included among the 10 who met the criteria in the normal-notch group. Conclusions: We developed a novel biopsy instrument with a 25 mm side-notch for longer tissue samples, increased correlation between tumor volume in biopsy and prostatectomy specimens, and decreased GS upgrading. These results suggested the utility of the long-notch needle in the selection of patients for AS.
Abstract 15552: Acute Estrogen-GPER1 Stimulation Preserves Mitochondrial Inner Membrane Protein (Mitofilin) From Degradation caused by Ischemia/Reperfusion Stress
Authors: Tanoya L. C Harris, Bjorn Olde, Fredrik Leeb-Lundberg, Jean C. Bopassa
Journal: Circulation (2014)

Introduction: We recently found that acute estrogen treatment delays the mitochondrial permeability transition pore opening and reduces ROS production after ischemia/reperfusion, suggesting that estrogen promotes mitochondrial integrity. As mitochondrial inner membrane protein (mitofilin) has been found to control mitochondrial cristae morphology and function, we investigated whether estrogen effect on mitochondrial integrity after ischemia/reperfusion involved regulation of mitofilin via G-Protein Coupled Estrogen Receptor1 (GPER1) activation. Methods: Isolated hearts from male WT (C57BL/6NCrL), and GPER1-/- mice were perfused using Langendorff technique, with and without estrogen (40 nM). Hearts were subjected to 20 min global ischemia followed by 10 min reperfusion. Mitochondria were isolated, and 2D-DIGE followed by mass spectrometry was performed. Mitofilin expression was confirmed by Western blot analysis in mitochondrial fractions. Mitofilin distribution in cardiomyocytes, and its spatial organization in single mitochondria were visualized using high resolution microscopy. Electron microscopy was used to observe the state of mitochondrial cristae morphology. Results: Analysis revealded 52 unique proteins of interest, in which mitofilin was identified. Immunoblot analysis confirmed an increased in mitofilin level with estrogen treatment as compared to control in WT but not in GPER1-/-. We found, as observed in non-ischemic myocytes, that mitofilin in estrogen-treated cardiomyocytes was distributed in the peri-membrane and T-tubules, while only peri-membrane mitofilin was more visible in control group. High resolution microscopy showed a better spatial organization of mitofilin in single mitochondria with estrogen treatment compared to control, in which mitofilin was almost absent. Electron microscopy revealded that mitochondrial morphology was preserved with estrogen treatment, as cristae were well organized compared to control, in which cristae were disrupted. Conclusion: These data indicate that estrogen up-regulates mitofilin expression during ischemia/reperfusion. Estrogen effect on mitofilin may contribute to improved mitochondrial integrity and function.
Mass spectrometry-based phosphoproteomics of tumor needle biopsies from patients (pts) with advanced solid tumors during treatment with protein kinase inhibitors.
Authors: Mariette Labots, Robin Beekhof, Jaco C. Knol, Maarten Neerincx, Richard R. de Haas, Henk Dekker, Thang V. Pham, Sander R. Piersma, Evan Henneberry, Johannes C. Van der Mijn, Maria Rovithi, Donald L. Van der Peet, Martijn R. Meijerink, Nicole C.T. van Grieken, Connie R. Jiménez, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2016)

11609 Background: Mass spectrometry-based phosphoproteomics of tumor tissue lysates provides a potential personalized medicine approach based on its global information on aberrantly activated signaling pathways and potential drug targets. Here, we report results of a clinical trial (NCT01636908) to evaluate the effect of protein kinase inhibitor treatment on tyrosine (pTyr) phosphoproteomic profiles of serial tumor needle biopsies in pts with advanced solid tumors. Methods: Tumor needle biopsies were obtained from 25 pts with advanced cancer before and after 2 weeks treatment with sorafenib (SOR), erlotinib (ERL), dasatinib (DAS), vemurafenib (VEM) or sunitinib (SUN) (5 pts/cohort), administered prior to or as standard palliative treatment. Using matched protein input for paired biopsies per pt, down-scaled phosphopeptide immunoprecipitation was performed using P-Tyr-1000 (PTMScan, CST) followed by LC-MS/MS (Q Exactive) measurement. MaxQuant was used for phospho-peptide/site identification and quantification. Fold-changes (Fc) were determined per biopsy pair. Results: For pre- and on-treatment pairs, median protein input was 2.0 mg per biopsy (range 0.8-2.9) for SOR/ERL/DAS and 1.1 mg (0.5-2.0) for VEM/SUN. Per biopsy, on average 440 ± 97 phoshopeptides were identified in SOR/ERL/DAS and 178 ± 64 in VEM/SUN. Unsupervised clustering analysis based on phosphopeptide intensities showed clustering of biopsies from individual pts. Supervised clustering based on differential phosphopeptides (Fc > 5 in ≥ 3/5 pts) per cohort separated pre- and on-treatment groups. Differential phosphopeptides were drug-specific. Inhibition of multiple (target) kinase activities related to clinical response was observed. Conclusions: In this study we show, for the first time, clinical feasibility of repeated pTyr-phosphoproteomics in tumor needle biopsies from pts with advanced cancer. Drug-specific changes in the phosphoproteome were found at 14 days on-treatment related to response. This approach will improve our understanding of individual tumor biology and enable development of phosphoproteomics-based personalized medicine. Clinical trial information: NCT01636908.
About safety of neuroprotectors in malignant brain tumors.
Authors: Eduard Evgenevich Rostorguev, Oleg Ivanovich Kit, Alla Ivanovna Shikhlyarova, Tatiana Albertovna Barteneva, Natalya S. Kuznetsova, Ivan Aleksandrovich Popov, Marina Igorevna Bragina, Elena Alekseevna Shirnina, Vladimir E. Rostorguev
Journal: Journal of Clinical Oncology (2018)

e14079 Background: Neuroprotectors have been used for more than half a century in the treatment of neurological diseases to protect brain cells from ischemia. The problem is also relevant in neurooncology, when brain damage caused by the tumor is accompanied by secondary ischemic injuries. However, the risk of stimulated tumor growth limits the use of biologically active protein-peptide complexes (PPC) with a polyvalent mechanism of action, which requires an experimental justification for their use. For this purpose, the effect of the tissue-specific PPC Cellex on the tumor growth in experimental animals was studied. Methods: The study included 10 outbred male rats with Guerin carcinoma (GC) and 28 female С57Bl6 mice with B16 melanoma (MB16). Cellex was injected intraperitoneally once a day for 7 days, starting from day 2 after the tumor transplantation. The equivalent therapeutic dose for rats was 0.06 mg/kg, for mice 0.1 mg/kg. The tumor volume and inhibition of tumor growth (ITG%) were determined. The animals were decapitated on day 6 after the end of treatment. The presence of lung metastases was determined in mice. Results: A comparative analysis of tumor volumes in rats with GC did not reveal significant differences between groups. PPC slightly inhibited the tumor growth, but the effect was not persistent and amounted for 13% and 20% on days 12 and 14, respectively. In mice, inhibition of melanoma growth at all observation periods did not reach 50% either (ITG = 14-8%). The necropsy of mice with MB16 showed occasional lung metastases in animals of both groups indicating that PPC did not stimulate melanoma metastasis. Conclusions: Intraperitoneal PPC Cellex did not stimulate the growth of experimental tumors – GC in outbred male rats and B16 melanoma in female С57Bl6 mice, which can be taken into account in clinical trials.