tbuckley/cabot-search huggingface dataset:
A novel and validated inflammation-integrated prognostic model for hepatocellular carcinoma (HCC).
Authors: Anthony W.H. Chan, Charing C.N. Chong, Paul B.S. Lai, Winnie Yeo, Ka Fai To, Stephen Lam Chan
Journal: Journal of Clinical Oncology (2017)

e15679 Background: Various serum inflammatory factors are implicated in pathogenesis and prognostication of HCC but none of them is incorporated into a HCC prognostic model. We aim to build an inflammation-integrated prognostic model without any radiological feature. Methods: A prospective-retrospective cohort of patients with HCC was accrued from 2001 to 2013, and was randomly spitted into training and validation cohorts. Cox proportional hazards model was used for univariable and multivariable survival analyses. The risk score was constructed by factors and their coefficients identified by multivariable Cox model. Results: The entire cohort was composed of 1315 patients (BCLC 0/A/B/C/D 73/533/237/425/47; Surgery/Locoablation/TACE/Systemic agent/BSC 538/128/318/122/209). In the training cohort (n=657), a novel model, PANALA score, was generated by using6 independent prognostic factors: 1.488*(Performance status &gt;0) – 0.057*Albumin + 0.098*Neutrophil – 50.4*Alkaline phosphatase -1 – 0.269*Lymphocyte + 0.11*ln(Alpha fetoprotein). PANALA outperformed other staging systems (Table) and allowed the prediction of survival of an individual patient. In the validation cohort (n=658), the prognostic performance of PANALA was still the most superior one. The goodness of fit of PANALA score in prediction of survival was evaluated by dividing patients into 4 equal quartiles by PANALA. In the quartile 1, overall survival between actual observation and prediction was highly comparable (6m survival: 100% vs. 95%, 3y survival: 80% vs. 79%, 5y survival: 72% vs. 74%; P=0.71). Discrepancies between observed and predicted survival were also insignificant in other quartiles. Moreover, PANALA was able to stratify each BCLC stage into 3 prognostically different subgroups. Conclusions: PANALA is a novel and validated model with high prognostic performance. [Table: see text]
P01.059 Technical features of a medical device generating alternating electric fields (Tumor Treating Fields) for the treatment of glioblastoma
Authors: M Graeb, A Kinzel, E Kirson
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme is a fatal and particularly difficult to treat disease. Therefore, novel therapeutic interventions to control glioblastoma are needed. Tumor Treating Fields (TTFields) are low-intensity (1–3 V/cm), intermediate frequency (100-300kHz) alternating electric fields that show anti-proliferative action in various cancer cells including glioblastoma. In the EF-14 phase 3 trial, adding TTFields to maintenance Temozolomide significantly improved median PFS and OS from randomization in newly diagnosed GBM. Currently, TTFields are approved for the treatment of adults with newly diagnosed and recurrent glioblastoma. TTFields are delivered at therapeutic intensities (intended field strength >1V/cm) by means of a portable medical device and transducer arrays (Optune® system). Here, the technical features to ensure efficacy and safety of the Optune system will be reviewed in detail. The Optune system is comprised of two main components - an electric field generator (the actual device) and insulated transducer arrays. The preset electric field generator generates TTFields at a frequency of 200 KHz and up to 707mA RMS output current. The size of this battery-powered device itself is 7.1 x 2.3 x 7.6 inches with a total weight of 1.5 lbs (without the battery). The main components of the user interface are the power switch, a TTFields button, error indicator, and a low battery indicator. The device is connected to 2 pairs of transducer arrays, each made of 9 ceramic discs with high dielectric constant. During treatment, each pair of transducer arrays generates an alternating electric field that changes its polarity 200,000 x per second (200kHz) for GBM. The electric fields switch between the transducer array pairs at every second. For patient safety, the transducer arrays are able to monitor temperature by means of 8 thermistors per array and temperatures beyond 41° C will automatically turn on an alarm and cause a treatment break. The Optune device is a highly sophisticated medical device intended for the treatment of glioblastoma. The device contains numerous technical features to ensure efficacy as well as patient safety. In summary, the design and technical features of the Optune device allows for treatment of glioblastoma while allowing patients to proceed with their activities of daily living.
Molecular analysis of thymidylate synthase in circulating tumor cells as a potential marker of response to therapy in locally advanced rectal cancer.
Authors: Virgilio Souza E Silva, Bianca Troncarelli Flores, Emne Ali Abdallah, Celso Lopes Mello, Samuel Aguiar, Renata Takahashi, Milena Shizue Tariki, Gustavo Gomes Mendes, Maria Leticia Gobo Silva, Vanessa da Silva Alves, Ludmilla T.D. Chinen
Journal: Journal of Clinical Oncology (2018)

e24059 Background: Analysis of Circulating tumor cells (CTCs) seems to be promising for detection, monitoring, and survival prediction of rectal carcinoma (RC). Thymidylate synthase (TYMS) enzyme acts in the 5-Fluorouracil (5-FU) metabolism, and when overexpressed, can confer resistance to this drug. 5-FU, a potent radiossensitizer, is routinely used in the neoadjuvant chemoradiation therapy (CRT) for locally advanced RC (LARC). We evaluate the TYMS messenger RNA (mRNA) expression in CTCs isolated from patients (pts) with LARC at diagnosis and also the protein expression in CTCs at diagnosis and post CRT and correlate TYMS mRNA and protein expression with tumor response to CRT. Methods: We performed CTCs analyses after filtration of 10 mL of blood on ISET, before and after CRT. We used RNAscope Technology to make chromogenic in situ hybridization (CISH) assay for TYMS. The immunocytochemistry (ICC) was performed using a standardized protocol with anti-TYMS (Sigma-Aldrich Life Science) and applied in samples collected before and after CRT. Results: We analyzed samples from 12 pts with LACR and TYMS mRNA was overexpressed in the CTCs of 10 pts. Notable, the two pts who had TYMS negative (-) mRNA expression, one had complete pathological response and the other substantial down-staging. These 2 pts did not express TYMS protein on ICC. In the positive (+) mRNA TYMS cases (10 pts), 50% presented response and none of them expressed the protein in the ICC on the CTCs post CRT. The other 50% of pts with mRNA + presented no response, but direct correlation with the + expression of the TYMS protein on the ICC after the CRT. The post treatment TYMS protein status strongly correlated with response, with 100% concordance, demonstrating the predictive role of TYMS protein expression on 5-FU treatment. In the no response group (5 pts), two pts was + for TYMS protein expression before and after the CRT, and three only after the CRT, justifying a potential clonal selection by the CRT and consequently resistance to the treatment. Conclusions: our preliminary results point the analysis of the expression of TYMS protein of CTCs as predictor marker of RC treated with 5-FU based neoadjuvant CRT.
Abstract 17710: School as a More Efficient Place for Resuscitation: Temporal Improvement in Resuscitation Attempts and Outcomes in School Students vs Young Adults in Japanese Nationwide Utstein Registry Study During 2005-2015
Authors: Noriko Yodoya, Yoshihide Mitani, Hiroyuki Ohashi, Hirofumi Sawada, Shoichiro Ohtsuki, Hidetoshi Hayakawa, Masahiro Hirayama
Journal: Circulation (2017)

Introduction: Out-of-hospital cardiac arrests (OHCA) of presumed cardiac origin in the youth which are witnessed by nonfamily members in the daytime are most effectively resuscitated by bystanders ...
There are more football injury prevention reviews than randomised controlled trials. Time for more RCT action!
Authors: Alessio Bricca, Carsten B Juhl, Mario Bizzini, Thor Einar Andersen, Kristian Thorborg
Journal: British Journal of Sports Medicine (2018)

Football is the most popular sport worldwide, and participation in football at any level is associated with numerous health benefits.1 However, participation in football at any level incurs a risk of sustaining musculoskeletal injuries.2 3 Effective injury prevention strategies are needed.

The first formal injury prevention randomised controlled trial (RCT) in football was published in 1983.4 We performed a scoping systematic review to provide an overview of the published articles on injury prevention in football.

A study protocol is available online at http://findresearcher.sdu.dk/portal/files/134191319/Protocol\_scoping\_revire_PURE.pdf. Although we primarily focused on RCTs, we also included systematic reviews and other studies investigating injury prevention strategies/interventions in football regardless of participant age, sex and level of participation.

Our literature search identified 3131 studies, with 98 studies being …
Pneumocystis jirovecii pneumonia associated with everolimus: Incidence and risk factors.
Authors: Melina Boutin, Michel Pavic, Robert Hanel, Alex Carignan
Journal: Journal of Clinical Oncology (2018)

e13058 Background: Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and is commonly used for the treatment of hormone-receptor-positive metastatic breast cancer, as well as metastatic renal cell carcinoma and neuroendocrine tumors. Lymphopenia and increased infectious risk are well known side effects, and the association between mTOR inhibitors and the risk of Pneumocystis jirovecii pneumonia (PJP) is well documented in the transplant setting, but it was only rarely reported in cancer patients. Methods: We conducted a retrospective review of all PJP events at our institution and analyzed the cases associated with everolimus. We also conducted a review of literature to confirm our findings. Results: From April 2015 to April 2017, two patients had a diagnosis of PJP while receiving everolimus at our institution, both for treatment of metastatic breast cancer. We found 13 other cases reported : 7 cases with breast cancer, 4 with renal cancer, and 2 with neuroendocrine tumors. PJP occurred after a median exposure of 10 weeks (range 2-50) and 12 of 15 patients had a lymphocyte count < 0,5 g/L, 3 patients also received low dose steroids. When looking at prospective trials and meta-analyses, no incidence of PJP was mentioned, although an increased risk of lymphopenia (15% grade 3-4) and increased risk of high-grade infection (RR 2,86; 95% CI 1,73-4,72; p < 0,001) were reported. Infections were not detailed more specifically, hence the true incidence of PJP is unknown. Conclusions: Oncologists should be aware of the increased risk of PJP associated with everolimus, and prophylaxis should be offered when additional risk factors are present.
Abstract 13147: Obstructive Sleep Apnea Associates With Elevated Leukocytes and Markers of Inflammation in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Glaucylara R Geovanini, Nancy S Jenny, Rui Wang, Steven J Shea, Joel D Kaufman, Matthew Allison, Naresh M Punjabi, Russell Tracy, Peter Libby, Susan Redline
Journal: Circulation (2016)

Introduction: Obstructive sleep apnea (OSA) is associated with incident cardiovascular disease (CVD), which may reflect dysregulation of pathways leading to atherosclerosis. Inflammation and adaptive immunity participate in the pathogenesis of atherosclerosis, and may be influenced by OSA-related stresses. No prior community-based study has examined the associations of OSA with both leukocytes and serum inflammatory markers. Hypothesis: Biomarkers of inflammation are associated with OSA severity in a community-based cohort. We particularly focused on White Blood Cell (WBC), which has not been well-studied in association with OSA. Since OSA has been associated more strongly with CVD in middle-age vs. old age, we explored potential age modification. Methods: We analyzed data from MESA participants who underwent polysomnography in conjunction with Exam 5 (2010-13) and had available biomarkers from that exam. The primary analysis (n=1344) modeled WBC count and Cystatin-C as outcomes (available for largest subset, n=1344), with log Apnea Hypopnea Index (AHI) as the exposure. Secondary analysis evaluated high-sensitivity C-reactive protein (hsCRP), fibrinogen, D-dimer, and intercellular-adhesion molecule-1 (ICAM-1) (n=228) as outcomes, and considered dichotomized OSA as absent (AHI &lt;5) or present (AHI ≥5) as the exposure. Results: The primary sample (n=1344) had a mean age 68.5 ±9 y, and was 47% male; 14% of individuals had severe OSA (AHI ≥30). Increasing AHI associated with male sex, body mass index (BMI), and a higher prevalence of diabetes (DM) and hypertension (HTN). After adjusting for age, sex, race, smoking, BMI, DM, HTN, and statins, AHI associated significantly with WBC (beta=0.017; p=0.034). Associations tended to be stronger in those age &lt;65 y (beta=0.031; p=0.011). However, the p for interaction was not significant. A fully adjusted model also showed elevated hsCRP in those with OSA (AHI ≥5) (beta=0.357; p=0.011). Associations with Cystatin-C, D-dimer, and ICAM-1 did not attain significance after adjustments. Conclusions: Elevation of WBC count and hsCRP in individuals with OSA suggests heightened inflammation and innate immunity as a novel mechanism that links OSA with increased cardiovascular risk.
Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression
Authors: Belal A. Mohamed, Nico Hartmann, Petros Tirilomis, Karolina Sekeres, Wener Li, Stefan Neef, Claudia Richter, Elisabeth M. Zeisberg, Lars Kattner, Michael Didié, Kaomei Guan, Jan D. Schmitto, Stephan E. Lehnart, Stefan Luther, Niels Voigt, Tim Seidler, Samuel Sossalla, Gerd Hasenfuss, Karl Toischer
Journal: Science Translational Medicine (2018)

Leaky ryanodine receptor does not contribute to heart failure progression, but its normalization reduces arrhythmias and thereby improves survival in mice.
Value of life and time: A survivorship perspective.
Authors: Jennifer M. Hinkel, Daniel B. Sexton, Justine Egan-Kunicki
Journal: Journal of Clinical Oncology (2017)

e18298 Background: Common tools to quantify value of life years after a cancer diagnosis include the Quality Adjusted Life Year (QALY). This measure is partly based on health utility states derived from Quality of Life (QoL) survey instruments such as the EQ-5D. Research has identified shortcomings in applying the QALY, including the potential for underestimating value. QoL surveys may fail to capture the full range of potential health states, or the values derived may fail to reflect patient perspectives of value. Methods: An online survey was piloted with a convenience sample of cancer survivors via two US survivor Facebook groups over two weeks in Jan. 2017 to explore these themes. Results: 116 complete responses were analyzed (of 123 respondents). Original diagnoses included solid tumors and hematologic malignancies, and respondents were between one and 32 years post-diagnosis (PoD). Most (101, 87%) had completed active treatment. A majority (85, 73%) rated PoD years as having more value than years pre-diagnosis (PreD). 83% (98) indicated that they felt their time is more valuable since their diagnosis. While the majority of respondents (57%) assigned a lower value to the 12 months immediately following diagnosis compared to the value of a PreD year, a majority (55%) also valued the most recent twelve months to have equal or greater value than a PreD year. Many assigned higher valuations to PoD years even when simultaneously reporting limitations in Activities of Daily Living (ADLs). Conclusions: Comparing survivor valuations of PoD life years to valuations derived by utility state instruments has not been heavily researched. This survey generates additional hypotheses. First, assuming PoD years hold lower value than PreD years may underestimate value compared to a survivor’s view. Second, QoL instruments may not be capturing positive changes in PoD years, some of which have been documented in psychology research, such as Post-Traumatic Growth or increased feeling of meaningfulness. Further investigation is imperative to ensure that value determinations have a solid evidentiary basis and reflect patient-centered viewpoints, particularly as the “value debate” influences patient access to care.
A phase II study of sorafenib and yttrium-90 glass microspheres for advanced hepatocellular carcinoma, BCLC stage C.
Authors: Ahmed Omar Kaseb, Reham Abdel-Wahab, Ravi Murthy, Manal Hassan, Kanwal Pratap Singh Raghav, Lianchun Xiao, Jeffrey Morris, Rony Avritscher, Bruno C. Odisio, Chimela Ohaji, Robert A. Wolff, James C. Yao, Armeen Mahvash
Journal: Journal of Clinical Oncology (2017)

4083 Background: Combined use of sorafenib and local therapy for treating unresectable hepatocellular carcinoma (HCC) is not well established. Notably, most common cause of death in HCC is liver failure, therefore we tested the promise of controlling the local tumors even in the setting of advanced/metastatic disease to improve survival. Our study aimed to assess the efficacy and safety of combined use of sorafenib and yttrium-90 resin microspheres (Y90 RMS) in unresectable HCC defined as Barcelona Clinic Liver Cancer class C. Methods: Between October 2013 and August 2016 we enrolled 40 advanced stage HCC patients, 38 patients were treated with sorafenib followed (after 4 weeks) with Y90 RMS at MD Anderson Cancer Center. Survival analysis was done to evaluate median overall survival (OS) and progression-free survival (PFS). We used modified Response Evaluation Criteria in Solid Tumors (RECIST) to assess response to treatment and the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 to evaluate the grading of treatment related toxicity. Results: The majority of our patients were males (74%), white (47%), 66% of patients had underlying liver cirrhosis, 26% had vascular invasion, and 26% had extrahepatic disease. The estimated median OS and 95% confidence interval (CI) in months was 18.46 (12.29 – NA) and the estimated PFS was 12.29 months (5.72 – 18.79). Stable disease (SD) was observed in 44.74% of patients, while 28.95% achieved partial response (PR). Grade III-IV adverse events included fatigue (n = 3), hyperbilirubinemia (n = 2), thrombocytopenia (n = 1), proteinuria (n = 1), hyponatremia (n = 1), elevated liver enzymes (n = 4), hypertension (n = 4), diarrhea (n = 1), nausea (n = 1) and vomiting (n = 2). Conclusions: This is the first prospective study to evaluate sorafenib followed by Y90 in HCC. Our study included patients with metastatic HCC and showed that combined use of sorafenib and Y90 was tolerable and was associated with longer OS and PFS compared to previous studies which evaluated sorafenib alone. However, future randomized phase III studies are warranted to assess sorafenib+/-Y90 in metastatc disease setting. Clinical trial information: NCT01900002.
IMMU-49. CYTOTOXIC T CELLS AND THEIR ACTIVATION STATUS ARE INDEPENDENT PROGNOSTIC MARKERS IN MENINGIOMAS
Authors: Christel Herold-Mende, Carmen Rapp, Christine Jungk, Felix Sahm, Katrin Lamszus, Ralf Ketter, Mario Löhr, Christian Senft, Manfred Westphal, Andreas von Deimling, Andreas Unterberg, Matthias Simon
Journal: Neuro-Oncology (2018)

Although clinically aggressive meningiomas (MGMs) are rare tumors, more effective therapies are urgently needed. As a prerequisite for successful immunotherapy we determined the infiltration and activation status of T cells in primary (p-) and recurrent (r-) MGMs and their impact on survival. Presence of tumor-infiltrating lymphocytes (TILs) was assessed in a large, clinically well-annotated study sample of 202 cases (n=123 pMGMs, and n=79 rMGMs) with a substantial proportion of higher-grade MGMs (n=43 WHO°I, n=97 WHO°II, n=62 WHO°III). TIL quantification was performed by a semi-automated analysis on whole tissue sections stained by multi-color immunofluorescence for CD3, CD8, FOXP3, and PD-1. Ranging from 0.01–24.88 %, median T cell infiltration accounted for 0.59 TILs per total cell count (TCC). Although there were no significant changes for the proportion of helper and cytotoxic T cells in pMGM of different WHO grades, higher numbers of cytotoxic T cells were associated with an improved progression-free survival (PFS) independent of prognostic confounders. rMGM were characterized by significantly lower numbers of TILs in general (median: 0.33 % per TCC), helper and cytotoxic T cells and a significant increase of regulatory T cells. As for the activation of TILs, about one third expressed the immune checkpoint molecule PD-1 and predominantly were CD8-positive. We observed a significant WHO-dependent decrease of PD-1+/CD8+ TILs which in univariate and multivariate analyses were associated with a poorer PFS. In line with these findings proportions of PD-1+/CD8+ TILs were significantly lower in rMGM arguing for PD-1 as an activation rather than an exhaustion marker. In summary, we were able to identify intratumoral cytotoxic TILs as well as of PD-1-expressing cytotoxic TILs as novel and easy applicable biomarkers for a better survival, which might facilitate the selection of patients who could benefit from immunotherapeutic approaches and mandates for an intervention in primary rather than recurrent tumors.
Therapeutic efficacy of a novel βIII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer.
Authors: Vivek K. Kashyap, Bilal B. Hafeez, Qinghui Wang, Saini Setua, Sonam Kumari, Andrew E. Massey, Murali M. Yallapu, Duane D. Miller, Wei Li, Meena Jaggi, Subhash C. Chauhan
Journal: Journal of Clinical Oncology (2018)

e14578 Background: The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic approaches. Tubulins play a major role in cell dynamics and are important molecular targets for cancer therapy. Among various tubulins, βIII and βIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available. In this study, we evaluated the therapeutic efficacy of VERU-111, a potent inhibitor of β-tubulin isotypes, in PanCa in vitro, and in vivo model systems. Methods: Effect of VERU-111 on proliferation, migration and invasion of human PanCa cells was performed using in vitro functional assays (MTS, wound healing, and Boyden chamber migrations). Effect of VERU-111 on the expression of β-tubulin isoforms was determined and compared with other clinical inhibitors of β-tubulin by Western blot, and qRT-PCR. Therapeutic efficacy of VERU-111 against PanCa was evaluated in an ectopic xenograft mouse model. Results: An orally bioavailable, small molecule inhibitor VERU-111, preferentially represses βIII and βIV tubulin isoforms via restoring the expression of miR-200c that directly targets these isoforms. Primarily, VERU-111 bind to cholchine binding sites and inhibit tubulin polymerization. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells in nanomolar range concentrations. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also showed significant (P < 0.01) inhibition of xenograft tumors in athymic nude mouse model. Excised xenograft tumors tissues were also analyzed for oncogenic signaling components, which showed potent inhibition of aforementioned oncogenic signaling compared to control. Conclusions: VERU-111 is an orally bioavailable, novel small molecule inhibitor of βIII/βIV tubulin isoforms with apparent efficacy in models of pancreatic cancer.