tbuckley/cabot-search huggingface dataset:
Standard of care vs reduced-dose chemoradiation after induction chemotherapy in HPV+ oropharyngeal carcinoma patients.
Authors: Hope Rainey, Elizabeth Roy, Isaiah Selkridge, Krzysztof Misiukiewicz, Vishal Gupta, Richard Lorne Bakst, David Y. Zhang, Tamar Kotz, Peter Som, Karen S. Anderson, Brett A. Miles, Eric Genden, Marita Teng, Marcelo Bonomi, Andrew Gregory Sikora, Elizabeth Demicco, Rachel Jia, Marshall R. Posner
Journal: Journal of Clinical Oncology (2017)

6069 Background: Locally advanced Human Papillomavirus (HPV) + oropharyngeal carcinoma (OPC) has a significantly better response, locoregional control and survival compared to non HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant side effects, leading to acute and life-threatening late morbidity. We studied whether reduced dose chemoradiation (rdCRT) after induction chemotherapy (IC) resulted in equivalent progression-free survival (PFS) compared to sdCRT + IC with decreased late morbidity. Methods: Patients with locally advanced OPC and &lt; 20 pack years (py) smoking history were tested for p16 and then HPV by type-specific PCR. After 3 cycles of docetaxel, cisplatin and fluorouracil (TPF) IC all HPV+/p16+ subjects underwent clinical and radiographic evaluation. Clinical responders were randomized to either sdCRT (70Gy) or rdCRT (56Gy) with weekly carboplatin (AUC 1.5) at a 1:2 ratio. The primary endpoint was 2 year PFS; the secondary endpoint was 2 year overall survival (OS). Toxicity, late morbidity and swallowing were monitored. Results: 23 patients were enrolled and 20 randomized, 8 to sdCRT and 12 to rdCRT; 2 were HPV- and 1 refused further therapy after IC and were not randomized. Median age was 56.5 yrs (range 36-78); 30% were African-American, 10% were Hispanic, 5% were female; 16 were HPV 16+ and 4 were other high risk (HR) variants; 60% never smoked, 25% were &lt; 10 py, and 15% were 10-20 py; 70% had high risk features: T4, N2c, or N3. Clinical response to TPF was 100%; 70% had a clinical complete response. As of February 1, patients have been followed for a median of 37.5 months (range 21.7 – 49.5). 2 year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures were local or regional and 2 of 3 occurred in non HPV16 HR variants. Conclusions: HPV+ OPC patients who received rdCRT after TPF IC had similar PFS/OS compared to those receiving sdCRT. These results uphold the potential clinical benefit of radiation dose reduction as a treatment option with comparable survival to the standard radiation dose. A Phase III trial comparing IC plus rdCRT to sdCRT alone or with IC is warranted in this population. Non-HPV16 HR variants may have a worse outcome. Clinical trial information: NCT01706939.
Implementation of a protocol of nutritional support in cancer patients.
Authors: Adrian Pablo Hunis
Journal: Journal of Clinical Oncology (2016)

e21617 Background: the identification of nutritional status (NS) of a patient (PT) with cancer (Ca) can impact the success of cancer treatment and their overall prognosis. Goals: Define the NS of Ca PT admitted to determine what relationship exists between the NS PT, type of treatment received and the nutritional risk (NR) of antineoplastic therapy, implement the use of nutritional supplements in PT with NR or malnutrition (MNT). Methods: a prospective, descriptive and analytical study where 52 Ca PT were evaluated during 2014. Results: the most prevalent type of Ca was colon (17.31%). The VGS initial GP (Subjective Global Assessment PT-generated) showed that 36.5% (n = 19) of the sample showed normal, 42.3% (n = 22) NR and 21.1% (n = 11) MNT. When they were assessed with BMI was seen that 82.7% (n = 43) of the sample showed normal, overweight or obese. As for the percentage weight change (PWC), this was severe in 30.7% (16) cases and significant in 21.2% (n = 11). Importantly, all PT had severe PWC (30.7%), 68.75% had a normal BMI, overweight or obese, but without statistical significance (p = 0.15). PT with gynecological Ca (86.7%) were those who had less weight loss, while PT with other types of Ca (pancreas, head and neck, and lung) were those who had a greater weight loss (60% ) (p = 0.006). Of the PT who were not supplemented 22.2% (n = 6) worsened their IN, 7.4% (n = 2) improved, while the rest remained (p = 0.0001) The mortality rate was 21.2% (n = 11) of the total, 27.3% and 45.5% of PT in NR and MNT respectively died (p = 0.008). Lung Ca was the main reason of death in these PT, continuing pancreatic and gastric Ca, in 37.5%, 33.3% and 28.6% respectively, although without statistical significance. (P = 0.67) Conclusions: PT come to the interconsultation when the EN is already deteriorated or advanced MNT. BMI, unlike PWC, is not a good indicator in these PT. In PT with gynecologic Ca more overweight and less weight loss is observed when compared with another Ca. In this study the PT in the NR is independent of antineoplastic treatment, more than half of PT facing therapy NR or MNT. Nutritional support is essential for nutritional intervention in these PT, even more so when indicated early.
Heterogeneity in early lesion changes on treatment as a marker of poor prognosis in patients (pts) with metastatic colorectal cancer (mCRC) treated with first line systemic chemotherapy ± biologic: Findings from 9,092 pts in the ARCAD database.
Authors: Fang-Shu Ou, Joleen Marie Hubbard, Pashtoon Murtaza Kasi, Jesse Dixon, Eric Van Cutsem, Leonard Saltz, Hans-Joachim Schmoll, Cornelis J. A. Punt, Richard M. Goldberg, Paulo Hoff, Jean-Yves Douillard, J. Randolph Hecht, Herbert Hurwitz, Carsten Bokemeyer, Charles Fuchs, Eduardo Diaz-Rubio, Daniel J. Sargent, Aimery De Gramont, Qian Shi, Axel Grothey
Journal: Journal of Clinical Oncology (2017)

3535 Background: CRC is known to be a heterogeneous disease. This study quantifies within pt heterogeneity in early lesion change rate (LCR) in the era of targeted agents compared to chemo alone and its potential impact on survival. Methods: Pts with 2-10 lesions measured at baseline were included. For each lesion, the early LCR was defined as the change in size (shrinking or growing) from baseline to 12 weeks on treatment. Within pt heterogeneity in early LCR among lesions was estimated by standard deviation (STD). A larger value of STD indicates larger variation of LCR per pt. Stratified multivariate Cox models were used to assess the associations between LCR STD with overall survival (OS). Adjusted hazard ratios (HR adj ) and 95% confidence intervals (CIs) are reported. Results: Data were available on 9,092 mCRC pts (median age 61; 60% male, 55% ECOG PS 0; 61% 2+ metastatic sites) enrolled in 16 1 st -line randomized trials, with 44%, 42%, and 10% of pts received chemo alone, + a VEGF inhibitor (VEGFi) or an EGFR inhibitor (EGFRi), respectively. LCR heterogeneity is the highest among pts received EGFRi but lowest among pts received VEGFi (Table). Overall, higher heterogeneity is associated with worst OS (HR adj 1.22, 95% CI (1.16, 1.27)). The effect is most pronounced in pts received VEGFi (interaction p=0.0012). Conclusions: There was heterogeneity observed in lesion size changes within pts. Its magnitude varies across treatment approaches, and was associated with poor survival. This preliminary result reveals the great potentials to define novel response endpoint and refine treatment decision-making by incorporating heterogeneities in lesion changes. [Table: see text]
Recent Developments in Understanding Barrier Mechanisms in the Developing Brain: Drugs and Drug Transporters in Pregnancy, Susceptibility or Protection in the Fetal Brain?
Authors: Norman R. Saunders, Katarzyna M. Dziegielewska, Kjeld Møllgård, Mark D. Habgood
Journal: The Annual Review of Pharmacology and Toxicology (2018)

Efflux mechanisms situated in various brain barrier interfaces control drug entry into the adult brain; this review considers the effectiveness of these protective mechanisms in the embryo, fetus, and newborn brain. The longstanding belief that the blood-brain barrier is absent or immature in the fetus and newborn has led to many misleading statements with potential clinical implications. The immature brain is undoubtedly more vulnerable to damage by drugs and toxins; as is reviewed here, some developmentally regulated normal brain barrier mechanisms probably contribute to this vulnerability. We propose that the functional status of brain barrier efflux mechanisms should be investigated at different stages of brain development to provide a rational basis for the use of drugs in pregnancy and in newborns, especially in those prematurely born, where protection usually provided by the placenta is no longer present.
<i>WNT6</i> is a novel oncogenic prognostic biomarker in human glioblastoma
Authors: Céline S. Gonçalves, Joana Vieira de Castro, Marta Pojo, Eduarda P. Martins, Sandro Queirós, Emmanuel Chautard, Ricardo Taipa, Manuel Melo Pires, Afonso A. Pinto, Fernando Pardal, Carlos Custódia, Cláudia C. Faria, Carlos Clara, Rui M. Reis, Nuno Sousa, Bruno M. Costa
Journal: Theranostics (2018)

Glioblastoma (GBM) is a universally fatal brain cancer, for which novel therapies targeting specific underlying oncogenic events are urgently needed. While the WNT pathway has been shown to be frequently activated in GBM, constituting a potential therapeutic target, the relevance of WNT6, an activator of this pathway, remains unknown. Methods: WNT6 protein and mRNA levels were evaluated in GBM. WNT6 levels were silenced or overexpressed in GBM cells to assess functional effects in vitro and in vivo. Phospho-kinase arrays and TCF/LEF reporter assays were used to identify WNT6-signaling pathways, and significant associations with stem cell features and cancer-related pathways were validated in patients. Survival analyses were performed with Cox regression and Log-rank tests. Meta-analyses were used to calculate the estimated pooled effect. Results: We show that WNT6 is significantly overexpressed in GBMs, as compared to lower-grade gliomas and normal brain, at mRNA and protein levels. Functionally, WNT6 increases typical oncogenic activities in GBM cells, including viability, proliferation, glioma stem cell capacity, invasion, migration, and resistance to temozolomide chemotherapy. Concordantly, in in vivo orthotopic GBM mice models, using both overexpressing and silencing models, WNT6 expression was associated with shorter overall survival, and increased features of tumor aggressiveness. Mechanistically, WNT6 contributes to activate typical oncogenic pathways, including Src and STAT, which intertwined with the WNT pathway may be critical effectors of WNT6-associated aggressiveness in GBM. Clinically, we establish WNT6 as an independent prognostic biomarker of shorter survival in GBM patients from several independent cohorts. Conclusion: Our findings establish WNT6 as a novel oncogene in GBM, opening opportunities to develop more rational therapies to treat this highly aggressive tumor.
Efficacy and safety of regorafenib compared to TAS-102 for refractory metastatic colorectal cancer.
Authors: Ana Beatriz Kinupe Abrahao, Yoo-Joung Ko, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2016)

e15010 Background: Recent studies have shown Regorafenib (R) and TAS-102 (TAS) to be superior to placebo (P) in refractory metastatic colorectal cancer (mCRC). However, no studies have directly compared R with TAS. We aimed to compare the efficacy and safety of R compared with TAS using indirect comparison methods. Methods: We conducted a systematic review using PubMed, Medline, Embase, Scopus and Cochrane database to identify published and unpublished studies up to November 2015 for randomized controlled trials (RCTs) for patients with mCRC, involving Regorafenib or TAS-102. Data including overall survival (OS), progression-free survival (PFS) and toxicity (Tox) were extracted. Pairwise direct meta-analyses (R vs. P and TAS vs. P) and indirect comparison (R vs. TAS) using network meta-analyses methods (R package “netmeta”) to preserve randomization were performed. Results: 914 citations were initially identified among which 3 RCTs fulfilled eligibility criteria (CORRECT, CONCUR and TAS-102) involving 1,764 patients (R: 641, TAS: 534, P: 589). Subgroups of patients (1,659) who had not received prior R or TAS were used to performed meta-analyses for efficacy. Results of efficacy and toxicity are shown in table. Conclusions: In this indirect comparison, R and TAS appeared to have similar efficacy. However, R appears to have more toxicity compared to TAS. Post-approval real world data focusing on the comparative toxicity of R and TAS is warranted. R vs. P (direct) TAS vs. P (direct) R vs. TAS (indirect) HR/OR 95% CI HR/OR 95% CI HR/OR 95% CI OS 0.71 0.60-0.83 0.69 0.57-0.83 1.02 0.80-1.32 PFS 0.45 0.39-0.52 0.47 0.39-0.56 0.96 0.76-1.21 Tox (all grades) 10.43 6.70-15.53 4.24 1.88-9.57 2.46 0.99-6.08 Tox (grades≥3) 7.22 5.08-10.26 2.12 1.57-2.87 3.40 2.14-5.42
A phase IIb of eryaspase in combination with gemcitabine or FOLFOX as second-line therapy in patients with metastatic pancreatic adenocarcinoma (NCT02195180).
Authors: Pascal Hammel, Jean-Baptiste Bachet, Iman El-Hariry, Fabienne Portales, Laurent Mineur, Jean-Philippe Metges, Christelle De La Fouchardiere, Christophe Louvet, Farid El Hajbi, Roger Faroux, Rosine Guimbaud, David Tougeron, Julien Volet, Thierry Lecomte, Christophe Tournigand, Christine Rebischung, Willy Berlier, Anu Gupta, Jerome Cros, Thierry Andre
Journal: Journal of Clinical Oncology (2017)

e15718 Background: L-asparaginase (L-ASP) hydrolyses asparagine (ASN) leading to depletion of this amino acid. While normal cells are protected from ASN requirement due to their ability to produce ASN,.leukemic lymphoblasts and most cancer cells have a very low level or even lack of L-asparagine synthetase (ASNS), and thus depend on serum ASN for their proliferation and survival. L-ASP depletes serum ASN, which in turn inhibits the protein synthesis, resulting in cell cycle arrest and apoptosis in susceptible cancer cells, especially pancreatic cancer cells Eryaspase, which is L-ASP encapsulated in red blood cells, recently showed an encouraging activity and improved safety profile compared to L-ASP in patients (pts) with relapsed ALL. Knowing that up to 70% of pancreatic adenocarcinomas (PC) have low or null ASNS expression (Bachet Pancreas 2015), prompted us to evaluate the efficacy and safety of eryaspase in combination with chemo in PC. Methods: This open label, multicenter phase II randomized study (2:1) enrolled pts with second-line metastatic PC. Pts eligible to gemcitabine or FOLFOX regimen (according to first line chemo) were randomized to chemo +/- eryaspase (100 IU/Kg D3 and D17 of 4-wk regimen) until disease progression Primary end point: progression free survival in pts with ASNS negative tumors (0/1+). ASNS expression was measured using immunohistochemistry and optical density. Key secondary endpoints: PFS in ASNS positive pts (2+/3+), overall survival, biomarkers ( KRASmutation, cell free DNA), and safety. Results: 141 pts were enrolled. Treatment was generally well tolerated, with no safety concerns based on IDMC reviews. ASNS expression was negative in 69%, and positive in 31% of the pts At the time of submission, PFS and OS analysis and the correlation of ASNS expression with clinical outcomes were not yet available but will be presented at the meeting. Conclusions: This is the largest set of PC pts tested for the expression of ASNS and treated in second line with an asparaginase combined with chemotherapy. The ASNS expression levels may be a potential therapeutic target and therefore predictive of response to eryaspase for the treatment of advanced PC. Clinical trial information: NCT02195180.
Immunotherapy in metastatic melanoma: When is it safe to stop?
Authors: Jemma Longley, Alec Paschalis (co-first author), Marcus Remer, James Bennett, Daniel R Muller, Ruth Stone, Ioannis Karydis, Oliver Donnelly, Christian H.H Ottensmeier, Matthew James Wheater
Journal: Journal of Clinical Oncology (2018)

e21518 Background: Optimal duration of immune checkpoint inhibitor therapy in patients with Metastatic Melanoma remains undefined. Current practice mirrors the approach taken in clinical trials recommending 2 years of anti-PD1 monotherapy either alone or following combination immunotherapy. Data on outcomes for patients who discontinue therapy early for reasons other than disease progression or who complete 2 years of treatment are limited. Methods: Patients with Metastatic Melanoma who received pembrolizumab monotherapy between 2014 and 2017 at University Hospital Southampton were identified through our electronic chemotherapy prescribing system. Patients discontinuing treatment for reasons other than disease progression were identified by retrospective medical record review and outcomes were analysed. Results: 132 patients received pembrolizumab monotherapy with 33 patients discontinuing treatment for reasons other than disease progression. The median PFS for this cohort was 29 months with a median follow up of 25 months. 12 patients stopped at 2 years or earlier in either complete or partial response; 4 of these subsequently progressed. 19 patients discontinued as a result of toxicity, with 10 subsequently progressing. 2 patients stopped within 6 months of treatment due to unrelated neurological decline and co-morbidities, and subsequently progressed. Following discontinuation of therapy, significant improvement in survival was observed with increasing duration pembrolizumab exposure (p = 0.002), with higher OS in patients receiving 6 to 12 months of treatment compared to those receiving less than 6 months of treatment (p = 0.004). However, no additional significant benefit was identified in patients treated longer than 12 months. Conclusions: Retrospective analysis of our experience suggests that while survival improves with increasing duration of pembrolizumab therapy, no additional significant benefit appears to be gained with treatment beyond 12 months. A future UK prospective trial will investigate discontinuation of therapy at 12 months to answer this question.
Abstract 13835: Accuracy of Prehospital Documentation of Hypoxia Compared to Continuous Non-Invasive Monitor Data Tracking in Major Traumatic Brain Injury
Authors: Octavio Perez, Daniel W Spaite, Eric Helfenbein, Bruce J Barnhart, Saeed Babaeizadeh, Chengcheng Hu, Vatsal Chikani, Joshua B Gaither, Kurt R Denninghoff, Samuel M Keim, Chad Viscusi, Duane Sherrill, Bentley J Bobrow
Journal: Circulation (2016)

Background: It is well established that prehospital hypoxia dramatically increases mortality in Traumatic Brain Injury (TBI). Thus, in EMS TBI research, case ascertainment and risk-adjustment are highly dependent upon documentation of in-field O 2 saturation. Objective: To compare the rate of hypoxia identified by EMS personnel and documented in EMS patient care records (PCR) vs the actual rate of hypoxia recorded by continuous, non-invasive monitor in TBI. Methods: A subset of major TBI cases (moderate/severe) in the EPIC EMS TBI Study (NIH 1R01NS071049) were evaluated (3/30/13-6/26/15). Cases from 4 EMS agencies that report continuous monitor data (Philips MRx™) as part of EPIC were included. All monitor data available for post-hoc review were displayed and accessible to the providers during EMS care. We compared PCR documentation of hypoxia (O 2 sat &lt;90%) to actual recorded monitor data on each patient (Fisher’s Exact Test; α=0.05). Results: 77 cases were included [median age: 52; 65% male]. The monitors displayed and recorded 16 hypoxic cases (20.8%), but only 6 (37.5%) were documented. Thus, while the rate of actual hypoxia was 20.8%, the case ascertainment was only 7.8% (6/77) when PCR documentation alone was used (p=0.036). Conclusion: Among patients with major TBI, monitor-identified hypoxia occurred much more frequently (20.8%) than was documented (7.8%). Only 37.5% of cases with actual hypoxia were recorded in the PCRs. This may be explained, in part, by the fact that pulse oximetry occurs continuously. Thus, ongoing care responsibilities and scene distractions may cause providers to miss low readings as they fluctuate moment-by-moment. This has significant clinical implications as a potential hidden contributor to poor outcomes if hypoxia goes unrecognized (and untreated) rather than simply not being documented. Furthermore, these findings have important implications for case ascertainment, confounding, and risk-adjustment in EMS TBI studies. Whenever possible, quality improvement and research projects should utilize continuous non-invasive monitor data to identify and evaluate hypoxic patients in the setting of TBI. These findings may also have implications for identifying hypoxia in EMS patients with other critical conditions.
Right-sided colorectal cancer (RC): Response to first-line chemotherapy in FIRE-3 (AIO KRK-0306) with focus on early tumor shrinkage (ETS) and depth of response (DpR).
Authors: Julian Walter Holch, Sebastian Stintzing, Swantje Held, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christoph Kahl, Frank Kullmann, Werner Scheithauer, Thomas Kirchner, Jobst C. von Einem, Dominik Paul Modest, Volker Heinemann
Journal: Journal of Clinical Oncology (2017)

3586 Background: Recent evidence suggests that benefit from anti-EGFR treatment is restricted to RAS wild-type left-sided colorectal cancer (LC) (Holch JW et al. Eur J Cancer 2017). However, these results are preliminary. We therefore investigated patients with RC enrolled in the FIRE-3 trial, which evaluated the efficacy of first-line FOLFIRI plus either cetuximab (cet) or bevacizumab (bev) in RAS wildtype mCRC. New metrics of tumor dynamics were used to characterize the patients. Methods: The splenic flexure was used to differentiate LC from RC. Survival analysis was done using Kaplan-Meier estimation and differences were expressed using Log-Rank test, hazard ratios (HR) and corresponding 95% confidence intervals. Central independent radiological data was used to calculate early tumor shrinkage ≥20% (ETS) and depth of response (DpR). Results: In total, 330 patients were assessable for central radiological evaluation. In patients with LC (n = 257), treatment with FOLFIRI + cet led to longer overall survival (OS) compared to FOLFIRI + bev (HR = 0.68, p = 0.016). In patients with RC (n = 68), OS was comparable between treatment arms (HR = 1.11, p = 0.715). In patients with RC and ETS &lt; 20%, OS was inferior in patients treated with FOLFIRI + cet. In patients who reached ETS ≥20%, a comparable OS was evident between treatment arms (for further details of efficacy in patients with RC see table). Conclusions: Patients with RC do not represent a uniform population. ETS ≥20% defines a subgroup of patients where comparable treatment efficacy was observed with regard to OS, ORR and DpR by addition of cetuximab vs. bevacizumab to FOLFIRI. [Table: see text]
TCT-225 Impact of frailty on a minimalist approach and early discharge following TAVR: insights from the 3M TAVR Study
Authors: Janarthanan Sathananthan, Sandra Lauck, John Cairns, Karin Humphries, Dale Murdoch, Mark Hensey, Richard Cook, Meijiao Guan, Julie Park, Yinshan Zhao, Robert Welsh, Jonathon Leipsic, Danny Dvir, Benjamin Tyrrell, Jonathan Afilalo, Faisal Alqoofi, James Velianou, Madhu Natarajan, Harindra Wijeysundera, Sam Radhakrishnan, Eric Horlick, Anita Asgar, Jean-Bernard Masson, Susheel Kodali, Tamim Nazif, Vinod Thourani, Vasilis Babaliaros, David Cohen, Martin Leon, John Webb, David Wood
Journal: Journal of the American College of Cardiology (2018)