tbuckley/cabot-search huggingface dataset:
Geriatric assessment (GA) reporting in real time in non-elective hospitalized older cancer patients.
Authors: Trevor Augustus Jolly, Allison Mary Deal, Nicole Markowski, Tucker Brenizer, Sharanda Kirk, Franklin Jones, Max S. Perlmutt, Kirsten A Nyrop, Hyman B. Muss
Journal: Journal of Clinical Oncology (2018)

e22045 Background: Older cancer patients (pts) have a high burden of potentially modifiable baseline functional deficits and can accumulate new deficits while hospitalized. This may lead to disability, functional decline, institutionalization, poor quality of life, and increased mortality. We explore the prevalence of GA-identified deficits in a cohort of non-electively hospitalized older cancer pts. Methods: We developed a web/tablet-based software platform for administering a modified GA (Hurria et al. Cancer 2005) to non-electively hospitalized pts, > 70 yrs old with pathologically confirmed malignancy within 72 hours of admission. Results: Complete abstracted data were available for 125 pts. Median age 75 (range 70-92), 53% female, 74% white, 78% greater than high school education, 17% living alone, 26% genitourinary cancers, 69% evaluated during treatment. Overall 94% had at least 1 deficit, with 49% reporting 5 or more. The majority of pts had a deficit related to physical function. Baseline deficits and referrals recommended are shown: Conclusions: Real time geriatric assessment reporting is feasible in non-electively hospitalized older cancer pts. We confirm prevalent baseline deficits in this population and will test whether providing physicians with a GA-report summarizing pt. deficits and recommending evidence-informed intervention impacts multidisciplinary referral rates, readmission and clinician satisfaction. GA-Identified deficits Deficit n (%) Referrals Physical Function 105 (84) Physical and/or occupational therapy 1 or more impaired IADL 82 (66) ADL score < 14 75 (60) Patient reported KPS < 80 62 (50) Professional assessed KPS < 80 51 (41) 1 or more falls 38 (30) Cognitive Impairment (Blessed Memory Orientation-Concentration Score ≥11) 27 (22) Memory disorders clinic No. of comorbidities ≥ 5 33 (27) Formal geriatric consultation Polypharmacy ( > 9 meds) 46 (37) Clinical pharmacist Nutrition Nutritionist Weight loss ≥ 10% in 6 months 45 (36) BMI < 18.5 kg/m2 10 (8) Psychosocial Psychosocial support team PHQ-9 Depression Inventory 29 (23) Mental Health Index (MHI) 33 (27) Depression Subscale Anxiety Subscale 34 (27)
The role of PET for predicting nodal response in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) treated with chemoradiotherapy (CRT): Results of a prospective multicenter trial.
Authors: Sandra Schmitz, Aline Van Maanen, Laura Rousseaux, Guy Andry, Stéphane Temam, Didier Dequanter, Sebastien Vergez, Benjamin Lallemant, Dominique De Raucourt, Franck Jegoux, Francois-Xavier Hanin, Vincent Gregoire, Marc Hamoir
Journal: Journal of Clinical Oncology (2017)

6013 Background: Controversy about neck management after CRT in patients with LA HNSCC persists due to low accuracy of CT/MR to asses the neck. As already demonstrated (Mehanna, NEJM 374, 2016), PET is an alternative to planned neck dissection (ND) thanks to its high negative predictive value (NPV). However, no conclusion could be drawn for patients (pts) with equivocal response (e.g. suspicion of residual disease on CT/MR but negative PET) because pathologic confirmation was lacking. Methods: Multicenter, prospective, nonrandomized trial including pts with LA HNSCC of oral cavity, oro- hypopharynx, larynx, staged N1, N2, N3, treated with CRT and evaluated 12 weeks after CRT by overall assessment (OA): clinical examination (CE), PET and CT/MR. ND was performed in incomplete regional response based on at least 1 positive evaluation method. Pathologic analyses (HE and KI67) were performed on ND samples. Primary objective was to determine the NPV and accuracy of PET as a single examination in the post CRT nodal assessment. Primary outcome was 2-year regional recurrence free survival rate (RRFSR). Results: 264/318 pts included completed full treatment and had post CRT OA. Median follow up was 40 months. No ND was proposed in 119 patients because of a negative OA; 145 patients had ND. The presence of viable cells was reported in 27 ND (18.6%). Sensitivity, specificity, PPV, NPV, accuracy of OA were 90.0%, 49.6%, 18.6%, 97.5%, 54.2% vs 69.7%, 75.3.%, 28.8%, 94.6%, 74.6% for PET alone. Kappa coefficient was of 0.838, indicating an almost perfect agreement. In pts with negative OA, RRFSR was 61.3% vs. 56.6% in pts with positive OA and ND (p=0.45). Using post CRT assessment with PET alone, RRFSR in pts with negative PET was 63.0% vs. 48.8% in pts with positive PET (p=0.04). Using PET assessment alone, 65/145 ND (44.8%) could have been avoided without compromising RRFSR. Conclusions: NPV using PET alone is 94.6%. Post CRT evaluation using only PET would have resulted in considerably fewer ND without jeopardizing neck control. PET alone is more accurate and more discriminant for predicting pts outcome. Clinical trial information: NCT00634777.
Genetic heterogeneity of <i>KRAS</i>-mutated NSCLC: Co-occurrence of potentially targetable aberrations and evolutionary background.
Authors: Matthias Scheffler, Michaela A. Ihle, Rebecca Hein, Sabine Merkelbach-Bruse, Johannes Braegelmann, Andreas H. Scheel, Sebastian Yves Friedrich Michels, Frank Ueckeroth, Anna Eisert, Leonie Gogl, Rieke Frank, Rieke Nila Fischer, Sophia Koleczko, Carsten Schaepers, Anna Kostenko, Florian Kron, Martin Hellmich, Martin L. Sos, Reinhard Buettner, Juergen Wolf
Journal: Journal of Clinical Oncology (2016)

9018 Background: KRAS mutations in non-small cell lung cancer (NSCLC) still remain therapeutically untargetable. Assuming that these mutations are not mutually exclusive with other driver aberrations, we set out this study in order to describe and analyze co-occurring mutations and their potential therapeutic impact. In a subset of patients with co-occuring driver mutations, we performed additionally whole-exome sequencing (WES) to define clonal and evolutional status of the mutations. Results were compared with data from The Cancer Genome Atlas' (TCGA) for NSCLC. Methods: In a timeframe of 20 months, 4507 patients of a local screening initiative (Network Genomic Medicine Lung Cancer) were analyzed using next-generation parallel sequencing (NGS). The NGS panel consisted of 102 amplicons and 14 genes: KRAS, PIK3CA, BRAF, EGFR, ERBB2, NRAS, DDR2, TP53, ALK, CTNNB1, MET, AKT1, PTEN and MAP2K1. In subsets of patients, fluorescence in-situ hybridization (FISH) was performed for MET, FGFR1, and HER2 amplification and for RET, ALK and ROS1rearrangements. Clinical parameters, therapy, survival and smoking status were also collected. Results: We identified 1207 patients (26.8%) harboring a KRAS mutation, whereof 1080 patients (89.5%) underwent the complete diagnostic panel. The most common mutation was G12C accounting for 41.2%. In a total of 308 patients (28.8%) additional aberrations could be detected, including MET (prevalence 15.3%), FGFR1 (5.0%) and HER2 (12.7%) amplification and mutations in PIK3CA (3.4%), DDR2 (4.4%), PTEN (1.9%), CTNNB1 (1.7%), BRAF (1.3%) and EGFR (1.4%). Less frequently, mutations within NRAS, AKT1, ALK, MET, and MAP2K1 could be detected. 459 patients (42.9%) had co-occurring TP53mutations.. WES on selected cases confirmed the presence of these mutations. Conclusions: To our knowlege our data represent the largest analysis of co-occuring mutations in KRAS- mutated NSCLC. They show that KRAS-mutated NSCLC represents a heterogenous group of tumors with a substantial portion harboring a wide spectrum of additional targetable mutations. Further studies will show whether these findings translate into new therapeutic options in KRAS-mutated NSCLC.
Risk of health-related quality of life events and pulmonary toxicities in patients with advanced neuroendocrine tumors treated with everolimus: A meta-analysis of phase 3 randomized controlled trials.
Authors: Kyaw Zin Thein, Anita Sultan, Sriman Swarup, Miguel Quirch, Lukman Aderoju Tijani, Fred L. Hardwicke, Catherine Jones, Sanjay Awasthi
Journal: Journal of Clinical Oncology (2018)

e16185 Background: Autocrine activation of mTOR signaling pathway, mediated via insulin-like growth factor 1, was shown to involve in neuroendocrine tumor (NET) progression. Everolimus (E), an oral mTOR inhibitor, is proven to be beneficial in patients with NET with notable toxicities. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of health-related quality of life (HRQOL) events and pulmonary toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2018 were queried. Phase 3 RCTs that mention HRQOL events and pulmonary toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Fixed effects model was applied. Results: 1133 patients with advanced NET were eligible. Studies compared E+ octreotide (O) vs O or E vs placebo. The RR of all-grade side effects were as follows: fatigue, 1.55 (95% CI: 1.26-1.92, p < 0.001); asthenia, 1.82 (95% CI: 1.24-2.69, p = 0.002); decreased appetite, 2.56 (95% CI: 1.76-3.75, p < 0.001); pyrexia, 5.36 (95% CI: 2.40-11.98, p < 0.001); rash, 3.66 (95% CI: 2.79-4.80, p < 0.001); pruritus, 2.24 (95% CI: 1.48-3.38, p < 0.001); cough, 6.09 (95% CI: 2.68-13.80, p < 0.001); dyspnea, 4.69 (95% CI: 2.20-9.97, p < 0.001); peripheral edema, 5.71 (95% CI: 3.46-9.43, p < 0.001); and pneumonitis, 31.30 (95% CI: 8.10-120.90, p < 0.001). The RR of high-grade side effects were as follows: fatigue, 2.55 (95% CI: 1.14-5.68, p = 0.02); asthenia, 1.70 (95% CI: 0.45-6.35, p = 0.42); decreased appetite, 0.46 (95% CI: 0.06-3.33, p = 0.44); rash, 2.95 (95% CI: 0.50-17.22, p = 0.22); dyspnea, 3.11 (95% CI: 0.59-16.26, p = 0.17); peripheral edema, 2.22 (95% CI: 0.37-13.32, p = 0.38); and pneumonitis, 6.63 (95% CI: 0.90-48.83, p = 0.06). Conclusions: Everolimus contributed to significant toxicity of all-grade HRQOL and pulmonary toxicities as well as high-grade fatigue. Timely recognition of pneumonitis, a major cause of morbidity and mortality, may help physicians in delivering proper supportive care.
ARID1A, a SWI/SNF subunit, is critical to acinar cell homeostasis and regeneration and is a barrier to transformation and epithelial-mesenchymal transition in the pancreas
Authors: Wenjia Wang, Scott C Friedland, Bing Guo, Michael R O’Dell, William B Alexander, Christa L Whitney-Miller, Diana Agostini-Vulaj, Aaron R Huber, Jason R Myers, John M Ashton, Richard F Dunne, Laurie A Steiner, Aram F Hezel
Journal: Gut (2018)

Objective Here, we evaluate the contribution of AT-rich interaction domain-containing protein 1A ( ARID1A ), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models. Design Mice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53 , were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes. Results Arid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a , leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a -mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation. Conclusions ARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a -deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.
P13 INCREASED EXPRESSION AND TRANSLOCATION OF KRUPPEL-LIKE FACTOR 4 AND SMOOTH MUSCLE ALPHA ACTIN AFTER BEING SUBMITTED TO ACUTE SHEAR STRESS IN AN EX-VIVO MODEL
Authors: Gustavo A Guida, Alex Ward, Vito D Bruno, Prof Sarah George, Rakesh Krishnadas, Prof Gianni, D Angelini, Mustafa Zakkar
Journal: Cardiovascular Research (2018)

Nanoparticles synthesised by thermal decomposition and coated with poly(maleicanhydride-alt-1octadecene), poly(ethyleneimine) or alendronate were characterised for core size, hydrodynamic size, surface potential and relaxivity.Targeting antibody was coupled to nanoparticles through bioorthogonal coupling chemistry.In vitro toxicity studies performed at 500, 50, 5 ug/ml [Fe] in RAW 264.7 murine macrophages.In vivo studies performed in ApoE-/-mice on western diet instrumented with a cuff on the left carotid on 3T Phillips Achieva.Histological staining for CD68, CX3CL1, elastin, tropoelastin, and Fe.Lead candidate was identified as 10 nm iron oxide core with poly(maleicanhydride-alt-1octadecene), -36.21 mV, 18.806 mmol -1 /s -1 .In vitro results show 50% cell viability after 48 hours at excess dose 50 ug/ml.In vivo results show SPIONs accumulate well in plaque but preliminary analysis suggests uptake is not specific.This work presents an exciting new MRI contrast agent which is still in circulation 24 hours postinjection with limited liver uptake, good accumulation in plaque, and limited toxicity in cell studies.
The immunomodulatory protein Dickkopf-1 (DKK1) defines a non-neuroendocrine subtype of metastatic castration-resistant prostate cancer (mCRPC) with low AR and low PSA expression.
Authors: David Wise, Joshua Armenia, Yu Chen, Peter Nelson, Nikolaus Schultz, Charles L. Sawyers, Howard I. Scher
Journal: Journal of Clinical Oncology (2017)

5054 Background: Advanced stagemCRPC can manifest AR-signaling independent growth typified by loss of AR and/or PSA expression in the absence of neuroendocrine (NE) features on biopsy. We sought to identify therapeutically relevant biomarkers of this highly resistant prostate cancer subtype. Methods: An unbiased differential gene expression analysis of non-neuroendocrine mCRPC biopsies was carried out comparing patients with AR low to patients with AR high disease in a discovery cohort (SU2C/PCF, 18 pts: 8 AR low , 10 AR high ) and validation cohort (Fred Hutchinson, 76 pts: 12 AR low , 64 AR high ). The AR and NE status of the biopsies were defined by AR and PSA mRNA expression and gene signatures representative of AR activity and NE lineage. An RNA sequencing-based signature of immune cell subsets was calculated using the Cibersort algorithm. Results: Differential gene expression analysis identified the secreted Wnt antagonist, DKK1, as significantly upregulated in AR low cases compared to AR high cases (11.2 RPKM vs. 0.28 RPKM, p &lt; 0.03) in our discovery cohort and confirmed in our validation cohort (9.2 FPKM vs. 0.99 FPKM, p &lt; 0.001). DKK1 protein was also found to be increased in non-neuroendocrine AR low relative to AR high prostate cancer in vitro cell and organoid models (858 pg/mg total protein vs. 2 pg/mg total protein, p &lt; 0.05) and patient-derived xenografts (28.6 FPKM vs. 0.78 FPKM, p &lt; 0.0001). Consistent with the role of DKK1 as a negative modulator of anti-tumor immunity, patient biopsies with the highest quartile of DKK1 expression showed an RNA signature consistent with lower levels of active NK cells (0.2% vs. 1.8%, p &lt; 0.005), and lower levels of CD8+ T cells (3.7% vs. 9.7%, p&lt; 0.005) compared to those with the lowest quartile of DKK1 expression. Conclusions: DKK1 represents a secreted biomarker that is disproportionately enriched in non-neuroendocrine mCRPCs that lack AR expression. Because DKK1 has been implicated as a suppressor of anti-tumor immunity and is a target of an existing neutralizing antibody, our results support the clinical evaluation of the role of DKK1 blockade in DKK1-positive AR-negative prostate cancer.
Olaratumab for the treatment of patients (pts) with advanced/metastatic soft tissue sarcoma (STS): Treatment patterns in the United States (US) during the first year post-approval.
Authors: Victor Manuel Villalobos, Lisa M. Hess, Yajun Zhu, Tomoko Sugihara, Pablo Lee, Volker Wacheck, Symantha A. Melemed, Andrew J. Wagner
Journal: Journal of Clinical Oncology (2018)

e23535 Background: Olaratumab (olara) is a fully human platelet-derived growth factor receptor alpha (PDGFR-α) receptor antagonist that received US Food and Drug Administration (FDA) accelerated approval in October 2016 for the treatment of adult patients with STS in combination with doxorubicin (dox) for whom an anthracycline-containing regimen is appropriate. This approval was based on a randomized Phase 2 study showing a statistically significant 11.8 months median overall survival benefit. This retrospective observational study was designed to understand the real-world treatment patterns of olara in the US during the first year following FDA approval. Methods: The Flatiron electronic medical records database includes HIPAA-compliant de-identified data from patients treated at 265 cancer clinics by > 2,500 oncologists. Data are refreshed every 30 days. Eligible patients were age 18+ who received olara after approval in Oct 2016 Descriptive analyses were conducted to summarize patient characteristics, duration of therapy, and treatment patterns as of Oct 2017 (data available at time of analysis). Results: There were 267 eligible patients in the Flatiron database [mean age 63.2 years (SD = 12.9); 52.8% female]. Consistent with the data source, 77.2% of patients were treated in community practices. Most patients were treated with olara-based therapy in the first- (n = 158, 59.2%) or second-line setting (n = 60, 22.5%). The majority (n = 238, 89.1%) received olara in combination with dox; 20 (7.5%) received olara monotherapy, 5 (1.9%) received olara with liposomal doxorubicin, and the remaining patients (n = 4, 1.5%) received olara with other agents. Of all patients, 41.2% had received olara-based therapy within 60 days of the end of the database. The recent FDA approval and proportion of patients who may not have completed therapy limit the ability to estimate duration of therapy at the time of analysis. Conclusions: These early data show that within the first year of approval, olara has been primarily used in combination with dox, consistent with the label. Future studies will evaluate the clinical outcomes of treatment as data mature.
Association between hospital volume, treatment patterns, and overall survival (OS) of patients with stage 3A non-small cell lung cancer (NSCLC).
Authors: Sri Harsha Tella, Anuhya Kommalapati, Apar Kishor Ganti
Journal: Journal of Clinical Oncology (2018)

8543 Background: There is significant heterogeneity in the treatment of stage IIIA NSCLC. We evaluated the therapeutic and survival disparities in IIIA NSCLC patients based on the hospital volume using National Cancer Data Base (NCDB). Methods: IIIA NSCLC patients diagnosed between 2004-2015 were included. We classified facilities by tertiles (T; mean patients with IIIA NSCLC treated/yr): T1: < 67.07; T2: 67.01 to 123.68 and T3: ≥123.68. We used SPSS to account for clustering of patients within centers (based on the volumes: lower, middle & higher 1/3rd of the cases) and Cox regression to determine the volume-outcome relationship, adjusting for patient demographics (age, sex, race), tumor characteristics (size, nodes and grade), insurance & therapy. Kaplan Meier estimates of OS were compared with log-rank test. Results: This analysis includes 101,110 patients treated at 1329 facilities. The median age at diagnosis was 68 yrs. The median annual facility volume was 91 patients/yr (range, 1- 798). Multivariable analysis showed that facility volume were independently associated with all-cause mortality (p < .0001). The unadjusted median OS by facility volume was: T1: 15 months (m), T2: 16 m, and T3: 19 m (P < .0001). Compared with patients treated at T3 facilities, patients treated at lower-tertile facilities had significantly higher risk of death [T2 hazard ratio (HR), 1.09 (95% CI, 1.07- 1.11); T1 HR, 1.11 (95% CI, 1.09 - 1.13)]. Patients treated at high volume centers were more likely to get surgery (27 vs 17%) and trimodality treatment (12% vs 9%) (p = 0.01). Chemo and radiation therapy patterns were similar among facilities. Receipt of surgical therapy was independently associated with prolonged OS. Compared to patients who received lobectomy, patients who received pneumonectomy had significantly higher risk of death HR, 1.32 (95% CI,1.3-1.4, p < 0.0001). Conclusions: Patients who were treated for stage IIIA NSCLC at T3 centers ( > 123 cases/yr) had a significant improvement in survival and are more likely to receive trimodality therapy. Therapy (%) Survival (%) Surgery Chemo Radiation Trimodality 1 yr 3yr 5 yr T1 (33%) 17 69 68 9 57 26 17 T2 (34%) 20 70 68 10 59 28 19 T3 (33%) 27 70 65 12 64 33 23
Impact on health status's primary caregivers of patients with cancer at National Cancer Institute Mexico an unmet need.
Authors: Oscar Galindo Vazquez, Abelardo Meneses-Garcia, Angel Herrera, Jose Luis Aguilar, Paula Cabrera-Galeana, Liliana Rivera-Fong, Miguel A. Alvarez
Journal: Journal of Clinical Oncology (2016)

e18019 Background:In developing countries most of the cancer patients (CP) are diagnosed in advanced stages. So they loosed their independence and the participation of the primary caregivers (PC) is very important to maintenance adherence treatment. It is reported that this PC have -as a consequence of the roll- restrictions on social life, financials reports, recreate activities and health status. Objective: Determine the impact of the process of caring CP in PC by the two validate questionnaires: psychometric properties of the General Health Questionnaire Goldberg 28 (GHQ-28) and the Beck Depression Inventory (BDI) in a sample of PC at National Cancer Institute Mexico where this questionnaire has not been used before. Methods: After the approval of the Ethics Committee, 276 primary caregivers accepted to participate and signed a informed consent before we applied the questionnaires. Participants completed concurrently the GHQ-28 and the Beck Depression Inventory BDI. Results: We have 205 women (74.3%) and 71 male (25.7%). The internal consistency of the overall scale showed a satisfactory index (α = 0.91). Cronbach's alphas of the subscale had a value of α = .86 (somatic symptoms) α = .76 (social function) this explains 53.42% of the variance. The validity through the correlation with the BDI showed significant results (Pearson r 0723-0427, p < 0.05). The majority of our PC was women and husbands or wives take mostly the roll. Conclusions: The relevance of the results shows that this population can present damages in their overall health throughout the process of caring for cancer patients. Characteristics % N 276 100 Age 16-77 Sex Male 71 25.7 Female 205 74.3 Education None 9 3.3 Primary 64 23.2 Junior High School 101 36.6 High School 66 23.9 College 25 9.1 PH 11 4.0 Relationship Wife/Husband 174 63.1 Son/Daughter 78 27.9 Others 24 0.9 Type of Cancer Breast Cancer 78 28.3 Head and Neck 21 7.6 Genitourinary 14 7.3 Gynecologic 37 10.9 Hematologic 15 14.5 Others 111 68.6