tbuckley/cabot-search huggingface dataset:
Use of SNP-array-based karyotyping for cytogenetic prognostication in unclassified cases of myelodysplasia and associated overlap disorders
Authors: B. Bhatnagar, R. V. Tiu, L. P. Gondek, C. O'Keefe, J. Huh, A. S. Advani, M. A. Sekeres, J. P. Maciejewski
Journal: Journal of Clinical Oncology (2009)

7016 Background: Myeloproliferative disorders (MPD) and myelodysplastic syndromes (MDS) often have overlapping features resulting in unclassifiable cases (MDS-U and MDS/MPD-U). Chromosomal abnormalities impact prognosis, but 50% of cases show normal karyotype by metaphase cytogenetics (MC). Single nucleotide polymorphism arrays (SNP-A) are novel karyotyping tools with superior resolution and ability to detect copy neutral loss of heterozygosity, a defect not detected by MC. Methods: MDS-U (N = 17) and MDS/MPD-U (N = 61) patients were selected from an MDS database (N = 720, median age = 76, median follow-up = 42 mos). SNP-A was performed on 67 patients and 751 controls. An algorithm for identification of somatic lesions was designed: 1) Lesions detected by MC and SNP-A required no further analysis; 2) Micro-duplications/ deletions overlapping with copy number variants (CNV) were excluded. Lesions not in CNV databases were confirmed by CD3 lymphocytes; 3) UPD &lt;25 Mb were unlikely somatic and excluded. Telomeric and interstitial (≥ 25 Mb) UPD were considered somatic. International Prognostic Scoring System (IPSS) was used to assess routine risk. Fisher's exact test was used for categorical variables. Overall (OS) and event-free (EFS) survival defined by the MDS working group criteria were analyzed by Kaplan Meier analysis (log-rank or Wilcoxon and 2-sided significance). Results: SNP-A yielded superior detection rate for chromosomal defects compared to MC (71% vs 47%, p = 0.008). UPD was seen in 17 patients and frequently involved chromosomes 1, 3, 6, 8, 11, 17. MDS/MPD-U and MDS-U patients had similar OS and EFS (OS = 42 vs. 45 mos, p = 0.13; EFS = 42 vs. 45 mos p = 0.63). SNP-A revealed a more complex karyotype in patients with advanced MDS. Furthermore, SNP-A karyotyping resulted in prognostic refinement of previously assigned IPSS: Unclassified cases = 6% versus 0%, int-1 = 45% versus 53%, int-2 = 6% versus 19%, high = 5% versus 8%. Overall, patients with new SNP-A lesions had worse OS and EFS (OS = 41 mos vs NR, p = 0.07; EFS = 32 vs 112 mos, p = 0.07). Conclusions: SNP-A karyotyping complements MC in detecting chromosomal defects in MDS-U and MDS/MPD-U. This technology will be helpful in refining diagnosis based on characteristic recurrent chromosomal lesions including UPD. No significant financial relationships to disclose.
Personalized cancer tests and services on the Internet: A website content analysis.
Authors: Stacy W. Gray, Katherine A. Janeway, Jane C. Weeks
Journal: Journal of Clinical Oncology (2013)

1553 Background: The Internet may facilitate the use of guideline endorsed “personalized” cancer tests and services by increasing awareness of and access to new technologies; however limited regulation over Internet marketing may also lead to the promotion of tests and services of unproven benefit. Methods: We identified 51 websites that sell personalized cancer medicine (PCM) tests and/or services by searching Google, Bing, and Yahoo (53 search terms per site, 30 results per search term), reviewing the medical literature, and abstracting information from the exhibitor list from a national oncology conference. Two independent coders evaluated website content. Discrepancies were resolved by consensus. Results: Sites most commonly promoted physicians/institutions selling PCM (49%), tumor analysis (47%, e.g., DNA, RNA, or protein analysis) or offered interpretive services (12%, e.g., cloud-based analytical systems to select personalized cancer therapies). Eighty-six percent of sites included information on the benefits of PCM whereas only 24% of the sites included information on the limitations of PCM (McNemar’s chi square =32, p&lt;0.001). Forty-three percent of sites included general cost information; of those sites, 23% provided an exact dollar figure and 24% included information on insurance reimbursement. Commercial sites were more likely to include cost information than educational and organizational sites (56% vs. 23%, chi square = 4.1, p=0.04). Cancer-related germline testing was offered by 27% of sites. Websites marketed guideline endorsed tests such as EGFR and KRAS mutation testing as well as tests that are not guideline endorsed such as in vitro and in-vivo (mouse) chemotherapy sensitivity testing, EMSY, ZNF703, and whole-exome sequencing. Conclusions: The clinical utility of “personalized” cancer tests and services marketed and sold over the Internet is highly variable. Patients and physicians need to evaluate PCM Internet sites with caution given the fact that benefit information is more common than limitation information and that unproven technologies are commonly promoted.
Prognosis of pT1a,bN0 breast cancer: Perception from the French oncology community—Results from the EURISTIC survey.
Authors: Marc Spielmann, David Azria, Jean Marc Classe, Florence Dalenc, Clarisse Dromain, Thomas Facchini, Anthony Goncalves, Philippe Liegeois, Moise Namer, Xavier B. Pivot, Yoann Pointreau, Anne Vincent-Salomon, Mercedeh Mahe
Journal: Journal of Clinical Oncology (2013)

e11607 Background: Although most early-stage breast tumors have a favourable outcome, some subgroups carry a higher recurrence risk. The objective of the EURISTIC Survey was to evaluate the perception French physicians have of the prognostic risk associated with the biopathological characteristics of tumors in pT1a,b N0 breast cancer. Methods: This 38 item postal survey was developed by an expert panel. 2,000 physicians involved in breast cancer treatment were contacted. Specialities involved were medical and radiation oncologists, surgeons, radiologists and pathologists. Results: The survey was conducted between September and December 2012. A total of 663 physicians responded (response rate = 33%). They stated treating an average of 50 breast cancer patients per month. 58% of physicians reported that tumour size was not considered a major parameter in this clinical setting. In the absence of an adjuvant treatment, the prognosis of T1a,bN0 carcinoma was perceived better if HR-positive rather than HER2-positive or triple-negative with a "positive" prognosis perception rated by 83%, 21% and 8% of physicians respectively. For pT1a,bN0 tumors, the criteria with the highest perceived prognostic risk were ranked as follows: HER2+ (29%), HR- (20%) elevated tumor grade (20%) and triple negative tumor (14%). The average size threshold for a "negative" prognostic rated tumor was 18 mm. This threshold was scaled up for HR-positive carcinoma (22 mm) and scaled down for HER2-positive (10mm) or triple negative carcinoma (7mm). Between 4 and 17 mm, there was a linear correlation between tumor size and perceived risk of recurrence with HER2-positive tumors always carrying a worse prognostic than HR-positive tumor (Table). Conclusions: French physicians have the perception that HER2-positivity and triple negative tumor biology strongly impact the prognosis of pT1a,b N0 carcinoma, independent of tumor size. [Table: see text]
Pharmacodynamic biomarkers of outcomes in the phase III study of lenvatinib in <sup>131</sup>I-refractory differentiated thyroid cancer (SELECT).
Authors: Makoto Tahara, Martin Schlumberger, Rossella Elisei, Mouhammed Amir Habra, Naomi Kiyota, Corina Dutcus, Jianbo Xu, Junming Zhu, Taro Hihara, Shannon McGrath, Mark Matijevic, Tadashi Kadowaki, Yasuhiro Funahashi, Steven I. Sherman
Journal: Journal of Clinical Oncology (2015)

6014 Background: Lenvatinib (LEN)–an oral multikinase inhibitor of VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT—significantly prolonged progression-free survival (PFS) vs placebo (PBO) in the SELECT study. Baseline (BL) Ang2 levels were previously identified as prognostic and predictive of LEN response, and increase in FGF23 levels is a surrogate pharmacodynamic biomarker of FGFR1 inhibition. Here we investigated serum circulating cytokine/angiogenic factors (CAFs) as potential pharmacodynamic biomarkers of LEN efficacy and disease progression in SELECT. Methods: Blood samples from 387/392 (99%) randomized patients (pts) were collected at baseline, cycle 1 day 15 (C1D15), day 1 of subsequent cycles, and treatment end. TG and CAF levels (Ang2, VEGF, sTie2, and FGF23) were measured by ELISA. Results: From cycle 1,VEGF levels were consistently elevated for pts on LEN, whereas Ang2 and sTie2 levels were consistently decreased compared with PBO. FGF23 levels increased by 20.8% (C1D15) and 28.6% (C2D1). Although TG decreases in LEN pts were correlated with tumor shrinkage (TS; P < 0.0001) and objective response rate (ORR; P < 0.05, through C9D1), TG decreases also occurred in pts with stable or progressive disease. Increased VEGF (P < 0.0001) and decreased Ang2 (P < 0.0001) and sTie2 (P < 0.0001) levels also correlated with TS, but not with ORR. Amongst LEN-treated pts with disease progression, decreased levels of TG (31/34 pts, P < 0.0001), Ang2 (32/38 pts, P < 0.0001), and sTie2 (39/42 pts, P < 0.0001) at C2D1 compared to BL were observed. However, at treatment end, increased levels of TG, Ang2, and sTie2 from C2D1 were observed in 79.4%, 78.9%, and 81.0% of these pts, respectively. In some cases, these increases occurred prior to disease progression. Conclusions: TG changes were correlated with TS and ORR in the LEN arm of SELECT; CAF analyses may provide additional information.Increased levels of VEGF and FGF23 may indicate that LEN is targeting these signaling networks in pts with RR-DTC in SELECT. Preliminary analyses of pts who progressed on LEN indicated elevated levels of Ang2 and sTie2. Further analyses of the Ang2/Tie2 axis using serum biomarkers are warranted. Clinical trial information: NCT01321554.
Larger size extracellular vesicle as early biomarker in patients with metastatic pancreatic cancer.
Authors: Dong Uk Kim, Francis A San Lucas, Matthew Cagley, Bret Stephens, Feven C Mulu, Jonathan Castillo, Vincent Bernard, Gauri R. Varadhachary, Matthew H. G. Katz, Hector A Alvarez, Anirban Maitra
Journal: Journal of Clinical Oncology (2017)

234 Background: Current research suggests that tumor-derived extracellular vesicles (EVs) play an important role in tumor progression especially with regard to metastasis. Atypically large EVs have been reported to have the ability to transport bioactive molecules through the blood stream. Therefore, EV physical properties such as diameters and concentrations may have a biological impact on tumor progression. However, it has not been described which characteristics are clinically relevant in the longitudinal assessment of tumor progression and chemo-response. Methods: Plasma from 19 metastatic PDAC patients was collected at treatment-naïve baseline and in more than 2 consecutive assessments during chemotherapy between May 2015 and July 2016. EVs from plasma were isolated using a sequential centrifugation protocol, confirmed as described previously and analyzed using the Particle Metrix (Zetaview, Diessen, Germany) and proprietary software. The clinical variables along with concentration and size distribution of EVs were analyzed to identify prognostic factors associated with chemo-response. Results: Mean EV size and concentration were 122.85 nm and 4.13x10 9 /mL plasma at treatment naïve baseline, 123.62 nm and 4.39x10 9 /mL plasma at first response assessment during chemotherapy. Median overall and progression-free survivals were 256 and 165 days, respectively. The change of CA 19-9 (hazard ratio 17.477, p = 0.001, 95% CI 0.995-1.045) and proportion of EVs larger than 150nm (hazard ratio 11.022, p = 0.017, 95% CI 3.183-95.964) was a significant independent predictor of progression-free survival at first response assessment during chemotherapy. In addition, we observed a dramatic increase in the proportion of larger EVs earlier than the increases in CA 19-9. Conclusions: Our data suggests that increases in the amounts of larger EVs are independent predictors of tumor progression and chemo-response in metastatic pancreatic cancer patients. Furthermore, the increases in the amounts of larger EVs may potentially be more clinically useful than CA19-9 in the earlier stages of progression. Concentrations of larger-sized EVs could be a valuable component of more sophisticated diagnostics in liquid biopsies.
Factors associated with outcome of secondary MDS and AML: Review of 2,182 patients at MDACC.
Authors: Francesco Paolo Tambaro, William G. Wierda, Guillermo Garcia-Manero, Jorge E. Cortes, Sherry Pierce, Mario Annunziata, Mimmo Ripaldi, Gautam Borthakur, Elias Jabbour, Farhad Ravandi, Stefan Faderl, Hagop Kantarjian
Journal: Journal of Clinical Oncology (2012)

6603 Background: Secondary acute myeloid leukemia (sAML) and myelodysplastic syndromes (sMDS) have been associated with prior treatment for other malignancies, particularly chemotherapy, and associated with high-risk features and poor clinical outcomes. Methods: We identified 2,182 patients (pts) (57% male) diagnosed with AML (n=1,073; all FAB/WHO represented) or MDS (n=1,109; 984 MDS, 125 MDS/MPD, all WHO represented) and who had 1 (n=1,907), 2 (n=239), or 3 (n=36) prior malignancies (PM). Pt characteristics and outcomes were analyzed. Results: The median age was 67 yrs. Prior hematological neoplasms (25%), breast (16%), prostate (16%), skin (9%) were most common. The prior malignancy reflected prior treatment, 1,252 pts underwent surgery, 939 received radiation, and 1,211 received chemotherapy alone or in combination; 124 were untreated. Types of prior malignancy and prior treatment associated with AML and MDS will be presented. Median time to AML/MDS was 64 months (mo) and 46 mo (p=0.000) for pts with 1 or &gt;1 PM, respectively, and correlated with type of PM (p=0.000) and previous monotherapy (surgery vs RT vs chemo) (p=0.020). For both AML and MDS, the incidence of poor-risk cytogenetics was nearly twice for pts who received prior chemotherapy compared to those who underwent surgery or radiation alone. Factors associated with survival in secondary AML and MDS are reported in the table. Conclusions: In conclusion, outcomes for pts with secondary AML and MDS are poor, especially for pts treated with prior chemotherapy. Type of prior malignancy and treatment are correlated with outcomes. Furthermore, greater number of prior malignancies correlates with inferior outcomes. [Table: see text]
Nervous system sequelae of chemotherapy treatment: Associations and proposed mechanisms.
Authors: Kelly N. H. Nudelman, Yang Wang, Brenna C. McDonald, Susan K. Conroy, Dori J. Smith, John D. West, Darren P. O'Neill, Noah Robert Zanville, Victoria Champion, Bryan P. Schneider, Andrew J. Saykin
Journal: Journal of Clinical Oncology (2014)

9652 Background: Breast cancer treatment with chemotherapy often results in neurotoxic sequelae including chemotherapy-induced peripheral neuropathy (CIPN) and cognitive dysfunction. Although CIPN and cognitive dysfunction are often viewed as separate phenomena, we hypothesized that these effects may be related. Methods: Breast cancer patients treated with (Ctx+, n=27) and without (Ctx-, n=26) chemotherapy and healthy controls (HC, n=26) were assayed post-surgery, pre-treatment and one month post-treatment. All but one Ctx+ treatment included paclitaxel or docetaxel. Peripheral neuropathy symptom severity (PNS) was evaluated with the sum of the self-reported FACT/GOG-Ntx 11-item scale, cerebral gray matter density (GMD) and perfusion were assessed using MRI, and cognitive complaints, depression, and fatigue were assessed with the Multiple Ability Self-Report Questionnaire (MASQ), the Center for Epidemiologic Studies Depression scale, and the Fatigue Symptom Inventory. Results: Chemotherapy treatment was associated with increased PNS and cognitive complaints (p<0.01), which remained significant after adjusting for fatigue and depression. PNS was associated with increased cerebral perfusion in the left anterior cingulate (LAC) gyrus, a region associated with pain processing. Interestingly, a previously published Ctx+ frontal GMD decrease in this cohort was correlated with the LAC perfusion change (p<0.01) and PNS change (p<0.01). Individuals with GMD decrease showed lower LAC perfusion and fewer PNS, while increased PNS were correlated with increased cognitive complaints (p<0.05) and depression and fatigue (both p<0.01). Conclusions: This is the first study to identify cerebral perfusion change associated with peripheral neuropathy symptoms in a breast cancer cohort. Our findings suggest that chemotherapy-associated gray matter decrease may also reduce LAC perfusion and associated pain perception. This finding and the observed relationships between CIPN symptoms, depression, fatigue, and cognitive complaints highlight the importance of further research on the causal pathways underlying these effects, and of developing therapies targeting this symptom cluster.
High‐Throughput Screening of Vascular Endothelium‐Destructive or Protective Microenvironments: Cooperative Actions of Extracellular Matrix Composition, Stiffness, and Structure
Authors: Yonghui Ding, Michael Floren, Wei Tan
Journal: Advanced Healthcare Materials (2017)

Pathological modification of the subendothelial extracellular matrix (ECM) has closely been associated with endothelial activation and subsequent cardiovascular disease progression. To understand regulatory mechanisms of these matrix modifications, the majority of previous efforts have focused on the modulation of either chemical composition or matrix stiffness on 2D smooth surfaces without simultaneously probing their cooperative effects on endothelium function on in vivo like 3D fibrous matrices. To this end, a high‐throughput, combinatorial microarray platform on 2D and 3D hydrogel settings to resemble the compositions, stiffness, and structure of healthy and diseased subendothelial ECM has been established, and further their respective and combined effects on endothelial attachment, proliferation, inflammation, and junctional integrity have been investigated. For the first time, the results demonstrate that 3D fibrous structure resembling native ECM is a critical endothelium‐protective microenvironmental factor by maintaining the stable, quiescent endothelium with strong resistance to proinflammatory stimuli. It is also revealed that matrix stiffening, in concert with chemical compositions resembling diseased ECM, particularly collagen III, could aggravate activation of nuclear factor kappa B, disruption of endothelium integrity, and susceptibility to proinflammatory stimuli. This study elucidates cooperative effects of various microenvironmental factors on endothelial activation and sheds light on new in vitro model for cardiovascular diseases.
Correlation of PTEN loss and PI3K/AKT/mTOR pathway upregulation with malignant peripheral nerve sheath tumor (MPNST) development and outcome.
Authors: Elizabeth Shurell, Maria Espera Vergara-Lluri, Yunfeng Li, Linh M Tran, Jonathan Nakashima, Kathleen Barzan, Brenna Tam, Nicholas Bernthal, William D. Tap, Jeffrey Eckardt, Frederick R. Eilber, Sarah M Dry, Hong Wu, Frederick C. Eilber
Journal: Journal of Clinical Oncology (2013)

10555 Background: MPNST is an aggressive soft tissue sarcoma often arising from preexisting neurofibromas (NF). Our previous study using murine models demonstrated that PTEN loss and PI3K/AKT/mTOR pathway upregulation is a potential mechanism of malignant transformation. The goal of this study is to determine whether a similar mechanism also drives human MPNST development. Methods: A tissue microarray was created from 144 surgical specimens (MPNST n=58, NF n=51, schwannoma n=11, and normal nerve n=24). Cores were stained in triplicate for PTEN and PI3K pathway-associated markers (PTEN, P-AKT, P-S6, GLUT1, SKP-2), other previously identified alterations (p53, p16, P-ERK and c-Myc) as well as tumor grade biomarkers Ki-67 and cleaved caspase 3. Density, intensity and subcellular localization of each marker were quantified and compared using linear regression and survival analysis was performed using Cox proportional hazards modeling. Results: Consistent with our mouse model study, P-S6, GLUT1 and SKP-2, downstream surrogate markers for PI3K pathway, are upregulated in MPNST compared to benign NF (p=0.002, p=0.000, p=0.016, respectively). Upregulated GLUT1 is notable as we have shown that FDG imaging can be used to stratify MPNST lesions from benign. In the 34 primary MPNST patients, PTEN protein expression correlated with improved disease specific survival (DSS) and disease free survival (DFS) (p=0.066 and p=0.014, respectively). In this cohort, large size (p=0.085), low PTEN (p=0.066), and low c-MYC (p=0.001) were associated with poor DSS. Large size (p=0.074), low PTEN (p=0.023), skp2 (p=0.097), p-AKT (p=0.086), and c-MYC (p=0.001) all correlated with poor DFS. NF-1 patients and spontaneous patients had different expression patterns associated with survival. NF-1 patients had improved DSS with high p53 (p=0.044) and smaller size (p=0.013), whereas spontaneous patients showed improved DSS only with increased c-MYC (p=0.008). Conclusions: PTEN loss and PI3K/AKT/mTOR pathway activation are important in MPNST development/prognosis and serves as a potential therapeutic target.
EXCAP exercise effects on cognitive impairment and inflammation: A URCC NCORP RCT in 479 cancer patients.
Authors: Karen Michelle Mustian, Michelle Christine Janelsins, Luke Joseph Peppone, Charles Stewart Kamen, Joseph John Guido, Charles E. Heckler
Journal: Journal of Clinical Oncology (2015)

9504 Background: Cognitive impairment (CI) is one of the most troublesome side effects experienced by patients, arises due to chronic inflammation, and impairs quality of life (QOL). We conducted a nationwide, multi-site, phase III RCT examining the efficacy of exercise for improving CI and inflammation through the URCC NCORP Research Base. Methods: Non-metastatic cancer patients receiving chemotherapy were randomized into 2 arms: 1) chemotherapy and 2) chemotherapy plus a 6-week (wk) exercise intervention--Exercise for Cancer Patients (EXCAP): a home-based, personalized prescription of aerobic walking and anaerobic resistance band training. CI and inflammation were assessed via the FACT-Cog and standard serum Luminex assays, respectively, at pre- and post-intervention. Results: 479 patients beginning chemotherapy were accrued (94% female, 84% breast cancer, mean age = 54). ANCOVAs controlling for baseline CI and chemotherapy cycle (1 wk, 2 wk, 3 wk) revealed significant differences in CI total score, perceived CI, impact of CI on QOL, and perceived CI by others (all p < 0.05) with a trend for differences in perceived cognitive ability (p < 0.10) between groups at post-intervention. Follow-up analyses showed exercise participants receiving 2 wk cycles of chemotherapy demonstrated less CI overall and across all domains (all p < 0.05) except perceived cognitive ability (p < 0.10) than controls at post-intervention. T-tests revealed an exercise-induced anti-inflammatory response with down-regulation of pro-inflammatory cytokines (IFNg, IL-8, IL-1b) and up-regulation of anti-inflammatory cytokines (IL-6, IL-10, sTNFra) in exercisers (all p < 0.05). Conversely, t-tests revealed down-regulation of IL-10 and less up-regulation of sTNFra in controls (all p < 0.05). Canonical correlations revealed a trend where changes in inflammation predicted changes in CI in exercisers (r = 0.33; p = .06), but not controls. Conclusions: EXCAP exercise improves CI and inflammation in patients receiving chemotherapy, and exercise-induced anti-inflammatory responses may elicit improvements in CI. Clinicians should consider prescribing EXCAP to reduce CI and inflammation. NCI UGCA189961 & K07CA120025. Clinical trial information: NCT00924651.