tbuckley/cabot-search huggingface dataset:
Next-generation RNA sequencing versus RNA microarray gene expression profiling for personalized medicine approaches in oncology: Lessons from relapsed and refractory neuroblastoma patients from the Neuroblastoma Medulloblastoma Translational Research Consortium (NMTRC).
Authors: Christina Kay Lettieri
Journal: Journal of Clinical Oncology (2014)

e22083 Background: RNA-sequencing (RNA-Seq) based on next generation approaches has emerged with several advantages to microarrays. We explored the differences in transcriptome analysis of neuroblastoma samples provided from the NMTRC on both technologies. Methods: Nine neuroblastoma patients provided 12 tumor samples; 31 reference tissue RNA samples and 4 control cell lines were included in the analysis. Illumina RNA gene expression arrays and RNA-Seq were performed on each sample. RNA-Seq and microarray transcripts were annotated using ENSEMBL GRCh37.66 gene models. Gene expression correlations were then analyzed for each technology individually, and the two technologies were compared with ranked gene expression using a Spearman correlation matrix. Results: RNA-Seq data showed better reproducibility over 7 time points, each approximately 1 month apart compared to microarray data performed over 2 time points approximately 6 months apart. Review of absolute number of genes detected by each technology per individual patient sample (RNA-Seq data with FPKM>0 and microarray p-value <0.05) showed 53% commonly expressed genes with both RNA-Seq and microarray. RNA-Seq revealed 16.8% more genes than microarray. Interestingly, both RNA-Seq and microarray were able to identify patients who were expressing MYCN higher than any body reference tissue but were originally classified as MYCN not amplified with traditional FISH methods. Heatmaps constructed from log transformed gene expression of 18 commonly mutated neuroblastoma genes from all patient samples revealed RNA-Seq data was able to distinguish more differences among the patient samples. Conclusions: RNA-Seq has superior reproducibility and dynamic range compared to microarray. Due to its improved resolution with digital reads of transcripts, more coverage of the transcriptome, and faster turn-around time, RNA-Seq should be very useful in gene expression analyses for real-time molecular phenotyping and personalized medicine approaches.
Incidence and severity of hypothyroidism and survival outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs).
Authors: Erin B. Bailey, Srinivas Kiran Tantravahi, Chesley E. Wells, Alli M. Straubhar, Julia A. Batten, Austin Poole, David D. Stenehjem, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2014)

e15580 Background: Thyroid dysfunction is a common adverse effect of VEGF TKIs. There are conflicting reports on survival benefit in association with hypothyroidism. Moreover, severity of hypothyroidism has not been correlated with survival outcomes in mRCC. Methods: From a single institutional database (2004-2013), we identified pts with mRCC receiving VEGF TKIs. Serial serum thyroid-stimulating hormone (TSH) values were collected, and at least two consecutive TSH values were required for inclusion. Progression free survival (PFS) and overall survival (OS) were assessed. Univariate and multivariate analyses were performed using the Kaplan-Meier method and COX Proportional Hazard models. Results: Of 125 pts treated with a VEGF TKI, 70 pts were eligible (median age 59 yrs, males 70%). The majority of pts had clear cell histology (74.3%) and were in the MSKCC (71.4%)and Heng (52.9%) intermediate-risk groups. Pts received the following TKIs: sunitinib (77.1%), sorafenib (12.9%), pazopanib (8.6%), and axitinib (1.4%). Thyroid dysfunction occurred in 45.7% of pts, of which 21.4% of pts had a TSH > 10 mIU/L during treatment. The median PFS and OS were significantly longer in pts with a TSH > 10 mIU/L compared with those with lower TSH values (Table). In the multivariate analysis, including age, sex, hand-foot syndrome (HFS), and risk criteria, a TSH > 10 mIU/L during TKI treatment remained significant for improvements in PFS and OS (PFS: HR 0.31, CI 0.11-0.73, p=0.0063; OS: HR 0.19, CI 0.04-0.58, p=0.0021). Conclusions: The severity of hypothyroidism (TSH > 10 mIU/L) directly correlates with improved survival outcomes in pts with mRCC treated with VEGF TKIs. Median PFS and OS with treatment-associated thyroid dysfunction in mRC. Thyroid status n PFS, months OS, months Euthyroid vs. TSH > ULN, but ≤ 10 mIU/L 55 10.6 vs. 7.3 (HR 0.84, CI 0.44-1.65, p=0.5939) 21.6 vs. 16.6 (HR 1.16, CI 0.56-2.59, p=0.6936) TSH > 10 mIU/L vs. TSH ≤ 10 mIU/L 70 48.1 vs. 8.3 (HR 0.33, CI 0.12-0.72, p=0.0041) n/a vs. 21 (HR 0.22, CI 0.05-0.61, p=0.0020) Appreviations: ULN, upper limit of normal; n/a, not achieved.
A phase II study of bevacizumab (Bev) and temsirolimus (Tem) in VEGF-refractory metastatic renal cell carcinoma (mRCC).
Authors: Kathleen Margaret Mahoney, SuChun Cheng, Rupal Satish Bhatt, Mekailah Simpson, Michael B. Atkins, Igor Puzanov, Sabina Signoretti, M Dror Michaelson, David F. McDermott, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2014)

4570 Background: Inhibiting VEGF and mTOR pathways are standard treatment approaches for patients (pts) with mRCC. Combinations of these agents have potential to improve efficacy. Here we report the activity and safety of the Bev and Tem combination in pts with clear cell (cc) and non-clear cell (ncc) mRCC who had failed prior VEGF blockade. Methods: In this phase II investigator-initiated multicenter study pts received Bev (10 mg/kg) IV q2 weeks and Tem (25 mg) IV weekly until progression of disease (PD) or unacceptable toxicity. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), median overall survival (OS), toxicity, and correlative studies. The design provided 88% power (10% alpha) to prove a progression free rate of 50% at 2 months. Results: Forty-one pts were enrolled and 40 were treated; 31 (77.5%) had good/intermediate risk per the IMDC criteria (Heng JCO 2009) and 13 (32.5%) had ncc histology. Thirteen (32.5%) had primary VEGF-refractory disease, in which best response on prior VEGF-targeted therapy was PD. Median prior therapies was 1 (75% sunitinib). Median PFS was 5.8 months. Median OS was 13.1 months as of 10/2013. There were no CR. Confirmed PR occurred in 7 pts (17.5%). Median PFS and ORR were 7.8 months and 15% (2/13) in pts with primary VEGF-refractory disease and 7.6 months and 7.6% (1/13) in pts with nccRCC. All grade and grade 3/4 toxicities, at least possibly attributable to Bev and Tem, were seen in 62% and 49%, respectively. Dose reduction occurred in 77.5% of pts and 27.5% were taken off study because of toxicity. Most frequent toxicities include fatigue, dyslipidemia, and proteinuria. The most serious toxicity included deep vein thrombosis (1), esophageal fistula (1), bowel perforation (1), cerebrovascular accident (1) and ventricular arrhythmia/cardiac arrest (1). Conclusions: Combining Bev and Tem in a VEGF-refractory mRCC population was possible with dose reductions, and resulted in longer than expected PFS in pts with primary VEGF-refractory disease and non clear cell histology, both 2 unmet needs in RCC. We are currently in the process of assaying pretreatment tumor samples for predictive biomarkers. Clinical trial information: NCT00782275.
Supporting the Educational, Research, and Clinical Care Goals of the Academic Trauma Center
Authors: Michael A. Vella, Ryan P. Dumas, Daniel N. Holena
Journal: JAMA Surgery (2019)

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NRG-GI002: A phase II clinical trial platform for sensitization testing using total neoadjuvant therapy (TNT) in rectal cancer.
Authors: Thomas J. George, Greg Yothers, Theodore S. Hong, Marcia McGory Russell, Y. Nancy You, William Parker, Samuel A. Jacobs, Katherine L. Pogue-Geile, Marc Jeffrey Gollub, William Adrian Hall, Osama E. Rahma, Lisa A. Kachnic, Namrata Vijayvergia, Norman Wolmark
Journal: Journal of Clinical Oncology (2018)

TPS876 Background: Locally-advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms (EA) in LARC. The EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk patient (pt) population with correlative biomarkers. Success of any EA will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC with any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, all pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. The first EA will assess the activity of veliparib with standard chemoRT. A second EA, testing pembrolizumab concurrently with and following chemoRT, is in development. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score for the EA vs control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional EAs added through protocol amendments. NCT02921256. Support: U10 CA-180868, -180822, UG-189867, U24CA196067; AbbVie Clinical trial information: NCT02921256..
Evolving patterns of care in the management of stage I non-seminomatous germ cell tumors: Data from the California Cancer Registry.
Authors: Stanley A Yap, Lindsay M Yuh, Rebecca Rankin Wagenaar, Christopher P Evans, Marc A. Dall'Era, Rosemary Donaldson Cress, Primo Lara
Journal: Journal of Clinical Oncology (2014)

4558 Background: Standard options for the management of stage I non-seminomatous germ cell tumors (NSGCT) following radical orchiectomy include active surveillance, retroperitoneal lymph node dissection (RPLND), or adjuvant systemic chemotherapy. However, few studies have assessed population-level practice patterns and how these have evolved over time. Here, we assess the shifting practice patterns across a 20 year timespan in the management of stage I NSGCTs. Methods: Using the California Cancer Registry, we reviewed all patients diagnosed with stage I NSGCT in California between 1988 and 2010. We determined whether primary treatment consisted of RPLND, chemotherapy, or surveillance, and their overall rates across the years. Other analyzed variables included patient age, socioeconomic status, race, year of diagnosis, and region. Predictors of treatment selection were assessed using logistic regression analysis. Results: A total of3,961 patients with stage I NSGCT were identified. The most common primary treatment was surveillance (48%), followed by RPLND (26%) and chemotherapy (24%). Significant changes in the rate of various treatment strategies were noted across the study period (p<0.01). Rates of surveillance increased from 35% in 1988 to 61% in 2010, while rates of chemotherapy remained relatively stable. However, rates of RPLND decreased from 44% in 1988 to 10% in 2010. Significant predictors of undergoing surveillance on multivariable logistic regression included diagnosis after 2006 (OR 1.52, CI 1.25-1.84) and age at diagnosis >60 years old (OR 1.63, CI 1.19-5.82). With a median follow-up of 96 months, 5-year overall survival (OS) rate among those undergoing RPLND, chemotherapy, or surveillance was 98%, 92%, and 97%, respectively. Conclusions: Treatment patterns in the management of stage I NSGCT have shifted with an increased utilization of surveillance and a concurrent decrease in the use of RPLND. Treatment patterns have evolved over the past 2 decades, where active surveillance is now the dominant strategy, potentially reflecting changes in perception of the oncologic safety and morbidity profile of such an approach.
Traumatic stress symptoms in patients with acute leukemia (AL).
Authors: Gary Rodin, Ashley Mischitelle, Christopher Lo, Anne Rydall, Aaron Schimmer, Lucia Gagliese, Mark D Minden, Charles Marmar, Rinat Nissim, Peter Fitzgerald, Camilla Zimmermann
Journal: Journal of Clinical Oncology (2014)

9577 Background: AL is associated with an immediate threat to life, an intensive treatment regimen, and substantial suffering relating to the disease and its prognostic uncertainty. This longitudinal study was undertaken to assess psychological and physical distress in the first 3 months following diagnosis or relapse of AL. We report here the findings at 3 months. Methods: Patients with newly diagnosed or recently relapsed acute myeloid, lymphoblastic and promyelocytic leukemia were recruited at Princess Margaret Cancer Centre within one month of diagnosis or relapse. Patients completed a baseline assessment and monthly follow-ups for 3 months. The frequency of traumatic stress symptoms that met criteria for acute stress disorder (ASD; symptoms above threshold <1 month) was determined. Multivariate regression analysis was used to identify predictors of traumatic stress symptoms. Self-report measures included: Stanford Acute Stress Reaction Questionnaire (SASRQ), Memorial Symptom Assessment Scale, CARES Medical Interaction Subscale, Experiences in Close Relationships-SF and FACIT SP-12. Results: 178 participants completed >3 time-points; mean age was 49+16 years, 58% male, 91.6% newly diagnosed, and 96.6% receiving chemotherapy with curative intent. Mean SASRQ score at baseline was 27.2+21.8 (range 0-97) and 27% reported symptoms >threshold for ASD at baseline. Of those who provided at least 3 assessments, 10% scored above cut-off 3 or more times; 12.4% twice; 20.8% only once; and 56.7% at no time. Regression analyses indicated that female gender, psychological symptoms, worse communication with health care providers, lower spiritual well-being and attachment anxiety were significant predictors of traumatic stress. Conclusions: Significant traumatic stress symptoms occurred in more than 40% of patients with AL within 3 months of diagnosis, which persisted in almost 25% of the sample across 3 or more time-points. Traumatic stress symptoms in this population are linked to a number of potentially treatable factors. Further research is needed to demonstrate the benefit of early psychological and palliative interventions.
Identification of a rare germ-line variant in the <i>TP53</i> 3’UTR in individuals with the Li-Fraumeni-like phenotype: A new mechanism of cancer predisposition?
Authors: Gabriel de Souza Macedo, Igor Araujo Vieira, Vanessa Cortez-Paixão, Juliana Giacomazzi, Karina Miranda Santiago, Maria Isabel Waddington Achatz, Patricia Ashton-Prolla
Journal: Journal of Clinical Oncology (2014)

11106 Background: Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-like Syndrome (LFL), are inherited disorders characterized by increased predisposition to multiple early-onset cancers and are associated to TP53 germline mutations. The rs78378222 (A>C) SNP, a rare variant located within the polyadenylation signal of TP53, was recently identified in a GWAS. It occurs at a frequency = 0.019 in Icelandic population and leads to impaired 3’-end processing of mRNA, conferring susceptibility to certain types of cancer. Methods: Considering that regulatory gene regions has not been considered in the TP53 molecular diagnostic, the purpose of this study was to assess the allelic frequency of this variant in a patients group composed by LFS/LFL families with (n=57) and without (n=131) TP53 germline mutation. To support the association, we also studied the evolutionary conservation of the TP53 polyadenylation signal in vertebrate species and the p53 immunohisthochemical pattern in tumors from carriers of different TP53 mutations. Results: The heterozygous genotype to rs78378222[C] was found in 7 patients fulfilling LFL criteria who tested negative for coding germline TP53 mutations. In the group of patients with coding region TP53 germline mutations we did not encounter rs78378222 [C] carriers. We also investigated the TP53 sequence at the polyadenylation signal of 63 therian mammals. None of these organisms presented any variation in the locus of the variant, evidencing strong evolutionary conservation. Finally, we assessed p53 expression by immunohistochemistry in tumors of carriers of known germline pathogenic TP53mutations and of the 3´UTR variant. In the first group we observed intense nuclear accumulation of p53 and in the second weak and a focal p53 immunostaining was identified. Conclusions: This is the first description of rs78378222[C] in LFL families, and our findings suggest a new carcinogenesis mechanism associated to this variant. However, further functional characterization studies and analysis of larger series of families with the LFS/LFL phenotype should be undertaken to confirm the s78378222[C] as a pathogenic variant associated with this disorder.
Rituximab in moderate to severe non-renal systemic lupus erythematosus: a reanalysis of the EXPLORER study
Authors: Marc Scherlinger, Claire Carcaud, Marie-Elise Truchetet, Thomas Barnetche, Pierre Duffau, Lionel Couzi, Julien Seneschal, Patrick Blanco, Estibaliz Lazaro, Christophe Richez
Journal: Annals of the Rheumatic Diseases (2019)

Many targeted therapies have been developed for systemic lupus erythematosus (SLE) in recent years and almost all have failed to meet their predesigned endpoints.1 Among these therapies, rituximab (RTX) has reported good results in several open-label studies,2 3 but failed to meet its primary endpoints in two randomised controlled trials (RCTs), EXPLORER and LUNAR.4 5 

Among the proposed explanations for these failures, the primary outcome criteria’s lack of sensitivity has been suggested.6 The availability of new SLE response criteria led us to reanalyse the EXPLORER study which assessed RTX efficacy in severe non-renal SLE, using four newly available scores: SLE Response Index-4 (SRI-4), a modified SRI-4 (including reduction of glucocorticoids ≤10 mg/day between days 169 and 365), a modified BILAG-based Clinical Lupus Assessment (mBICLA) and a modified Lupus Low Disease Activity Score (mLLDAS), (online supplementary file 1 for details on criteria).7 8 ### Supplementary data

[annrheumdis-2018-214833supp001.docx] 

The EXPLORER trial was a 52-week, –multicentre, randomised, double-blind placebo-controlled trial of RTX in 257 patients with moderately to severely active non-renal SLE (online supplementary table 1). Patients were randomised at a 2:1 ratio to receive intravenous RTX (1000 mg) or placebo on days 1, …
Heregulin expression level as a predictive biomarker for patritumab efficacy.
Authors: Matthias Schneider, Sabine Blum, Christin Wenzl, Johannes Bange, Selam Ogbagabriel, Daniel J. Freeman, Jens Ruhe
Journal: Journal of Clinical Oncology (2014)

2618 Background: Activation of the receptor tyrosine kinase HER3 and its oncogenic downstream signaling pathways are thought to be critically involved in the development of various cancer types, including non-small cell lung cancer (NSCLC). HER3 serves as a scaffold for PI3K/AKT signaling via heterodimeric interaction with other HER family members, which can be mediated by binding of heregulin (HRG), the natural high affinity ligand for HER3. Patritumab (P) is an internalizing, fully human anti-HER3 monoclonal antibody that competes with HRG for receptor binding. We examined whether HRG expression correlates with P efficacy in vitro and in vivo. Methods: Protein and phosphoprotein levels in tumor cell lines were determined by western blot. Endogenous HRG mRNA expression was analyzed by RT-PCR. To examine signaling in vitro, tumor cells were treated with 10 µg/ml of P. Cells then remained untreated or were stimulated with recombinant HRG for 1 hour prior to lysis. Cell lysates were analyzed for HER3/pHER3- and AKT/pAKT-levels. To determine the efficacy of P in vivo, mice bearing ~200 mm3 tumor xenografts were treated with P twice weekly, and tumor volumes were assessed. Results: Cell lines endogenously expressing HRG showed decreased HER3- and AKT-phosphorylation following treatment with 10 µg/ml of P, whereas no inhibitory effects of P were observed in HRG-negative cell lines. Remarkably, while HCC1569 cells are normally insensitive to P, the addition of exogenous HRG conveyed sensitivity to these cells. In line with these in vitro observations, HRG expression was found to correlate with P single-agent efficacy in 13/15 in vivo tumor models, from a range of tissue types. In contrast, neither levels of HER3 expression nor levels of HER3 phosphorylation were found to consistently correlate with P single-agent efficacy. Conclusions: Unlike HER3 expression or activation, HRG expression reliably correlated with P-mediated inhibition of signaling in vitro and tumor growth inhibition in vivo. Based on these data, HRG expression levels were nominated as the primary predictive biomarker for P efficacy and were clinically evaluated in the HERALD phase 1b/2 trial in patients with NSCLC (Mendell-Harary et al., von Pawel et al. ASCO 2014).
Forty Percent of MDS Patients Wish They Received Red Blood Cell Transfusions at Higher Hemoglobin Thresholds Than They Currently Are: A Multinational Transfusion Audit
Authors: Rena Buckstein, Rebecca Starkman, Yulia Lin, Simon J. Stanworth, David Bowen, Lea Harrison, Sophie Wintrich, Jeannie Callum
Journal: Blood (2018)