tbuckley/cabot-search huggingface dataset:
Targeted next-generation sequencing of melanoma patient samples to reveal mutations in non-protein coding regions of targetable oncogenes.
Authors: Doug Hanniford, Carlos N Martinez, Igor Dolgalev, Michael William Lattanzi, Eleazar Vega-Saenz de Miera, Eric Michael Robinson, Chloe Goldman, Adriana Heguy, Tomas Kirchhoff, Iman Osman, Eva Hernando
Journal: Journal of Clinical Oncology (2016)

9559 Background: Next-generation sequencing has enabled an unprecedented view of the genetics of tumorigenesis. For tumor types associated with carcinogenic insults as central drivers of tumor initiation, such as smoking-associated lung cancer and UV-associated cutaneous melanoma, the genetics of individual patient tumors is highly complex. For these tumor types, power analyses suggest that determination of moderate to low frequency driver mutations requires sequencing of thousands of patient tumors. Moreover, the genetics of non-protein coding regions, such as promoters and enhancers, and non-coding RNAs, have been insufficiently characterized. Methods: We performed targeted in-solution DNA capture followed by next-generation sequencing for a cohort of 96 patient tumors and matched germline DNA. Our targeted panel consisted of 144 protein coding genes, including their UTRs and regulatory regions, for previously nominated and candidate melanoma driver genes, a set of microRNA implicated in melanoma biology, and a set of lncRNA dysregulated during melanomagenesis. Results: Of the 96 sequenced tumors, 93 samples yielded evaluable sequencing data. We observed mutational loads, UV signatures, and frequencies of key melanoma driver genes (i.e. BRAF, NRAS, NF1) consistent with previous studies. Our patient cohort contained recurrent IDH1R132C mutations (6.5%) at increased frequency than initial reports, further validating this oncogene as a possible driver of melanoma tumorigenesis. In addition, we observed recurrent or clustered single nucleotide variants (SNVs) in regulatory regions of pharmacologically targetable oncogenes. Additional validation and molecular analyses are in progress to confirm the incidence and address the impact of novel SNVs in the corresponding genes’ expression and function. Conclusions: Our study expands the mutational landscape of the melanoma genome. Identification of recurrent and clustered mutations in regulatory regions may yield novel insights into melanoma biology or suggest novel treatment strategies, underscoring the need for continued genomic characterization of melanoma patient tumors.
A glimpse of Cre-mediated controversies in epicardial signalling
Journal: Cardiovascular Research (2016)

Among the many important aspects of cardiac development, formation of the epicardium and the underlining signalling pathways that direct the mobilization and differentiation of epicardial cells have been one of the highly pursued research subjects within the past decade. These epicardium-derived cells (EPDCs) are reported to contribute to several critical cell types which include cardiac myofibroblasts and coronary smooth muscle contributing to the formation of the coronary vasculature network within the developing embryonic heart.1 Recent data suggesting that epicardial progenitor cells (EPCs) can contribute to newly formed cardiomyocytes in injured hearts2,3 has drawn further attention into the mechanisms of epicardiogenesis, as the successful use of epicardial cells in cell replacement therapies will undoubtedly have a high clinical impact on treating heart disease. To achieve this goal, a better understanding of the molecular mechanism that drive epicardiogenesis will be required.

As the outermost cell layer of the vertebrate heart, the epicardium is derived from the proepicardial organ (PE), which originates from splanchnic mesenchyme within the septum transversum that is juxtaposed near the venous pole of the embryonic day 9.5 (E9.5) mouse heart (E22 for human). EPCs detach from the PE, migrate into pericardial cavity, and adhere to the myocardial surface where they rapidly spread to form a mesothelial monolayer covering the atria, atrioventricular canal, and ventricles, and in doing so, establish a primary epicardium by E10.5 in the mouse. Two days later, at E12.5, some of the primary epicardial cells undergo an epithelial to mesenchymal transition to convert into highly mobile and developmentally plastic EPDCs ( Figure 1 ). These EPDCs proceed to invade the subepicardial matrix and subsequently migrate into the myocardium, where they differentiate into interstitial …
Small‐Sized Cationic miRi‐PCNPs Selectively Target the Kidneys for High‐Efficiency Antifibrosis Treatment
Authors: Xinran Geng, Mengbi Zhang, Xuandi Lai, Lishan Tan, Jianyu Liu, Meng Yu, Xiulong Deng, Jianqiang Hu, Aiqing Li
Journal: Advanced Healthcare Materials (2018)

Abstract Small‐sized cationic miRi (microRNA‐21 inhibitor)‐PCNPs (low molecular weight chitosan (LMWC)‐modified polylactide‐ co ‐glycoside (PLGA) nanoparticles (PLNPs)) with special kidney‐targeting and high‐efficiency antifibrosis treatment are fabricated through coupling miRi, PLGA, and LMWC. In the miRi‐PCNPs, easily degraded miRi is encapsulated in PCNPs and thus prevented from degradation by nuclease. Cytotoxicity, immunotoxicity, and systemic toxicity assays and in vitro and ex vivo fluorescence imaging suggest that PCNPs possess excellent biocompatibility, higher cellular uptake efficiency, and selective kidney‐targeting capacity. Western blotting, pathological staining, and real‐time polymerase chain reaction analyses show that the therapeutic effect of miRi‐PCNPs on kidney fibrosis is much higher than that of miRi, which is mainly through suppressing transforming growth factor beta‐1/drosophila mothers against decapentaplegic protein 3 (TGF‐β1/Smad3) and extracellular signal–regulated kinases/mitogen‐activated protein kinase signaling pathway by inhibiting the expression of microRNA‐21. For example, the tubule damage index and tubulointerstitial fibrosis area in the miRi‐PCNPs group are ≈2.5‐fold lower than those in the saline and bare miRi groups. The miRi‐PCNPs with special kidney‐targeting and high‐efficiency antifibrosis treatment may represent a promising strategy for designing and developing a therapeutic treatment for kidney fibrosis.
TCT-610 Outcomes of Transcatheter Aortic Valve Replacement compared to Surgical Aortic Valve Replacement in patients with prior Chest Radiation
Authors: Yohan Chacko, Xinyaun Zhang, Karolina Jaluba, Anson Lee, D. Craig Miller, Alan C. Yeung, Brian Kim, William Fearon
Journal: Journal of the American College of Cardiology (2018)
Prospective, multinational, observational study of real-world treatment outcomes with pazopanib in patients with advanced or metastatic renal cell carcinoma (PRINCIPAL study).
Authors: Manuela Schmidinger, Giuseppe Procopio, Robert E. Hawkins, Angel Rodriguez Sanchez, Sergio Vazquez, Narayanan Srihari, Haralabos Kalofonos, Aristotelis Bamias, Petri Bono, Chaitali Babanrao Pisal, Yulia Hirschberg, Luca Dezzani, Qasim Iftikhar Ahmad, Eric Jonasch
Journal: Journal of Clinical Oncology (2018)

4574 Background: PRINCIPAL (NCT01649778) was the largest prospective real-world effectiveness and safety study of pazopanib (PAZ) in patients (pts) with renal cell carcinoma (RCC). Methods: Pts with advanced and/or metastatic clear cell RCC were enrolled within 30 days of initiating first-line PAZ. Follow-up data on progression, survival, and safety was collected approximately every 3 months until death, consent withdrawal, or loss to follow-up, for up to 30 months. Primary efficacy end points were median overall survival (mOS), median progression-free survival (mPFS), and overall response rate (ORR). Safety measures included frequency of adverse events (AEs), serious AEs, and AEs of special interest. Results: Among 657 pts who received ≥1 dose of PAZ, 76.3% completed the study (33.0% completed 30 months of follow-up and 43.2% died). Median enrollment age was 66 years, with 57.2% aged ≥65 years. 4.1%, 62.6%, and 33.3% of pts were grouped as favorable, intermediate, or poor risk by Heng criteria, respectively. Most pts (84%) initiated treatment at 800 mg, and the median treatment time with or without dose interruption was 6.9 and 7.6 months, respectively. mPFS and mOS are shown in the Table. Among the measurable disease population (n = 168), ORR was 30.3%, median duration of response was 11.0 months (95% confidence interval [CI] 8.6-14.6), and time to response, evaluated every 3 months, was 3.0 months (95% CI 2.9-3.1). Most pts had an AE (74.0%) that led to dose adjustment/interruption in 49.3% and treatment discontinuation in 14.6%. The most frequent ( > 10%) drug-related AEs were hypertension (20.9%), diarrhea (11.3%), and increased alanine aminotransferase (11.0%). Conclusions: Real-world effectiveness and safety outcomes in the PRINCIPAL study were consistent with clinical trials and support the first-line use of PAZ across all risk groups of pts with advanced or metastatic RCC. Clinical trial information: NCT01649778. mPFS, months (95% CI) mOS, months (95% CI) All pts 10.4 (9.3-12.0) 29.9 (24.7-NR) Heng risk group · Favorable 16.1 (11.6-26.0) NR (28.6-NR) · Intermediate 12.5 (10.3-15.4) 32.9 (32.9-NR) · Poor 6.7 (5.8-9.1) 14.8 (12.2-19.5) NR, not reached.
Active Surveillance as First-Line Management of Papillary Microcarcinoma
Authors: Yasuhiro Ito, Akira Miyauchi
Journal: Annual Review of Medicine (2018)

Papillary thyroid microcarcinoma (PMC) is defined as papillary thyroid carcinoma ≤10 mm. Active surveillance of PMC without high-risk features, such as clinical node metastasis, distant metastasis, and clinical evidence of significant extrathyroid extension, was initiated in two Japanese hospitals in the mid-1990s. This strategy was incorporated into guidelines in Japan in 2010 and in the United States in 2015. In studies conducted by the two hospitals, most PMCs grew very slowly or did not grow, and none of the patients during active surveillance showed distant metastasis or died of thyroid carcinoma. Furthermore, none of the patients who underwent surgery after progression signs were detected showed significant recurrence. Therefore, we conclude that active surveillance should be the first line in management of low-risk PMC, because it is safer and less costly than immediate surgery. Active surveillance helps in avoiding adverse events of surgery and is an economical strategy.
Early assessment of treatment effect in advanced lung adenocarcinoma via longitudinal ctDNA analysis.
Authors: Xiaoju Max Ma, Liu Xi, Stephanie Yaung, Nalin Tikoo, Aarthi Balasubramanyam, Christine Ju, Dan Klass, Alexander F. Lovejoy, Amrita Pati, Owen Solberg, Yuqiu Jiang, Hans-Peter Adams, Birgit Wehnl, Michael Thomas, Felix Lasitschka, Michael Meister, Marc Schneider, Felix Herth, John F. Palma, Thomas Muley
Journal: Journal of Clinical Oncology (2018)

12088 Background: Despite routine use of chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients, the knowledge of optimal prognostic methods is still limited to imaging-based methods. We hypothesized that an early response assessed by mutant molecules count in plasma could predict the treatment effect. Methods: We employed AVENIO ctDNA Surveillance Kit, a 197-gene NGS assay, which allowed us to perform longitudinal ctDNA analysis and measure the mutant molecules per milliliter-of-plasma (MMPM), which quantifies ctDNA at the variant level. The association between changes in ctDNA levels and survival was evaluated in advanced lung adenocarcinoma subjects. Post-treatment MMPM values were compared with the MMPM value at baseline and/or the previous treatment timepoint. Results: At baseline (b0), we identified variants in all (93/93) subjects to enable ctDNA monitoring. From the training cohort (50 subjects), we were able to set the cutoff of 40 for the mean MMPM at post-first treatment cycle (p1). Applying the MMPM cutoff of p1 to the validation cohort (43 subjects with stage IV lung adenocarcinoma, from a prospective, observational study) low levels of ctDNA toward the end of first treatment cycle was associated with better progression-free survival (PFS) (P = 0.0088 HR 0.4; 95% CI 0.20 - 0.83) and overall survival (OS) (P = 0.0026 HR 0.32; 95% CI 0.15 - 0.71). The prognostic value is increased by applying the Continuous Responder algorithm, defined by a continuous drop in ctDNA levels represented by mean MMPM reduction over time (p2 < p1 < b0), to a mean MMPM below 8 at p2. As a result, continuous responders 13/43 (30%) were associated with a better therapy response indicated by PFS (P = 0.028 HR 0.45; 95% CI 0.23 - 0.90) and OS (P = 0.0074 HR 0.3; 95% CI 0.12 - 0.77). The continuous responders demonstrated a median overall survival benefit of 11.25 months over the poor responders. Conclusions: A decrease in post-treatment ctDNA level measured by NGS was associated with better prognosis in advanced lung adenocarcinoma. An early assessment of treatment effect can be measured by mutant molecule counts in the plasma within 1 or 2 treatment cycles.
Computer extracted features of cancer nuclei from H&amp;E stained tissues of tumor predicts response to nivolumab in non-small cell lung cancer.
Authors: Xiangxue Wang, Cristian Barrera, Priya Velu, Kaustav Bera, Prateek Prasanna, Monica Khunger, Arjun Khunger, Vamsidhar Velcheti, Anant Madabhushi
Journal: Journal of Clinical Oncology (2018)

12061 Background: Immune checkpoint inhibitors have recently been FDA-approved for use in advanced stage non-small cell lung cancer (NSCLC). These drugs target the PD-1 receptor or its ligand PD-L1, but treated patients only have a response rate of about 20%. It is thus crucial to identify which patients will derive maximal benefit from such treatments, especially since the current gold standard biomarker, detection of tissue-based PD-L1 expression, has been shown to be inadequate. Previous studies have shown that computer extracted features of nuclear shape and texture are predictive of recurrence in early stage NSCLC. The goal of this work is to evaluate the role of features of nuclei shape and arrangement in the tumor in predicting response to Nivolumab for NSCLC. Methods: The study included 56 patients with NSCLC from two different institutions who had had pre-treatment tumor biopsies and were treated with Nivolumab. The patients were split into two categories, responders and non-responders, that were determined by clinical improvement and radiologic assessment through RECIST criteria. The 245 features from tumor nuclei included standard measures used to characterize shape and texture of nuclei as well graph based features that capture the distinct spatial arrangement of the nuclei. Features were extracted from tumor regions manually annotated on digitized H&E images by two expert pathologists. Results: A statistical feature selection method determined the top five tumor nuclear features from the training set. These features included the spatial arrangement of nuclei and variance in nuclear shape and chromatin structure. A machine learning classifier trained with these top five features yielded an AUC = 0.65 on the training set (n = 32) and an AUC = 0.6 on the independent validation set from a separate institution. (n = 24). Conclusions: Computer extracted features of cancer nuclei were found to distinguish between patients who did and did not respond to Nivolumab immunotherapy. Validation is needed on larger cohorts from multiple different sites.
Successful generation of patient derived xenografts and patient derived 3D cultures as preclinical models for breast cancer.
Authors: Verena Imke Isabel Kiver, Guido Gambara, Karolin Fuchs, Bernadette Brzezicha, Caroline Schweiger, Philipp Jurmeister, Olga Gorea, Susen Burock, Cornelia Liedtke, Maria Margarete Karsten, Nikola Bangemann, Jens U. Blohmer, Carsten Denkert, Christian RA Regenbrecht, Jens Hoffmann, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2018)

12080 Background: The establishment of patient-derived preclinical models in breast cancer has been a challenge for many years. We report our successful experience in establishing breast cancer patient derived xenografts (PDX) and patient derived 3D cultures (PD3D). Methods: Tumor tissue samples (twice 3mm diameter) from breast cancer patients undergoing surgery were collected by a team of gynecologists and pathologists. Ischemia time was minimized. Small tumor fragments were transplanted to immunodeficient NOG mice. The other part was used to establish a cell culture on serum free organoid media in the presence of growth hormones and, in case of hormone receptor positive breast cancer, estradiol supplementation. To address the question whether the genetics features of the model have changed during the process of engraftment and expansion the established models are currently undergoing molecular profiling. Results: Since May 2017 28 breast cancer samples have been processed. The sample characteristics are summarized in the table. Currently we have one PDX established, 18 in passage and 9 have not engrafted. Breast cancer PD3D organoids had a take rate of 56% under our culture conditions. Moreover, hormone receptor positive breast cancer PD3D models were successfully established as PD3D with a take rate of 37.5%. Conclusions: A high take rate under improved culture conditions provided a versatile method of patient-derived preclinical model generation. Take rates and distribution of breast cancer subtypes. Samples Her2 -, HR- (TNBC) Her2-, HR+, Her2+, HR - Her2+, HR+ PDX N 28 11 15 1 1 PDX established 1 1 N/A N/A N/A PDX eliminated 9 5 3 1 N/A Take rate 9.9% 9.9% N/A N/A N/A PDX in passage 18 5 12 N/A 1 PD3D N 24 8 14 1 1 PD3D established 9 3 4 1 N/A PD3D eliminated 7 5 1 N/A 1 Take rate 56.3% 37.5% 80% 100% 0 PD3D in culture 9 N/A 9 N/A N/A
Room to move: Physical activity and exercise barriers in the cancer clinic.
Authors: Katharine Quain, Elizabeth O'Donnell, Giselle Katiria Perez, Julia Rabin, Elyse R. Park, Jeffrey M. Peppercorn
Journal: Journal of Clinical Oncology (2017)

e21601 Background: Exercise can improve outcomes and quality of life following cancer diagnosis. The American College of Sports Medicine (ACSM) recommends 150 minutes of moderate aerobic activity for patients with cancer. We sought to evaluate exercise patterns and barriers to exercise among patients presenting for follow-up care. Methods: Patients were recruited from the outpatient cancer clinic and completed a self-administered survey focused on symptoms, lifestyle and needs. Participants reported height, weight, weekly time performing moderate-to-vigorous aerobic activity, time spent strength training and perceived barriers to exercise. Descriptive statistics characterized the sample and patterns of exercise. An independent-samples t-test examined differences in strength training between patients currently on and off treatment; Chi-square examined differences among those meeting or not meeting ACSM activity guidelines. Results: Of 637 patients surveyed, 590 (93%) completed exercise questions (55% female; median age 60-69). The most common cancer diagnoses were breast (26%), hematologic (18%) and gastrointestinal (12%). Over half (57%; n = 352) were overweight (BMI ≥ 25) and 26% (n = 161) were obese (BMI ≥ 30). Patients engaged in moderate-to-vigorous aerobic exercise an average of 110 min/week and in strength training for 30 min/week. 71% did not meet ACSM aerobic exercise guidelines; 62% reported no strength training and 29% reported no exercise. 76% of respondents reported at least one barrier to exercise. Common barriers included other illness (35%), lack of free time (21%), fatigue (8%) and boredom with exercise (8%). Most participants (60%; n = 351) decreased exercise after cancer diagnosis. Participants currently on therapy were significantly less likely to meet ACSM aerobic activity guidelines (p = 0.04) and reported doing less strength training (p &lt; 0.001) than those not on therapy. Over half of participants (53%) expressed interest in receiving more information about exercise and physical activity services. Conclusions: There is potential to improve activity, fitness and cancer outcomes through increasing exercise among patients with cancer. Accessible, engaging exercise interventions are needed.
The spatial distribution of brain metastasis.
Authors: Emory McTyre, Michael Henry Soike, Michael LeCompte, Cristina M Furdui, Jingyun Lee, Shadi Qasem, Stacey O'Neill, Thomas Lycan, Richard Barcus, Pierre L. Triozzi, Jimmy Ruiz, Stephen B Tatter, Michael Chan, Christopher T Whitlow
Journal: Journal of Clinical Oncology (2018)

e14000 Background: The spatial distribution of brain metastasis has historically been assumed to be uniform; however, emerging evidence suggests that certain tumor characteristics may be associated with non-uniform spatial distributions. In this study we further investigate the associations between brain metastasis characteristics and the uniformity of the spatial distribution of brain metastasis across histology and proteomic expression data. Methods: From January 2000 to May 2017, a total of 1,599 patients with 5,389 brain metastases were treated with stereotactic radiosurgery (SRS). All DICOM images and associated segmented brain metastasis volumes were registered to a standard brain template with defined region of interest (ROI) atlases for cortical, subcortical, and cerebellar ROIs. Chi-squared tests were performed to identify ROIs in which there was a higher observed frequency of brain metastasis than expected per ROI volume. Logistic regression was performed for each histology and protein of interest to determine the association between these factors and the occurrence of brain metastasis within each ROI. Results: The ROI with the highest likelihood of brain metastasis per unit volume was the precentral gyrus, with 4.9 metastases / cm3 (p < 0.0001). In contrast, the temporal pole had significantly fewer brain metastases per unit volume than expected (0.98 metastases / cm3, p < 0.0001). Adenocarcinoma histology was associated with the highest relative frequency of cerebellar brain metastasis, with a total of 21.6% of adenocarcinoma lesions occurring in the cerebellum (p < 0.0001). Proteins associated with cerebellar metastasis included migration and invasion enhancer 1 (β = 0.22, p = 0.0005), double-strand break repair protein MRE11A (β = 1.60, p = 0.0007), growth factor receptor-bound protein 7 (β = 0.21, p = 0.0009) and HER2/neu (β = 0.09, p = 0.001). Conclusions: There is significant non-uniformity in the spatial distribution of brain metastasis. Within the cortical brain there is non-uniformity across histology, with the highest rate of metastasis occurring in the precentral gyrus. Adenocarcinoma has a high propensity for cerebellar metastasis compared to other tumor histologies. HER2/neu expression is associated with cerebellar metastasis.