tbuckley/cabot-search huggingface dataset:
Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing
Authors: Jonas Demeulemeester, Parveen Kumar, Elen K. Møller, Silje Nord, David C. Wedge, April Peterson, Randi R. Mathiesen, Renathe Fjelldal, Masoud Zamani Esteki, Koen Theunis, Elia Fernandez Gallardo, A. Jason Grundstad, Elin Borgen, Lars O. Baumbusch, Anne-Lise Børresen-Dale, Kevin P. White, Vessela N. Kristensen, Peter Van Loo, Thierry Voet, Bjørn Naume
Journal: Genome biology (2016)

Single-cell micro-metastases of solid tumors often occur in the bone marrow. These disseminated tumor cells (DTCs) may resist therapy and lay dormant or progress to cause overt bone and visceral metastases. The molecular nature of DTCs remains elusive, as well as when and from where in the tumor they originate. Here, we apply single-cell sequencing to identify and trace the origin of DTCs in breast cancer. We sequence the genomes of 63 single cells isolated from six non-metastatic breast cancer patients. By comparing the cells' DNA copy number aberration (CNA) landscapes with those of the primary tumors and lymph node metastasis, we establish that 53% of the single cells morphologically classified as tumor cells are DTCs disseminating from the observed tumor. The remaining cells represent either non-aberrant "normal" cells or "aberrant cells of unknown origin" that have CNA landscapes discordant from the tumor. Further analyses suggest that the prevalence of aberrant cells of unknown origin is age-dependent and that at least a subset is hematopoietic in origin. Evolutionary reconstruction analysis of bulk tumor and DTC genomes enables ordering of CNA events in molecular pseudo-time and traced the origin of the DTCs to either the main tumor clone, primary tumor subclones, or subclones in an axillary lymph node metastasis. Single-cell sequencing of bone marrow epithelial-like cells, in parallel with intra-tumor genetic heterogeneity profiling from bulk DNA, is a powerful approach to identify and study DTCs, yielding insight into metastatic processes. A heterogeneous population of CNA-positive cells is present in the bone marrow of non-metastatic breast cancer patients, only part of which are derived from the observed tumor lineages.
Novel image analysis tools for evaluating the androgen receptor in the prostate needle biopsy: Impact on future systems-based outcome models.
Authors: G. Fernandez, P. Ajemba, F. Khan, V. Bayer-Zubek, Q. Liu, M. J. Donovan
Journal: Journal of Clinical Oncology (2011)

56 Background: A systems-based model was previously developed and validated to predict disease progression (DP) using pretreatment clinical data and standardized, robust prostate needle biopsy (PNB) tissue metrics. We sought to apply novel, advanced immunofluorescent (IF) image analysis methods to re-assess PNB androgen receptor (AR) and Ki67 expression profiles and identify cut-points useful for understanding and guiding therapeutic decision making. Methods: Pretreatment clinical features and PNB H&amp;E / IF images on 306 patients (91% cT1-T2b, 66% PSA&lt;/=10ng/mL; 49% Gleason biopsy score &lt;/=6) from the original study cohort were obtained. IF images were re-processed using a novel CK18 and DAPI algorithm to optimize segmentation of the tumor (epithelial) nuclear (TEN) and stromal compartments. The original threshold for determining TEN Ki67was retained. An enhanced image analysis approach was applied to calculate the normalized ratio of maximum AR levels in TEN to stromal nuclei. Feature performance was evaluated with the concordance index (CI); AR and Ki67 cut-point (CP) analysis and new multivariate models were completed. Results: Increasing amounts of Ki67 and two new AR features reflecting different percentages of the maximum AR level in TEN were associated with a shorter time to DP (Ki67 CI0.37, AR-ratio 21, CI0.30 and AR-ratio 22, CI0.33). Several cut-points were identified including: Ki67 CP 0.04, hazard ratio (HR) of 3.1, p-value 0.0005 (sensitivity 64%, specificity 68%); ARratio-21 CP 0.90, HR 3.8, p-value 0.0001 (sensitivity 78%, specificity 73%) and ARratio-22 CP 0.87, HR 2.2, p-value 0.013 (sensitivity 68%, specificity 68%). A multivariate model for predicting DP consisted of 4 weighted features including the biopsy Gleason score, the ARratio-22, and two morphometric (H&amp;E&amp;IF) variables. Conclusions: Novel image analysis methods to analyze biomarker attributes in PNB specimens confirm and enhance our understanding of AR and Ki67 in disease progression. Such approaches will become useful tools for finalizing biomarker cut-points, performing pharmacodynamic assessment and establishing parameters for guiding therapy. [Table: see text]
Abstract 3059: miR-518c-5p promotes the metastasis of oral cancer cells in a CXCR4-dependent and -independent manner
Authors: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Tetsuya Tamatani, Hirokazu Nagai, Hitoshi Kawamata, Youji Miyamoto
Journal: Cancer Research (2015)

Abstract We have demonstrated that CXCR4 system is involved in the metastatic process of oral cancer. Recently, we identified the miR-518c-5p as a downstream target of the CXCR4 system, which was involved in the metastasis of B88, a CXCR4-expressing oral cancer cell line (2014 AACR annual meeting). In this study, we examined the function of miR-518c-5p in an oral cancer cell line, CAL27, which did not express CXCR4 and did not exhibit metastatic potential in vivo. We transfected a miR-518c expression vector into parental CAL27 cells and isolated a stable transfectant, CAL27-518c. We could detect the upregulation of miR-518c-5p in the miR-518c transfectants compared with mock cells, which was completely inhibited by treatment with the miR-518c-5p LNA inhibitor. The growth and migration of CAL27-518c cells were significantly enhanced compared with those of mock cells. The miR-518c-5p inhibitor significantly impaired the enhanced cell growth and migration of CAL27-518c cells, indicating that these phenomena were mainly dependent on the expression of miR-518c-5p. Next, we examined the function of miR-518c-5p in vivo. miR-518c or mock transfectants were inoculated into the masseter muscle or the blood vessels of nude mice. Tumor volume, lymph nodes metastasis, and lung metastasis were significantly increased in the mice inoculated with miR-518c transfectants. These results indicate miR-518c-5p promotes the metastasis of oral cancer in a CXCR4-dependent and -independent manner. Citation Format: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Tetsuya Tamatani, Hirokazu Nagai, Hitoshi Kawamata, Youji Miyamoto. miR-518c-5p promotes the metastasis of oral cancer cells in a CXCR4-dependent and -independent manner. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3059. doi:10.1158/1538-7445.AM2015-3059
Anti-CD117 (c-Kit) Monoclonal Antibodies Deplete Human Hematopoietic Stem Cells and Facilitate Their Replacement in Humanized NOD/SCID/IL2Rγ−/− Mice: A Non-Toxic Conditioning Regimen for Allotransplantation
Authors: Aaron C. Logan, Agnieszka Czechowicz, Benjamin V. Kelley, Theingi M. Thway, Ivan Magana, Mark R. Krampf, Jessica Poyser, Roger P. Hollis, Donald B. Kohn, Irving L. Weissman, Judith A. Shizuru
Journal: Blood (2012)
Demographic and prognostic factors in ampullary adenocarcinoma: A retrospective review of 74 sequential cases undergoing multidisciplinary management between 1997 and 2009.
Authors: Robert de Wilton Marsh, David J. Bentrem, Marshall Baker, Susan Stocker, Eric Brown, Mark S. Talamonti
Journal: Journal of Clinical Oncology (2012)

334 Background: Ampullary adenocarcinoma represents 1% of GI cancers but accounts for almost 30% of Whipple operations at major centers. Prognosis falls between that of pancreatic and duodenal cancer, but demographic and prognostic factors are not fully delineated. A better understanding of the biology of this disease is essential both for patient care and for the optimal design of future studies. Methods: Retrospective review, with patient consent, of an IRB approved comprehensive common surgical database at two academic institutions. This database included all cases operated on for ampullary adenocarcinoma between 1997 and 2009. Demographics and factors thought to have potential relevance for prognosis by literature review were examined, where available, via Kaplan Meier and/or Cox models. Results: 74 cases were identified: 50 had conventional and 22 pylorus preserving Whipple procedures with 2 unresectable cases. Demographics: 38 males, 36 females; 64 Caucasian, 6 African American and 4 others; age 23-83, median 63.08 years. Tumor characteristics: Tis -1, T1-10, T2-22, T3-27, T4-12, Unknown-2; N0-35, N1-38, Unknown-1; pre-existing adenomas in 37 (50%). Tumor markers: CEA 2/34 and CA 19-9 16/37 tested were abnormal. Adjuvant therapy given (chemo and/or chemoRT): 33/74. Status: 34 patients alive and 41 deceased with a median follow-up of 22 months. Factors associated with poor outcome: Perineural invasion (PNI) p = 0.02; Pre-existing adenoma p = 0.001; Weight loss of 10 lbs or more p = 0.01; RBC transfusion in the OR p = 0.001. Factors not statistically prognostic: T stage, lymph nodal status, lymphovascular invasion, jaundice, CEA or CA 19-9 values and absence of adjuvant therapy. Pancreaticobiliary versus intestinal subtype could not be assessed as this was rarely reported. Conclusions: This dataset describes the demographics of patients sequentially treated for ampullary adenocarcinoma over 12 years, and identifies PNI, weight loss, pre-existing adenoma and transfusion in the OR as adverse factors. These prognostic factors (and potentially histologic subtype) should be considered in patient care and future study design.
Quality of life after pelvic radiotherapy with hypofractionated IMRT boost and long-term hormone therapy for locally advanced prostate cancer.
Authors: H. C. Quon, P. Cheung, D. A. Loblaw, G. Morton, E. Szumacher, C. Danjoux, R. Choo, G. Thomas, A. Kiss, A. Deabreu
Journal: Journal of Clinical Oncology (2011)

75 Background: Combined radiotherapy (RT) and long-term hormonal therapy (HT) is a standard treatment option for high-risk prostate cancer. Dose escalated RT alone has been shown to improve disease free survival. Increased sensitivity of prostate cancer to high doses per fraction has led to hypofractionation as a method to radiobiologically escalate dose.We report on the quality of life of patients treated with combined hypofractionated RT and HT. Methods: A prospective phase I/II study enrolling patients with any of: clinical T3, PSA ≥20, or Gleason 8-10. Forty-five Gy (1.8 Gy/fraction) was delivered to the pelvic nodes with a concomitant 22.5 Gy intensity-modulated RT boost to the prostate, for a total of 67.5 Gy (2.7 Gy/fraction) in 25 fractions over 5 weeks. Hormonal therapy was administered for 2-3 years. Patient reported outcomes were measured at baseline and every 6 months using the validated Expanded Prostate Cancer Index Composite (EPIC) questionnaire, which measures urinary, bowel, sexual, and hormonal domains. Results: Sixty patients with a minimum 24 months of patient-reported outcomes were analyzed. Mean scores comparing baseline to 24 month values are reported. There were no statistically significant changes in the urinary summary scores (86.3 vs. 86.0, p=0.45) or any of the urinary subscales (function, bother, incontinence, irritative/obstructive). Domain summary score decreases were observed in: bowel by 4.4% (94.7 vs. 90.3, p&lt;0.01), sexual by 27% (44.5 vs. 17.5, p&lt;0.01), and hormonal by 11.9% (93.1 vs. 81.2, p&lt;0.01). Examining time trends in outcomes, most changes occurred within the first 6 months with smaller changes thereafter. Conclusions: Hypofractionated RT combined with long-term HT is associated with good patient-reported urinary and bowel outcomes at 24 months. Sexual and hormonal summary scores are affected, largely due to continued androgen deprivation therapy. Further follow-up is needed to document patient reported outcomes after testosterone recovery. No significant financial relationships to disclose.
Dose to the muscles of fecal continence during radiation therapy for prostate cancer.
Authors: Adam Waggoner, Michael Brown, Brent Tinnel, John B Halligan, Timothy Brand, Joseph P Brooks, Stephanie Ninneman, Grant Hughs, Dusten Macdonald
Journal: Journal of Clinical Oncology (2012)

86 Background: Radiation therapy for prostate cancer can lead to loss of fecal continence; our understanding of the dose-volume relationships of this late toxicity continues to develop. The external anal sphincter (EAS), internal anal sphincter (IAS), and the three parts of the levator ani muscle, the puborectalis (PRM), the pubococcygeus (PCM), and the illiococcygeus (ICM), all contribute to fecal continence. We developed a reproducible method for contouring these muscles and in this preliminary study evaluate whether decreased planning target volume (PTV) margins lead to potentially clinically significant decreases in dose to these muscles during definitive radiation therapy for prostate cancer. Methods: Muscles involved in fecal continence were contoured for 10 consecutive patients on a prospective study of reduced PTV margins for treating low-to-intermediate risk prostate cancer with intensity-modulated radiation therapy (IMRT) using an electromagnetic localization system. IMRT plans to a prescribed dose of 7740 cGy were developed using 10mm PTV margins (5mm posteriorly), and compared with actual treatment IMRT plans using 3mm circumferential PTV margins. Decreases in dose were evaluated for statistical significance using an unpaired t-test. Results: Reducing PTV margins decreased the mean PTV volume from 176.2 ml to 91.9 ml. Mean doses to the EAS, IAS, and rectum (REC) decreased significantly; from 11.0 Gy to 4.1 Gy (p=0.005), from 30.5 Gy to 15.0 Gy (p = 0.004), and from 43.7 Gy to 35.6 Gy (p=0.006) respectively. Decrease in the mean dose to the PRM was nearly statistically significant, 48.7 Gy to 34.6 Gy (p = 0.055). Decreases in mean doses to the PCM and ICM were not statistically significant; from 61.9 Gy to 55.2 Gy (p = 0.107), and from 40.7 Gy to 34.8 Gy (p = 0.176), respectively. Conclusions: Using electromagnetic tracking to reduce PTV margins leads to a significant decrease in dose to the muscles of fecal continence, with mean dose decreases in a range that may be clinically significant.
The Value of 99mTc ECD SPECT With Statistical Image Analysis on Enhancing the Early Diagnosis of Primary Progressive Aphasia
Authors: Cheng-Yu Wei, Pai-Yi Chiu, Po-Nien Hou, Hiroshi Matsuda, Guang-Uei Hung
Journal: Clinical Nuclear Medicine (2016)

A 64-year-old woman with poor short-term memory was first suspected as early Alzheimer disease. 99mTc ECD brain SPECT was arranged for differential diagnosis. A small area of mild hypoperfusion was noted in the left temporal lobe on conventional display. Further statistical analysis of SPECT with an easy Z-score imaging system showed large areas of distinct hypoperfusion in left precentral and perisylvian cortical areas, compatible with typical pictures of nonfluent variant primary progressive aphasia (PPA), but no involvement in areas characteristic for Alzheimer disease. Further detailed neuropsychological examination and 6 months of clinical follow-up confirmed the final diagnosis of PPA.
Phyllodes tumor of the breast treated with a multimodality approach: A single-institution retrospective analysis.
Authors: N. P. Joshi, S. Mallick, S. Pandit, P. K. Julka, A. Gandhi, H. Kunhiparambath, D. Sharma, G. K. Rath
Journal: Journal of Clinical Oncology (2011)

e11552 Background: Studies describing outcomes for phyllodes tumor of the breast are scarce. We explored the results of multimodality management at our institute for this disease. Methods: We retrospectively analysed our database for cases between 1994 & 2009. Adjuvant radiation was 50 Gy in 25 fractions after modified radical mastectomy (MRM) or 66 Gy equivalent after wide local excision (WLE). Chemotherapy was Ifosfamide & Anthracycline based. Survival (overall [OS] & disease free survival [DFS]) were calculated using Kaplan Meier method. Log-rank test was used to compare survival distribution. These were correlated with age (<40 vs. >40 years), tumor size (<15cm vs. >15cm), grade (benign/borderline vs. high), margin status (positive/close vs. negative) & type of surgery, WLE vs. MRM. The data was analysed using SPSS 16. Results: 33 patients were analysed. Median age at presentation was 36 years (range: 17-55 years). 7(21.2%) patients underwent WLE whereas 26 (78.7%) underwent MRM. 25(75%) patients had high grade tumors while 8 (25%) had borderline tumors. The median size was 13.6 cm (range: 3-24 cm). Margin was positive/close in 10 patients, free in 15 & unknown in 8. 4 patients had palliative radiation for local/metastatic disease. 7 patients received adjuvant chemotherapy & 4 received palliative chemotherapy. 2 patients achieved complete response of lung metastasis with chemotherapy, 1 achieved stable disease while one progressed after chemotherapy. Median follow up was 23 months. Estimated 5 year OS was 85% & estimated 5 year DFS was 77%. Only grade was found to correlate with survival. There was a trend for better OS with low grade – 193.6 vs. 160.2 months for high grade (p=0.08, log rank). The DFS favoured low grade – 193.6 vs. 82.9 months for high grade (p=0.02, log rank). Conclusions: Phyllodes tumor of the breast is a rare & heterogeneous entity. Our results correlate with that of others for grade. An appreciable number are amenable to WLE despite large tumor size & breast conservation rates are comparable with those for carcinoma. Multiagent chemotherapy deserves further study in adjuvant & metastatic setting.
Personalized Diabetes Management Using Electronic Medical Records
Authors: Dimitris Bertsimas, Nathan Kallus, Alexander M. Weinstein, Ying Daisy Zhuo
Journal: Diabetes Care (2016)

OBJECTIVE Current clinical guidelines for managing type 2 diabetes do not differentiate based on patient-specific factors. We present a data-driven algorithm for personalized diabetes management that improves health outcomes relative to the standard of care. RESEARCH DESIGN AND METHODS We modeled outcomes under 13 pharmacological therapies based on electronic medical records from 1999 to 2014 for 10,806 patients with type 2 diabetes from Boston Medical Center. For each patient visit, we analyzed the range of outcomes under alternative care using a k-nearest neighbor approach. The neighbors were chosen to maximize similarity on individual patient characteristics and medical history that were most predictive of health outcomes. The recommendation algorithm prescribes the regimen with best predicted outcome if the expected improvement from switching regimens exceeds a threshold. We evaluated the effect of recommendations on matched patient outcomes from unseen data. RESULTS Among the 48,140 patient visits in the test set, the algorithm’s recommendation mirrored the observed standard of care in 68.2% of visits. For patient visits in which the algorithmic recommendation differed from the standard of care, the mean posttreatment glycated hemoglobin A1c (HbA1c) under the algorithm was lower than standard of care by 0.44 ± 0.03% (4.8 ± 0.3 mmol/mol) (P &amp;lt; 0.001), from 8.37% under the standard of care to 7.93% under our algorithm (68.0 to 63.2 mmol/mol). CONCLUSIONS A personalized approach to diabetes management yielded substantial improvements in HbA1c outcomes relative to the standard of care. Our prototyped dashboard visualizing the recommendation algorithm can be used by providers to inform diabetes care and improve outcomes.
CD3 Depleted Hematopoietic Peripheral Blood Stem Cell Grafts in Children with Refractory Hematologic Malignancies Undergoing Transplantation from Mismatched Related Donors.
Authors: Gregory A. Hale, Kimberly A. Kasow, Richard Lovins, Joseph P. Woodard, Wing H. Leung, Usman Yusuf, Edwin M. Horwitz, Deo K. Srivastava, Xin Tong, Ely Benaim, Rupert Handgretinger
Journal: Blood (2005)
Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis
Authors: Chengguo Wei, Li Li, Madhav C. Menon, Weijia Zhang, Jia Fu, Brian Kidd, Karen L. Keung, Christopher Woytovich, Ilana Greene, Wenzhen Xiao, Fadi Salem, Zhengzi Yi, John Cijiang He, Joel T. Dudley, Barbara Murphy
Journal: Journal of the American Society of Nephrology (2016)

Renal fibrosis is the common pathway of progression for patients with CKD and chronic renal allograft injury (CAI), but the underlying mechanisms remain obscure. We performed a meta-analysis in human kidney biopsy specimens with CAI, incorporating data available publicly and from our Genomics of Chronic Renal Allograft Rejection study. We identified an
Desialylation Induces Apoptosis and Phagocytosis of Platelets in Patients with Prolonged Isolated Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Qian-ming Wang, Xiao-Hui Zhang, Fei-er Feng, Chen-cong Wang, Wei Han, Huan Chen, Lan-ping Xu, Xiao Jun Huang
Journal: Blood (2014)
Diagnostic microRNA serum profile in pancreatic cancer.
Authors: Nicolai Aagaard Schultz, Christian Dehlendorff, Jens Werner, Thor Schutt Svane Nielsen, Dan Calatayud, Nathalia Giese, Benny Vittrup, Kaspar Nielsen, Julia S. Johansen, Klaus Kaae Andersen
Journal: Journal of Clinical Oncology (2012)

160 Background: MicroRNAs (miRs) regulate genes with important roles in oncogenesis, angiogenesis and tissue differentiation. MiRs have high tissue-specific expression patterns and are interesting new biomarkers with a potential for earlier diagnosis of pancreatic cancer (PC). The aim was: 1) to identify a panel of diagnostic miRs in serum that can separate patients with PC from patients with chronic pancreatitis (CP) and healthy subjects (HS); and 2) to use statistical methods that make the analysis of the miR panel less sensitive to known methodological day-to-day variation. Methods: RNA was purified from serum according to SOP in pretreatment samples stored at −80°C from two prospective studies of 139 patients with PC (101 were operated and 38 had locally or metastatic PC), 17 patients with CP and 50 healthy subjects from 4 University Hospitals. MiR expression was measured using TaqMan Array Human MicroRNA A and B cards (v3.0 Applied Biosystems) profiling 768 miR. Raw miR expression values were checked for outliers. In a univariate selection method the rank of each miR (miRs were ranked for each subject) was related to PC using logistic regression. MiRs with p-values below 0.000001 were tested in a multivariate analysis. Results: Serum samples from 206 patients had acceptable miR. After exclusion of miRs that was undetermined in ≥20% of samples 85 miRs were considered in the univariate analysis and 12 of these subsequently included in the multivariate model. Seven miRs were significantly associated with PC. For all miRs in the diagnostic panel decreased expression is associated with PC. Conclusions: We present a diagnostic panel of 7 miRs in serum that discriminates samples from patients with PC from patients with CP and HS. The 7 miRs were selected with a rank-based method, which is a novel non-parametric method for data processing in miRNA array studies. [Table: see text]