tbuckley/cabot-search huggingface dataset:
Retrospective analysis of treatment-induced peripheral neuropathy (TIPN) in multiple myeloma (MM).
Authors: Thomas Martin, Sumeet Panjabi, Robert Imani, Emmanuel Anum, Deborah P. Lubeck
Journal: Journal of Clinical Oncology (2013)

e19530 Background: Peripheral neuropathy (PN) is commonly present at MM diagnosis and exacerbated or induced by MM treatments. TIPN poses significant morbidity, and may result in therapy modifications (TM). We examined the “real-life” onset and severity of TIPN in newly diagnosed patients (pt) receiving anti-MM therapies. Methods: Medical records from a US community oncology network were reviewed. Newly diagnosed MM pt treated between 1/1/08 and 7/1/10, ≥18 years, and followed for ≥24 months were eligible. The protocol pre-defined inclusion of an equal number of TIPN and non-TIPN cases. Regimen-related TIPN was based on clinician judgment and/or correspondence of TIPN with regimen start/end dates. Uni- and multi-variate (MV) analyses examined association of demographic and regimen characteristics with TIPN, TIPN severity, and TM. Results: In all, 716 MM records were screened; 367 were deemed ineligible or incomplete. Of 349 eligible records, 229 were abstracted, 10 had unusable data, and 219 formed the analytic set; 120 records were excluded since the accrual target (N=225) had been met. Average age of pts was 67.0 years, 49.3% were female, 57.5% Caucasian, and 36.0% African-American (AA). A majority (56.6%) had 1 regimen prior to 1 st disease progression, 26.0% had 2 and 17.4% had &gt;2 regimens. Overall, 138/219 (63.0%) developed PN, 123/219 (53.7%) with documented TIPN. TIPN developed during 1 st line therapy in the majority 110/123 (89.4%). Univariate analysis revealed that TIPN pt were younger, more likely to be AA, and treated more frequently with bortezomib-based regimens BTZ-BR (63.3 v 9.3%). MV analysis showed TIPN was associated with BTZ-BR (OR=14.5, 95% CI=6.5-32.2), but not age, race, gender, and diabetes. BTZ-BR compared to non BTZ-BR were associated with severe and grade 3/4 TIPN (79.3 v 20.7%; χ 2 =5.36, p=0.02), and TM (65.7 v 34.3%, χ 2 =5.57, p=0.02). Notable TM included dose reductions (66.7 v 33.3%) and delays (83.3 v 16.7%). Conclusions: In this study of newly diagnosed MM pt, TIPN developed frequently during 1st line therapy. BTZ-BR were associated with TIPN that was severe and resulted in greater TM. While this analysis represents a small pt population, the results are provocative and warrant further study.
Evaluation of novel formulations for transarterial chemoembolization: combining elements of Lipiodol emulsions with Drug-eluting Beads
Authors: Marcus Caine, Ting Chung, Hugh Kilpatrick, Zainab Bascal, Sean Willis, Yiqing Tang, Thierry de Baere, Matthew Dreher, Andrew Lewis
Journal: Theranostics (2019)

There are currently two methods widely used in clinical practice to perform transarterial chemoembolization (TACE). One is based on mixing an aqueous drug with an iodized oil (Lipiodol) and creating an emulsion that is delivered intraarterially, followed by embolization with a particulate agent. The other is based on a one-step TACE using Drug-eluting Beads (DEBs) loaded with drug. It is not recommended to mix Lipiodol with DEBs due to incompatibility. For the first time, novel DEB: Lipiodol: doxorubicin (Dox) emulsions are identified using lyophilized polyvinyl alcohol (PVA) hydrogels (non-iodinated or iodinated) DEBs.15 DEB emulsions (50mg Dox) were assessed for stability and deliverability in vitro and in vivo in a swine model. Dox release from selected formulations was measured in vitro using a vascular flow model and in vivo in a VX2 rabbit tumor model.Both DEB formats were shown to be able to form emulsions, however only Iodinated DEBs consistently met defined handling criteria. Those based on the non-iodinated DEB achieved >99%+ Dox loading in <5 minutes but were generally less stable. Those prepared using iodinated DEBs, which are more hydrophobic, were able to form stable Pickering-like emulsions (separation time ≥ 20 minutes) and demonstrated handling, administration and imaging observations more akin to Lipiodol™ TACE emulsions in both embolization models. Controlled Dox release and hence beneficial in vivo pharmacokinetics associated with DEB-TACE were maintained.This study demonstrates that it is possible to formulate novel DEB emulsions suitable for TACE that combine positive elements of both Lipiodol™ based and DEB-TACE procedures.
Prolyl isomerase Pin1 plays a dual role in cell proliferation and apoptosis by isomerizing orphan receptor TR3
Authors: Hangzi Chen, Guideng Li, Choy Leong Hew, Yih-Cherng Liou, Qiao Wu
Journal: Cancer Research (2008)

100  Pin1 plays an important role in regulating a subset of phosphoproteins by isomerizing their Ser/Thr-Pro motifs through the post-phosphorylation mechanism. Although Pin1 was originally identified as an essential mitotic regulator, accumulating evidence has demonstrated Pin1 implications in several other cellular processes. In the present study, we revealed that Pin1 is involved in cell proliferation and apoptosis by regulation the functions of an orphan receptor TR3. We first characterized TR3 as a novel substrate for Pin1. Consequently, we identified three major Ser-Pro sites in TR3 that mediate distinct regulatory roles of Pin1. These include (1) phosphorylation of TR3 by ERK and JNK at Ser95, Ser140 and Ser434 to facilitate the recognition and binding of Pin1; (2) Ser95 as the key site for Pin1 to enhance TR3 protein stability by inhibiting TR3 degradation; (3) Ser434 as the isomerizing site of Pin1 to activate TR3 transcriptional activity. Furthermore, we found that Pin1 could help to recruit TR3 to the cyclinD2 and E2F1 promoters by enhancing DNA binding activity of TR3, resulting in an induction of cyclinD2 and E2F1 expression, thereby contributing to cell proliferation. On the other hand, Pin1 could assist TR3 in nuclear export and mitochondrial targeting in response to TPA, hence initiating cell apoptosis. We further confirmed the regulatory role of Pin1 on TR3 by an in vivo tumor formation assay using nude mice injected with Pin1-siRNA stably HeLa cells. Taken together, our results demonstrate for the first time that Pin1 plays a dual role in cell proliferation and apoptosis by isomerizing different motifs of TR3.
Mutation Patterns Identify Adult Patients with De Novo Acute Myeloid Leukemia (AML) Aged 60 Years or Older Who Respond Favorably to Standard Chemotherapy: an Analysis of Alliance Studies
Authors: Ann-Kathrin Eisfeld, Jessica Kohlschmidt, Krzysztof Mrózek, James S. Blachly, Christopher J. Walker, Deedra Nicolet, Shelley Orwick, Andrew Carroll, Richard M. Stone, Eunice S. Wang, Jonathan E. Kolitz, Bayard L. Powell, Albert de la Chapelle, John C. Byrd, Clara D. Bloomfield
Journal: Blood (2017)
Optical coherence tomography guided cystoscopy in diagnosis and management of clinical bladder tumors
Authors: C. S. Lee, M. Mishail, W. C. Waltzer, J. Liu, Z. Wang, Y. Pan
Journal: Journal of Clinical Oncology (2007)

15518 Background: Optical coherence tomography (OCT) is a novel tool that permits high-resolution cross-sectional imaging of bladder urothelium during cystoscopy. OCT delineates morphological features of the bladder urothelium, the lamina propria, and the muscularis layer based on their backscattering patterns. We hypothesize that application of microelectromechanical systems (MEMS) mirrors for OCT can improve cross-sectional image resolution of bladder lesions. We report preliminary results from our prospective non-randomized study using MEMS mirror OCT imaging during cystoscopy. Methods: Following our institutional IRB approval, a prospective correlative study was performed evaluating the role of cross-sectional OCT in diagnosis and treatment of bladder cancers. OCT cystoscopy was performed in thirty patients undergoing cystoscopy or transurethral resection for suspected bladder tumors. Any suspicious lesions or tumors seen on cystoscopy were either biopsied or resected as per standard of care. The primary endpoints were patient safety and the correlation between OCT images and histology. Results: Bladder cancer was identified in twenty five patients by pathological evaluation. Twenty four out of twenty five patients were correctly diagnosed with cross-sectional OCT imaging. Four out of five patients with benign lesions were correctly identified. There was one false positive and one false negative in our series. Overall sensitivity and specificity of cross-sectional OCT in diagnosing bladder cancer was 96 and 80%, respectively. There were no complications related to OCT cystoscopy. Axial and lateral resolutions were 10 and 12 microns, respectively. The field of view was measured at 4.5 mm with the depth of penetration measured to be 2 mm. Conclusions: OCT cystoscopy is a promising new tool in diagnosis of bladder cancer. Our preliminary data suggests OCT with MEMS mirrors resulted in high resolution images that may aid in the diagnosis of bladder cancer during cystoscopy. Application of OCT cross sectional imaging may have additional benefits: improved diagnosis, identification of surgical margins, and more complete resection of bladder tumors. No significant financial relationships to disclose.
scAlign: a tool for alignment, integration, and rare cell identification from scRNA-seq data
Authors: Nelson Johansen, Gerald Quon
Journal: Genome biology (2019)

scRNA-seq dataset integration occurs in different contexts, such as the identification of cell type-specific differences in gene expression across conditions or species, or batch effect correction. We present scAlign, an unsupervised deep learning method for data integration that can incorporate partial, overlapping, or a complete set of cell labels, and estimate per-cell differences in gene expression across datasets. scAlign performance is state-of-the-art and robust to cross-dataset variation in cell type-specific expression and cell type composition. We demonstrate that scAlign reveals gene expression programs for rare populations of malaria parasites. Our framework is widely applicable to integration challenges in other domains.
Assessment of Calcineurin Inhibitor-Associated Neurotoxicity in Patients with Sickle Cell Disease Receiving a Matched Sibling Donor or T-Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Katharina Kleinschmidt, Juergen Foell, Johannes Schulte, Beatrix Pfirstinger, Anja Troeger, Charalampos Aslanidis, Daniel Wolff, Matthias Edinger, Ernst Holler, Wolfgang Herr, Angelika Eggert, Selim Corbacioglu
Journal: Blood (2018)
Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST).
Authors: Michael C. Heinrich, Robin Lewis Jones, Margaret von Mehren, Sebastian Bauer, Yoon-Koo Kang, Patrick Schoffski, Ferry Eskens, Olivier Mir, Philippe Alexandre Cassier, Cesar Serrano, William D. Tap, Jonathan C. Trent, Piotr Rutkowski, Shreyaskumar Patel, Sant P. Chawla, Eyal Meiri, Teresa Zhou, Khalid Kevin Mamlouk, Maria Roche, Suzanne George
Journal: Journal of Clinical Oncology (2019)

11022 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Updated results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥ 1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Safety from the overall population (30-600 mg doses) and efficacy in the response evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 (56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with median duration of response (mDOR) of 10.2 months (95% CI: 7.2-NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3-NE). Most AE were grade 1-2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3-4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2 nd and 3 rd line therapies and shows unprecedented activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.
Identification and characterization of SP cells in human lung adenocarcinoma SPC-A1 cells
Authors: Y. Zhu, L. Chen
Journal: Journal of Clinical Oncology (2009)

e22230 Background: There has been an increasing interest in recent years in the role stem cells play in health and disease. With an extensive understanding of their biology, a major role for stem cells in the malignant process has been proposed and the existence of cancer stem cells(CSCs) has been confirmed in hematopoietic malignancies, brain cancer, and solid organ malignancies including breast, prostate, colon, and pancreatic cancer. Lung cancer is the leading cause of cancer mortality in most large cities of China. It is possible that lung cancer contains cancer stem cells responsible for its malignancy. The aim of this study is to identify, characterize and enrich the CSC population that drives and maintains lung adenocarcinoma growth and metastasis. Methods: Side population (SP) cell analysis and sorting were applied to established human lung adenocarcinoma cell line and an attempt to further enrich them by preliminary serum-free culture before fluorescence activated cell sorting(FACS) was done. Stem cell properties of SP cells were evaluated by their proliferative index, colony-forming efficiency, tumorigenic potential, bi-differentiation capacity and the expression of common stem cell surface markers. Results: Lung cancer cells could grow in a serum-free Medium (SFM) as non-adherent spheres similar to neurospheres or mammospheres. The proportion of SP cells in cell spheres was significantly higher than that in cells grown as monolayers. SP cells had a greater proliferative index, a higher colony-forming efficiency and a greater ability to form tumor in vivo. SP cells were both CCA positive and SP-C positive while non-SP cells were only SP-C positive. Flow cytometric analysis of cell phenotyping showed that SP cells expressed CD133 and CD44, the common cell surface markers of cancer stem cells, while non-SP cells only expressed CD44. Conclusions: SP cells existed in human lung adenocarcinoma cell lines and they could be further enriched by preliminary serum-free culture before FACS sorting. SP cells possessed the properties of cancer stem cells. No significant financial relationships to disclose.
Apoptosis induction in mammary tumors in mice improves the intratumoral distribution and efficacy of oncolytic viral therapy
Authors: Satoshi Nagano, Jean Perentes, Rakesh Jain, Yves Boucher
Journal: Cancer Research (2007)

4945  The large size of viral vectors limits their distribution through the interstitial matrix (IM) and the narrow space between tumor cells. We hypothesized that the induction of apoptosis in tumor cells would create large void spaces in the tumor that could enhance the intratumoral distribution and thus the anti-tumor efficacy of replication-competent Herpes Simplex Virus (HSV). We have recently shown that paclitaxel/TRAIL improves the distribution of HSV injected into human MDA-MB-435S tumors implanted in the mammary fat pad and that HSV-infected cells were predominantly located in the periphery of apoptotic areas. In the present study, we determined the effect of paclitaxel/TRAIL on the IM composition and on tumor growth before and after the intratumoral injection of HSV, and developed a genetic approach to regulate the levels of apoptosis in tumors. To determine if a reduction in IM content could influence the viral distribution, we stained MDA-MB-435S sections for collagen I and hyaluronan. Paclitaxel/TRAIL treatment had no effect on the collagen I content but significantly increased the levels of hyaluronan in tumors. Therefore, the increased distribution of HSV was not associated to a decrease in collagen or hyaluronan content. To test if paclitaxel/TRAIL-induced apoptosis improves the therapeutic efficacy of oncolytic viral therapy, we measured the volume of MDA-MB-435S tumors in thefollowing treatment groups, (1) saline plus vehicle, (2) saline plus HSV, (3) HSV plus paclitaxel (15 mg/Kg) /TRAIL (500 µg/mouse) or (4) Paclitaxel/TRAIL plus HSV. The average tumor doubling time was (1) 23.7 ±2.1, (2) 38.8 ±3.9, (3) 46 ±2.9 and (4) 59 ±4.7 days. The administration of paclitaxel/TRAIL before the intratumoral injection of HSV produced a significantly longer tumor growth delay than the injection of HSV followed by paclitaxel/TRAIL (p
Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): Final results of SARC028 expansion cohorts.
Authors: Melissa Amber Burgess, Vanessa Bolejack, Scott Schuetze, Brian Andrew Van Tine, Steven Attia, Richard F. Riedel, James S Hu, Lara Emily Davis, Scott H. Okuno, Dennis A. Priebat, Sujana Movva, Damon R. Reed, Sandra P. D'Angelo, Alexander J. Lazar, Emily Zhi-Yun Keung, Denise K. Reinke, Laurence H. Baker, Robert G. Maki, Shreyaskumar Patel, Hussein Abdul-Hassan Tawbi
Journal: Journal of Clinical Oncology (2019)

11015 Background: Immune checkpoint inhibitors have demonstrated activity in multiple tumor types but their activity in soft tissue sarcomas remains limited. In the multicenter phase II study, SARC028, the anti-PD-1 antibody, P demonstrated objective responses that were largely restricted to UPS and LPS subtypes. We now report outcomes from 2 expansion cohorts of SARC 028 in advanced UPS and LPS. Methods: To further confirm the clinical activity of P in UPS and LPS, we enrolled an additional 30 pts in each of 2 expansion cohorts for a total of 40 UPS and 40 LPS pts. Primary endpoint was investigator-assessed response by RECIST v1.1. Secondary endpoints were safety, progression-free survival (PFS), 12-week PFS rate, and overall survival (OS). An ORR of 25% was considered clinically meaningful and &lt; 10% was considered to show lack of efficacy. P was to be considered a success if 8 or more of 40 enrolled patients had a PR or better (1-sided α = 0.042, 82% power). Pts age ≥18 with advanced, refractory UPS or LPS received 200 mg of P IV every 3 weeks until progression or unacceptable toxicity. Results: Preliminary results from the first 10 pts in each of the UPS and LPS cohorts have been reported. We now present summary data after enrolling an additional 30 pts in each cohort. The ORR in the UPS cohort was 23% (9/40), with an additional 5/30 PRs observed in the expansion cohort (total 2 CRs, 7 PRs). In the LPS cohort, the ORR was 10% (4/39 evaluable pts), with an additional 2/30 PRs observed (total 4 PRs). Median PFS for the UPS group was 3 months [95% CI: 2, 5] and 2 months [95% CI: 2, 4] for the LPS group. 12-week PFS rate was 50% in UPS [95% CI: 35, 65] and 44% in LPS [95% CI: 28, 60]. The UPS group had a median OS of 12 months [95% CI: 7, 34] and 13 months [95% CI: 8, NR] for the LPS group. P was well tolerated with no unexpected toxicities. Conclusions: The UPS cohort achieved its primary endpoint, however the activity of P in UPS deserves further evaluation in a randomized study. The activity of P was not confirmed in the LPS cohort. Ongoing biomarker analyses may direct better patient selection and guide future combination strategies. Clinical trial information: NCT02301039.
Patterns in circulating microRNA in black (B) versus white (W) patients with triple-negative (TN) breast cancer (BC).
Authors: Iuliana Shapira, Annette Lee, Michaela Oswald, Lora Rose Weiselberg, David Ballard, Emanuela Taioli, Kit Cheng, Sabeen Fatima Mekan, Myra F. Barginear, Mary Keogh, Cathleen Mason, Daniel R. Budman
Journal: Journal of Clinical Oncology (2012)

1046 Background: Breast cancer is by far more common in W than in B women. Black women have more aggressive disease that occurs almost a decade earlier, it is usually triple negative and has a lower survival. Objectives to determine 1) if plasma miRNA expression differs between B and W women, and 2) if variation in miRs may explain the observed survival difference in TNBC in W compared to B women. Methods: We determined miRNA profiles in plasma collected before removal of breast tumors in three groups of W and B women: 1) normal controls (N), 2) TN and 2) ER/PR positive BC. Expression miRNA profiling of 754 miRNAs on the ABI Open Array detected 101miRNAs in plasma. We compared miRNA expression in cancer patients and race-matched controls. A moderated t-statistic through the R/Bioconductor 'limma' was used to compare the mean response between subject factors of interest. Results with a p&lt;0.05 were considered statistically significant. Characteristics: 32 patients were included in this analysis (mean age 50 years; range 31-68), 10 had stage III TNBC (5 B &amp; 5 W); 10 had stage III ER/PR+BC (5 B, 5 W); and 12 were controls (6 B, 6 W) Results: W TNBC patients overexpressed (15 fold higher than normal) 20 miRs in plasma (let-7d, let7g, miR-103, -10a, 15a, -9, -99b, -181a, -18a, -502, -187, -365 and others), these miRs were not found in any of the B patients. Six microRNAs (such as miR-34a, -127 and others) were 15 fold higher than normal controls in B cancer patients, these miRs were not detected in W patients with TNBC. Four miRs in B and 8 miRs in W were not previously reported in association with breast cancer suggesting that they may be connected to the host response. Conclusions: The striking difference in the patterns of plasma miRNA expression between B and W patients may provide the key to the large difference in outcome between these groups when receiving similar treatments, the worse prognosis group may carry the miRs that promote metastasis. The seed-soil hypothesis may explain the better prognosis in W patients. W women may carry those miRNAs that support an “exaggerated” response to systemic treatment, while the B may have the miRs that favour metastasis.