tbuckley/cabot-search huggingface dataset:
Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma
Authors: Hervé Avet-Loiseau, Rafael Fonseca, David Siegel, Meletios A. Dimopoulos, Ivan Špička, Tamás Masszi, Roman Hájek, Laura Rosiñol, Vesselina Goranova-Marinova, Georgi Mihaylov, Vladimír Maisnar, Maria-Victoria Mateos, Michael Wang, Ruben Niesvizky, Albert Oriol, Andrzej Jakubowiak, Jiri Minarik, Antonio Palumbo, William Bensinger, Vishal Kukreti, Dina Ben-Yehuda, A. Keith Stewart, Mihaela Obreja, Philippe Moreau
Journal: Blood (2016)
Case 10-1972
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, Edward C. Franklin, Benjamin Castleman
Journal: New England Journal of Medicine (1972)

Presentation of CaseA 47-year-old woman was admitted to the hospital because of fatigue.She had enjoyed vigorous health until one year previously, when she began to be fatigued easily and to experience musculoskeletal "aching" pain that principally affected the arms, thighs and calves; the pain was aggravated by physical exertion and relieved by rest, with residual soreness of the affected muscles. Concurrently, there was the onset of numbness and weakness of the hands, particularly at night, and pain in the jaw on chewing. Nine months before admission hoarseness developed. Three months later an x-ray film of the chest was . . .
Anti-CD38 Pretargeted Radioimmunotherapy Demonstrates Therapeutic Efficacy In a Human Multiple Myeloma Mouse Xenograft Model
Authors: Damian J. Green, Nural N. Orgun, Mark D. Hylarides, John M. Pagel, Donald K. Hamlin, D. Scott Wilbur, Yukang Lin, Amiee L. Kenoyer, Shani L. Frayo, William I. Bensinger, Ajay K. Gopal, Johnnie J. Orozco, Theodore A. Gooley, Brent L. Wood, Oliver W. Press
Journal: Blood (2011)
Abstract PL03-02: The AML genome(s)
Authors: Timothy J. Ley
Journal: Cancer Research (2016)

Abstract Acute Myeloid Leukemia (AML) is a clonal disorder of hematopoietic stem/progenitor cells. These cells have been shown to accumulate random mutations as a function of time; however, some of these mutations are non-random and can cause the expansion of the stem cells that contain them, creating a benign ‘preleukemic’ state that has recently been dubbed “Clonal Hematopoiesis of Indeterminate Potential” (CHIP). As these clones expand, they can occasionally acquire additional mutations that create a profound advantage for these cells, yielding an AML “ founding clone”. Founding clones generate subclones that have unique properties that are probably defined by the specific mutations that they contain. These subclones, found in virtually all AML cases, shape the responses of AML patients to therapy, and often contribute to relapse. Clonal heterogeneity is therefore a hallmark of AML at presentation, and approaches to assess risk of relapse must take this into account. Further, approaches to cure this disease will probably require successful targeting of the mutations that initiate the disease, which are the only ones that are found in all the cells within the tumor. Frequently, the initiating mutations that expand the preleukemic clone are persistent when patients are in clinical remission, strongly suggesting that these events are important for relapse. The precise mechanisms by which canonical initiating events predispose to AML are largely unknown, but many of these mutations do cause significant changes in the epigenome that are probably relevant for pathogenesis. Citation Format: Timothy J. Ley. The AML genome(s). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr PL03-02.
구연 : 타목시펜이 실험적 문맥주위부 간섬유화 및 베타1 형질전환 성장인자의 발현에 미치는 영향
Authors: 김성훈, 정영화, 김정아, 최민희, 이윤정, 신정우, 류수형, 장명국, 김인숙, 최원범, 이재균, 박능화, 임영석, 이한주, 유은실, 이영상, 서동진
Journal: Clinical and Molecular Hepatology (2003)

배경/목적: 최근에 연자 등은 간암 세포주를 이용한 실험을 통해, 타목시펜이 간섬유화 과정에 중요한 역할을 하는 TGF-β1의 발현을 억제함을 보고하여, 타목시펜이 간섬유화를 지연시킬 가능성을 시사하였다. 이에, 본 연구에서는 실험적 문맥주위부 간섬유화 동물 모델에서 타목시펜이 간섬유화 정도에 미치는 영향을 직접적으로 분석하고 TGF-β1의 발현억제 여부를 규명하고자 하였다. 대상과 방법: 체중 200-250g의 Sprague-Dawley 백서 50마리에 Allyl alcohol(0.62 mmol/kg)을 복강내에 주 2회, 8주간 주사하여 문맥주위부 간섬유화를 실험적으로 유도하였다. 실험군 30마리 중, 각각 10마리의 백서에는 같은 기간동안 타목시펜 1, 5 및 10 mg/Kg를 매일 경구로 동시투여하였다.(타목시펜 동시투여군) 나머지 20 마리의 백서는 대조군으로 이용하여(allylalcohol 투여군) 실험군의 간섬유화 정도, 간조직내 교원질 함량 및 혈장내 TGF-β1의 농도와 비교분석하였다. 간섬유화의 정도는 Castilla-Cortaza 등과 Oberti 등이 보고한 방법에 따라 numerical scoring system을 적용하여 1점에서 14점까지 정량화하였다. 간조직내 교원질 함량은 Dye-binding procedure를 이용하여 측정하였으며, 혈장내 TGF-β1 농도를 ELISA법으로 측정하였다. 결과: 1) 1, 5 및 10mg/Kg의 타목시펜 동시투여군에서 간섬유화 점수는 각각 9.0＋1.1, 8.3＋1.3 및 7.9＋1.3 으로서 타목시펜의 용량이 증가함에 따라 감소하는 경향을 보였으며, 10 mg/Kg 타목시펜 투여군에서는 allylalcohol 투여군의 9.4＋1.9에 비해 통계적으로 유의한 감소를 나타냈다. (p＝0.018) 2) 1, 5 및 10 mg/Kg의 타목시펜 동시투여군에서 간조직내 교원질 함량은 각각 134＋7.12, 127＋12.0 및 119＋16.6 ug collagen/mg protein으로서 타목시펜의 용량이 증가함에 따라 감소하는 경향을 보였으며, 10 mg/Kg 투여군에서는 allylalcohol 투여군의 141＋39.1에 비해 통계적으로 유의한 감소를 나타냈다. (p＝0.045) 3) 1, 5 및 10mg/Kg의 타목시펜 동시투여군에서 혈장내 TGF-β1 농도는 각각 288＋31.0, 282＋35.2 및 231＋66.0 pg/mL 로서 타목시펜의 용량이 증가함에 따라 감소하는 경향을 보였으며, 10 mg/Kg 투여군에서는 allylalcohol 투여군의 312 + 59.6에 비해 통계적으로 유의한 감소를 나타냈다. (p＝0.007) 결론: 이와 같은 결과는, 타목시펜이 용량 의존적으로 TGF-β1의 발현을 억제함으로써 실험적 문맥주위부 간섬유화 정도를 감소시킬 수 있음을 시사하는 소견으로 보인다.
Abstract 3183: Delivery of point-of-care management to patients with gynecologic malignancies using comprehensive genomic profiling
Authors: Lorna Rodriguez-Rodriguez, Kim M. Hirshfield, Veronica Rojas, Siraj Ali, Robert S. DiPaola, Darlene Gibbon, Sara Isani, Aliza Leiser, Gregory M. Riedlinger, Shridar Ganesan
Journal: Cancer Research (2016)

Abstract INTRODUCTION: Gynecologic cancers were estimated to occur in 98,280 women in 2015 in the United States and result in 30,440 deaths (Siegel 2015). The most common forms of gynecologic cancers occur in the ovary and uterine corpus (Siegel, 2015). Various reasons for poor outcome in these cancers include the late stage of the disease at the time of diagnosis and therapy resistance. We sought to elucidate alternate treatment avenues based on the genomic profiles of recalcitrant or rare gynecologic tumors. In the process, we aim to determine both the clinical utility and the feasibility of using comprehensive genomic profiling (CGP) during clinical care to identify clinically relevant tumor genomic alterations for these patients while enabling point-of-care management. METHODS: As part of our ongoing prospective clinical trial, we report on the initial 69 patients with gynecologic cancers that were refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic mutations and alterations were reviewed by members of an expert, multidisciplinary institutional molecular tumor board (MTB). Consensus recommendations by the MTB were provided to the treating physician on genomically targeted, clinically relevant, FDA-approved, on- and off-label therapies and clinical trials. The outcomes were assessed. RESULTS: Study outcomes were available for 64 patients. On average, patients had 4.97 genomic alterations per tumor (range 1-46), while the time from the testing laboratory report to the formulation of recommendations by the MTB was approximately 3-4 weeks. Targeted treatment options were recommended by the MTB for 93% of patients; 39% of these patients had the MTB-based recommendations implemented by the treating physician. A response or clinical benefit was seen in 56% of the patients receiving MTB-based targeted therapy. CONCLUSION: These data suggest that alternatives to standard therapies for recalcitrant gynecologic cancers can be found though CGP and subsequent analysis from members of an expert, multidisciplinary institutional MTB. The formulation of clinical recommendations by an MTB based on tumor genomic profiling results is a feasible option. Further research is needed to understand how this approach shapes clinical decision making. Citation Format: Lorna Rodriguez-Rodriguez, Kim M. Hirshfield, Veronica Rojas, Siraj Ali, Robert S. DiPaola, Darlene Gibbon, Sara Isani, Aliza Leiser, Gregory M. Riedlinger, Shridar Ganesan. Delivery of point-of-care management to patients with gynecologic malignancies using comprehensive genomic profiling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3183.
Abstract 448: Expression of Galectins in high grade serous ovarian cancer
Authors: Marilyne Labrie, Laudine Communal, Maria-Claudia Vladoiu, Pascal Dupont, Anne-Marie Mes-Masson, Yves St-Pierre
Journal: Cancer Research (2016)

Abstract Ovarian cancer (OC) is the 5th leading cause of cancer-related deaths in the Western world. Despite improvements in various treatments, the five-year survival of patients with advanced stage disease remains less than 40%. Approximately 70% of malignant OCs are attributed to the high-grade serous carcinoma (HGSC) histological subtype, which is typically treated by a surgical tumor debulking followed by platinum/taxane chemotherapy. Unfortunately, although approximately 80% of patients respond well to the initial chemotherapy treatment, a large portion of patients develop drug resistance during subsequent cycles of chemotherapy. The non-uniformity of response to therapy complicates the clinical decision-making process and reflects the genetic complexity that gives rise to intra-tumor heterogeneity. Clearly, there is an urgent need to develop reliable clinical biomarkers to identify patients at different levels of risk for specific outcomes. Here, we have investigated the expression of galectins (gal) in HGSC and examined their potential as biomarkers. Galectins have been shown to play a dual role in cancer progression. When released in the extracellular space by cancer cells, they are particularly efficient in creating an immunosuppressive tumor microenvironment, both locally and systemically. Inside cancer cells, they provide cancer cells with increased resistance to apoptosis induced by chemotherapeutic agents. Using tissue microarrays constructed from formalin fixed paraffin embedded tissues from 209 patients with HGSC, we have identified a new protein signature that takes into account the expression of galectins in both cancer and stromal cells. Our study showed that increased protein expression of stromal gal-1 and epithelial gal-8/9 in primary tumors was associated with a poor response to treatment in patients with HGSC. This signature also increased the predictive value of CA-125 on five-year disease-free survival, chemotherapy treatment response and five-year overall survival. Univariate and multivariate analyses revealed that gal-8 and gal-9 were both independent predictors of chemoresistance and overall survival, respectively. From a fundamental point of view, our project also contributes to better define the heterogeneity of the disease. Overall, these data provide a rational for further studies of Galectins in OC. Citation Format: Marilyne Labrie, Laudine Communal, Maria-Claudia Vladoiu, Pascal Dupont, Anne-Marie Mes-Masson, Yves St-Pierre. Expression of Galectins in high grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 448.
Abstract 2563: Analysis of a novel gene in relation to bladder cancer GWAS signals within the 20p12.2 region
Authors: Rouf Banday, Wusheng Yan, Candace D. Middlebrooks, Eniko Kiss, Ludmila Prokunina-Olsson
Journal: Cancer Research (2016)

Abstract Background: Genome-wide association studies (GWAS) of bladder cancer risk recently identified several signals on chromosome 20p12.2 marked by single nucleotide polymorphisms (SNPs) rs6104690, rs62185668 and rs6108803 (Figueroa et al, HMG, 2015). Interestingly, associations of SNPs rs62185668 and rs6108803 were significantly stronger for the risk of muscle-invasive (stages T2-T4) compared to non-muscle-invasive (stages Ta and T1) bladder cancer, suggesting that detailed analysis of these signals could further our understanding of aggressive bladder cancer. Methods: We used data from The Cancer Genome Atlas (TCGA) bladder cancer set (n = 412) and an independent RNA-seq dataset for 12 bladder tissues. qRT-PCR analysis was performed with custom TaqMan assays in an additional set of 40 tumor and 40 adjacent normal bladder tissue samples. RNAscope in situ hybridization analysis with custom probes was used to evaluate mRNA expression in bladder tissue microarrays that included 7 pairs of normal-tumor bladder tissues. Results: At a distance of more than 300 and 800 Kb, JAG1 and BTD3 are the closest genes to the GWAS signals in the 20p12.2 region. Analysis of TCGA data did not show significant association of JAG1 and BTD3 expression with genotypes of 20p12.2 GWAS markers analyzed through TCGA-genotyped proxies SNPs rs6040291 and rs6074214. Using RNA-seq data in an independent set of 12 bladder tissue samples, we discovered a novel putative gene in the 20p12.2 region. Cloning of this gene from bladder tumor tissue and annotation by several methods showed two alternative splicing forms, designated as major and minor transcripts. Expression of the major transcript in bladder tumors was significantly increased with the rs6104690-A allele (P = 0.014), which is associated with increased risk of bladder cancer. SNPs with stronger association with muscle-invasive bladder cancer (rs62185668 and rs6108803) showed weaker or non-significant associations with expression of this novel transcript (P = 0.037 and P = 0.42, respectively). This transcript might be protein-coding as it is predicted to have several open reading frames for short peptides, or it may be a long non-coding RNA (lncRNA). RNAscope analysis in bladder tumors showed nuclear expression of the major transcript. Functional analysis of this novel gene in relation to bladder cancer is underway. Conclusions: A novel gene might be related to the GWAS signals within the 20p12.2 region and the risk of bladder cancer. Citation Format: Rouf Banday, Wusheng Yan, Candace D. Middlebrooks, Eniko Kiss, Ludmila Prokunina-Olsson. Analysis of a novel gene in relation to bladder cancer GWAS signals within the 20p12.2 region. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2563.
A Model to predict severity of drug‐induced liver injury in humans
Authors: Minjun Chen, Jürgen Borlak, Weida Tong
Journal: Hepatology (2016)

Drug‐induced liver injury (DILI) is a major public health concern, and improving its prediction remains an unmet challenge. Recently, we reported the Rule‐of‐2 (RO2) and found lipophilicity (logP ≥3) and daily dose ≥100 mg of oral medications to be associated with significant risk for DILI; however, the RO2 failed to estimate grades of DILI severity. In an effort to develop a quantitative metrics, we analyzed the association of daily dose, logP, and formation of reactive metabolites (RM) in a large set of Food and Drug Administration‐approved oral medications and found factoring RM into the RO2 to highly improve DILI prediction. Based on these parameters and by considering n = 354 drugs, an algorithm to assign a DILI score was developed. In univariate and multivariate logistic regression analyses the algorithm (i.e., DILI score model) defined the relative contribution of daily dose, logP, and RM and permitted a quantitative assessment of risk of clinical DILI. Furthermore, a clear relationship between calculated DILI scores and DILI risk was obtained when applied to three independent studies. The DILI score model was also functional with drug pairs defined by similar chemical structure and mode of action but divergent toxicities. Specifically, for drug pairs where the RO2 failed, the DILI score correctly identified toxic drugs. Finally, the model was applied to n = 159 clinical cases collected from the National Institutes of Health's LiverTox database to demonstrate that the DILI score correlated with the severity of clinical outcome. Conclusions : Based on daily dose, lipophilicity, and RM, a DILI score algorithm was developed that provides a scale of assessing the severity of DILI risk in humans associated with oral medications. (H epatology 2016;64:931‐940)
Proteasome Inhibitor Bortezomib Induces Apoptosis in Prednisone-Resistant Childhood Acute Lymphoblastic Leukemia Cells.
Authors: Stefanie Junk, Melchior Lauten, Gunnar Cario, Nicole Wittner, Martin Schrappe, Brigitte Schlegelberger, Nils von Neuhoff
Journal: Blood (2009)
Cardiac outcomes in women receiving aromatase inhibitors as adjuvant endocrine therapy for breast cancer.
Authors: Esther Park, Maysa M. Abu-Khalaf, Christos Hatzis, Johanna M. LaSala, Andrea Silber, Erin Wysong Hofstatter, Tara Beth Sanft, Raymond Russell
Journal: Journal of Clinical Oncology (2014)

e11501 Background: Aromatase inhibitors (AIs) have been reported to increase the risk of cardiotoxicity in women with early stage breast cancer (BC). This study was performed to further elucidate the cardiac side effects and associated risk factors. Methods: We retrospectively identified 496 women in the Yale Nuclear Cardiology database who were diagnosed with BC between August 2003 and April 2011. Their records were reviewed for treatment histories and baseline risk factors (age, BMI, CAD, HTN, DM, smoking, and family history of cardiac disease). The patients (pts) were divided into mutually exclusive groups according to what they received as endocrine therapy: 1) tamoxifen, 2) AIs, 3) sequential (tamoxifen + AIs, in either order), and 4) none. The endpoint was cardiac ischemia, based on a diagnosis of myocardial infarction or an abnormal stress test. Results: Median age was 51 (range 26-83). There were 67 (14%) in the tamoxifen group, 168 (34%) in the AI group, 125 (25%) in the sequential group, and 136 (27%) in the no endocrine therapy group. Fifteen pts (3%) experienced cardiac ischemia; 10 were in the AI group (6.0%), 1 in the tamoxifen group (1.5%), 1 in the sequential group (0.8%), and 3 in the no endocrine therapy group (2.2%). The sequential group had a significantly lower incidence of cardiac ischemia compared to the AI group (OR=0.128, 95% CI 0.003-0.922, p=0.027). By logistic regression, older age, smoking, and left sided irradiation (LSI) were significantly associated with cardiac ischemia (OR=1.122, 95% CI 1.038-1.212, p=0.004; OR=4.920, 95% CI 1.143-21.173, p=0.032; and OR=4.239, 95% CI 1.135-15.832, p=0.032 respectively). Anthracycline and/or herceptin exposure were not associated with increased risk. Conclusions: The sequential group experienced a significantly lower incidence of cardiac ischemia compared to the AI group. The results suggest that AIs have cardiotoxic effects that can be modulated by tamoxifen’s potentially cardioprotective effects. Older age, smoking, and LSI were the only risk factors significantly associated with cardiac ischemia. Based on these findings, pts receiving AIs alone should be monitored for evidence of cardiac ischemia and have aggressive risk factor modification.
Implantable left ventricular assist device approaching an alternative for end-stage heart failure
Authors: Patrick M. McCarthy, Karen B. James, Robert M. Savage, Rita Vargo, Kay Kendall, Hiroaki Harasaki, Robert E. Hobbs, Fredric J. Pashkow
Journal: Circulation (1994)

Background The implantable left ventricular assist device (LVAD) was designed to provide circulatory support as an alternative to heart transplantation or to continued medical therapy of end-stage heart failure. Initial experience with the implantable LVAD used as a bridge to heart transplantation provides a clinical opportunity to study the function of the device and adaptation by the patient. Methods and Results Nineteen heart transplant candidates (mean age, 50 years; 17 males) underwent insertion of the HeartMate LVAD as a bridge to heart transplantation from December 1991 to November 1993. All patients were in cardiogenic shock on inotropes, and 16 (84%) were on an intra-aortic balloon pump
OC-007 Haemopoetic Stem Cell Transplantation For Severe Resistant Crohn’s Disease: Preliminary Evidence For Durable Benefit: Abstract OC-007 Table 1
Authors: C Hawkey
Journal: Gut (2014)

<h3>Introduction</h3> The Autologous Stem Cell Transplantation International Crohn’s Disease (ASTIC) Trial shows haemopoetic stem cell transplantation (HSCT) to be effective over one year in Crohn’s disease, but its durability remains to be established. <h3>Methods</h3> ASTIC is a multicentre parallel group randomised controlled trial in patients with impaired quality of life due to Crohn’s Disease that is resistant to established treatments. All patients undergo stem cell mobilisation before HSCT given immediately (one month: early HSCT) or after a delay of thirteen months (late HSCT). This abstracts describes currently available data over 2 years and includes the first report of changes occurring in the first year transplantation in the late HSCT group. <h3>Results</h3> A full analysis of progress over one year has shown a reduction in Crohn’s Disease Activity Index (CDAI) from 326 (range 163–512) to 162 (12–506) and in the SES-CD endoscopic score from 13 (5–33) to 3 (0–200) in patients following early HSCT (n = 23) compared to 354 (91–581) to 298 (70–589, active vs control p = 0.01) and 13.5 (0–36) to 7 (1–27, active vs control p = 0.02) respectively in the control group prior to transplantation (n = 22). The Table shows data for those patients (approximately 50%) with full data currently available to two years (one year after transplantation in the control group). Scores for the IBD-Q quality of life index improved from 123 (103–144) to 165 (125–206) following early HSCT and were maintained at 157 (126–213). Scores rose from 108 (79–136) to 147 (108–188) in the year following delayed HSCT. <h3>Conclusion</h3> If full data (available June 2014) confirm these preliminary results, it would support the notion that improvements in CDAI, endoscopic appearances and quality of life benefit persist and may possibly increase over the second year following transplantation. One year data in the delayed group show a similar magnitude of effect to that seen in patients undergoing early transplantation. <h3>Disclosure of Interest</h3> None Declared.