tbuckley/cabot-search huggingface dataset:
Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance
Authors: Salvador Alonso, Daniela Hernandez, Yu-ting Chang, Christian D. Gocke, Megan McCray, Ravi Varadhan, William H. Matsui, Richard J. Jones, Gabriel Ghiaur
Journal: Journal of Clinical Investigation (2016)

Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in bortezomib (BTZ) resistance. However, the mechanisms involved in these interactions are not completely understood. We previously showed that expression of CYP26 in BM stromal cells maintains a retinoic acid–low (RA-low) microenvironment that prevents the differentiation of normal and malignant hematopoietic cells. Since a low secretory B cell phenotype is associated with BTZ resistance in MM and retinoid signaling promotes plasma cell differentiation and Ig production, we investigated whether stromal expression of the cytochrome P450 monooxygenase CYP26 modulates BTZ sensitivity in the BM niche. CYP26-mediated inactivation of RA within the BM microenvironment prevented plasma cell differentiation and promoted a B cell–like, BTZ-resistant phenotype in human MM cells that were cocultured on BM stroma. Moreover, paracrine Hedgehog secretion by MM cells upregulated stromal CYP26 and further reinforced a protective microenvironment. These results suggest that crosstalk between Hedgehog and retinoid signaling modulates BTZ sensitivity in the BM niche. Targeting these pathological interactions holds promise for eliminating minimal residual disease in MM.
Preliminary results of a phase I trial of ABT-888, a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with cyclophosphamide.
Authors: A. R. Tan, D. Gibbon, M. N. Stein, R. A. Moss, V. Karantza, H. Lin, M. Gounder, A. P. Chen, M. J. Egorin, R. S. DiPaola
Journal: Journal of Clinical Oncology (2010)

3000 Background: ABT-888 is a potent, oral inhibitor of PARP-1 and PARP-2. In preclinical studies, ABT-888 enhances the cytotoxicity of cyclophosphamide (C). We conducted a phase I study to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of ABT-888 and C, and PAR levels in peripheral blood mononuclear cells (PBMCs). Methods: Patients with advanced cancer (ECOG PS 0-2) were enrolled. Dose escalations of ABT-888 (10–50 mg) every 12 h on days 1-4 plus C (450-750 mg/m2) on day 3 every 21 days were evaluated. Blood samples were collected during cycles 1 and 2 for measurement of ABT-888, C, and PAR. Results: 18 patients received ABT-888/C (mg/m2) at doses of 10/450 (3), 20/450 (3), 50/450 (6), 50/600 (3), and 50/750 (3). Mean age 55 years (37-76); 11 females; 7 males. Tumor types were breast (5), ovarian (4), and other (9). Mean cycles were 4 (1–16). Drug-related toxicities (mostly grade 1 or 2) were fatigue (28%), neutropenia (11%), thrombocytopenia (6%), and vomiting (6%). DLT of grade 2 thrombocytopenia that caused a delay of >2 weeks in starting cycle 2 occurred in a NHL patient treated with 50/450 of ABT-888/C. No further DLTs have been observed with dose escalation of C to 600 and 750 mg/m2. PK analysis showed a dose proportional increase in ABT-888 AUC. ABT-888 reached steady-state plasma concentrations by D3. The AUC0-inf (μ g·h/mL) and clearance (L/h) of ABT-888 at 50 mg were not significantly changed on cycle1 D1 (2.71 ± 0.8) and (19.6 ± 4.5), compared to cycle 2 D1 (2.68 ± 1.2) and (21.6 ± 7.5), respectively. The AUC and clearance of C were not altered by ABT-888 (p>0.15). Eleven patients had PARP inhibited by >50% in PBMCs by day 4. One patient with prostate cancer had a partial response and >90% inhibition of PARP activity in PBMCs; 4 patients (male breast cancer, bladder, NSCLC, and colon) had stable disease > 8 weeks. Conclusions: ABT-888 50 mg every 12 h can be safely combined with 750 mg/m2 of C. ABT-888 does not alter the PK of C. PARP inhibition occurs in PBMCs with ABT-888 at steady-state. Activity of the combination was observed. Accrual is ongoing to determine the MTD of ABT-888/C. This work is supported by NCI U01-CA132194 (NJ) and NCI U01-CA099168 (PA). No significant financial relationships to disclose.
Identification of Basophils as Source of Hepatocyte Growth Factor (HGF) In CML: a Potential Trigger of Disease Acceleration.
Authors: Sabine Cerny-Reiterer, Karl J. Aichberger, Harald Herrmann, Gregor Hoermann, Barbara Peter, Leonhard Muellauer, Matthias Mayerhofer, Peter Valent
Journal: Blood (2010)
Hyperoxidized albumin modulates neutrophils to induce oxidative stress and inflammation in severe alcoholic hepatitis
Authors: Sukanta Das, Jaswinder Singh Maras, Md. Shabir Hussain, Shvetank Sharma, Paul David, Sukriti Sukriti, Saggere Muralikrishna Shasthry, Rakhi Maiwall, Nirupama Trehanpati, Tej P. Singh, Shiv Kumar Sarin
Journal: Hepatology (2016)

Albumin is a potent scavenger of reactive oxygen species (ROS). However, modifications in albumin structure may reduce its antioxidant properties and modulate its immune‐regulatory functions. We examined alterations in circulating albumin in severe alcoholic hepatitis (SAH) patients and their contribution to neutrophil activation, intracellular stress, and alteration in associated molecular pathways. Albumin modifications and plasma oxidative stress were assessed in SAH patients (n = 90), alcoholic cirrhosis patients (n = 60), and healthy controls (n = 30) using liquid chromatography/mass spectrometry and spectrophotometry. Activation and intracellular ROS were measured in healthy neutrophils after treatment with purified albumin from the study groups. Gene expression of SAH neutrophils was analyzed and compared to gene expression from healthy neutrophils after stimulation with purified albumin from SAH patient plasma. SAH‐albumin showed the highest albumin oxidative state ( P &lt; 0.05) and prominent alteration as human nonmercaptalbumin 2 ( P &lt; 0.05). Plasma oxidative stress (advanced oxidative protein product) was higher in SAH versus alcoholic cirrhosis patients and healthy controls ( P &lt; 0.05). Neutrophil gelatinase‐associated lipocalin, myeloperoxidase, and intracellular ROS levels were highest in SAH‐albumin‐treated neutrophils ( P &lt; 0.05). Genes associated with neutrophil activation, ROS production, intracellular antioxidation, and leukocyte migration plus genes for proinflammatory cytokines and various toll‐like receptors were overexpressed in SAH neutrophils compared to healthy neutrophils ( P &lt; 0.05). Expression of the above‐mentioned genes in SAH‐albumin‐stimulated healthy neutrophils was comparable with SAH patient neutrophils, except for genes associated with apoptosis, endoplasmic reticulum stress, and autophagy ( P &lt; 0.05). Conclusions : In patients with SAH, there is a significant increase in albumin oxidation, and albumin acts as a pro‐oxidant; this promotes oxidative stress and inflammation in SAH patients through activation of neutrophils. (H epatology 2017;65:631‐646).
Carfilzomib Overcomes Resistance to Bortezomib in the Human Lagk-1A Multiple Myeloma Xenograft Model
Authors: Eric Sanchez, Mingjie Li, Abigail Gillespie, Nika M Harutyunyan, Gigi Garzio, Joseph Ben-Zvi, Jillian Gottlieb, George Tang, Cathy Wang, Haiming Chen, James R. Berenson
Journal: Blood (2014)
Hemochromatosis? When Bloodletting Is Not the Cure
Authors: Florence-Damilola Odufalu, Katherine Harris
Journal: JAMA Internal Medicine (2016)

This case of an asymptomatic woman in her 30s who presented for a baseline physical examination and was given nonrecomended liver function screening and phlebotomy following misdiagnosis highlights the importance of emphasizing clinical judgment in ordering and assesing test results.
Limited value of routine iron studies prior to initiation of erythropoietin therapy in patients with ovarian cancer
Authors: G. Riebandt, S. A. South, K. Odunsi, S. Lele, K. Rodabaugh
Journal: Journal of Clinical Oncology (2007)

19677 Background: Anemia is a common consequence of cancer which significantly impacts patient quality of life. The mainstay of treatment for cancer- and chemotherapy-related anemia is erythropoietin therapy. However, approximately 30% to 50% of patients will not respond to these growth factors. The literature attributes this lack of response to functional iron deficiency, when iron stores are normal but the body cannot meet the increased rate of erythropoiesis. We evaluated the iron status of patients with ovarian malignancies receiving chemotherapy and erythropoietin therapy to establish a baseline for implementation of an intervention service. Methods: After obtaining Institutional Review Board approval, we identified 55 ovarian cancer patients receiving erythropoietin therapy from January to December 2005. We then performed a retrospective chart review for patients who had iron studies available. Results: Thirty-four patients had complete iron studies performed, while an additional 10 had only a ferritin level obtained. The mean hemoglobin for all patients was 9.9g/dl (6.9–13.1) with a mean MCV (mean corpuscular volume) of 92.7fl. Four (12%) patients were iron deficient based on ferritin &lt;100ng/ml and iron saturation &lt;20%. However, these patients had normal MCVs, indicating iron deficiency was not the etiology of their anemia. A few patients were assessed for B12 and folate deficiency, but none were identified. Interestingly, we had 22 patients with elevated ferritin levels (greater than 322ng/ml), with the highest being 2178ng/ml. Conclusions: Our results identified a few patients who were iron deficient, but none were diagnosed with iron deficiency anemia. Therefore, the role of routine iron screening in patients with a normal MCV prior to initiation of erythropoietin therapy is in question. We believe that functional iron deficiency may contribute to anemia in our population. Therefore, we suggest that all patients receive iron supplementation at erythropoietin therapy initiation. We plan to prospectively assess the optimal route of iron administration in ovarian cancer patients in order to improve the response rate to erythropoietic growth factors. No significant financial relationships to disclose.
Kinetics of Plasma-Cell Chimerism after Allogeneic Stem Cell Transplantation by Real-Time PCR and Its Value To Quantify Minimal Residual Disease in Patients with Multiple Myeloma.
Authors: Nicolaus Kroeger, Maria Zagrivnaja, Sabine Schwartz, Anita Badbaran, Tatjana Zabelina, Francis Ayuk, Axel Zander, Boris Fehse
Journal: Blood (2005)
Optimal Cervical Cancer Screening in Women Vaccinated Against Human Papillomavirus
Authors: Jane J. Kim, Emily A. Burger, Stephen Sy, Nicole G. Campos
Journal: JNCI Journal of the National Cancer Institute (2016)

Current US cervical cancer screening guidelines do not differentiate recommendations based on a woman's human papillomavirus (HPV) vaccination status. Changes to cervical cancer screening policies in HPV-vaccinated women should be evaluated.We utilized an individual-based mathematical model of HPV and cervical cancer in US women to project the health benefits, costs, and harms associated with screening strategies in women vaccinated with the bivalent, quadrivalent, or nonavalent vaccine. Strategies varied by the primary screening test, including cytology, HPV, and combined cytology and HPV "cotesting"; age of screening initiation and/or switching to a new test; and interval between routine screens. Cost-effectiveness analysis was conducted from the societal perspective to identify screening strategies that would be considered good value for money according to thresholds of $50 000 to $200 000 per quality-adjusted life-year (QALY) gained.Among women fully vaccinated with the bivalent or quadrivalent vaccine, optimal screening strategies involved either cytology or HPV testing alone every five years starting at age 25 or 30 years, with cost-effectiveness ratios ranging from $34 680 to $138 560 per QALY gained. Screening earlier or more frequently was either not cost-effective or associated with exceedingly high cost-effectiveness ratios. In women vaccinated with the nonavalent vaccine, only primary HPV testing was efficient, involving decreased frequency (ie, every 10 years) starting at either age 35 years ($40 210 per QALY) or age 30 years ($127 010 per QALY); with lower nonavalent vaccine efficacy, 10-year HPV testing starting at earlier ages of 25 or 30 years was optimal. Importantly, current US guidelines for screening were inefficient in HPV-vaccinated women.This model-based analysis suggests screening can be modified to start at later ages, occur at decreased frequency, and involve primary HPV testing in HPV-vaccinated women, providing more health benefit at lower harms and costs than current screening guidelines.
Treatment of HER2-negative metastatic breast cancer (MBC) with bevacizumab (BEV) plus paclitaxel (TXL): A single-center phase II study.
Authors: A. Inno, A. Strippoli, G. Nazzicone, A. Quaranta, M. Di Salvatore, A. Galiano, C. Bagalà, M. Basso, C. Pozzo, A. Cassano, A. Astone, C. Barone
Journal: Journal of Clinical Oncology (2011)

e11509 Background: The addition of BEV to chemotherapy in the first-line treatment of HER2-negative MBC has been evaluated in several trials, resulting in an improvement in progression-free survival (PFS), but not overall survival (OS); moreover, concerns have been raised about the safety since some bevacizumab-related events, although rare, could be life-threatening. Further data could clarify the risk/benefit balance of BEV in MBC. Methods: Inclusion criteria included: histologically confirmed HER2-negative MBC, age ≤ 75 years, PS ECOG ≤2, no previous cytotoxic treatment for metastatic disease; patients (pts) with uncontrolled hypertension, clinically significant cardiovascular disease, bleeding, or concurrently treated with anticoagulants/thrombolytic agents for therapeutics purposes were excluded from the trial. Brain metastases were not an exclusion criterion. Presuming a PFS of 6 months for pts treated with TXL alone, the calculated sample size with minimax design was 39 to detect a 50% improvement (from 6 to 9 months) by the addition of BEV with a statistical power of 80% and alpha error ≤5%. Therefore, we prospectively treated 39 pts with: BEV (10 mg/kg, d 1, 15) and TXL (90 mg/m2, d 1, 8, 15) every 28 days. Results: Overall response rate was 58.8%, median PFS 11 months and OS 33 months. Main G3-4 toxicities were neutropenia (9%), hypertension (8%), fatigue (6.5%) and paresthesiae (6.5%). Noteworthy, 5 deaths occurred during the treatment, 2 for bowel perforation, 1 for febrile neutropenia, 1 for liver failure and 1 for brain haemorrhage, and might be treatment-related. Both bowel perforations occurred in pts with peritoneal carcinosis whereas brain haemorrhage occurred in a patient without known central nervous system metastases. Conclusions: Consistently with data from phase III studies, our results suggest that BEV plus TXL is an effective treatment for HER2-negative MBC; however, a possible 12.8% treatment-related mortality deserves extreme caution when using BEV in this context and claims for a careful pts selection.
The relationship between the serum collagen-type1 n-telopeptide (NTx) levels and bone metastasis of lung cancer.
Authors: M. Tamiya, T. Hirashima, K. Matsui, N. Morishita, H. Suzuki, N. Okamoto, S. Sasada, M. Kobayashi, Y. Kusunoki
Journal: Journal of Clinical Oncology (2010)

e18095 Background: Bone metastasis is an important factor for determining the appropriate treatment for lung cancer patients; further bone metastasis influences prognosis as well as the quality of life of the patients. Methods: Tumor staging wasperformed at our department during the initial treatment of lung cancer. I measured the serum collagen-type1 N-telopeptide (NTx) levels of these patients; further, the serum NTx levels were correlated to the presence of bone metastasis during staging. Results: I studied 92 lung cancer cases (males: 66 and females: 26), (adenocarcinoma: 50, squamous cell carcinoma: 26, small cell carcinoma: 15, and other tumors: 1). Bone metastasis was present in 39 cases. The average serum NTx level of bone metastasis (+) patients is 25.1 and that of bone metastasis (-) patients is 16.5, and there was a difference intentionally with p < 0.001. The cutoff value of serum NTx for bone metastasis of lung cancer was estimated using receiver operating characteristic (ROC) curve; the optimal cutoff value was determined to be 19.7 (sensitivity: 71.8%, and specificity: 79.2%). Moreover, I determined the relationship between the levels of calcium/inostiolphosphate/alkaline phosphatase/lactate dehydrogenase (Ca/IP/ALP/LDH) in blood collected at this time and Performance Status (PS), and bone metastasis. Multivariate analysis revealed a significant difference in the serum NTx levels with p < 0.001. Conclusions: In light of these findings, I suggest that the measurement of the serum NTx levels was simple, and it served as a diagnostic marker of bone metastasis in lung cancer. No significant financial relationships to disclose.
Use of Chemotherapy and Immunotherapy the Last Four Weeks of life in Patients with Lymphoma in An Anticancer Center with Focus On the Impact of Time Period (1998-2002 and 2003-2008).
Authors: Catherine Sebban, Hervé Ghesquieres, Corinne Carcel, Philippe Rey, Therese Gargi, Yves Devaux, Frederic Gomez, Giselle Chvetzoff, Pierre Biron, David Coeffic, Jean-Yves Blay, Bertrand Favier
Journal: Blood (2009)
Individualized therapy for persistent asthma in young children
Authors: Anne M. Fitzpatrick, Daniel J. Jackson, David T. Mauger, Susan J. Boehmer, Wanda Phipatanakul, William J. Sheehan, James N. Moy, Ian M. Paul, Leonard B. Bacharier, Michael D. Cabana, Ronina Covar, Fernando Holguin, Robert F. Lemanske, Fernando D. Martinez, Jacqueline A. Pongracic, Avraham Beigelman, Sachin N. Baxi, Mindy Benson, Kathryn Blake, James F. Chmiel, Cori L. Daines, Michael O. Daines, Jonathan M. Gaffin, Deborah Ann Gentile, W. Adam Gower, Elliot Israel, Harsha Vardhan Kumar, Jason E. Lang, Stephen C. Lazarus, John J. Lima, Ngoc Ly, Jyothi Marbin, Wayne Morgan, Ross E. Myers, J. Tod Olin, Stephen P. Peters, Hengameh H. Raissy, Rachel G. Robison, Kristie Ross, Christine A. Sorkness, Shannon M. Thyne, Stanley J. Szefler
Journal: Journal of Allergy and Clinical Immunology (2016)
MicroRNA Expression Profiling of CLL B Cells From Relapsed/Refractory CLL Patients Reveals a Signature Group of Genes That Are Associated with Clinical Responses: Results of An ECOG Trial E2903.
Authors: Neil E. Kay, Haesook T. Kim, Stefano Volinia, Carlo M. Croce, Diane F. Jelinek, Sanford Kempin, Martin S. Tallman
Journal: Blood (2009)
Palliative Care–Led Meetings for Families of ICU Patients
Authors: Edward W. Martin
Journal: JAMA (2016)

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A genomic signature of chemotherapeutic multidrug resistance provides a rational approach to identify patients for targeted therapy in advanced solid tumors
Authors: A. Anguiano, S. Mori, J. Chang, V. Vlahovic, M. J. Kelley, G. Ginsburg, H. Dressman, J. R. Nevins, A. Potti
Journal: Journal of Clinical Oncology (2007)

10613 Background: Multidrug resistance (MDR), the process by which cells resist many structurally and functionally unrelated drugs, remains a major challenge for cancer treatment. Strategies to reliably predict MDR will revolutionize cancer therapy. Methods: We made use of in vitro drug sensitivity data on 47 FDA approved chemotherapeutic agents from the NCI-60 database coupled with Affymetrix microarray data, to develop a gene expression signature of chemotherapeutic MDR, using a 'metagene’ approach to gene expression analysis (Potti et al, Nature Medicine, 2006). The capacity of the MDR signature to predict in vitro and in vivo resistance was evaluated in multiple independent cell line and patient cohorts. Results: A gene expression signature of chemotherapeutic MDR developed from cancer cell lines using a novel ‘metagene’ approach can accurately predict patients resistant to standard chemotherapeutic agents, including multi-drug regimens. This includes cohorts of patients with early stage breast cancer (n = 171; accuracy: 75.5%, sensitivity: 49.3%, specificity: 92%), patients who received neoadjuvant chemotherapy (n = 51; accuracy: 78.5%, sensitivity: 73.7%, specificity: 92.3%), and ovarian cancer (n = 105; accuracy: 83.8%, sensitivity: 71.8%, specificity: 93.7%). We further show that MDR signature expression is an independent prognostic factor in early stage breast cancer (p = 0.02, odds ratio: 3.49) and a large cohort of non-small cell lung cancer (p = 0.03, odds ratio: 5.70), in a multivariate analysis. Finally, to identify a rational therapeutic strategy in patients with the MDR phenotype, we have integrated the prediction of MDR with profiles of oncogenic pathway deregulation (Bild A, Nature, 2006) and show that targeting the Src pathway using a Src specific inhibitor (SU6656) circumvents MDR in the in vitro setting. Conclusions: The development of a gene expression signature of MDR, that can predict resistance to commonly used cytotoxic chemotherapies, provides a rational approach to developmental therapeutics, by identifying novel 'customized’ candidate drugs (e.g. targeting Src) for further clinical development. No significant financial relationships to disclose.
Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Induction Therapy For Newly Diagnosed Light Chain Amyloidosis
Authors: Donna E. Reece, Madeline Phillips, Beryl Chung, Christine I. Chen, Esther Masih-Khan, Rodger E. Tiedemann, Suzanne Trudel, Victor H Jimenez-Zepeda, Vishal Kukreti
Journal: Blood (2013)