tbuckley/cabot-search huggingface dataset:
A phase Ib dose escalation trial of isatuximab (SAR650984, anti-CD38 mAb) plus lenalidomide and dexamethasone (Len/Dex) in relapsed/refractory multiple myeloma (RRMM): Interim results from two new dose cohorts.
Authors: Ravi Vij, Nikoletta Lendvai, Thomas G. Martin, Rachid C. Baz, Frank Campana, Florent Mazuir, Eric Charpentier, Don M. Benson
Journal: Journal of Clinical Oncology (2016)

8009 Background: Isatuximab (ISA), a humanized anti-CD38 monoclonal antibody, has demonstrated activity in patients (pts) with RRMM in combination with Len/Dex in an ongoing Phase 1b study (NCT01749969). Overall response rate (ORR) was 63% at ISA 10 mg/kg Q2W (n = 24). Here, we report data from 2 new cohorts evaluating a higher ISA dose and a different administration schedule. Methods: Pts with RRMM ( ≥ 2 prior MM therapies) were sequentially enrolled to ISA 10 or 20 mg/kg (weekly × 4 doses, then every 2 wks; initial infusion rate 175 and 250 mg/h at 10 and 20 mg/kg, respectively) plus Len 25 mg (days [D]1–21) and Dex 40 mg (D1, 8, 15, and 22), in 28-day cycles. Primary objective: to determine the maximum tolerated dose (MTD). Results: An additional 26 pts were treated in the 2 cohorts: median age 65 (42–76) yrs; median yrs from diagnosis 4.5 (1.8–16.6). Median 4.5 (1–8) & 6 (3–10) prior lines of therapy at 10 & 20 mg/kg, respectively; Len-refractory (67% & 86%), pomalidomide+carfilzomib-refractory (25% & 64%), immunomodulatory drug+proteasome inhibitor-refractory (50% & 86%). At data cut-off (Dec 2015), median duration of dosing was 21.5 wks (10 mg/kg) and 9.9 wks (20 mg/kg); 13 pts remain on treatment. 4 pts discontinued therapy due to adverse events (AEs) (grade [Gr] 3 infusion-associated reactions [IARs] [n = 3], dose-limiting toxicity of Gr 3 pneumonia [n = 1]), all at 20 mg/kg in Cycle 1; these pts were excluded from the efficacy analysis. Most frequent AEs were fatigue (46%), pyrexia (35%) and diarrhea (31%). IARs occurred in 65% of pts, mostly Gr ≤ 2, and > 90% during 1st infusion. MTD has not been reached. In evaluable pts, ORR (IMWG criteria; confirmed responses) was 50% in both cohorts (10 mg/kg [n = 12]: VGPR 25%; PR 25%. 20 mg/kg [n = 10]: VGPR 20%; PR 30%). Clinical benefit rate ( ≥ MR) was 83% and 50% in the 10 and 20 mg/kg cohorts, respectively. Median time to 1st response was 4 (4–16) wks. Conclusions: The combination of ISA ≥ 10 mg/kg and Len/Dex was generally tolerated and clinically active in heavily pretreated RRMM. Responses were observed after approximately 4 wks. PK, biomarker, and longer term follow-up data will be presented. Clinical trial information: NCT01749969.
18F-DOPA PET/CT Physiological Distribution and Pitfalls
Authors: Ferdinando F. Calabria, Agostino Chiaravalloti, Marielise L. Jaffrain-Rea, Maddalena Zinzi, Pasqualina Sannino, Giuseppe Minniti, Domenico Rubello, Orazio Schillaci
Journal: Clinical Nuclear Medicine (2016)

F-DOPA PET/CT is potentially helpful in the management of patients with low-grade brain tumors, movement disorders, and somatic neuroendocrine tumors. We describe the whole-body physiological distribution of F-DOPA uptake.We examined 215 patients with F-DOPA PET/CT. Among these, 161 had brain scans and 54 had whole-body scans.Physiological distribution was negligible in the brain, with the exception of basal ganglia, whereas greatest activity was noted in the liver, pancreas, other exocrine glands, and the urinary system. Incidental tracer uptake sites were identified in 5.5% of patients. Some of these findings were due to inflammation, whereas in most cases, uptake was seen in benign tumors of the brain or in the endocrine or exocrine glands.F-DOPA uptake may be seen in inflammatory tissue or benign tumors. Correlations with history, physical examination, laboratory examination, CT, MRI, and histology are necessary for optimal diagnosis.
Needle-based confocal endomicroscopy for evaluation of malignant lymph nodes – a feasibility study
Authors: Petros Benias, Lionel D’Souza, Haris Papafragkakis, Joseph Kim, Manju Harshan, Neil Theise, David Carr-Locke
Journal: Endoscopy (2016)

Current modalities for lymph node staging in cancer can be limited. We sought to evaluate the feasibility of needle-based confocal laser endomicroscopy (nCLE) at the time of endoscopic ultrasound (EUS) and to describe the nCLE features that distinguish between benign, malignant, and inflammatory lymph nodes.We collected data on 28 consecutive patients during EUS staging of malignancy or assessment of enlarged lymph nodes. Patients underwent nCLE at the time of EUS followed by fine needle biopsy. nCLE images were correlated with the patients' final histopathology.All 28 patients successfully underwent nCLE during EUS without adverse events. There were 17 cases of carcinoma, 4 lymphoid malignancies, and 7 benign lymph nodes. We characterized the various nCLE features of the lymph node capsule and cortex. Features of carcinoma, such as clusters of dark pleomorphic tumor cells, were identified and found to correlate well with the final pathology. Lymphoid malignancies often had enlarged follicles, but this was inconsistent.nCLE of lymph nodes at the time of EUS is feasible and appears to be safe. Dark pleomorphic cells were readily identified in all of the malignant lymph nodes and correlated with tumor cells seen on histology.
Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease
Authors: Baris Boyraz, Diane H. Moon, Matthew Segal, Maud Z. Muosieyiri, Asli Aykanat, Albert K. Tai, Patrick Cahan, Suneet Agarwal
Journal: Journal of Clinical Investigation (2016)

The telomerase RNA component (TERC) is a critical determinant of cellular self-renewal. Poly(A)-specific ribonuclease (PARN) is required for posttranscriptional maturation of TERC. PARN mutations lead to incomplete 3' end processing and increased destruction of nascent TERC RNA transcripts, resulting in telomerase deficiency and telomere diseases. Here, we determined that overexpression of TERC increased telomere length in PARN-deficient cells and hypothesized that decreasing posttranscriptional 3' oligo-adenylation of TERC would counteract the deleterious effects of PARN mutations. Inhibition of the noncanonical poly(A) polymerase PAP-associated domain-containing 5 (PAPD5) increased TERC levels in PARN-mutant patient cells. PAPD5 inhibition was also associated with increases in TERC stability, telomerase activity, and telomere elongation. Our results demonstrate that manipulating posttranscriptional regulatory pathways may be a potential strategy to reverse the molecular hallmarks of telomere disease.
Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma
Authors: P Ravi, S Kumar, J T Larsen, W Gonsalves, F Buadi, M Q Lacy, R Go, A Dispenzieri, P Kapoor, J A Lust, D Dingli, Y Lin, S J Russell, N Leung, M A Gertz, R A Kyle, P L Bergsagel, S V Rajkumar
Journal: Blood Cancer Journal (2016)

Abstract We studied 190 patients with smoldering multiple myeloma (SMM) at our institution between 1973 and 2014. Evolving change in monoclonal protein level (eMP) was defined as ⩾10% increase in serum monoclonal protein (M) and/or immunoglobulin (Ig) (M/Ig) within the first 6 months of diagnosis (only if M-protein ⩾3 g/dl) and/or ⩾25% increase in M/Ig within the first 12 months, with a minimum required increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig. Evolving change in hemoglobin (eHb) was defined as ⩾0.5 g/dl decrease within 12 months of diagnosis. A total of 134 patients (70.5%) progressed to MM over a median follow-up of 10.4 years. On multivariable analysis adjusting for factors known to predict for progression to MM, bone marrow plasma cells ⩾20% (odds ratio (OR)=3.37 (1.30–8.77), P =0.013), eMP (OR=8.20 (3.19–21.05), P &lt;0.001) and eHb (OR=5.86 (2.12–16.21), P =0.001) were independent predictors of progression within 2 years of SMM diagnosis. A risk model comprising these variables was constructed, with median time to progression of 12.3, 5.1, 2.0 and 1.0 years among patients with 0–3 risk factors respectively. The 2-year progression risk was 81.5% in individuals who demonstrated both eMP and eHb, and 90.5% in those with all three risk factors.
Abstract DDT01-01: PT2385: First-in-class HIF-2α antagonist for the treatment of renal cell carcinoma
Authors: Eli M. Wallace, Zhaodan Cao, Tzuling Cheng, Robert Czerwinski, Darryl D. Dixon, Xinlin Du, Barry Goggin, Jonas Grina, Megan Halfmann, Guangzhou Han, Heli Huang, John A. Josey, Melissa A. Maddie, Sarah Olive, James Rizzi, Stephen T. Schlachter, Hui-Ling Tan, Bin Wang, Keshi Wang, Paul M. Wehn, Shanhai Xie, Rui Xu, Hanbiao Yang
Journal: Cancer Research (2015)

Abstract Hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, are transcription factors that mediate cellular response to changes of oxygen supply. These proteins become stabilized under hypoxia and subsequently activate the expression of genes to facilitate cell survival and proliferation. HIF proteins are activated in many types of cancers due to the tumor hypoxic microenvironment and have been implicated in cancer initiation, progression and metastasis. The oncogenic role of HIF-2α is pertinent in clear cell renal carcinoma (ccRCC). In the majority of ccRCC tumors, the von Hippel-Lindau protein (VHL) that targets HIF-2α for degradation is inactivated, leading to the accumulation of HIF-2α and the activation of genes that drive kidney cancer tumorigenesis. We have identified small molecules that bind to the PAS-B domain of HIF-2α protein and block it's dimerization with ARNT (aryl hydrocarbon receptor nuclear translocator, HIF-1β), a prerequisite for its transcriptional activities. Specifically, we describe PT2385, a selective, orally active HIF-2α antagonist with potent anti-cancer activity in mouse models of ccRCC. PT2385 is currently under evaluation in Phase I clinical trials for the treatment of ccRCC. Citation Format: Eli M. Wallace, Zhaodan Cao, Tzuling Cheng, Robert Czerwinski, Darryl D. Dixon, Xinlin Du, Barry Goggin, Jonas Grina, Megan Halfmann, Guangzhou Han, Heli Huang, John A. Josey, Melissa A. Maddie, Sarah Olive, James Rizzi, Stephen T. Schlachter, Hui-Ling Tan, Bin Wang, Keshi Wang, Paul M. Wehn, Shanhai Xie, Rui Xu, Hanbiao Yang. PT2385: First-in-class HIF-2α antagonist for the treatment of renal cell carcinoma. [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 DDT01-01. doi:10.1158/1538-7445.AM2015-DDT01-01
Everolimus-associated pneumonitis in Asian metastatic renal cell carcinoma patients.
Authors: Joo Hoon Kim, Min Hwan Kim, Beodeul Kang, Min Hee Hong, Eun Yonug Kim, Hye-Jeong Lee, Sun Young Rha
Journal: Journal of Clinical Oncology (2014)

e15596 Background: The aim of this study is to evaluate the incidence, clinical characteristics and implication as a predictive factor of everolimus-associated pneumonitis (EAP) in metastatic or unresectable renal cell carcinoma (RCC) patients in Asian population. Methods: We analyzed 71 consecutive RCC patients who received everolimus for metastatic or unresectable disease between August 2011 and May 2013 in our institution. We retrospectively reviewed clinical characteristics, survival, and radiologic examinations of patients. EAP was defined as the development of pulmonary infiltration after everolimus exposure with exclusion of infection or alternative pulmonary disease. Results: Of 71 everolimus-treated RCC patients, we found development of EAP in 11 patients (15.5%). The median time to the development of pneumonitis from everolimus initiation was 2.1 months. The proportion of ever-smokers was significantly higher in patients with pneumonitis than patients without pneumonitis (81.8% vs. 46.7%, p = 0.048), and other clinical characteristics were not different between two groups. The cumulative smoking dosage measured by pack-year was a significant predictive factor for development of pneumonitis in multivariate logistic regression model adjusted by age, sex, and treatment duration (Odd ratio 1.06; 95% Confidence interval 1.01-1.12, p = 0.028). All grade 2 pneumonitis in 9 patients were resolved by dose reduction or cessation of everolimus, and 2 patients with grade 3 pneumonitis were recovered by systemic corticosteroid therapy without mortality. Progression free survival (PFS) on everolimus and overall survival (OS) from the diagnosis of metastatic or unresectable disease were not different between patients with pneumonitis and without pneumonitis. (median PFS, 4.7 vs. 3.9 months, p = 0.662; median OS, 31.1 vs. 41.7 months, p= 0.940) Conclusions: The incidence of EAP in Asian RCC patients was similar to the incidence in global population. Pulmonary toxicity of everolimus should be cautiously followed up in RCC patients during everolimus treatment because of its considerable incidence and favorable response to early therapeutic interventions.
P0288 : CXCR4 inhibition reverts immunosuppressive tumor microenvironment and facilitates Anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma
Authors: T. Reiberger, C. Yunching, R.R. Ramjiawan, R.R. Ng, T. Hato, Y. Huang, E.C. Unan, T.P. Reddy, C. Fan, P. Huang, N. Bardeesy, A.X. Zhu, R.K. Jain, D.G. Duda
Journal: Journal of Hepatology (2015)
Sensitive and Specific Antibody Probes Directed Against The Erythropoietin Receptor – From Basic Studies To Clinical Implementation
Authors: Drorit Neumann, Florinda Melendez, Kyle Matchett, Julian Aragones, Nathalie Ben-Califa, Heidelinde Jaekel, Ludger Hengst, Andre Bernadini, Ulf Brockmeier, Joachim Fandrey, Fritz Grunert, Moshe Mittelman, Mohamed El-Tanani, Markus Thiersch, Edith Schneider-Gasser, Max Gassmann, David Dangoor, John Thompson, Terence Lappin, Perry Maxwell
Journal: Blood (2013)
Abstract 5201: Identification of growth factors that promote the proliferation and drug resistance of human primary acute B lymphoblastic cells
Authors: Peng Li, Zhiwu Jiang
Journal: Cancer Research (2016)

Abstract Bone marrow mesenchymal stem cells (BMMSCs) contribute the survival, expansion, and drug resistance of leukemic cells. However, how BMMSCs promote the proliferation and drug resistance of leukemia remains to be poorly understood. Here, we derived a BM-derived stromal cell line that supported unlimited growth of human primary acute B lymphoblastic leukemic cells (B-ALL) by physical contacts with B-ALL cells and secreting growth factors. Nevertheless, its capacity of promoting primary B-ALL proliferation was abolished once the cell line was induced to differentiate into adipocytes. In xenograft models, we demonstrate that the presence of adipocytes suppressed the engraftment of primary B-ALL cells while the decrease of adipocytes enhanced the reconstitution of B-ALL. Consistently, we observed that the increase of numbers and diameters of adipocytes was correlated with remission after chemotherapy treatments in B-ALL patients. By comparing the global transcription profiles between the BM stromal cells and the adipocytes that were derived from the cell line, we identified a combination of cytokines and adherent proteins that were able to support the long-term growth of human primary B-ALL cells and desensitize them to chemotherapy drugs in a stromal-free culture condition. Furthermore, we showed that the PI3K/AKT pathways were involved in chemotherapy-induced resistance because targeting these signaling pathways increased the chemotherapy sensitivity of B-ALL in xenografts. Collectively, our results uncovered the mechanisms of BMMSCs supporting the survival, expansion, and drug resistance of human B-ALL cells. Citation Format: Peng Li, Zhiwu Jiang. Identification of growth factors that promote the proliferation and drug resistance of human primary acute B lymphoblastic cells. [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 5201.
NRF2 at the Interface of Oxidative and Endoplasmic Reticulum Stress Pathways Is a Critical Integrator of Bortezomib Response in Mantle Cell Lymphoma in Vitro and In Vivo.
Authors: Marc A Weniger, Edgar Gil Rizzatti, Patricia Perez Galan, Delong Liu, Peter J Munson, Nalini Raghavachari, Therese White, Megan M Disinski, Wyndham H Wilson, Adrian Wiestner
Journal: Blood (2009)
Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis
Authors: Bianca Balbino, Riccardo Sibilano, Philipp Starkl, Thomas Marichal, Nicolas Gaudenzio, Hajime Karasuyama, Pierre Bruhns, Mindy Tsai, Laurent L. Reber, Stephen J. Galli
Journal: Journal of Allergy and Clinical Immunology (2016)
The impact of socioeconomic status upon specialist consultation, treatment, and outcomes for pancreatic adenocarcinoma.
Authors: J. E. Carroll, M. M. Murphy, J. K. Smith, J. P. Simons, S. Ng, Z. Zhou, J. F. Tseng
Journal: Journal of Clinical Oncology (2010)

4077 Background: Quality outcome metrics for pancreatic adenocarcinoma (PC) have been described. However, the impact of socioeconomic status (SES) on quality outcome metrics for PC needs further elucidation. Methods: Linked SEER-Medicare databases 1991-2005 were queried for patients (pts) with PC. Pts with locoregional, nonmetastatic disease were identified and stratified into SES quintiles based hierarchically upon census tract, zip code median income, and per capita income data; these were then dichotomized into “low SES” and “high SES,” with the lowest quintile (mean income = $23,254.03, ≈2x U.S. mean poverty threshold) defining “low SES.” Univariate and Kaplan-Meier (KM) analyses characterized associations between SES group, patient characteristics, and therapy. Logistic regression models were constructed to assess SES as a predictor of specialist consultation (surgeon, medical or radiation oncologist) and receipt of therapy (resection, chemotherapy, radiation) after adjusting for age, gender, race, marital status, and comorbidity. Results: Of 20,191 total pts, 7,655 had locoregional disease; 1,597 (21%) of these were low SES. Low SES pts had worse overall survival on KM curves (log-rank, p < 0.0001). On univariate analyses, low SES pts tended to be older (p < 0.0001), female (p = 0.014), black (p < 0.0001), unmarried (p < 0.0001), and had more comorbidities (p < 0.0001). Low SES pts had less frequent specialist consultation, chemotherapy, radiation, and resection than high SES pts (all p < 0.0001). Multivariate analyses demonstrated that low SES negatively predicted consultation with a medical oncologist (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.78-0.98) and surgeon (OR 0.82, CI 0.71-0.94). Overall, low SES pts were less likely to receive chemotherapy (OR 0.81, CI 0.72-0.92) and resection (OR 0.80, CI 0.70 0.91). Furthermore, a subset of low SES pts receiving surgical consultation was less likely to undergo resection (OR 0.84, CI 0.73-0.97). Conclusions: Socioeconomic disparities exist in specialist consultation and therapy utilization for potentially resectable PC. These barriers may represent discrete points for intervention with specialist referral and therapy. No significant financial relationships to disclose.
Abstract 3725: B-Raf inhibition-induced paradoxical activation of MEK/ERK signaling enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells
Authors: You-Take Oh, Jiusheng Deng, Ping Yue, Shi-Yong Sun
Journal: Cancer Research (2016)

Abstract B-Raf inhibitors have been used for the treatment of some B-Raf-mutated cancers such as melanoma and thyroid cancer. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B-Raf, but lead to a paradoxical activation of MEK/ERK signaling in Ras-mutant cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation. Given the critical role of MEK/ERK signaling in the positive regulation of DR5 expression as we have previously demonstrated, this study focuses on determining the impact of B-Raf inhibition on DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Using chemical and genetic approaches, we have demonstrated that the B-Raf inhibitor PLX4032 induces DR5 upregulation exclusively in Ras-mutant cancer cells; this effect is dependent on Ras/c-Raf/MEK/ERK signaling activation. PLX4032 induces DR5 expression at transcriptional levels, largely due to enhancing CHOP/Elk1-mediated DR5 transcription. Pre-treatment of Ras-mutated cancer cells with PLX4032 sensitizes them to TRAIL-induced apoptosis; this is also a c-Raf/MEK/ERK-dependent event. Collectively our findings highlight a previously undiscovered effect of B-Raf inhibition on the induction of DR5 expression and the enhancement of DR5 activation-induced apoptosis in Ras-mutant cancer cells. Our results may suggest a novel therapeutic strategy against Ras-mutated cancer cells by driving their death due to DR5-dependent apoptosis through B-Raf inhibition. (This study was supported by Emory Winship Cancer Institute Robbins Scholar awards to YTO and to JD and Halpern Research Scholar award to SYS. SYS is a Georgia Research Alliance Distinguished Cancer Scientist and Halpern Research Scholar) Citation Format: You-Take Oh, Jiusheng Deng, Ping Yue, Shi-Yong Sun. B-Raf inhibition-induced paradoxical activation of MEK/ERK signaling enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. [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 3725.