tbuckley/cabot-search huggingface dataset:
Phase II trial of the combination of ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL).
Authors: Lorenzo Falchi, Michael J. Keating, Xavier C. Badoux, William G. Wierda, Susan Mary O'Brien, Susan C. Smith, Sijin Wen, Hagop Kantarjian, Alessandra Ferrajoli
Journal: Journal of Clinical Oncology (2012)

6516^ Background: Based on the activity of ofatumumab and lenalidomide as monotherapy, we evaluated efficacy and tolerability of the combination in pts with relapsed CLL. Methods: Thirty-six pts entered this phase II study. All pts had an indication for therapy, adequate liver/renal function and received prior fludarabine. Ofatumumab IV was given weekly for 4 weeks (300mg w 1; 1,000 mg w 2-4), monthly during months 2-6, and every other month during months 7-24. Lenalidomide 10 mg PO/day started on day 9 and continued for 24 months. Responses were assessed (2008 IWG criteria) at month 3, 6 and every 6 months. Results: Thirty-four pts are evaluable. Median age was 64 yrs (34-82), 59 % of the pts had Rai stage III-IV disease, median β-2M level was 4.1 mg/dL (1.7-16), 62 % of the pts had unmutated IgHV, 26% del(17p) and 12% del(11q). Median number of prior treatments was 2 (1-8), all pts had been treated with FCR and 29% were fludarabine-refractory. The overall response (OR) rate is 65% (22 pts); 7 pts (21%) achieved a complete response (CR) including 4 MRD-negative CR, and 15 pts (44%) achieved a partial response (PR). Twelve pts are still on therapy. Median duration of response has not been reached with a median follow up of 13 months. Seven pts discontinued therapy despite ongoing response: HSCT (3 pts), toxicity (2 pts) and physician choice (2 pts); 3 pts discontinued therapy because of loss of response (at 12, 16 and 16 months). Eighty-two % of the pts are alive. No deaths occurred on therapy, 6 deaths occurred after therapy discontinuation: CLL (4), HSCT (1) and CLL/lung cancer (1). Lenalidomide daily dose was 10 mg (9 pts), 7.5 mg (4 pts), 5 mg (13 pts), &lt;5 mg (8 pts). G3-4 toxicities included neutropenia (16 pts, 47%), thrombocytopenia (3 pts, 9%) and anemia (2 pts, 6%). One pt (3%) experienced G4 pulmonary embolism while on ESAs. One pt (3%) had G3 infusion reaction to ofatumumab. Fourteen G3 infections occurred: pneumonia (4), fever/bacteremia (5), parotitis (1), cellulitis (2), HZV (1), and CNS toxoplasmosis (1). G1-2 tumor flare reaction occurred in 8 pts (24%). Conclusions: The combination of ofatumumab and lenalidomide was well tolerated. It induced durable responses in 65% of FCR pre-treated pts with relapsed CLL.
Gene expression of metastatic biopsies for prediction of response to palliative chemotherapy in breast cancer.
Authors: Theodoros Foukakis, Julie Lorent, Nicholas Tobin, Linda Sofie Lindström, Jonas C. S. Bergh, Thomas Hatschek
Journal: Journal of Clinical Oncology (2015)

1044 Background: To date, no clinically useful predictive tests for chemotherapy in breast cancer (BC) are available. Several studies have tried to identify predictive gene expression signatures in the neoadjuvant setting, but no data are available for metastatic BC. Methods: Patients with advanced breast cancer were treated with epirubicin and paclitaxel with or without capecitabine as first-line treatment in the Swedish Phase 3 TEX trial. For 111 patients, a metastatic biopsy was obtained at baseline for gene expression profiling (Affymetrix array GPL10379). PAM50 molecular subtypes and published gene modules related to immune response or proliferation were investigated as predictors of objective response to chemotherapy (by RECIST 1.0) and progression-free survival (PFS). Results: 102 patients were evaluated and 58 had an objective response. Table shows the PAM50 classification and the response within each subtype. Nine patients achieved a complete response, 6 of them were classified as basal-like and 3 as luminal B. Median PFS was significantly higher in luminal tumors than in non-luminal (16.5 vs. 8 months, hazard ratio = 2.2, 95% confidence interval (CI) = 1.4-3.4, p < 0.001 by log-rank test). A high immune response module was predictive of response to chemotherapy for the whole cohort (Odds ratio (OR) = 1.61, 95% CI 1.02-2.64) and for luminal tumors (OR = 2.91, 95% CI 1.32-7.75), but not for basal-like tumors (OR = 0.87, 95% CI 0.34-2.25). The PAM50 proliferation index was positively associated with response in patients with estrogen receptor (ER) negative tumors (OR = 2.58, 95% CI 1.06-7.83). Conclusions: A high immune gene module was predictive of chemotherapy response in metastatic breast cancer, but this was restricted to the subgroup of luminal tumors. ER negative tumors with high proliferation rate had a higher probability to respond to chemotherapy. Clinical trial information: nct01433614.Objective responses within PAM50 molecular subtypes. PAM50 subtype Objective Response non-responders responders Basal-like 10 (40.0%) 15 (60.0%) Her2 enriched 15 (51.7%) 14 (48.3%) Luminal A 6 (60.0%) 4 (40.0%) Luminal B 11 (34.4%) 21 (65.6%) Normal-like 2 (33.3%) 4 (66.7%)
One Hundred Twenty Years of Koala Retrovirus Evolution Determined from Museum Skins
Authors: M. C. Avila-Arcos, S. Y. W. Ho, Y. Ishida, N. Nikolaidis, K. Tsangaras, K. Honig, R. Medina, M. Rasmussen, S. L. Fordyce, S. Calvignac-Spencer, E. Willerslev, M. T. P. Gilbert, K. M. Helgen, A. L. Roca, A. D. Greenwood
Journal: Molecular Biology and Evolution (2013)
A phase I trial of palbociclib and paclitaxel in metastatic breast cancer.
Authors: Amy Sanders Clark, Peter J. O'Dwyer, Daniel Heitjan, Priti Lal, Michael D Feldman, Maryann Gallagher, Colleen Redlinger, Christopher Colameco, David Lewis, Kelly Zafman, Melissa Langer, Mark Alan Rosen, Keerthi Gogineni, Angela R. Bradbury, Susan M. Domchek, Kevin R. Fox, Angela DeMichele
Journal: Journal of Clinical Oncology (2014)

527 Background: Palbociclib (Palb) is an oral CDK 4/6 inhibitor that is under development in breast cancer as a single agent and in combination with endocrine therapy. Preclinical studies suggest that Palb synergizes with paclitaxel (Pac) when given on an alternating schedule. We conducted a Phase I trial investigating the combination of weekly Pac and alternating Palb to synchronize the cell cycle in the tumors of patients (pts) with metastatic breast cancer. Methods: Pts with tumors expressing Rb protein, adequate organ function, and ≤3 prior cytotoxic metastatic regimens were eligible. Prior taxane was allowed. Palb was dose-escalated in a standard 3+3 design and taken on days 2-6, 9-14, 16-20 of each 28 day cycle. Pts received Pac 80mg/m2 weekly for 3 cycles; thereafter, Pac was administered on days 1, 8 and 15. After 6 cycles of therapy, pts had the option to drop the Pac and continue on Palb alone. Toxicity was assessed weekly and response was assessed every 2 cycles using RECIST 1.0. Results: The table below shows Palb dose level, enrollment, dose limiting toxicities (DLT), number of patients with Grade 3/4 neutropenia (NTP) and response (partial response (PR), stable disease (SD) or progressive disease (PD)). 8 patients had previously received a taxane. The only DLT was grade 3 AST and ALT (LFT). Among 11 pts with PR or SD, 8 pts continued on therapy >6 months and 4 >12 months. 11 pts are off study; 10 for PD, and one for toxicity (NTP in cycle 17) and 3 remain on study. Median time on treatment is 8 cycles. Conclusions: Combination Pac and Palb is safe and well tolerated. Prolonged tumor responses were seen. However, because uncomplicated grade 3/4 NTP was common and frequently led to dose reduction or dose interruption with 5-day Palb dosing, an additional Phase 1 expansion to examine Palb 100mg on a 3-day schedule (days 2-4, 9-11 and 16-18) is underway. Clinical trial information: NCT01320592. Starting dose level Palb Number (total 15) DLT Grade 3/4 NTP (n) Final dose Palb mg (n) Dose interruption (n) Best response (n) 50 mg 3 0 0 50 (1) 50 (1) 50 (1) No (2) Yes (1) PR (1) SD (1) PD (1) 75 mg 3 0 2 75 (1) 50 (1) 25 (1) No (1) Yes (2) PR (2) SD (1) 100 mg 6 0 5 100 (2) 75 (3) 25 (1) No (1) Yes (5) PR (2) SD (1) PD (3) 125 mg 3 1-LFT 3 75 (1) 50 (2) No (0) Yes (3) PR (1) SD (2)
Phase I: Veliparib with cisplatin (CP) and vinorelbine (VNR) in advanced triple-negative breast cancer (TNBC) and/or <i>BRCA</i> mutation-associated breast cancer.
Authors: Eve T. Rodler, Julie Gralow, Brenda F. Kurland, Melissa Griffin, Rosa Yeh, John A. Thompson, Peggy Porter, Elizabeth M. Swisher, Vijayakrishna K. Gadi, Larissa A. Korde, Hannah M. Linden, Georgiana Kehr Ellis, Stacie Peacock Shepherd, Vincent L. Giranda, Xiaoyu Chai, Jeannette Hammond, Reina Hibbert, Bojana Askovich, Jennifer M. Specht
Journal: Journal of Clinical Oncology (2014)

2569 Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) have activity in tumors with DNA repair defects, including BRCA 1/2 deficient cancers. CP is synergistic with the PARPi veliparib in xenografts, and has anti-tumor activity in TNBC and BRCA1 deficient breast cancer. VNR shows preclinical synergy with CP and the combination has efficacy in metastatic breast cancer (MBC). We hypothesize that veliparib combined with CP and VNR is active in TNBC and will be most effective in tumors with DNA repair defects. Methods: To determine maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic profiles, and anti-tumor activity, patients (pts) with TNBC and/or BRCA1/2+ MBC received CP 75 mg/m2 day 1, VNR 25 mg/m2days 1, 8 and escalating doses of veliparib (V) orally BID days 1-14, every 21 days for 6-10 cycles followed by maintenance V. Results: 45 pts enrolled in 9 cohorts. Treatment was tolerated well; MTD was not reached. 36 pts (80%) had at least 1 prior metastatic regimen (range 1-11). BRCA mutation status was: BRCA1+ (n=9); BRCA2+ (n=3); negative (n=24); unknown (n=9). BID V dose cohorts were: 20 mg (n=4); 30 mg (n=3); 40 mg (n=6); 60 mg (n=8); 80 mg (n=5 ); 120 mg (n=6); 160 mg (n=3); 200 mg (n=7); and 300 mg (n=3). DLT occurred at 40 mg BID in 1 pt with grade (gr) 4 thrombocytopenia, 60 mg BID (gr 4 neutropenia + fever, n=1), and 200 mg BID (gr 3 neutropenia + fever, n=1). Most common adverse events (AEs) were nausea, anemia, fatigue, mainly gr 1/2. Most common gr 3/4 AEs were neutropenia (n=13), anemia (n=11), thrombocytopenia (n=6). Of 38 evaluable pts, 21 (55%) responded (2 CR, 19 PR), 13 (34%) had SD, and 4 had PD, as best response. One pt with CR remains on trial for 42+ cycles. Response was 73% in BRCA 1/2+ pts (6/11 PR; 2/11 CR), 53% in BRCA1/2- pts (11/21 PR) and 33% in unknown status pts (2/6 PR). Analyses of PK and correlative predictors of response will be presented. Conclusions: Veliparib at the recommended phase II dose of 300mg BID combined with CP and VNR is well tolerated. BRCA mutation carriers and pts with sporadic TNBC, including heavily pretreated pts, responded. We plan to investigate the contribution of veliparib to cisplatin-based therapy in a randomized trial. Clinical trial information: NCT01104259.
Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer’s-like impairment in mice
Authors: Gabrielle L. Sell, Thomas B. Schaffer, Seth S. Margolis
Journal: Journal of Clinical Investigation (2017)

Accumulation of amyloid-β (Aβ) protein may cause synapse degeneration and cognitive impairment in Alzheimer's disease (AD) by reactivating expression of the developmental synapse repressor protein Ephexin5 (also known as ARHGEF15). Here, we have reported that Aβ is sufficient to acutely promote the production of Ephexin5 in mature hippocampal neurons and in mice expressing human amyloid precursor protein (hAPP mice), a model for familial AD that produces high brain levels of Aβ. Ephexin5 expression was highly elevated in the hippocampi of human AD patients, indicating its potential relevance to AD. We also observed elevated Ephexin5 expression in the hippocampi of hAPP mice. Removal of Ephexin5 expression eliminated hippocampal dendritic spine loss and rescued AD-associated behavioral deficits in the hAPP mice. Furthermore, selective reduction of Ephexin5 expression using shRNA in the dentate gyrus of presymptomatic adolescent hAPP mice was sufficient to protect these mice from developing cognitive impairment. Thus, pathological elevation of Ephexin5 expression critically drives Aβ-induced memory impairment, and strategies aimed at reducing Ephexin5 levels may represent an effective approach to treating AD.
BEVATEM: Phase II single-center study of bevacizumab in combination with temozolomide in patients (pts) with first-line metastatic uveal melanoma (MUM): First-step results.
Authors: Sophie Piperno-Neumann, Vincent Servois, Francois-Clement Bidard, Pascale Mariani, Corine Plancher, Bernard Asselain, Nora Vago-Ady, Laurence Desjardins
Journal: Journal of Clinical Oncology (2012)

8546 Background: Overall survival (OS) of MUM pts remains poor. In our retrospective series of 470 MUM pts, median OS was 13 months, ranging from 3 to 12 and 21 months for best supportive care, systemic treatment and surgery groups respectively, stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma. Intravitreal application of antiangiogenic agents is used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. Bevacizumab suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental uveal melanoma. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and bevacizumab. Methods: Phase II study, modified 2-step Fleming plan; with expected 6-month progression-free survival (PFS) rates of 15% with chemotherapy and 40% with BEVATEM, 35 pts are to be recruited for a power of 94% (α and β risk 3 and 6%). After the first 17 pts, the study will be continued and another 18 pts will be enrolled in the second step if ≥3 evaluable pts show stable disease or response. Primary endpoint: 6-month PFS according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. Treatment schedule: Temozolomide 150mg/m2 d1-d7 and d15-d21 oral route, Bevacizumab 10 mg/kg d8 d22 IV infusion, 6 cycles (d1=d28) then Bevacizumab maintenance until toxicity or progression. Results: From May 2010 to January 2011, 17 pts were enrolled according to the first step of the study: 3/17 achieved disease control at 6 months, second step is on going with 26/35 pts already recruited. One patient with minor response in liver and lung metastases is under Bevacizumab maintenance for 12 months. Safety of BEVATEM is as good as expected. Liver perfusion CT study showed decrease in blood flow and blood volume before lesion size decrease in one stable patient. Conclusions: BEVATEM study in first line MUM pts is on going, showing promising results in the first step of 17 pts.
Ethnic disparities in the impact of breast cancer on the workforce: A pilot study.
Authors: Victoria Susana Blinder, Carolyn E Eberle, Sujata Patil, Julia Ramirez, Thelma McNish, Sang-Hee Min, Niyati Bhagwati, Susan Lee, Clifford A. Hudis, Kevin C. Oeffinger, Francesca Gany
Journal: Journal of Clinical Oncology (2015)

e17600 Background: Return to work (RTW) is understudied in immigrant breast cancer survivors (BCS), who are less likely to have work accommodations associated with increased RTW (e.g. sick leave). Our hypothesis is that immigrant BCS are at higher risk of job loss than US-born BCS. The goals of this pilot were to test, translate, & refine a survey of RTW in 4 languages & assess the feasibility of peer control recruitment in immigrant BCS. Methods: Eligibility: stage 0-III breast cancer, active treatment (chemo/radiation) or < 1 month from surgery, working at time of diagnosis, speak English, Korean, Mandarin, or Spanish. BCS were asked to nominate 5 peers: same race/ethnicity, working, < 5 years older/younger than BCS. Surveys were administered at baseline & 4 months after last treatment (corresponding time for peers). Baseline surveys were online in clinic (BCS) & followed by cognitive debriefing interviews or by phone (peers). Follow-up surveys were online at home, or by phone (participant choice). Results: 40 BCS & 36 peers completed baseline English surveys until saturation was reached. Surveys were then translated. 27 BCS (9 per language) & 6 peers completed baseline translated surveys until saturation was reached. Control recruitment in non-English speakers was limited by concerns about privacy & study burden. However, 13/14 (93%) English- & 14/17 (82%) non-English-speaking BCS provided the name of a best friend who was working at baseline (question added to serve as alternate control due to low peer accrual). In cognitive debriefing interviews BCS noted questions about job type & clinical data were unclear. These were modified to increase response accuracy & retested in all 4 languages. 51 BCS (76%) & 28 peers (67%) completed follow-up surveys; 42 (82%) BCS & 27 (96%) peers were working. In exploratory analyses BCS working at follow-up more likely to be US-born, English-speakers, college-educated, have sick leave benefits. Conclusions: Challenges to surveying immigrants required modifications to optimize recruitment & data accuracy. Control recruitment was poor in non-English speakers. However, asking about the work status of a best friend was successful. This question has been added to our ongoing study, for which this was a pilot.
Atomic Layer Deposition of a Silver Nanolayer on Advanced Titanium Orthopedic Implants Inhibits Bacterial Colonization and Supports Vascularized de Novo Bone Ingrowth
Authors: Aine Devlin‐Mullin, Naomi M. Todd, Zahra Golrokhi, Hua Geng, Moritz A. Konerding, Nigel G. Ternan, John A. Hunt, Richard J. Potter, Chris Sutcliffe, Eric Jones, Peter D. Lee, Christopher A. Mitchell
Journal: Advanced Healthcare Materials (2017)

Joint replacement surgery is associated with significant morbidity and mortality following infection with either methicillin-resistant Staphylococcus aureus (MRSA) or Staphylococcus epidermidis. These organisms have strong biofilm-forming capability in deep wounds and on prosthetic surfaces, with 103 -104 microbes resulting in clinically significant infections. To inhibit biofilm formation, we developed 3D titanium structures using selective laser melting and then coated them with a silver nanolayer using atomic layer deposition. On bare titanium scaffolds, S. epidermidis growth was slow but on silver-coated implants there were significant further reductions in both bacterial recovery (p < 0.0001) and biofilm formation (p < 0.001). MRSA growth was similarly slow on bare titanium scaffolds and not further affected by silver coating. Ultrastructural examination and viability assays using either human bone or endothelial cells, demonstrated strong adherence and growth on titanium-only or silver-coated implants. Histological, X-ray computed microtomographic, and ultrastructural analyses revealed that silver-coated titanium scaffolds implanted into 2.5 mm defects in rat tibia promoted robust vascularization and conspicuous bone ingrowth. We conclude that nanolayer silver of titanium implants significantly reduces pathogenic biofilm formation in vitro, facilitates vascularization and osseointegration in vivo making this a promising technique for clinical orthopedic applications.
Association of low total lymphocyte count with overall and disease-free survival in patients with resected pancreatic adenocarcinoma receiving the GM-CSF secreting pancreatic tumor vaccine in combination with adjuvant chemoradiation.
Authors: Aaron Schueneman, Elizabeth Sugar, Jennifer Uram, Elaine Bigelow, Joseph M. Herman, Barish H Edil, Elizabeth M. Jaffee, Lei Zheng, Dan Laheru
Journal: Journal of Clinical Oncology (2012)

e14585 Background: Pancreatectomy, though necessary for potential cure of pancreatic ductal carcinoma (PDA), can be associated with immune dysregulation. Low total lymphocyte count (TLC) has been found to be a poor prognostic indicator in several different tumor types. The goal of this study was to determine whether low TLC could affect response to therapy and survival in resected pancreatic cancer patients who received a GMCSF-secreting cell-based tumor vaccine (GVAX) in addition to standard adjuvant therapy. Methods: Retrospective analysis of 60 patients enrolled in a phase II trial evaluating the safety, efficacy and immune activation of GVAX tumor vaccine administered in an adjuvant setting in resected PDA. Blood counts were analyzed from 8 weeks after surgery and then monthly after the completion of adjuvant chemoradiation. Results: The TLC just prior to the first vaccine was 1977 (range: 700-3890) and 10 patients had TLC &lt; 1500. After adjusting for the prognostic factors identified in the original study (lymph node + and margin status), OS was significantly lower for those patients with TLC &lt; 1500 (median 18.4 mos., 95% CI: 8.63 to infinity) as compared to those with TLC &gt; 1500 (median 28.4 mos., 95% CI: 23.9 to 32.6, hazard ratio [HR] = 2.43, 95% CI: 1.09 to 5.41, p = 0.03). TLC &lt; 1500 prior to first vaccine was also associated with shorter disease free survival (HR: 3.18 p &lt; 0.01). Adjuvant chemoradiation consistently decreased TLC with a mean reduction of 1224 (range 450 to 2740). After adjuvant therapy, TLC &lt; 500 was associated with reduced OS (HR: 4.86, 95% CI: 1.70 to 13.87, p &lt; 0.01). Conclusions: Low TLC after surgery and after adjuvant chemoradiation is associated with poor survival in patients who receive pancreatic GVAX. This result suggests that immune suppressive conditions associated with current standard pancreatectomy and chemoradiation significantly compromise the efficacy of immunotherapy. Less invasive laparoscopic surgical approaches that result in less immune dysregulation and chemotherapy regimens that have lower immunosuppression should be considered.