tbuckley/cabot-search huggingface dataset:
Trastuzumab plus GM-CSF for patients with trastuzumab-resistant, HER2-overexpressing metastatic breast cancer: Pilot study
Authors: N. T. Ueno, G. Rondon, P. Williams, R. E. Champlin, J. L. Murray, M. Cristofanilli, M. Royce, R. B. Walter, R. L. Theriault, G. N. Hortobagyi, V. Valero
Journal: Journal of Clinical Oncology (2005)

803 Background: Preclinical data suggest that the anti-tumor activity of trastuzumab (Herceptin) is partly due to antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine) enhances ADCC by stimulating a variety of effector cells, including natural killer cells. In this pilot study, we tested the clinical antitumor effect of Herceptin plus GM-CSF in women with Herceptin-resistant metastatic breast cancer. Methods: Eligible patients (pts) had measurable, HER2-overexpressing, metastatic breast cancer; progressive disease (PD) after Herceptin ± chemotherapy; and good performance status (ECOG 0–1). Herceptin was given at 4 mg/kg IV followed by 2 mg/kg every wk for 4 wk (1 cycle). GM-CSF was given at 250 mcg/m2 SC daily until absolute neutrophil count (ANC) >10,000/mm3, then every other day while ANC was below 10,000/mm3. Treatment was continued until PD or intolerable toxicity. The primary endpoint was tumor response (including stable disease [SD]); disease was restaged every 8 wk. Results: Thirteen women (median age 49 y, range, 27–71) with median 2.5 prior systemic treatments for metastatic disease (range 1–4), and 2 Herceptin failures (range 1–2) were entered with a median of 1 metastatic disease site (range 1–4); 3 pts had hormone-receptor-positive disease. Pts were given a median of 2 cycles Herceptin + GM-CSF (range 1–8). Ten pts were evaluable for response (1 did not complete the first cycle due to protocol violation and 1 was enrolled too recently for evaluation). Three pts (27.7%) had disease controlled: 2 have had SD for 4 months and 1 has had SD for 8 months. Three pts had transient reversible grade III toxicity (infection, dyspnea, headache) of uncertain relation to GM-CSF; 4 pts had grade I/II skin rash. Conclusions: In this pilot study, Herceptin + GM-CSF stabilized metastatic breast cancer previously treated and progressing on Herceptin. This approach warrants further investigation in a phase II study to determine if this response results from an increase in ADCC activity from GM-CSF. No significant financial relationships to disclose.
Incidence and outcomes of patients with late recurrence of Wilms tumor (WT): The international experience.
Authors: M. H. Malogolowkin, F. Spreafico, J. Dome, N. Breslow, H. van Tinteren, K. Pritchard-Jones, M. van den Heuvel, C. Bergeron, J. De Kraker, N. Graf
Journal: Journal of Clinical Oncology (2011)

9544 Background: Overall survival of previously untreated children with WT has improved dramatically over the past 40 years. Most relapses occur within 2 years of diagnosis and subsequent survival varies between 40 -80%. Late recurrences (LR) greater than 5 years are uncommon. We determined the incidence of LR and the outcomes of these patients. Methods: We reviewed the case report forms of patients enrolled onto 10 large phase III trials (NWTS-1 to 5, SIOP-9301, AIEOP-CNR-92, UKW-1 to 3). Results: Of the 13,330 patients enrolled onto these studies, 70 (0.5%) had a LR as their first event. Characteristics of these patients are shown in the Table. Conclusions: Approximately 50% of patients with LR of WT survived. Recurrence in the contralateral kidney represented only 15 % of the LR and was associated with a better outcome than the rest of the group (9/11 are alive/NED). No other risk factor including time to relapse, site of relapse or initial therapy was associated with outcome. Due to the varied therapies used at time of LR we are unable to make any conclusions about salvage treatment. Since LR is a rare event, regular long-term monitoring for recurrence is not justified after 5 years from diagnosis. Alive 34 patients Dead 36 patients Stage I: 8; II: 7; III: 7; IV: 5; V: 7 I: 8; II: 11; III: 7; IV: 3; V: 7 Histology at time of initial diagnosis Favorable (63) Anaplasia (3) Missing data (4) 32 1 1 31 2 3 Number of patients treated at diagnosis with 3 drugs XRT 9 11 13 15 Site of relapse Lung (15) Lung + other (5) Abdomen (24) Contralateral kidney (11) Other (7) Missing data (8) 5 3 13 9 3 1 10 2 11 2 4 7 Mean time to relapse Years (range) 7.7 (5.1–14.7) 8.2 (5.1–17.3)
Impact of lenalidomide on the antiproliferative effect of gemcitabine/carboplatin (GC) and gemcitabine/cisplatin (GP) against urothelial carcinoma (UC) cells in vitro.
Authors: A. B. Apolo, A. Tepede, K. M. Reece, D. K. Price, W. L. Dahut, W. D. Figg
Journal: Journal of Clinical Oncology (2011)

e15164 Background:Although urothelial carcinoma (UC) is a chemosensitive malignancy, responses are not durable and most patients with metastatic UC die from their disease. New strategies are needed. Both pre-clinical and clinical data support targeting angiogenesis in UC and other solid tumors. Lenalidomide is an anti-angiogenic and a potent immunomodulatory agent that has demonstrated activity in hematological malignancies. There are no in vitro data of single agent direct activity against solid tumor cells and few data regarding the combination of lenalidomide and standard of care chemotherapeutic agents, such as cisplatin (P), carboplatin (C) and gemcitabine (G). We explored in vitro combinations of lenalidomide, GC and GP to improve possible treatment options for UC. Methods: The effects of lenalidomide alone and in combination with GC or GP, on UC cell proliferation were studied. UC T24 cells were exposed to various concentrations of lenalidomide (0, 0.5uM, 1uM) for 24 hours. This was followed by treatment with a combination of G (10nM) and C (1nM and10nM), or G (10nM) and P (10ug/ml) for 48 hours. As a control, each drug was treated for 48 hours alone. Cell proliferation was assessed by an ELISA BrdU assay. Results: Lenalidomide alone had no effect on the proliferation of UC T24 cells, whereas G, C, and P had moderate anti-proliferative activity. With the combination of lenalidomide with GC or GP there was a clear and dose-dependent enhancement of anti-proliferative activity in T24 cell lines. Conclusions: These studies support the potential utility of lenalidomide in combination with GC or GP in the treatment of patients with solid tumors including UC. A phase I trial of lenalidomide in combination with GC in metastatic UC has is currently under way. The mechanism by which lenalidomide affects UC cells and the enhancement of chemotherapy cytotoxicity remains to be elucidated.
Lenalidomide and Rituximab Following Autologous Stem Cell Transplantation for B-Cell Non-Hodgkin Lymphoma Is Associated with Unacceptable Myelotoxicity
Authors: Robert Dean, Brad Pohlman, Lisa Rybicki, Amanda L. Maggiotto, Jennifer Bates, Stephen D. Smith, Brian J. Bolwell, John Sweetenham
Journal: Blood (2011)
Microbes Are Associated with Host Innate Immune Response in Idiopathic Pulmonary Fibrosis
Authors: Yong Huang, Shwu-Fan Ma, Milena S. Espindola, Rekha Vij, Justin M. Oldham, Gary B. Huffnagle, John R. Erb-Downward, Kevin R. Flaherty, Beth B. Moore, Eric S. White, Tong Zhou, Jianrong Li, Yves A. Lussier, MeiLan K. Han, Naftali Kaminski, Joe G. N. Garcia, Cory M. Hogaboam, Fernando J. Martinez, Imre Noth
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Differences in the lung microbial community influence idiopathic pulmonary fibrosis (IPF) progression. Whether the lung microbiome influences IPF host defense remains unknown.Objectives: To explore the host immune response and microbial interaction in IPF as they relate to progression-free survival (PFS), fibroblast function, and leukocyte phenotypes.Methods: Paired microarray gene expression data derived from peripheral blood mononuclear cells as well as 16S ribosomal RNA sequencing data from bronchoalveolar lavage obtained as part of the COMET-IPF (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in Idiopathic Pulmonary Fibrosis) study were used to conduct association pathway analyses. The responsiveness of paired lung fibroblasts to Toll-like receptor 9 (TLR9) stimulation by CpG-oligodeoxynucleotide (CpG-ODN) was integrated into microbiome–gene expression association analyses for a subset of individuals. The relationship between associated pathways and circulating leukocyte phenotypes was explored by flow cytometry.Measurements and Main Results: Down-regulation of immune response pathways, including nucleotide-binding oligomerization domain (NOD)-, Toll-, and RIG1-like receptor pathways, was associated with worse PFS. Ten of the 11 PFS-associated pathways correlated with microbial diversity and individual genus, with species accumulation curve richness as a hub. Higher species accumulation curve richness was significantly associated with inhibition of NODs and TLRs, whereas increased abundance of Streptococcus correlated with increased NOD-like receptor signaling. In a network analysis, expression of up-regulated signaling pathways was strongly associated with decreased abundance of operational taxonomic unit 1341 (OTU1341; Prevotella) among individuals with fibroblasts responsive to CpG-ODN stimulation. The expression of TLR signaling pathways was also linked to CpG-ODN responsive fibroblasts, OTU1341 (Prevotella), and Shannon index of microbial diversity in a network analysis. Lymphocytes expressing C-X-C chemokine receptor 3 CD8 significantly correlated with OTU1348 (Staphylococcus).Conclusions: These findings suggest that host–microbiome interactions influence PFS and fibroblast responsiveness.
Clinical and pathologic characteristics of patients with PI3K-mutant breast cancers.
Authors: M. Cooper Lloyd, Melinda Sanders, Maria Gabriela Kuba, Jaime Farley, Darson Lai, Zengliu Su, Ingrid A. Mayer, Julie Ann Means-Powell, Cindy Vnenzak-Jones, Mia Alyce Levy, William Pao, Carlos L. Arteaga, Vandana Gupta Abramson
Journal: Journal of Clinical Oncology (2013)

8 Background: Mutations in PIK3CA are the most common somatic alterations in breast cancer and represent a potentially useful therapeutic target. As more PI3K pathway inhibitors enter the clinical arena, it is important to understand the characteristics of patients harboring mutations. This study seeks to identify the clinico/pathological characteristics of PI3K mutant breast cancers in patients evaluated at Vanderbilt University Medical Center. Methods: Molecular profiling (SNaPShot) was used to detect mutations in three genes in the PI3K pathway (PIK3CA, PTEN, AKT1). Electronic medical records of breast cancer patients whose tumors underwent testing from June 2010 to January 2013 were reviewed. PI3K mutation rates, histological tumor grade, receptor status (ER/PR/HER2), and recurrence-free survival were tabulated. Results: Three hundred evaluable tests were identified, with PI3K mutations detected in 83/300 (28%). Patients with PI3K mutations were more likely to be ER/PR positive (73% vs. 48%; p&lt;0.001) and less likely to be HER2 positive (6.0% vs. 20.7%, p=0.0022). Only 6/83 patients (7.2%) with triple negative cancers harbored PI3K mutations. 32% of patients with PI3K mutations participated in clinical trials, versus 25% without. Conclusions: Tumors with PI3K mutations were more likely to be ER/PR positive, of intermediate grade, and associated with longer recurrence-free survival. Patients with PI3K mutations were more likely to participate in clinical trials. These data and the potential eligibility of patients harboring mutations for clinical trials support the prognostic and clinical utility of SNaPShot testing for all breast cancer patients at a tertiary care center. [Table: see text]
The efficacy and safety of low-molecular-weight heparins (LMWHs) compared with vitamin K antagonists (VKAs) in the treatment of recurrent venous thromboembolism (VTE) in patients with cancer: An analysis of randomized clinical trials
Authors: C. P. Escalante
Journal: Journal of Clinical Oncology (2008)

9609 Background: Patients with cancer are at higher risk of recurrent venous thromboembolism (VTE) and bleeding complications. Recently, anticoagulant therapies utilizing low-molecular-weight heparins (LMWHs) for up to 6 months have shown improved efficacy and safety over vitamin K antagonists (VKAs). However, individual LMWHs have not been compared with each other, and currently there is no standard of practice for the use of LMWH in this setting. Methods: Computerized queries of PubMed, MEDLINE, the American Society of Hematology abstract database, and the American Society of Clinical Oncology abstract database were performed to identify randomized clinical trials comparing LMWHs with VKAs in the treatment of acute VTE in patients with cancer. Results: Results: LMWHs are associated with lower rates of recurrent VTE and similar rates of bleeding when compared with VKA therapy (see table). Enoxaparin was as effective as VKA as prolonged VTE treatment in patients with cancer. Tinzaparin reduced the risk of recurrent VTE by half but the difference was not statistically significant at the end of the 3-month treatment period. Dalteparin is the most extensively studied LMWH in this setting, and it demonstrated a 52% relative risk reduction in recurrent VTE (P=0.002). Dalteparin may also be associated with increased survival, as it demonstrated a 50% reduction in overall mortality in patients without metastatic disease at randomization in a CLOT trial post-hoc analysis. Conclusions: Evidence exists that long-term LMWHs have a similar safety profile to VKAs, but are more efficacious in preventing recurrent VTE in patients with cancer. Dalteparin is the only LMWH with regulatory approval in this setting. RCTs of long- term LMWH therapy combined with VKA Trial Number of Randomized Patients Comparator/Treatment Period Recurrent VTE (LMWH vs VKA) Bleeding (LMWH vs VKA) CANTHANOX* N=147 Enoxaparin 1.5 mg/kg once daily vs VKA; 3 months 2/71 (2.8%) vs 3/75 (4%)(P=0.09); RR=0.7 5/71 (7%) vs 12/75 (16%) ONCENOX* N=101 Enoxaparin 1.5 mg/kg once daily vs enoxaparin 1.0 mg/kg twice daily vs VKA; 3 months No differences in recurrent VTE No differences in major bleeding CLOT N=676 Dalteparin 200 IU/kg once daily for 1 month, then 150 IU/kg once daily for 5 months vs VKA; 6 months 27/336 (8%) vs 53/336 (15.7%); RR=0.48 47/336 (14%) vs 63/336 (18.8%) LITE N=200 Tinzaparin 175 IU/kg once daily vs VKA; 3 months 3-month analysis: 6/100 (6%) vs 10/100 (10%) 12-month analysis: 16/100 (16%) vs 7/100 (7%) (P=0.044); RR=0.44 27/100 (27%) vs 24/100 (24%) * Trial discontinued due to low enrollment. No significant financial relationships to disclose.
CLU inhibition using OGX-011 as an adjuvant therapeutic strategy for HSP90 inhibition in prostate cancer.
Authors: F. Lamoureux, M. Yin, A. Zoubeidi, M. E. Gleave
Journal: Journal of Clinical Oncology (2011)

4573 Background: Prostate cancer (PCa) responds initially to anti-androgen therapies, however, progression to castration resistant disease (CRPC) frequently occurs. Several small molecule inhibitors of HSP90 show promise in CRPC and other cancers. However, most HSP90 inhibitors (17-AAG or PF-04928473 and its prodrug PF-04929113) trigger the elevation of HSPs (HSP90, 70, 27 and clusterin), which lead to tumor cell survival and treatment resistance. We hypothesized that targeting clusterin (CLU) using siRNA or the antisense drug, OGX-011, may enhance HSP90 inhibitors-induced cell death in PCa. Methods: Inducible and constitutive CLU and other HSP mRNA and protein levels were measured by real-time RT-PCR and immunoblot assays. The combination of OGX-011 with PF-04928473 or 17-AAG was evaluated in vitro on LNCaP and PC3 cells growth and apoptosis. The HSP90 inhibitor PF-04929113 was evaluated in combination with OGX-011 in vivo in athymic mice bearing castration resistant LNCaP xenografts, while the combination of OGX-011 with 17-AAG was evaluated in PC3 xenografts. Results: In prostate tumor cell lines, PF-04928473 and 17-AAG induced expression of HSPs in a dose and time dependent manner, and especially CLU at RNA and protein level, by increasing HSF-1 nuclear translocation and transcription activity. In vitro, OGX-011 synergistically enhanced the activity of HSP90 inhibitors on cell growth and apoptosis with increased sub-G1 fraction and PARP cleavage. These biologic events were accompanied by decreased expression of HSPs, Akt, AR and PSA, and HSF-1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 15mg/kg), potentiated the effect of orally administered HSP90 inhibitors (PF-04929113: 25mg/kg; 17-AAG: 50mg/kg), significantly inhibiting tumor growth by 80% and prolonging survival in PC3 and castrate resistant LNCaP xenograft model compared to the HSP90 inhibitors alone. Conclusions: These results indicate that HSP90 inhibitor-mediated induction of CLU expression can be attenuated by OGX-011, with synergistic effects on delaying progression of CRPC. This work was supported by the Canadian Institutes of Health Research fellowship.
Cancer genetic counseling services (GCS) in a community-based cancer center (CBCC) in rural Nebraska: Effect of National Community Cancer Centers Program (NCCCP).
Authors: M. S. Copur, S. Percich, A. Jordan, A. M. Obermiller, F. R. Loberiza, H. Benzel, J. Langford-Karre, M. Mickey, M. Norvell, L. Friesen, M. Bolton, K. Mleczko, R. C. Ramaekers
Journal: Journal of Clinical Oncology (2011)

e16508 Background: Rapidly evolving genetic and genomic technologies have renovated our approach to cancer screening, prevention, and therapy, leading to individualized medicine era. Majority of cancer patients (pts) are diagnosed and treated in the community but few CBCCs have resources to provide GCS. NCCCP aims to create a CBCC network addressing the full cancer-care continuum. Identifying pts and delivering GCS in the community setting is one of the NCCCP goals. Methods: Between April 2009 and January 2011, genetic counselors (GCs), employed through NCCCP grant, collected medical/family history, provided psychosocial and cancer risk assessment, personal risk management, pre/post test counseling, and genetic testing for cancer patients/families at Saint Francis Cancer Treatment Center (SFCTC). Prior to NCCCP (July 2007-March 2009) GCS were provided by oncologists/nurse practitioners. 21-month GCS data before and after availability of NCCCP-provided GCs were gathered and compared. Results: Prior to NCCCP, there were 925 new cancer cases with 14 pts receiving variable and inconsistent GCS, compared to 946 cases with 74 pts receiving full GCS after NCCCP (Chi-square, two-tailed P<0.0001).Before NCCCP, 3 (21%) of 14 pts qualified/accepted genetic testing identifying 1 patient with BRCA gene mutation. After NCCCP, 22 (30%) of 74 pts qualified/accepted genetic testing identifying 4 patients with BRCA gene mutation. (Two-tailed Fisher’s exact P= 0.75). The odds of having genetic testing after the initiation of NCCCP was 55% more (OR 1.55, 95%CI 0.35-7.81) than before NCCCP. All 22 genetic-tested pts received post-test counseling and were offered personally tailored cancer risk management.Triggered by post-test counseling, a screening breast MRI in a 36-year old daughter revealed an early stage breast cancer leading to curative therapy. Conclusions: Adequate delivery of GCS were greatly enhanced by the availability of professional GCs through NCCCP grant by increasing physician/patient awareness and reducing time/procedural burden. CBCCs may greatly benefit from GCS, which will ultimately reduce morbidity and mortality from familial cancer.
Long-term survivors in glioblastoma multiforme (GBM): An Irish experience.
Authors: M. Teo, D. M. Graham, P. O'Dea, C. Drake, C. Keohane, S. O'Reilly, E. J. Moylan, D. G. Power
Journal: Journal of Clinical Oncology (2011)

e12516 Background: GBM is an aggressive malignancy with a poor outcome. Retrospective studies have correlated clinicopathologic and molecular variables with prognosis and constructed nomograms predicting outcome. We identified long-term survivors (LTS) in an Irish neuro-oncology center and investigated associations with patient and tumoral variables. Methods: A prospectively maintained database was reviewed for patients (pts) treated at our institution for GBM between Aug 04 and Dec 09. LTS were defined as pts with overall survival (OS) >2 years. OS was calculated from date of diagnosis to death or last follow-up. All pts had at least 2 yrs follow-up. Clinical and pathological characteristics and outcomes were reviewed. Results: Fourteen (9.7%) of 145 GBM pts were identified as LTS. Median OS was 35.1 months (range: 25.4-69.5) compared with 8.9 (range: 0-69.5) in the overall cohort. Ten LTS were male (71%). Median age at diagnosis was 55 yrs (range: 27-73). Primary sites were: 12 cerebral (86%); 1 spinal (7%) and 1 cerebellopontine angle (7%). Ten LTS presented with neurologic symptoms (71%). ECOG performance status (0-4) was documented in 13 LTS: 0 in 29% and 1 in 64% of pts. In 11 LTS (79%) the tumor was optimally debulked; 3 had biopsy only. One pt had radiologic diagnosis later confirmed on biopsy. Histologic subtypes were: 6 conventional GBM (43%), 3 giant cell (21%) and 5 small cell (36%) variants. Thirteen LTS (93%) received cranial radiation with median dose of 60Gy. One pt was previously treated for astrocytoma preventing further radiation. Concurrent chemoradiation was administered to 10 pts (71%), temozolomide in 9 and BCNU in 1. Twelve pts (86%) had tumor progression at a median of 20.2 mos after diagnosis (range: 4.8-31.2). Four LTS had multiple relapses (range 2-3). Four had >1 line of treatment (range 2-5), 4 had further surgery (29%). Four pts are alive including 2 with no evidence of progression after 1st line therapy. Conclusions: In pts treated at our center almost 10% of GBMs were LTS and were characterised by optimal debulking, a high proportion of giant cell GBMs, baseline ECOG ≤1, multiple relapses and lines of treatments. Molecular analyses of these tumors, e.g. MGMT and IDH1 status, is ongoing and may yield further prognostic information.
Collateral Damage: a Mechanism for Hematopoiesis-Restricted Mhag-Specific T Cells to Play a Role in the Effector Phase of GvHD.
Authors: Boris van der Zouwen, Alwine B. Kruisselbrink, Peter A. Von Dem Borne, Roelof Willemze, J.H. Frederik Falkenburg, Inge Jedema
Journal: Blood (2009)