tbuckley/cabot-search huggingface dataset:
Mimotopes of the disialoganglioside GD2 elicit anti-GD2 antibodies recognising GD2 on melanoma cells
Authors: K. H. Brämswig, A. B. Riemer, E. Förster-Waldl, A. Pollak, C. C. Zielinski, H. Pehamberger, H. N. Lode, O. Scheiner, E. Jensen-Jarolim
Journal: Journal of Clinical Oncology (2006)

12505 Background: The disialoganglioside GD2, a carbohydrate antigen, is expressed on all tumors of neuroectodermal origin, including melanoma, sarcoma, neuroblastoma and small cell lung cancer. Due to its specific expression on tumor surfaces, GD2 is an attractive target for immunotherapy. The mouse/human chimeric antibody form ch14.18 was already applied in melanoma and neuroblastoma trials as passive immunotherapy. We aimed to replace the poorly immunogenic ganglioside with highly immunogenic peptides, in order to establish an active immunotherapy. Methods: We used the ch14.18 antibody to select GD2 mimotopes. In the present study, two mimics of the ch14.18 epitope were chosen for immunogenicity evaluation. The mimics were coupled to KLH (keyhole limpet hemocyanin) in order make them more immunogenic. Three groups of BALB/c mice were immunized i.p with the mimotope conjugates (GRL-KLH or DGG-KLH), or the carrier protein KLH alone. Results: BALB/c mice immunized with the mimotope conjugates indeed showed a specific humoral immune response towards the purified original antigen GD2 in ELISA, and also against the natural GD2 melanoma cell lysate in Western Blots. As the elicited antibodies were of the IgG isotype, the mimotope conjugates are capable of recruiting T cell help and inducing memory phenomena. Conclusion: We are able to show that an epitope of the carbohydrate antigen GD2 can successfully be translated into immunogenic peptide epitope mimics. Moreover, immunizations with these mimics induced IgG antibodies again recognizing the original antigen. We thus provide evidence that GD2 mimotopes are suitable candidates for active immunotherapy of GD2 expressing tumors. The work was supported by BioLife Science GmbH, Vienna, Austria; by project grant #10965 of the Austrian National Bank Science Fund; and by the Center of Excellence in Clinical and Experimental Oncology (CLEXO), Austrian Federal Ministry of Education, Science and Culture (GZ200.062/2-VI/1/2002). A.B. Riemer and K.H. Brämswig are recipients of Hans &amp; Blanca Moser Fund scholarships. The work was also supported by DFG (Lo635–2) and Fördergesellschaft Kinderkrebs-Neuroblastomforschung to H.N.Lode. [Table: see text]
Cognitive Dysfunction in Older Adults With Diabetes: What a Clinician Needs to Know
Authors: Medha N. Munshi
Journal: Diabetes Care (2017)

One of the challenges of managing older adults with diabetes is the individualization of care in people with multiple comorbid conditions. Although macrovascular and microvascular complications of diabetes are well recognized, there is a lack of awareness regarding other conditions such as cognitive dysfunction, depression, and physical disabilities. Cognitive dysfunction is of particular importance because of its impact on self-care and quality of life. In this Perspective, I discuss common and practical questions faced by clinicians managing diabetes in older adults who also have cognitive dysfunction.
Decreased TGFBR1 signaling and breast cancer.
Authors: Clark Henegan, Lakisha Moore-Smith, Nengjun Yi, Habibul Ahsan, Alice S Whittemore, Boris Pasche
Journal: Journal of Clinical Oncology (2013)

1548 Background: We previously identified TGFBR1*6A (rs11466445), a hypomorphic TGF-beta type 1 receptor variant that is associated with cancer risk, has impaired TGF-beta signaling capability, and enhances the migration and invasion of breast cancer cells (Cancer Res 2008, 68:1319). Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of breast cancer (Mol Biol Rep 2010 37:3227; PLoS One 2012,7(8). Rs7034462 is a single nucleotide polymorphism (SNP) in a noncoding region more than 9 kilobases upstream of TGFBR1 exon 1, which has been shown to be associated with decreased TGFBR1 expression similar to TGFBR1*6A (J Exp Clin Cancer Res 2010, 29:57). In this study we tested the hypothesis that rs7034462 may be associated with breast cancer risk. Methods: rs7034462 was genotyped in DNA obtained from patients with breast cancer and their unaffected sisters recruited by the Breast Cancer Family Registry (B-CFR). Results: The median age of cases and controls was 48.8 and 47.6 years, respectively. Using a simple case-control genetic association analysis for this family-matched population, rs7034462 was found to be associated with breast cancer risk. Conclusions: TGFBR1 rs7034462 is emerging as a low penetrance breast cancer susceptibility allele suggesting that two distinct TGFBR1 SNPs, each associated with decreased TGFBR1 expression, may modulate breast cancer risk. [Table: see text]
Preemptive versus deferred lamivudine in preventing chemotherapy (CT) interruptions in hepatitis B (HBV) carriers with non-hematological malignancy—preliminary report of a randomized phase III study
Authors: R. K. Ngan, H. Y. Yiu, H. C. Cheng, C. K. Kwan, T. W. Lam, D. Tsang, P. Kwok, W. W. Cheng, K. H. Au, K. H. Wong, T. C. Yip
Journal: Journal of Clinical Oncology (2007)

LBA19684 Background: About 10% cancer patients (pts) are HBV carriers in endemic areas, who have a risk of HBV reactivation with CT preventable by Lamivudine (Lam). Methods: Pts seropositive for HBV surface antigen (HBsAg+) planned to receive ≥ 4 cycles of CT for non-hematological malignancy were randomized to receiving either preemptive Lam during and for 8 weeks after CT (arm I), or observation only and deferred Lam at biochemical hepatitis reactivation (arm II). All pts had normal liver enzymes &amp; clotting profiles, age 18–75 &amp; KPS &gt;50 before entry. Serial clotting profile, liver enzyme and HBV DNA levels were monitored during CT and for 15 weeks post-CT. The endpoints include % of CT interruptions due to HBV reactivation (primary), HBV reactivation %, CT drug dose intensity levels &amp; HBV reactivation-free survival (all secondary). 110 pts are estimated to give a power of 90% to detect the projected difference in the primary endpoint at 2-sided alpha error of 0.05. Results: Pt accrual was completed in 1/07. As at 3/07, 92 (81%) of the 114 pts randomized have completed the study or died, and were included for analysis. Breast &amp; lung cancer constituted 71% of the cancers. There was no statistical difference in pt, cancer, CT, or viral characteristics between the 2 arms. Results are summarized in table . All 4 pts with CT interruptions and 11/14 pts with HBV reactivation had breast cancer. No difference in CT drug dose intensity levels was observed. Steroid used in the anti-emetic regimen was a significant factor in predicting viral reactivation in arm II pts in multivariate analysis. Conclusions: Although the incidence of CT interruptions was low in unselected pts without preemptive Lam, it was much higher in breast cancer pts despite deferred Lam, who also had significant rates of biochemical hepatitis &amp; viral reactivation. Preemptive Lam should be given to breast cancer pts, &amp; considered in other cancer pts receiving CT who are HBsAg+. [Table: see text] No significant financial relationships to disclose.
First-in-human study assessing safety and tolerability of REGN1979, a novel CD20xCD3 bispecific antibody, in patients with CD20+ B-cell malignancies previously treated with anti-CD20 therapy.
Authors: Carrie M. Brownstein, Lieve Adriaens, Rajat Bannerji, Julio C. Chavez, Ronald Levy, Stephen Maxted Ansell, Ranjana H. Advani, Snehal Patel, Ana Kostic, Pamela Trail, Israel Lowy, Holbrook Edwin Kohrt
Journal: Journal of Clinical Oncology (2015)

TPS3089 Background: REGN1979 is a human bispecific antibody based on an IgG4 isotype modified to reduce Fc binding, designed to bridge CD20-expressing cells to cytotoxic T-cells by binding to the CD3 subunit of the TCR complex. Bridging results in targeted killing of CD20+ cells by T-cells that is independent of typical requirements for specific TCR recognition of a target cell. T-cell activation requires CD20, a well-validated surface target for B-cell malignancies. This MOA is distinct from that of other available anti-CD20 antibodies, and may provide additional therapeutic benefit to patients with CD20+ malignancies, including those who have relapsed after anti-CD20 therapy. REGN1979 has been shown to specifically kill CD20+ tumor cells in vitro, and has shown potent in vivo anti-tumor activity in several mouse models (established Raji tumors and B16_hCD20)( Varghese B et al. ASH 2014. Abstract 4501). In cynomolgus monkeys, REGN1979 at doses ≥ 0.01 mg/kg depleted peripheral and tissue CD20+ B-cells to similar levels achieved with significantly higher doses of rituximab (30 mg/kg). At ≥ 0.1 mg/kg, REGN1979 depleted B-cells in spleen, mesenteric lymph nodes, and thymus to undetectable levels. Methods: This open label, multicenter, Phase 1, FIH study (NCT02290951) uses a 3+3 dose-escalation design with a 28-day DLT observation period to assess both acute and late toxicity. Each dose level (DL) has an initial dose followed by a second and subsequent higher dose, if the initial dose was tolerated. Patients receive REGN1979 IV weekly during a 4-week induction period at their assigned DL, then monthly for 5 additional doses. There will be parallel independent dose escalation cohorts for patients with NHL and CLL at each DL. After determining the recommended dose for further study, there will be an expansion phase with independent cohorts for patients with indolent NHL, aggressive NHL, and CLL. The primary objective is to assess the safety, tolerability, and DLTs of REGN1979. Secondary objectives include characterization of the PK profile, immunogenicity, and preliminary anti-tumor activity of REGN1979. Enrollment is ongoing. Clinical trial information: NCT02290951.
Tumor genotype and clinical outcomes for 229 patients with non-small cell lung cancer.
Authors: Regan M. Duffy, Grant Roesler, Andrea Warrick, Carol Beadling, Kathryn Schuff, Christopher L. Corless, Alan Sandler, Ariel Lopez-Chavez
Journal: Journal of Clinical Oncology (2013)

e19141 Background: Advances in genetic analysis have created a successful paradigm shift in the treatment of advanced lung cancer. Prior studies characterizing molecular profiles in lung cancer have been limited by analysis of a restricted number of genes and lack of clinical outcomes correlation. To overcome these limitations, this study investigates a prospective cohort of lung cancer patients using an expanded molecular profile and evaluates clinical outcomes. Methods: Non-small cell lung cancer (NSCLC) patients enrolled from April 1, 2011 through December 31, 2012 are included in this analysis. Formalin-fixed, paraffin-embedded tumor tissue was analyzed, using mass spectrometry-based panel of multiplexed assays (through July 31, 2012) or using next-generation sequencing detecting hydrogen-ions generated during DNA polymerization (using Ion Torrent from August 1 through December 31, 2012). Clinical information was collected at enrollment and throughout the study. Results: Analysis of 229 enrolled patients revealed 52% women, 95% had ECOG performance status 0-2, 89% Caucasian, and 28% never smokers. Successful molecular analysis (at least one successful analysis) occurred in 178 patients. Fifty-one patients had insufficient tissue for any successful molecular analysis. One hundred twenty-five mutations were detected among ninety-seven patients. The most frequent mutations included KRAS (28%), TP53 (20%), EGFR (13%), ALK translocations (6%), and BRAF (3%). At the time of analysis, 49% of the study population was deceased. Of the deceased, 37% harbored at least one genetic mutation within their tumor sample. Overall survival for those with mutations was 22.7 months, compared to overall survival for those without mutations of 23.3 months. Conclusions: Our analysis contributes to the growing body of data on molecular abnormalities in NSCLC by expanding the knowledge of common and less-commonly documented mutations, as well as characterizing the clinical outcomes associated with the mutations documented. These data emphasize the diversity of mutations and outcomes for NSCLC, and highlight the need for additional research of prognostic genetic markers and improvements in targeted therapies.
Cervical and colorectal cancer screening among breast cancer (BrCa) survivors followed in either a breast center (BC) or a breast survivorship clinic (SvC) at The University of Texas M.D. Anderson Cancer Center
Authors: A. L. Olson, T. Bevers, M. Guzman, R. L. Theriault, G. N. Hortobagyi, K. M. Hahn
Journal: Journal of Clinical Oncology (2009)

e20506 Background: An essential component of cancer survivorship care includes the prevention and early detection of new cancers. We sought to determine if documentation of appropriate cervical and/or colon cancer screening differed between BrCa survivors followed in our BC (patients &lt; 5 yrs from diagnosis of invasive BrCa or with active BrCa issues) and those seen in our SvC (patients with history of DCIS or ≥ 5 yrs from invasive BrCa diagnosis). Methods: IRB approval was obtained for this retrospective study. 5,982 BrCa survivors were seen for follow-up in our BC or SvC between 7/1/05 and 12/31/06. 2,811 BC patients and 1191 SvC patients (total = 4,002) met inclusion criteria: 1) not receiving chemotherapy, radiation, or undergoing surgical evaluation; 2) no evidence of recurrent BrCa; 3) ≥ 12 months from BrCa diagnosis, 4) no active GYN or GI complaints. Results: BrCa survivors followed our SvC were significantly more likely to have provider documentation of both cervical and colon cancer screening than those followed in our BC (72% versus 22.7%, and 68.4% versus 14.5%, respectively; both p values &lt;0.001). Although nursing documentation of cervical cancer screening is required in both centers, SvC patients were more likely to have this documented than those in the BC (95.3% versus 56.5%, respectively; p &lt;0.001). Nursing documentation of colon cancer screening is required in SvC (84.2% documented) but not in the BC (3.5% documented). Conclusions: BrCa survivors receiving care in our survivorship clinic were more likely to have nursing or provider documentation of cervical and/or colon cancer screening. Strategies that trigger documentation of non-BrCa screening take advantage of the “teachable moment” during a routine visit- thereby promoting the long-term health of cancer survivors. No significant financial relationships to disclose.
Prognostic and predictive effects of<i> KRAS</i> mutation subtype in completely resected non-small cell lung cancer (NSCLC): A LACE-bio study.
Authors: Frances A. Shepherd, Abderrahmane Bourredjem, Elisabeth Brambilla, Caroline Domerg, Jean-Yves Douillard, Martin Filipits, Stephen L. Graziano, Pierre Hainaut, Pasi Antero Janne, Thierry Le Chevalier, Gwenael Le Teuff, Jean-Pierre Pignon, Robert Pirker, Lesley Seymour, Jean-Charles Soria, Miquel Taron, Ming Sound Tsao
Journal: Journal of Clinical Oncology (2012)

7007 Background: We reported previously that KRAS is weakly prognostic and not significantly predictive of benefit from adjuvant chemotherapy (ACT) in NSCLC (Tsao et al. Proc ESMO 2012, Abst 4217). In colorectal cancer (CRC), KRAS mutation predicts resistance to EGFR monoclonal antibodies, but recent reports suggest that this may not be true for all mutation subtypes (De Roock et al. JAMA 2010). Smoking-related KRAS mutations in NSCLC differ from those of CRC. To explore the influence of KRAS mutation subtype, we undertook an analysis of KRAS subtype in LACE-Bio. Methods: KRAS mutation was determined in blinded fashion in 3 laboratories by direct sequencing. Exploratory analyses were performed to identify relationships between mutation status and subtype, overall (OS) and disease-free survival (DFS) using a Cox model stratified by trial and adjusted for covariates. Results: KRAS subtype was available in 1,532 patients (756 observation [OBS], 776 ACT). There were 300 mutations (275 codon 12, 24 codon 13, 1 codon 14). In the OBS arm, there was no difference in prognosis for OS for codon 12 (Hazard Ratio [HR] mutation v wild-type [WT] KRAS 1.04, CI .77-1.4) or codon 13 (HR 1.01, CI 0.47-2.17) mutations. A trend for benefit from ACT was observed in WT (HR ACT v OBS 0.89 CI 0.76-1.04, p=0.15) but not in patients with codon 12 mutations (HR 0.95, CI .67-1.35, p=0.77). In patients with codon 13 mutations, chemotherapy was deleterious (HR 5.78, CI 2.06-16.2, p&lt;0.001), test for equality among 3 HRs p=0.002. Results were similar for DFS. Among codon 12 mutations, there was no prognostic effect based on specific amino acid substitution. Patients with G12A or G12R mutations appeared to derive greater benefit from ACT (HR 0.66 p=0.48) compared to those with G12C or G12V (HR 0.94 p=0.77) or G12D or G12S (HR 1.39 p=0.48) or WT, but the differences were not significant (comparison of 4 HRs p=0.76). Conclusions: In this study, patients with KRAS codon 13 mutations had significantly poorer outcomes with ACT. These results require further confirmation and should be interpreted with caution in view of the small number of patients with codon 13 mutations. Supported by unrestricted grants from Sanofi Aventis and LNCC.
Patient, public, and oncologists’ attitudes toward rationing medical care.
Authors: Keerthi Gogineni, Katie Shuman, Derek Chinn, Carol Cosenza, Mary Ellen Colten, Floyd Jackson Fowler, Ezekiel J. Emanuel
Journal: Journal of Clinical Oncology (2013)

6518 Background: Lowering health care costs is critical. Patients with cancer (PT) and oncologists (MD) regularly make decisions regarding interventions with potentially marginal benefit but substantial expense. What are the attitudes of PT, the public (GP), and MD on ways to control costs? Methods: In 2012, surveys were completed by 326 adult PT (Response Rate (RR)=72%), a random sample of 891 U.S. adults (RR=50%) and 245 MD (RR=55%). Results: A majority thought Medicare spending was a big or moderate problem (76% PT; 75% GP; 97% MD) and that Medicare could spend less without causing harm (66% PT; 70% GP; 74% MD). Respondents attributed rising costs to multiple factors including drug companies charging too much (94% PT; 90% GP; 94% MD) and insurance company profits (88% PT; 88% GP; 83% MD). Many also thought physicians and hospitals provided unnecessary tests and treatments (RX) (69% PT; 81% GP; 70% MD). Regarding solutions, most supported refusing to pay for expensive care if an equally effective, less expensive alternative was available or if therapy did not improve survival or quality of life (QOL). Few respondents were willing to refuse payment for RX that extend life by 4 months. Conclusions: The majority of those sampled view Medicare costs as a substantial problem and pharmaceutical and insurance companies as significant contributors. The GP in particular believe physicians and hospitals add considerably to the cost problem. A majority favor not paying for more expensive RX when cheaper ones are equally effective or if RX do not improve survival or QOL. MD were accepting of an independent oversight panel however this was met with resistance by PT and the GP. Currently, Medicare and other payers do not consistently follow such practices. [Table: see text]
Alterations in small leucine-rich proteoglycans in right-sided colorectal cancer.
Authors: Maria Del Pilar Solis Hernandez, Olivia Pilar García-Suárez, Ivan Fernández-Vega, Luis M Quirós, Beatriz García
Journal: Journal of Clinical Oncology (2017)

652 Background: Colorectal cancer (CRC) is a heterogeneous disease, and there are anatomic, functional and molecular differences between the tumors of the proximal and distal colorectum. Various molecular phenotypes have been associated with aggressive subtypes in these pathologies, and several of these markers show a relationship with proteoglycans, which in turn show significant alterations in colon tumors, which affect both their core proteins and their glycosaminoglycan chains. Small leucine-rich proteoglycans (SLRPs) constitute a family of molecules encoded by 18 distinct genes. They are grouped into five classes and may appear coupled to different glycosaminoglycan chains ––including chondroitin/dermatan sulfate or keratan sulphate–– or not, depending on the specific species. They are ubiquitously expressed in extracellular matrices, and have been found involved in the regulation of organ size and shape during embryonic development. In this study we investigate the expression patterns of SLRPs in right-sided CRCs. Methods: A transcriptomic approach was used, employing qPCR to analyze SLRP core protein transcriptions. Immunohistochemical techniques were also used to analyze tissue expression of particular genes showing significant expression differences of potential interest. Results: Only two proteins displayed significant alterations: biglycan appeared overexpressed approximately 4 fold (p = 0.015), and osteoglycin decreased about 4 fold (p = 0.05). Transcripts for epiphycan, opticin, nyctalopin and podocan-like 1 were not detected in most patients, while chondroadherin was detected in 50% of healthy tissues but not in CRCs. Expression of lumican, decorin, keratocan, asporin, ECM2, fibromodulin, PRELP, tsukushi, podocan and osteoadherin was detected, but with no significant differences compared to healthy tissue. Conclusions: Normal mucosa of the large bowel expresses most SLRPs, and two, biglycan and osteoglycin, appeared altered in right-sided CRCs. These alterations could be related to binding of different ligands and modulation of homeostasis.