tbuckley/cabot-search huggingface dataset:
Selecting peptides for breast cancer treatment.
Authors: Eloah Rabello Suarez, Helena Bonciani Nader, Maria Aparecida Silva Pinhal, Auro Del Giglio
Journal: Journal of Clinical Oncology (2012)

e13016 Background: HER2 is a member of epidermal growth factor family of receptors that is an essential mediator of cell proliferation and differentiation. In breast cancer patients, HER2 overexpression is associated with aggressive disease, chemo and hormone therapy resistance and poor prognosis. Currently, a HER2 specific monoclonal antibody, trastuzumab, is in use as a treatment for these breast cancer cases; however, there are many reports of resistance to this treatment. As an alternative we have selected specific peptides to HER2 using a phage display technology. Methods: A cyclic 7 aminoacids random peptide library had been panned using an external domain of recombinant HER2. After each round of binding assays, peptides were sequenced and two were selected. Cellular viability, migration and apoptosis/necrosis induced by these peptides were evaluated using SKBR3 cells. Confocal microscopy was used to determine the peptides co-localization with acidic vesicles and heparan sulfate. Western blotting was performed to evaluated some cell signalling pathways induced by these peptides. Results: The peptides were able to reduce the cell viability and migration around 50% alone and 85% in association. Tavelorb was able to induce apoptosis/ necrosis in 70% of SKBR3 cells and when associated with Hercid, the effect has increased to 90%. These peptides co-localize with acidic vesicles around 40-50%. The peptides and trastuzumab co-localized with heparan sulfate around 70%. The association between Hercid and Tavelorb inhibits Akt (pSer473) and the proteins enrolled in this pathway, as GSK3 and the transcription factor c-myc, however Akt inhibition is not dependent of PTEN. In addition, this peptides decreases BCL-XL, and MCL-1, while enhance Bax. The most important effect of this peptides is the reduction in β-catenin expression. Interestingly, p53 is downregulated in the presence of trastuzumab showing a mechanism by some tumors could be resistant to this therapy. Conclusions: The association of peptides has a very effective antitumoral effect in vitro, and their action seems to be HS dependent. The data propose a potential use of these peptides as a future alternative for breast cancer treatment. Supported by FAPESP, CNPq, CAPES.
A Phase II study of T900607 (T607) in subjects with chemotherapy-naïve unresectable hepatocellular carcinoma (HCC)
Authors: C. R. Garrett, C. R. Becerra, R. Chan, M. Hirmand
Journal: Journal of Clinical Oncology (2004)

4125 Background: T607 (a compound related to T67) is a novel irreversible tubulin inhibitor currently undergoing Phase 2 investigation for the treatment of various malignancies. Methods: In this Phase 2 study, subjects with chemotherapy-naïve unresectable HCC received T607 as a weekly 1-hour infusion at a dose of 100 mg/m2. Results: 37 subjects were enrolled in 11 centers from July 2002 to November 2003. Subject follow-up is ongoing; to date, 23 subjects have had at least one follow-up radiographic assessment (performed every 6 weeks) and are currently evaluable for best response assessment: 1 (4%) subject with a partial response (PR), 13 (57%) subjects with stable disease and 9 (39%) subjects with disease progression. A >50% reduction in alpha-fetoprotein (AFP) was observed in 2 of 15 (13%) subjects with baseline AFP >200 ng/mL (and at least one follow-up AFP measurement); 1 of these 2 subjects had a PR. Available safety data for 34 subjects indicate that the most frequent adverse events considered related to T607 were rigors (38%), pyrexia (32%), nausea (32%), vomiting (21%), anemia (21%), fatigue (15%), and anorexia (12%). No drug-related grade 4 adverse events were reported. Median nadir hematologic laboratory values were: ANC 5,040 cells/mm3, Hgb 10.4 g/dL, and platelets 179,000 cells/mm3. Conclusions: These results support that T607 is well-tolerated and has moderate activity in subjects with HCC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Tularik, Inc. Tularik, Inc. Tularik, Inc.
Comment on Anjana et al. Incidence of Diabetes and Prediabetes and Predictors of Progression Among Asian Indians: 10-Year Follow-up of the Chennai Urban Rural Epidemiology Study (CURES). Diabetes Care 2015;38:1441–1448
Authors: Tomoyuki Kawada
Journal: Diabetes Care (2015)

Anjana et al. (1) conducted a 9.1-year follow-up study targeting 1,376 individuals aged ≥20 years to elucidate the predictors of progression to dysglycemia, which included diabetes and prediabetes. They adopted the Cox proportional hazards model, and hazard ratios (95% CI) of independent variables were presented. I am satisfied with the adequate number of new-onset diabetes or prediabetes events, and I have some queries on their study.

First, significant predictors of progression to dysglycemia from normal glucose tolerance in their study were age, family history …
Abstract IA01: Immunologic heterogeneity of cancer: Determinants of response and resistance to immunotherapy
Authors: Suzanne L. Topalian
Journal: Clinical Cancer Research (2015)

Abstract Complex interactions between the immune system and cancer influencing tumor invasion, metastasis, and treatment outcomes are poorly understood. Similar to the influence of intra- and inter-tumoral genetic heterogeneity on response and resistance to molecularly targeted therapies, immunologic heterogeneity may explain the outgrowth of resistant tumor clones under the selection pressure of immunotherapy. Evidence for this phenomenon emerged from the results of high-dose IL-2 therapy, with responding metastases showing brisk CD8+ T cell infiltration, while non-responding lesions in the same patients were lymphocyte-poor. It has also been shown in patients receiving adoptive cell transfer therapies (TILs, CARs), with initial tumor regression followed by the outgrowth of tumors that have down-regulated target antigens. More recently, clinical experience with drugs blocking immune checkpoint molecules such as CTLA-4, PD-1 and PD-L1 has revealed unconventional response patterns in 5-10% of patients, including mixed tumor regressions (simultaneous progression/regression at different metastatic sites in an individual patient). Our investigations of the immunosuppressive ligand PD-L1, expressed by many human tumors, as a potential biomarker of response to anti-PD-1 therapy have revealed intra-tumoral as well as inter-tumoral heterogeneity of expression. Within individual tumor lesions, PD-L1 protein expression (IHC) can be patchy or focal, co-localizing with lymphoid infiltrates. Further study on a molecular level revealed expression of IFN-g in the same microenvironment as PD-L1, along with PD-1 and other immunosuppressive molecules, generating the adaptive immune resistance hypothesis. Examination of PD-L1 protein expression in multiple tumor lesions from individual patients showed variability over time and at distinct anatomic sites, consistent with the dynamic and context-dependent nature of immune responses, suggesting that inter-lesional variability could influence susceptibility to anti-PD-1 or PD-L1 therapy. Innovative approaches such as neoadjuvant immunotherapy trials or rapid autopsy analysis are needed to gain a deeper knowledge of tumor immunologic heterogeneity and potential intersections with genetic heterogeneity. This will be critical to understanding the evolution of anti-tumor immunity and developing more effective immune-based and combinatorial therapies. This work was supported by grants from Bristol-Myers Squibb, the National Cancer Institute (R01 CA142779), the Melanoma Research Alliance, the Barney Family Foundation, the Dermatology Foundation, and Stand Up To Cancer. Citation Format: Suzanne L. Topalian. Immunologic heterogeneity of cancer: Determinants of response and resistance to immunotherapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA01.
General practitioners' knowledge and use ofliving wills
Authors: M. Ashby, M. Wakefield, J. Beilby
Journal: BMJ (1995)

<h3>Objective.</h3> Subcutaneous (SC) abatacept (ABA) is comparable to intravenous (IV) formulation in terms of efficacy and safety profile. Our work analyzed the switch to SC formulation from IV administration in patients with rheumatoid arthritis. <h3>Methods.</h3> Fifty-one patients treated with SC ABA were included. Clinical data were obtained from clinical charts. <h3>Results.</h3> Fourteen patients relapsed and needed to return to the IV administration. Neither clinical and laboratory features nor the previous therapies were identified as risk factors for SC formulation inefficacy. Disease activity decreased after the return to IV infusions. <h3>Conclusion.</h3> SC ABA showed a risk of relapse in 27% of cases. The reinsertion of the IV administration quickly reinstated disease control.
Is indicated after long term treatment with heparin
Authors: C. Nelson-Piercy, M. De Swiet
Journal: BMJ (1995)

EDITOR,—There is an important omission from the clinical indications for bone densitometry listed in J E Compston and colleagues' review article1—namely, long term treatment with heparin, which causes osteoporosis.2 The most common indication for long term heparin is thromboprophylaxis in pregnant women. It is our policy to treat women at high risk of thromboembolism (those with a history of …
Diagnosis of Metastatic Malignant Melanoma by Fine Needle Aspiration Biopsy: A Clinical and Pathologic Correlation of 298 Cases&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M D Perry, H F Seigler, W W Johnston
Journal: JNCI Journal of the National Cancer Institute (1986)

Fine needle aspiration biopsies (FNABs) from 298 lesions in patients with suspected metastatic melanoma were studied. The results were correlated either with histopathologic diagnoses on resected lesions or with prolonged clinical follow-up. Of 165 malignant aspirates, 160 were confirmed either by surgical resection (65 cases) or by an appropriate clinical course (95 cases). Of the 107 benign lesions with adequate follow-up, 73 were confirmed as benign. There were 25 false negatives: 19 were inadequate samples, and 6 were presumed failures of needle localization. No interpretative errors were identified. Although 3 cases of FNAB-diagnosed malignant melanoma could not be confirmed by surgical biopsy, the cytologic findings were typical of malignant melanoma. Clinical follow-up, however, suggested that the cytologic diagnosis was in error. One case of a second unrelated malignancy (an adenocarcinoma of the lung) was correctly diagnosed with the use of FNAB. Because of its high degree of accuracy, FNAB has proved useful in the differential diagnosis of subcutaneous nodules, enlarged lymph nodes, and lung nodules.
Calibrating clinically significant effects in survival and response endpoints in cancer clinical trials.
Authors: A. C. Dueck, D. J. Sargent, P. J. Novotny, P. A. Decker, H. Nelson, R. Qin, J. A. Sloan
Journal: Journal of Clinical Oncology (2011)

6130 Background: Clinically significant effect sizes have been the focus of much research for assessing patient-reported outcomes (PROs). Methods such as the empirical rule effect size or ½ standard deviation (SD) method are useful for efficient design and improved interpretation of clinical studies. While the concept of clinical significance is ubiquitous in PRO research, it is less standardized in clinical trials involving tumor response and survival endpoints. Methods: We applied the ½ SD rule to survival and response endpoints to define clinically significant effect sizes. We present clinically significant effect sizes for expected mean and median survival using the exponential distribution and response rate using the binomial distribution. We apply the method to published studies. Results: The clinically significant effect size for survival endpoints is 50% of the expected mean survival or roughly 72% of the expected median survival. A small effect size (1/5 SD) is 20% or roughly 29% of the expected mean or median survival, respectively. For example, a recent study of lapatinib alone vs in combination with trastuzumab reported a median survival difference of 12.6 weeks (39 vs 51.6 weeks) with a p-value of 0.11. This translates into an effect size of 0.22 SD, which calibrates to a small effect. Further, Booth et al. (JCO, 2008) summarized results for 321 randomized clinical trials. Applying our method indicates that survival effect sizes ranged from very small (0.01 SD) to very large (1.5 SD). The clinically significant effect size for response endpoints is a function of the expected response rate. For a 50% expected response rate, the clinically significant effect size is 25% and a small effect size is 10%. Conclusions: This method allows for more ready interpretation of the clinical significance of survival and response studies. It allows for direct cross study comparison even if the endpoints are different. It also facilitates study design as it builds clinical significance into the study directly. Cancer clinical trials seem to be designed with smaller effect sizes for survival than for tumor response and PRO endpoints.
Abstract 20594: Variation of Radiation Usage and Current Practice in the Pediatric Cardiac Catheterization Laboratory - A Multicenter Study by the CCISC (Congenital Cardiovascular Interventional Study Consortium)
Authors: Daisuke Kobayashi, Thomas J Forbes
Journal: Circulation (2014)

Introduction:  Reduction of radiation dosage is an important task of quality improvement in pediatric cardiac catheterization laboratories. Comparison of data with a benchmark allows intra and inter-institutional comparisons to be made. To date, institutional variation of catheterization practices focusing on radiation dosage has not been well described.   Hypothesis:  We hypothesized that radiation dosage significantly vary between institutions and there may be significant effect of frame rate on radiation dosage.   Methods:  This was a multicenter observational study of children undergoing catheterizations in pediatric laboratories. Utilizing normalized air Kerma area product (P KA ) by body weight (P KA /BW, μGym 2 /kg) as a standardized measure, institutional variation and trend of radiation dosage from 2009 to 2013 were analyzed. Cases were broken down into interventional, diagnostic, and transplant right ventricular transplant biopsy. These cases were further categorized into high (30 frame/sec for cine and 15 for fluoroscopy) and low (15 and 7.5, respectively) frame rate groups and the effect of frame rate on radiation dosage was assessed.   Results:  Among 8267 procedures from 16 institutions, P KA /BW was significantly variable between institutions ( p  KA /BW of diagnostic and interventional procedures over 5 years, despite no significant change in fluoroscopic time. High frame rate group had significantly higher P KA /BW ( p    Conclusions:  P KA /BW appeared to be a useful standardized measure of radiation dose to compare between institutions. Significant variation of radiation dosage suggests a need of quality control in this field. Use of lower frame rates significantly lowered radiation dosages for similar procedural types. A concerted effort should be made to lower the frame rates in labs with consistently higher radiation usage.
Evolution of the expression of the Gld gene in the reproductive tract of Drosophila.
Authors: N M Schiff, Y Feng, J A Quine, P A Krasney, D R Cavener
Journal: Molecular Biology and Evolution (1992)

During the preadult development of Drosophila melanogaster, the GLD (glucose dehydrogenase) gene (Gld) is expressed in a variety of tissues, including the immature reproductive tract. At the adult stage the expression of Gld becomes largely restricted to the reproductive tract of males and females. We examined the expression of GLD in the adult reproductive tract of 50 species in the genus Drosophila, as well as in those of a few representative species from four other closely related genera. GLD exhibits considerable organ-specific diversity in the reproductive tract of males and females. Among these species, five male GLD phenotypes and six female GLD phenotypes were found. In contrast, the preadult expression of GLD in representative species from each distinct adult pattern type was determined and found to be highly conserved in both the immature reproductive tract and non-reproductive organs. Moreover, the set of reproductive organs that express GLD during preadult development is equivalent to the sum of the five male and six female adult GLD phenotypes. To initially define the contribution of cis- versus trans-acting factors responsible for differences in adult GLD expression between two of these species--D. melanogaster and D. pseudoobscura--we transferred the D. pseudoobscura Gld to the genome of D. melanogaster and investigated its expression. GLD expression patterns of these transformants displayed characteristics that are unique to both species, suggesting the presence of both cis- and trans-acting differences between these two species.
Phase III study of <i>nab</i>-paclitaxel (<i>nab</i>-P) plus gemcitabine (Gem) versus Gem alone in patients (pts) with metastatic pancreatic adenocarcinoma (mPC): Subgroup analysis of Canadian pts from the MPACT trial.
Authors: Mustapha Ali Tehfe, Scot D. Dowden, Hagen F. Kennecke, Robert Hassan El-Maraghi, Bernard Lesperance, Felix Couture, Richard Letourneau, Darryl Neil Penenberg, Alfredo Romano, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (2015)

439 Background: Weekly nab-P + Gem is a new option for first-line treatment (Tx) of mPC. In the MPACT trial, nab-P/Gem demonstrated superior overall survival (OS; primary endpoint) vs Gem alone as first-line Tx of mPC (Table). Here we report a subgroup analyses evaluating the efficacy and safety outcomes with nab-P + Gem vs Gem alone from the Canadian cohort of the MPACT trial. Methods: Previously untreated pts (N = 861) with mPC were randomized 1:1 (stratified by Karnofsky Performance Status [KPS], region, and the presence of liver metastases) to receive nab-P 125 mg/m 2 + Gem 1000 mg/m 2 on days 1, 8, and 15 of each 28-day cycle or Gem 1000 mg/m 2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: 63 pts from Canada enrolled in the MPACT trial. Baseline pt characteristics were well balanced. Median age was 61 years and KPS was similar for both groups and comparable to the intent-to-treat (ITT) populations. Primary lesion in the pancreatic head was more common among pts in the nab-P + Gem vs Gem arm (55% vs 30%); use of biliary stent was similar (33% nab-P + Gem; 27% Gem). Median OS and progression-free survival (PFS) were longer with nab-P + Gem vs Gem (Table). Median Tx duration was 4.2 mo with nab-P + Gem vs 3.2 mo with Gem. Use of subsequent therapy was 30% in the nab-P + Gem arm vs 43% in the Gem arm. The median relative dose intensity for Gem was similar in each arm (81% nab-P + Gem vs 85% Gem). The most common grade ≥ 3 AEs for nab-P + Gem vs Gem were neutropenia (22% vs 10%), fatigue (34% vs 33%), and neuropathy (25% vs 0%). Conclusions: Canadian pts participating in MPACT were similar to the ITT population and nab-P + Gem was well tolerated and showed improved median OS, PFS, and ORR vs Gem alone, although not statistically significant (likely due to the small number of pts). Clinical trial information: NCT00844649. [Table: see text]
Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: Results of the randomised MRC ASTEC and NCIC CTG EN.5 trial
Authors: J. Orton, P. Blake
Journal: Journal of Clinical Oncology (2007)

5504 Background: Patients with stage I endometrial cancer at high risk of relapse generally receive adjuvant EBRT following surgery, despite lack of evidence that radiotherapy improves overall survival (OS). ASTEC/EN.5 was designed to investigate whether OS is improved by adjuvant EBRT. An important secondary outcome was pelvic recurrence-free survival. Methods: Patients were randomised to receive immediate EBRT (with linear accelerator delivering 40–46Gy in 20–25 fractions to pelvis) or no EBRT until clinically indicated. Vault brachytherapy (4Gy in 2 fractions (HDR) or 15Gy (LDR)) could be used regardless of EBRT allocation. Centers were required to specify in advance whether brachytherapy would be offered to all patients or to none. The study was powered both to 1) detect a 9–10% absolute improvement in 5-year OS with adjuvant EBRT; and 2) reliably exclude an absolute 5% difference in 5-year OS when combined with other major studies (PORTEC and GOG 99). Results: Between Oct 1996 to Apr 2005, 906 patients (452 EBRT, 454 no EBRT) were randomised internationally. Pre-treatment characteristics were well balanced: median age 66 years; 98% of women WHO PS 0–1; 30% with lymph nodes removed at surgery; 84% endometrioid histology; depth of invasion to endometrium only, inner half and outer half of myometrium 3%, 20% and 77%, respectively; degree of differentiation to grade 1, 2, and 3 26%, 42%, and 31%, respectively. 92% patients in EBRT arm received immediate treatment, 90% receiving all protocol specified treatment. 2% patients in no EBRT arm received immediate EBRT. Brachytherapy was given to 52% patients in both arms. Morbidity was higher in EBRT arm, 56% compared with 24% in no EBRT arm reporting complications of treatment. Grade 3 or higher toxicity was rare. With a median follow-up of 46 months at the time of analysis, 117(13%) have died and 136(17%) have recurred or died. 130 deaths are required to detect a 10% difference in 5-year OS with 5% significance level and 90% power and this will be achieved by April 2007. Conclusions: Compliance was high. Serious complications were rare. The ASTEC/EN.5 trial alone and in combination with PORTEC and GOG99 will answer the question of the benefit of post-operative adjuvant EBRT in patients with endometrial cancer. No significant financial relationships to disclose.
T-Cell Frequencies In MCL Are Of Prognostic Importance In a Large Population-Based Cohort
Authors: Lina Nygren, Stefanie Baumgartner-Wennerholm, Jeppson-Ahlberg Åsa, Monika Klimkowska, Agata M Wasik, Patrik Andersson, Daren Buhrkuhl, Birger Christensson, Björn Engelbrekt Wahlin, Eva Kimby, Birgitta Sander
Journal: Blood (2013)