tbuckley/cabot-search huggingface dataset:
Using ANG4043, a brain-penetrant anti-HER2 mab, to increase survival in a murine intracranial breast tumor model.
Authors: Jean E Lachowicz, Michel Demeule, Anthony Regina, Sasmita Tripathy, Christian Che, Jean-Christophe Currie, Simon Lord-Dufour, Emilie Houle, Jean-Paul Castaigne
Journal: Journal of Clinical Oncology (2013)

e13013 Background: Treatments for metastatic brain tumors originating from HER2-positive breast disease are limited due to the inability of most anti-tumor agents to enter the brain. While the selectively permeable blood-brain barrier (BBB) restricts access of therapeutics such as mAbs to the brain, transcytosis of hormones, nutrients, and other homeostatic modulators is mediated by endogenous receptors such as LRP1, low density lipoprotein receptor-related protein 1. We have created a family of peptides (Angiopeps) that are recognized by LRP1 and enter the brain via transcytosis. Using these proprietary Angiopeps, we have created novel, brain-penetrant Peptide-Drug Conjugates. An iterative process of linker selection and reaction condition optimization led to the discovery of ANG4043, consisting of the Angiopep An2 attached to a trastuzimab biosimilar. This brain-penetrant peptide-mAb conjugate, which displays HER2 binding affinity and in vitro anti-proliferative properties similar to that of the native mAb, was tested in a murine model of breast tumor brain metastases. Methods: Athymic nude mice were stereotactically implanted 1.5 mm anterior and 2.5 mm lateral to bregma with 1X10 6 BT-474 cells twelve days prior to initiation of drug treatment. Body weight and morbidity/mortality were monitored daily. Results: Median survival in the control group was 45 days, compared with 68 days and 80 days for the 5 mg/kg (p = 0.0005) and 15 mg/kg (p = 0.0003) groups, respectively, demonstrating a 52% and 78% improvement over the control group. Conclusions: These data demonstrate that ANG4043 increases survival in a mouse HER2-positive intracranial tumor model. These results extend the validation of An2 conjugation beyond small molecules and peptides to include larger molecules such as therapeutic mAbs for development of new brain-penetrant anti-tumor therapeutics.
Cyclin B1, D1 overexpression and its correlation with clinical prognostic factors in ovarian carcinoma
Authors: J. W. Kim, Y. T. Kim, H. Y. Kim, M. H. Kang, J. H. Kim, S. H. Kim, S. W. Kim, B. S. Yoon
Journal: Journal of Clinical Oncology (2006)

15067 Background: The change of cell cycle is one of the characteristics of cancer. The various proteins related to the cell cycle have been revealed and their expression in ovarian carcinoma has been demonstrated. Therefore, this study was conducted to determine the expression of cyclin B1, D1 and evaluate the relationship between cyclin B1, D1 and clinical prognostic factors in patients with ovarian carcinoma. Methods: 41 fresh ovarian tissue samples including 36 ovarian carcinomas and 5 normal ovarian tissues were surgically obtained at YUMC from May 2002 to February 2005. Cyclin B1, D1 expression were detected using the quantitative real-time RT-PCR and Western blot analysis. For clinical prognostic factors, age, stage, grade, histopathology, LN metastasis, residual tumor size, CA 125 and DNA flow cytometry were evaluated. Results: By quantitative real time RT-PCR, the mean 2 −ΔΔCT value of cyclin B1 and D1 mRNA in ovarian carcinoma was 5.83 ± 12.03, 17.60 ± 22.20, slightly higher than that of the control. (p = 0.67, 0.07). The mean value of relative protein levels of cyclin B1 and D1 in Western blot analysis was also higher in ovarian carcinoma (1.30 ± 0.73, 1.81 ± 1.28, respectively) (p = 0.76, 0.06). No significant relationship of cyclin B1, D1 expression and clinical prognostic factors was observed. Conclusions: The expression of cyclin B1, D1 in ovarian carcinoma was higher than that of the control, although there was no statistical significance. This suggests that cyclin B1, D1 might be involved in the tumorigenesis and the progression of malignancy. Even though there was no significant correlation between cyclin expression and prognostic factors, further studies are needed assessing the relationship between cyclin expression and survival rate to elucidate the role of cyclin as a prognostic factor in ovarian carcinoma. No significant financial relationships to disclose.
Effects of weekly bevacizumab and gemcitabine/oxaliplatin with or without dasatinib on heavily pretreated patients with recurrent or persistent cervical cancer.
Authors: Masashi Takano, Yoshihiro Kikuchi, Yuji Ikeda, Naoki Sasaki, Tomoko Goto, Hiroko Kouta, Ryoko Kikuchi, Kazuya Kudoh, Tsunekazu Kita, Kenichi Furuya
Journal: Journal of Clinical Oncology (2012)

e15579 Background: Prognoses of patients with recurrent and metastatic cervical cancer who received treatment including radiotherapy are commonly dismal. In such clinical settings effective treatment modalities are waited. Thus, we attempted to explore effects of weekly bevacizumab (B) and gemcitabine/oxaliplatin (GEMOX) with or without dasatinib (D). Methods: Ten cases with recurrent and metastatic CC after intensive treatment including radiotherapy were treated by weekly B (2mg/kg) and GEM (300mg/m 2 )/ OX (30mg/m 2 ) with or without D (50mg/day) (3 weeks, one week rest) with written informed consents. The treatment was continued until development of progressive disease (PD) or unmanageable adverse effects. Adverse effects were analyzed according to NCI-CTCAE v3. The responses were evaluated by RECIST criteria. Results: In RECIST evaluation, one (10%) of 10 patients had complete remission (CR) and 4 (40%) had partial remission (PR). Overall response rate was 50%, and response was observed in four (80%) of 5 cases combined with D, and 1 (20%) of 5 patients without D. It is noteworthy that response was observed in 3 (60%) of 5 adenocarcinoma patients. Median progression-free survival (PFS) and overall survival (OS) were 6 months and 13 months, respectively. Hematological adverse effects more than grade 1 were not observed. Neurotoxicity, nasal bleeding, and general fatigue were frequently observed, but these were all grade 1. There was no toxicity-related death, and the regimen was well tolerated. Conclusions: The present preliminary study demonstrated weekly B and GEMOX with or without D was effective in heavily pretreated cervical cancer patients with tolerable toxicities, especially in patients with adenocarcinoma. These results warrant further study in such clinical settings.
Genotype–phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis
Authors: J.K. Simpson, M. Martinez‐Queipo, A. Onoufriadis, S. Tso, E. Glass, L. Liu, T. Higashino, W. Scott, C. Tierney, M.A. Simpson, R. Desomchoke, L. Youssefian, A.H SaeIdian, H. Vahidnezhad, A. Bisquera, J. Ravenscroft, C. Moss, E.A. O'Toole, N. Burrows, S. Leech, E.A. Jones, D. Lim, A. Ilchyshyn, N. Goldstraw, M.J. Cork, S. Darne, J. Uitto, A.E. Martinez, J.E. Mellerio, J.A. McGrath
Journal: British Journal of Dermatology (2019)

Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype–phenotype correlation in some populations. We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype–phenotype correlation. Deep phenotyping was undertaken by history‐taking and clinical examination. DNA was screened for mutations using a next‐generation sequencing ichthyosis gene panel and Sanger sequencing. Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self‐improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype. These data refine genotype–phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype–phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.
Statistics on mortality following acute myocardial infarction in 842 897 Europeans
Authors: Oras A Alabas, Tomas Jernberg, Mar Pujades-Rodriguez, Mark J Rutherford, Robert M West, Marlous Hall, Adam Timmis, Bertil Lindahl, Keith A A Fox, Harry Hemingway, Chris P Gale
Journal: Cardiovascular Research (2019)

Abstract Aims To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments. Methods and results National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 patients, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART)] and the UK [n = 247, 662 529 patients, Myocardial Ischaemia National Audit Project (MINAP)] between 2003 and 2013. There were lower rates of revascularization [STEMI (43.8% vs. 74.9%); NSTEMI (27.5% vs. 43.6%)] and pharmacotherapies at time of hospital discharge including [aspirin (82.9% vs. 90.2%) and (79.9% vs. 88.0%), β-blockers (73.4% vs. 86.4%) and (65.3% vs. 85.1%)] in the UK compared with Sweden, respectively. Standardized net probability of death (NPD) between admission and 1 month was higher in the UK for STEMI [8.0 (95% confidence interval 7.4–8.5) vs. 6.7 (6.5–6.9)] and NSTEMI [6.8 (6.4–7.2) vs. 4.9 (4.7–5.0)]. Between 6 months and 1 year and more than 1 year, NPD remained higher in the UK for NSTEMI [2.9 (2.5–3.3) vs. 2.3 (2.2–2.5)] and [21.4 (20.0–22.8) vs. 18.3 (17.6–19.0)], but was similar for STEMI [0.7 (0.4–1.0) vs. 0.9 (0.7–1.0)] and [8.4 (6.7–10.1) vs. 8.3 (7.5–9.1)]. Conclusion Short-term mortality following STEMI and NSTEMI was higher in the UK compared with Sweden. Mid- and longer-term mortality remained higher in the UK for NSTEMI but was similar for STEMI. Differences in mortality may be due to differential use of guideline-indicated treatments.
Defining a FISH chromosomal aneusomy panel for predicting lung cancer in the setting of CT-detected lung nodules.
Authors: Wilbur A. Franklin, Margaret Skokan, Marina T Lewis, William Feser, Holly J Wolf, York E Miller, Daniel Merrick, Anna E Barón, Marileila Varella-Garcia
Journal: Journal of Clinical Oncology (2012)

10580 Background: Early detection of lung cancer by CT is supported by the National Lung Screening Trial; but while sensitivity of CT is high, specificity is low. Biomarkers to predict the malignant nature of CT detected lung nodules would have great clinical utility. We previously found in a nested case-control study that a 4-target chromosomal aneusomy (CA) FISH panel exhibited sensitivity/specificity of 76%/88% in sputum samples of heavy smokers obtained within 18 months of lung cancer diagnosis. We hypothesized that CA-FISH may be an effective biomarker to assist with clinical decisions in the setting of CT detected lung nodules of indeterminate etiology and attempted to identify a more effective reagent. Methods: Homebrew probes encompassing genomic sequences of EGFR, NXK2-1, PIK3CA, MYC, BRF2, SOX2, PPMID, FGFR1 and the commercial reagent LSI D5S721/D5S23 (Abbott Molecular) were combined in 2-4-target FISH assays to investigate tissue copy number in early stage lung squamous cell carcinoma (SCC, N=19) and adenocarcinoma (AC, N=20). Logistic regression models were used to estimate predictive discrimination [sensitivity, specificity, area under the ROC curve (AUC)]. Results: Copy number gain was largely detected for all markers (mean range 3.39 - PPMID to 4.67 - MYC). Mean copy number of PI3CA, BRF2, SOX2 and FGFR1 were significantly higher in SCC than AC, while NKX2 and MYC were marginally higher in AC than SCC. Gene amplification was detected for all 9 markers, most frequently for SOX2 and FGFR1 (6 and 5 cases) with significant overlap between FGFR1/BRF2 and SOX2/PIK3CA. Based on the AUC results and the existence of targeted inhibitors, the probe set EGFR/FGFR1/MYC/PIK3CA was selected as a candidate for further development as an adjunct to CT screening for early detection. For this selected set,the optimal cutoff based in the linear predictor from logistic regression yields a sensitivity and specificity of 0.85. Conclusions: A highly sensitive/specific CA-FISH probe set was identified which may well complement CT screening in the early diagnosis of lung cancer. This probe set will be tested in the setting of CT detected lung nodules. (Supported by LUNGevity and NCI-Lung Cancer SPORE grants).
Does quality of treatment-related harms reporting affect conclusions about superiority of treatment?
Authors: R. S. Mhaskar, A. Kumar, H. Soares, M. Schell, B. Djulbegovic
Journal: Journal of Clinical Oncology (2009)

6607 Background: It is often not known if harms were considered in the overall benefit-risk evaluation in deciding about the superiority of treatments. Here we present a study examining the relationship between researchers’ conclusions about the superiority of treatment with quality of treatment-related harms reporting. Methods: We reviewed all consecutive phase III randomized clinical trials (RCTs) conducted by Southwest Oncology Group from 1960 to 2003 (117 RCTs involving 139 comparisons enrolling 58,908 patients). We extracted data on primary outcomes [overall survival (OS), event free survival (EFS)], and treatment-related mortality (TRM). We classified the quality of reporting as good, intermediate or poor. Association of superiority of treatment and harms reporting was evaluated using chi-square test and meta-analytic techniques. Results: 76% of studies (106/139) reported TRM. Of these, the quality of reporting of harms was considered as “good” in 36% (38/106) of studies, “intermediate” in 55% (58/106), and “poor” in 9% (10/106). Investigators judged experimental treatments to be superior in 34% of trials (48/139) while standard treatment was superior in 66% (91/139). TRM data was reported in 75% (36/48) of results favoring experimental treatments and 78% (70/91) of results favoring standard treatments. There was no association between superiority of a treatment and TRM reporting (p = 0.80) or quality of harms reporting (p = 0.83). The pooled hazard ratio (HR) for OS in RCTs reporting TRM was 0.94 (95% CI: 0.90, 0.99) and for RCTs not reporting TRM was 0.99 (95% CI: 0.89, 1.09) (test of heterogeneity p = 0.06). The pooled HR for EFS among RCTs reporting TRM was 0.88 (95% CI: 0.83, 0.94) and for RCTs not reporting TRM it was 1.01 (95% CI: 0.79, 1.29) (test of heterogeneity p = 0.07). Additionally, the pooled HR for OS and EFS did not show any bias in reporting of harms according to harms reporting quality. Conclusions: Investigators’ conclusion regarding the superiority of experimental or standard treatment does not appear to be associated with outcome reporting bias for harms. Investigators judge both harms and benefits when they draw conclusions about treatment superiority. No significant financial relationships to disclose.
Prospective evaluation of clinical and biological parameters to predict clinically relevant denutrition in cancer patients undergoing surgery
Authors: S. Antoun
Journal: Journal of Clinical Oncology (2006)

18611 Background: Denutrition increases surgery morbidity and mortality in cancer patients. Methods: This study aimed to compare the relative value of different scores widely used to measure denutrition. During 3 months for all of the patients requiring heavy carcinologic surgery we checked: weight loss over 10%, body mass index (BMI), serum albumin, transthyretin (Tt), Buzby index, Pronostic Inflammatory Nutritional Index (PINI), Ottery score (PG-SGA). Other data like the surgical procedure, duration of surgery, cancer status were also recorded. Morbidity was defined by infectious and non-infectious major complications (IMC, NIMC), length of stay (Ls) in hospital, and death at 1 and 6 months. Results: 275 patients from 8 French Cancer Centers were included (167 were female, median age: 58 years). In multivariate analyses albumin level (&lt;30 g/l) is the only significant predictor of surgical morbidity, with the duration of the surgical procedure. Ottery score was the most sensitive among clinical parameters. Weight loss was significantly correlated with survival. Conclusions: Serum albumin and weight loss are useful parameters to consider in cancer patient requiring surgery; they are easy to monitor and should be part of pre-operative check-up in those patients. [Table: see text] No significant financial relationships to disclose.
Upregulation of flt3 expression within the bone marrow Lin-Sca1+kit+ stem cell compartment is accompanied by loss of self renewal capacity but sustained ability to reconstitute B and T lymphopoiesis
Authors: S Jacobsen, J Adolfsson, O J Borge, D Bryder, K Theilgaard-Mönch, I Åstrand-Grundström, E Sitnicka, Y Sasaki
Journal: Immunity (2015)
STING (or SRC) Like an ICB: Priming the Immune Response in Pancreatic Cancer
Authors: Stanley I. Gutiontov, Ralph R. Weichselbaum
Journal: Cancer Research (2019)

Abstract Pancreatic adenocarcinoma is associated with a poor prognosis and resistance to immune checkpoint blockade. Zhang and colleagues demonstrate that inhibiting DNA repair by pharmacologic blockade or siRNA silencing of ataxia telangiectasia mutated (ATM) increases type I IFN release via a cGAS/STING-independent, SRC-dependent mechanism in models of pancreatic cancer. Furthermore, combining ATM inhibition and radiotherapy amplifies type I IFN signaling, increases programmed death ligand 1 (PD-L1) expression, tumor CD8+ T cells, and proinflammatory tumor macrophages. Finally, the combination of ATM silencing, radiotherapy, and PD-L1 blockade markedly improves in vivo murine tumor responses, supporting further investigation of this promising approach in pancreatic adenocarcinoma. See related article by Zhang et al., p. 3940
Association of polymorphisms in genes related to cell cycle (<i>ERP29</i>, <i>LEF1</i>, <i>MCC</i> and <i>PTCH1</i>) and DNA transcription factors (<i>IKBKAP</i> and <i>ZNF415</i>) with base of tongue squamous cell carcinoma risk.
Authors: Carmen Silvia Passos Lima, Benilton Carvalho, Renata Pellegrino, Leticia Khater, Carlos Takahiro Chone, Gustavo Jacob Lourenco
Journal: Journal of Clinical Oncology (2013)

6073 Background: Recently, we found 6.609 genetic single nucleotide polymorphisms (SNPs) with distinct frequencies between base of tongue squamous cell carcinoma (BTSCC) patients and controls. The study was performed using high-resolution DNA microarrays genotyping (Affymetrix). The SNPs identified never have been previously described with BTSCC risk. Some SNPs of interest were located in genes related to cell cycle (ERP29, LEF1, MCC and PTCH1) and DNA transcription (IKBKAP and ZNF415) and they were selected to validation process. Objective: Validate the SNPs ERP29 c.*293A&gt;G (rs7114); LEF1 c.*1213A&gt;G (rs2107028) and g.127267A&gt;G (rs4245926); MCC c.*5077A&gt;G (rs7033); PTCH1 g.27369025G&gt;A (rs16909856) and g.27369324G&gt;A (rs16909859); IKBKAP c.3214T&gt;A (rs3204145) and ZNF415 c.*443A&gt;G (rs3814) associated to BTSCC risk. Methods: Genomic DNA from 49 BTSCC patients and 49 controls was genotyping by TaqMan assays (Applied Biosystems). The differences between groups were analyzed by logistic regression model. Power analysis (PA) was used to verify the effect of sample size on the results obtained. Results: Eight SNPs identified by Affymetrix were validated by TaqMan assays. The frequencies of ERP29 c.*293AG+GG (30 vs 11%, P=0.03; PA=65%), LEF1 c.*1213AA+AG (95 vs 80%, P=0.02; PA=61%) and g.127267AA+AG (93 vs 78%, P=0.02; PA=56%), MCC c.*5077AA+AG (85 vs 64%, P=0.008; PA=67%), PTCH1 g.27369025GG+GA (90 vs 73%, P=0.005; PA=58%) and g.27369324GG+GA (90 vs 73%, P=0.008; PA=58%), IKBKAP c.3214TT+TA (90 vs 72%, P=0.01; PA=62%) and ZNF415 c.*443AA+AG (59 vs 41%, P=0.02; PA=43%) were more common in patients than in controls. Individuals with these genotypes were at 2.9(CI95%: 1.1-8.4), 3.9 (CI95%: 1.4-11.2), 4.0 (CI95%: 1.2-14.7), 3.5 (CI95%: 1.2-11.9), 5.0 (CI95%: 1.7-16.9), 4.5 (CI95%: 1.5-15.2), 4.1 (CI95%: 1.4-12.9), and 3.9 (CI95%: 1.2-13.7)-fold increased risks for BTSCC than others, respectively. Conclusions: Our data present for the first time evidence that inherited abnormalities in ERP29, MCC, LEF1, PTCH1, IKBKAP, and ZNF415 genes may be important determinants of BTSCC. Financial support: FAPESP and FINEP.