tbuckley/cabot-search huggingface dataset:
Epidermal growth factor receptor (EGFR) immunohistochemistry: Comparison of antibodies (Abs) and cut points to predict benefit from gefitinib in a phase III placebo-controlled study in advanced non-small cell lung cancer (NSCLC)
Authors: R. Dziadziuszko, F. R. Hirsch, M. Varella-Garcia, N. Thatcher, H. Mann, C. Watkins, G. Speake, B. Holloway, P. A. Bunn, W. A. Franklin
Journal: Journal of Clinical Oncology (2007)

7576 Background: Tumor tissues obtained from the ISEL phase III trial assessing the efficacy of gefitinib vs placebo in chemotherapy-pretreated NSCLC were used to evaluate two Abs (DAKO and Zymed) and assess whether different cut points of EGFR protein expression improved prediction of response and survival benefit from gefitinib. Methods: EGFR protein expression in tumor samples was assessed by immunohistochemistry using DAKO EGFR pharmDx kit (scoring percent of tumor cells with positive staining, predefined cut point of =10%) and Zymed monoclonal Ab clone 31G7 (scoring proportion of positive cells times staining intensity [scale 0–400], predefined cut point of =200). Results: Clinical characteristics of the patients (pts) assessed with DAKO (n=379) and Zymed (n=357) Abs reflected the overall study population (N=1692) with the exception of fewer never-smokers and Asians. Of the pts evaluated with DAKO/Zymed Abs, females represented 32%/31%; never-smokers, 13%/14%; Asians, 6%/4%; adenocarcinomas, 44%/42%; and 88%/88% of pts were refractory to most recent chemotherapy. With the above criteria, 70% of tumor samples were scored as positive using DAKO Ab and 68% using the Zymed Ab (agreement between assessments 76%). The objective response rates in gefitinib treated EGFR-positive pts defined with various cut points with DAKO Ab (=1% to =90%) varied between 8% and 12%, and with Zymed Ab (score =50 to =350), between 10% and 13%. Lower cut points with the DAKO Ab provided the best discrimination between EGFR positive and EGFR negative patients in terms of survival hazard ratios (HRs) comparing gefitinib to placebo, with a significant treatment/cut point interaction for the 10% cut point (p=0.049). A similar trend was noted for Zymed Ab, although the discrimination between HRs was less apparent and not significant for any cut point analyzed. Conclusion: Assessment with DAKO PharmDx kit, according to percentage of positive staining, may provide more accurate prediction of survival benefit for gefitinib-treated pts than assessment with Zymed Ab and staining index. Use of higher cut points to define positivity does not improve discrimination of the test. No significant financial relationships to disclose.
UK should change law on surrogacy to help commissioning parents, report says
Authors: Clare Dyer
Journal: BMJ (2015)

The United Kingdom’s 30 year old law on surrogacy is “out of date and in dire need of reform,” concludes a wide ranging review of the practice that surveyed commissioning parents, surrogate mothers, and professionals involved in surrogacy.1

Under current law dating back to 1985, the surrogate mother is the legal mother of a baby born by surrogacy, and her husband or partner, if he consented, is the legal father. The surrogate mother …
How can CEA and CA15–3 be used for estimation of the clinical status and effectiveness of therapy during metastatic breast cancer?
Authors: P. Stieber, D. Lässig, M. Untch, D. Nagel, V. Heinemann
Journal: Journal of Clinical Oncology (2004)

755 Background: Tumor markers like CEA and CA 15–3 are often used in follow up care of breast cancer, but mainly due to a lack of knowledge, experience but also confidence- the actual situation is more to observe kinetics than to react on these results. Therefore we try to validate the significance of CEA and CA15–3 in the course of metastatic disease. Patients and Methods: We performed our study in a group of 101 breast cancer patients who developed metastatic lesions. The patients mostly suffered from bone (n=54), liver (n=51), lung (n=35) and lymph node metastases (n=39). All patients were treated by systemic therapies. On the basis of changing therapeutic regimes we totally monitored 223 different courses of therapies including endocrine (n=29), chemotherapeutic (n=73), antibody (n=7) and combined (n=114) treatments. CEA (AxSYM/Abbott) and CA15–3 (Elecsys/Roche) were mostly determined every 3 or 4 weeks, the therapeutic response was assessed by UICC-criteria. Results: Meanwhile we evaluated CEA and CA15–3 at first diagnosis of metastases and at every further moment of progression/new metastases. At first metastatic disease CEA was in 53% above the 95th percentile of healthy individuals and CA 15–3 in 74% (19 % CEA and CA 15–3 negative) with enhancing percentage of sensitivity with increasing numbers of further events 'progressive disease (PD)' (2nd PD CEA 52% / CA15–3 69%, 3rd PD 65 % / 80%, 4th PD 74% / 93%), decreasing number of false negatives (3% 4th PD) and a general shift of the value levels of CEA (ng/ml) / CA 15–3 (U/ml) with the number of events, e.g. the medians 1st PD CEA 2.7 / CA 15–3 43.4; 2nd PD 2.6 / 46.2; 3rd PD 5.3 / 78.5; 4th PD 8.8 / 92.5). Conclusion: Our results show a clear correlation between CEA /CA 15–3 and the number of events as well as effectiveness of therapy. No significant financial relationships to disclose.
A new genomic approach to describe the natural history of node negative breast cancer patients
Authors: M. Saghatchian, R. Lidereau, S. Delaloge, S. Koscielny, A. Kauffmann, S. Michiels, M. Mathieu, E. Brain, P. Dessen, V. Lazar, T. Tursz
Journal: Journal of Clinical Oncology (2006)

10058 Background: Breast cancer is a heterogeneous and complex disease beyond good/bad prognosis groups. Previous studies identified prognostic tools that are undergoing inter-group validation. Our present study aims at better defining pre-malignant vs. malignant lesions and tumors that will give local vs. distant metastases (DM) or early vs. late DM. Methods: We selected 3 groups of patients (pts) in a consecutive series of node-negative breast cancers with a very long follow-up (&gt;10 years (y)) and available frozen tumor samples. Pts who did not receive any adjuvant treatment were selected: 60 with no relapse after 10 y, 29 with early DM before 5 y and 18 with late DM after 5y. Genomic profiling on 44K Agilent pangenomic arrays taking as reference non-relapsing pts (after 10y) or normal breast (Clonetech) allowed us to select specific genes related to DM occurrence or tumorigenesis. Random permutations were performed to assess the statistical significance of our prediction accuracy. Results: 1- we identified a 141 gene-profile and related genes distinguishing tumors with early DM from tumors with late DM (71% prediction accuracy). 2- Similarly, we identified a 285-gene signature for late DM vs. no relapse at 10 y (80% prediction accuracy). Genes were further classified according to family clusters allowing description of genes involved in DM occurrence. 3- a total of 435 genes were also significantly over-expressed in at least 90% of 148 tumours (compared to normal breast). Among those, a selection of the most significant genes were analysed for RT-PC expression throughout the various steps of tumour development (normal breast, benign tumors, in situ carcinomas, invasive carcinomas). Among the 15 most upregulated genes listed, 3 unknown genes appear, that are overexpressed in 98% of the tumors with an average fold change &gt; 11 and are currently explored. Discussion: In this unique series of untreated node-negative breast cancers, identification of molecular profiles of early and late DM could be useful in better early prediction of breast cancer outcome. Based on genomic analysis, a molecular gene based classification of progression from benign tissue to aggressive tumors allows to dissect pathways towards malignancy and to identify early diagnostic markers or targets for prevention. No significant financial relationships to disclose.
Increased Incidence of Cytomegalovirus Disease After Autologous CD34-Selected Peripheral Blood Stem Cell Transplantation
Authors: Leona A. Holmberg, Michael Boeckh, Heather Hooper, Wendy Leisenring, Scott Rowley, Shelly Heimfeld, Oliver Press, David G. Maloney, Peter McSweeney, Lawrence Corey, Richard T. Maziarz, Frederick R. Appelbaum, William Bensinger
Journal: Blood (1999)
IMPS-06LOW DOSE RADIATION INDUCED IMMUNOMODULATION OF PEDIATRIC MEDULLOBLASTOMA
Authors: Arabinda Das, Daniel G. McDonald, Ramin Eskandari, Amy-Lee Bredlau, Kenneth N. Vanek, Joseph M. Jenrette, Sunil J. Patel
Journal: Neuro-Oncology (2015)

Medulloblastoma (MB) is the most common malignant brain tumor in children, and has been historically classified based on clinical markers (patient age, presence of metastases at diagnosis, extent of resection) and histopathological characteristics (classic, desmoplastic/nodular, and large cell/anaplastic). However, the recent gene expression profiling of a large number of tumors across multiple studies has provided evidence of four distinct medulloblastoma molecular subgroups (Wnt, Shh, Group 3, and Group 4), associated with remarkably different prognoses. While current therapies for medulloblastoma are often toxic, and not always effective, immunotherapy, designed to target these subgroups, may offer therapeutic improvement. Although monoclonal antibody (mAb) therapy has not yet been shown to be effective for the treatment of brain tumors, recent data indicate that radiation therapy can induce immunogenic modulation characterized by cell-surface phenotypic changes leading to augmented tumour cell/cytotoxic T-cell interaction. We examined the ability of radiation to upregulate mAb therapy targets. Our data showed that low dose radiation significantly increased cell-surface and total protein expression of mAb targets CD137 (a member of the TNF receptor superfamily), FGF, CD20, HER2, Major Histocompatability Complex (MHC) class I and intercellular adhesion molecule-1 (ICAM-I) in 3 out of 3 medulloblastoma cell lines. These findings highlight a mechanism for combining radiation with immunotherapy, to potentially expand the effect of targeted therapy in brain tumor treatment.
Cascade regulation of PPARγ2 and C/EBPα signaling pathways by celastrol impairs adipocyte differentiation and stimulates lipolysis in 3T3-L1 adipocytes
Authors: Seung Kug Choi, Sunmi Park, Subin Jang, Hun Hee Cho, Siwoo Lee, Seungkwon You, Sang-Hyuk Kim, Hyun-Seuk Moon
Journal: Metabolism (2016)
Phase I trial of cetuximab (C) and dasatinib (D) in patients (pts) with advanced solid malignancies
Authors: F. R. Esteve, R. G. Stoller, A. Josephson, J. R. Grandis, M. J. Egorin, A. E. Argiris
Journal: Journal of Clinical Oncology (2008)

14668 Background: D is a small molecule inhibitor of several kinases, including SRC, c-KIT, PDGFR, and BCR-ABL. Preclinical data suggest that the interactions between Epidermal Growth Factor Receptor (EGFR) and SRC are important for tumor growth and that combined inhibition of EGFR and SRC may lead to improved therapeutic effect. We designed a phase I and pharmacokinetic (PK)/pharmacodynamic (PD) study of D and C, a chimeric IgG1 monoclonal anti-EGFR antibody. Methods:Eligible were pts with advanced solid malignancies who had received any number of prior regimens but without EGFR or SRC inhibitors, ECOG performance status (PS) 0–2, QTc interval on baseline EKG of 450 msec or less, and adequate laboratory parameters. C was administered intravenously on a weekly schedule at a dose of 250 mg/m2 (after a loading dose of 400 mg/m2 on cycle 1, day 1) on days 1,8, and 15 and D once daily, orally on a continuous schedule, days 1–21. Cycles were repeated every 21 days until progression of disease or intolerable toxicities. We used a standard up-and-down dose escalation scheme to assign pts on 3 dose levels: 1- 100 mg QD, 2- 150 mg, 3- 200 mg. PK and PD studies of D were performed on day 0 (prior to starting cetuximab) and day 15 of cycle 1. Results: 11 pts have been enrolled: dose level 1, 3 pts; dose level 2, 7 pts; and dose level 3, 1 pt. Median age was 58 years (46–69); 9 males; 2 females; PS 0, 5 pts; PS 1, 6 pts; and median number of prior regimens 2 (0–3). Pts have received 1–6 cycles of C and D. Compliance with D was > 95%. 1/6 evaluable pts on dose level 2 developed grade (G) 3 headache (HA) which was the only dose-limiting toxicity (DLT). In addition, G 1–2 HA was experienced by the 10 other pts. In all cases, HA started on cycle 1, day 1, after the C loading dose, and resolved in 1–3 days. 2 pts developed pleural effusions (G2 and G3). Of 9 evaluable pts, 4 (follicular thyroid carcinoma, salivary duct carcinoma, soft tissue sarcoma, and adenocarcinoma of unknown primary) had SD as best response. Conclusion: D 100–150 mg QD was safely combined with C with early onset, self-limited headache as the predominant toxicity. Accrual continues on dose level 3 (D 200 mg QD) and PK/PD studies are planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb
WITHDRAWN: One-pot synthesis of dimethyl cyclodextrin polyrotaxanes through thermoresponsive formation of polypseudorotaxanes
Authors: Satoki Egashira, Taishi Higashi, Jun Li, Xia Song, Jingling Zhu, Masatoshi Taniyoshi, Fumitoshi Hirayama, Keiichi Motoyama, Hidetoshi Arima
Journal: Asian Journal of Pharmaceutical Sciences (2015)

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
Oncogenicity of Two Strains of Chicken Sarcoma Virus for Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J. Spencer Munroe, Chester M. Southam
Journal: JNCI Journal of the National Cancer Institute (1964)

Two strains of Rous chicken sarcoma virus, one supplied by Dr. W. R. Bryan of the National Cancer Institute, Bethesda, Maryland, and the other by Dr. L. A. Zilber of the Gamaleya Institute of Epidemiology and Microbiology, Moscow, have been investigated for their oncogenicity in rats. Both virus strains were recovered in diminishing titer from tissues of newborn and “conditioned” adolescent rats, up to day 21 after inoculation with a tumor mince. Of 102 rats inoculated when newborn with the Bryan strain of virus, only 1 developed a solid tumor. Of 221 rats inoculated when 5 to 6 weeks old, with or without conditioning (X ray and cortisone, alone or combined, and 3-methylcholanthrene), 6 developed solid tumors in the cervical, axillary, or inguinal region. After injection of the Bryan material, virus was not demonstrated in any of these tumors. After the Zilber strain of chicken sarcoma was injected into 162 newborn to 7-day-old rats, 73 developed cystic hemorrhagic tumors in the cervical, axillary, and inguinal regions. Solid tumors developed in 4 rats at the site of previously cystic tumors. When rats were inoculated at 2 to 6 weeks of age, no cystic tumors developed, but solid tumors appeared in 5 of 45 rats given injections of this material at this age. Infective virus was demonstrated in the capsule of some cysts up to 11 weeks after inoculation. Older cysts and solid tumors yielded no virus. The cystic rat tumors consisted of multiple endothelium-lined cysts in a loose fibromatous or myxomatous stroma. In older cystic lesions the cyst lining was stratified, probably as a result of hypertrophy and hyperplasia of the endothelial cells. Cysts, in the early stages, were filled with a straw-colored fluid that later became hemorrhagic. Neutralization studies indicated that these two strains of chicken sarcoma were antigenically dissimilar. The solid tumors were fibromas, but in some of them small cystic lesions persisted and former cystic areas solidified by fibrosis could be detected. Conditioning had no discernible effect on the pathogenicity of the Bryan virus.
Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis
Authors: Rachael Natrajan, Heba Sailem, Faraz K. Mardakheh, Mar Arias Garcia, Christopher J. Tape, Mitch Dowsett, Chris Bakal, Yinyin Yuan
Journal: PLoS Medicine (2016)

Background The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters. Methods and Findings We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D) in solid tumors, termed the tumor ecosystem diversity index (EDI), using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2) breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10−4, hazard ratio = 1.47, 95% CI 1.17–1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26–2.52). Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size. Conclusions To our knowledge, this is the first study to couple unbiased measures of microenvironmental heterogeneity with genomic alterations to predict breast cancer clinical outcome. We propose a clinically relevant role of microenvironmental heterogeneity for advanced breast tumors, and highlight that ecological statistics can be translated into medical advances for identifying a new type of biomarker and, furthermore, for understanding the synergistic interplay of microenvironmental heterogeneity with genomic alterations in cancer cells.
Bortezomib (VEL) Based Regimens in Multiple Myeloma (MM) Patients with Renal Impairment (RI): A Preliminary Retrospective Italian Multicenter Study
Authors: Massimo Gentile, Stefania Ciolli, Maria Teresa Petrucci, Sara Galimberti, Giuseppe Mele, Antonio Francesco Casulli, Donato Mannina, Eugenio Piro, Graziella Pinotti, Salvatore Palmieri, Lucio Catalano, Vincenzo Callea, Massimo Offidani, Pellegrino Musto, Sara Bringhen, Luca Baldini, Patrizia Tosi, Francesco Di Raimondo, Mario Boccadoro, Antonio Palumbo, Michele Cavo, Fortunato Morabito
Journal: Blood (2008)
Efficacy of intraoperative radiofrequency ablation (IRFA) combined or not with resection to treat unresectable colorectal metastases, with or without preoperative chemotherapy: The ARF2003 Study (NTC 00210106): Preliminary results
Authors: Y. Becouarn, S. Mathoulin-Pélissier, M. Rivoire, A. Ayav, J. Arnaud, A. Sa Cunha, R. Brunet, M. Fonck, C. Bellera, S. Evrard
Journal: Journal of Clinical Oncology (2009)

4095 Background: Only few patients suffering from colorectal metastases (CRM) can have surgery and thus hope for a 40% 5-year survival rate. Adding IRFA to resection may improve the efficacy of surgery. Methods: The primary objective was to evaluate the efficacy of IRFA combined or not with resection in terms of 3-month complete hepatic response (CHR) in patients with unresectable CRM. Secondary endpoints were overall survival (OS), disease-free survival (DFS), morbidity and quality of life. A phase II study based on a Simon's two-stage design was conducted in 6 university French hospitals. Number of subjects estimated was 53, with 19 for the 1 st stage. At the end of the 1 st stage, 12 CHR were required to continue recruiting. At the end of 2 nd stage, 37 CHR would be required to claim efficacy. Results: Fifteen of the first 19 patients exhibited CHR allowing the study to pursue accrual which ended in Nov 08; some patients are still followed up. As of Nov 08, data had been collected on 47 patients (mean age 61 years): 6 had RFA alone (13%), 37 had RFA and resections (82%), 2 could not be treated (4%). Median number of CRM was 5 (1–12). All had chemotherapy pre-op and 12 post-op (29%). Three-month data were available for 36 patients: 1 patient died on the 3 rd week following intervention. Scans were available for 35 patients (independently reviewed). Of these, 29 had CHR (83%); 13 had 3-month morbidity (37%). The median follow-up was 15 months. One-year OS and DFS rates were 92.3% and 26% respectively. Analysis on all 53 patients will be communicated in June 09. Conclusions: These preliminary results suggest that IRFA combined or not to resection may be efficient in treating unresectable diseases despite their more aggressive pattern. This corroborates the EORTCC CLOCC Trial findings which demonstrated IRFA superiority upon chemotherapy alone. IRFA could thus be valuably associated to resection in treating patients with colorectal metastases that resection alone could not handle. No significant financial relationships to disclose.
Clinical characterization of node-negative non-small cell lung cancer: Results of a prospective investigation
Authors: I. Yoshino, Y. Ichinose, A. Nagashima, S. Takeo, A. Motohiro, T. Yano, T. Ishida, K. Yamazaki, K. Sugio, K. Yasumoto, Y. Maehara
Journal: Journal of Clinical Oncology (2006)

7218 Background: 20 to 30% of clinical stage IA non-small cell lung cancer cases were revealed to be node-positive by pathologic examination of resected specimens. In this prospective study, the clinical features of a truly node-negative population were prospectively investigated to search for candidates of a lesser resection or of a stereotactic radiotherapy. Methods: The clinical data and radiographic features of high-resolution computed tomography (HR-CT) were registered before operation in 169 clinical stage IA lung cancer patients, who were scheduled to undergo a standard lobectomy and systemic mediastinal node dissection. The nodal metastasis was pathologically defined, while the clinical factors associated with the presence of the nodal metastasis were evaluated. Results: In 130 evaluable cases, 16 of 114 adenocarcinoma and 3 of 16 other NSCLC were node-positive. Among all parameters, positivity of the serum carcinoembryonic antigen (CEA) was the only factor significantly associated with nodal metastasis (p = 0.0074). When we focused on adenocarcinomas, the serum CEA, retraction sign and intratumoral air-space on HR-CT were suggested to be predictive factors for lymph node metastasis with hazard ratios of 12.44 (p = 0.0003), 6.53 (p = 0.0533) and 0.17 (0.0073), respectively. In combination with the radiologic features of HR-CT imaging, none of 18 CEA-negative/retraction-negative cases and 3 of 65 CEA-negative/air-space positive cases showed nodal metastasis, in which the incidence of nodal metastasis was significantly lower than the counterparts with respective p-values of 0.0015 and 0.037. The tumor size and the proportion of ground glass attenuation were not associated with the incidence of nodal metastasis. Conclusions: The serum CEA and HR-CT features thus allowed us to identify node-negative lung adenocarcinomas. In clinical stage IA adenocarcinoma cases, a standard operation should be considered when positive serum CEA and/or retraction sign on HRCT is noticed. No significant financial relationships to disclose.