tbuckley/cabot-search huggingface dataset:
Effect of lapatinib on accumulation of inactive HER2 at the cell membrane and on antibody-dependent cellular cytotoxicity (ADCC) mediated by trastuzumab: A novel mechanism for the enhanced effects of combined anti-HER2 therapy
Authors: M. Scaltriti, C. Verma, M. Guzman, J. Jimenez, J. Parra, K. Pedersen, S. Landolfi, S. Ramon y Cajal, J. Arribas, J. Baselga
Journal: Journal of Clinical Oncology (2008)

3594 Background: Lapatinib is a HER2 tyrosine kinase inhibitor that has clinical activity in HER2 overexpressing (HER2+) breast cancer. In vitro and clinical studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. In order to dissect the differential mechanims of these agents, we have studied the effects of lapatinib and trastuzumab on receptor expression and signaling and have explored a new potential mechanism underlying the profound antitumor activity of the combination. Methods: HER2+ breast cancer cells SKBR3 and MCF7-HER2 were treated with lapatinib, trastuzumab or both. Assays of receptor expression, phosphorylation, signalling and tumor growth were performed. Trastuzumab-dependent cellular cytotoxicity was measured with different levels of HER2 expression and doses of lapatinib. Results: Lapatinib treatment of HER2+ breast cancer cells inhibited HER2 phosphorylation, prevented ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modelling techniques we further demonstrated that the lapatinib-induced accumulation of HER2 lead to stabilization of inactive HER2 homo- and hetero-dimers. Accumulation of HER2 induced by lapatinib and downregulation of HER2 mediated by trastuzumab were also observed in vivo, where the combination of the two agents triggered complete tumor remission in all cases after 10 days of treatment. Lapatinib-induced accumulation of HER2 at the cell surface markedly enhanced trastuzumab-mediated ADCC. Conclusions: Lapatinib results in a marked accumulation of inactive HER2 receptors at the cell surface both in vitro and in vivo. This increase in receptors number at the cell surface enhances ADCC by trastuzumab. We propose that this is a novel mechanism that may be clinically relevant and exploitable in the therapy of patients with HER2+ tumors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech
Difficulties in the integration of psychological and medical practices
Authors: H N Brown, N E Zinberg
Journal: American Journal of Psychiatry (1982)

The authors, who support in principle the important goal of integrated psychological and physical care, discuss five sources of difficulty in the practical application of such integration: 1) differences in values and, consequently, in systems of practice, 2) training influences, 3) differences in dealing with emotions, 4) conflicting patient expectations, and 5) limitations on the degree of intimacy tolerable in professional relationships. They suggest that practitioners and educators take these difficulties into account without abandoning a holistic perspective.
NIMG-08EVALUATION OF 2HG MR SPECTROSCOPY IN RELATION TO DISEASE ACTIVITY IN GLIOMAS
Authors: Ricky Chen, Karen Salzman, Andrew Prescot, Amiee Maxwell, Randy Jensen, Adam Cohen, Howard Colman
Journal: Neuro-Oncology (2015)

The oncometabolite 2-hydroxyglutarate (2HG) is produced by mutated isocitrate dehydrogenase (IDH). Magnetic resonance spectroscopy (MRS) detects 2HG noninvasively and has been reported to accurately identify IDH mutated tumors. 2HG-MRS may be able to help monitor disease activity over time, adding significantly to the diagnostic utility of conventional MRI. To evaluate implementation of 2HG spectroscopy and relationship to disease state, we performed 2HG-MRS on 21 patients with known glioma or MRI abnormalities suspicious for glioma (without prior biopsy) at our institution. When pathology was available, cases were assessed for diagnosis and tumor grade, IDH and 1p19q status as well as treatment history and clinical course. Analysis of 2HG-MRS results were done blinded to known IDH status. In 12 tumors with known IDH status, 9 cases were IDH-mutated, and 3 IDH-wildtype, and 5 were 1p19q-codeleted (and thus necessarily IDH-mutated). Out of all 21 patients, 8 were positive for 2HG by MRS and 13 were negative. In tumors with known IDH mutation, there was concordance with positive 2HG-MRS in 4 of 9. Due to this unexpected rate of apparent false negative 2HG-MRS, the 5 discordant cases were further reviewed. Three were clinically and radiographically stable by conventional MRI post treatment, so it is possible that absence of detectable 2HG reflected lack of active disease. However, 2 cases were negative for 2HG-MRS despite apparent progressive radiographic disease by conventional MRI. In contrast, all 4 concordant cases showed evidence of active or progressive tumor by conventional MRI. 2HG-MRS can aid conventional MRI in identification of IDH mutated gliomas non-invasively and may provide a more definitive assessment of treatment response for IDH mutated gliomas. However, it remains possible that some of our discordant cases represent insufficient sensitivity of 2HG-MRS, and further investigation is needed to optimize the sensitivity and specificity of 2HG-MRS for this purpose.
A phase III randomized study of surgery alone or surgery plus preoperative gemcitabine-cisplatin in early-stage non-small cell lung cancer (NSCLC): Follow-up data of Ch.E.S.
Authors: G. V. Scagliotti, U. Pastorino, J. F. Vansteenkiste, L. Spaggiari, F. Facciolo, T. Orlowski, A. Maiorino, M. Hetzel, C. Visseren-Grul, V. Torri
Journal: Journal of Clinical Oncology (2008)

7508 Background: This phase III study tested the hypothesis whether 3 preoperative cycles of gemcitabine-cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients (pts) with stage IB- IIIA NSCLC. Methods: Chemotherapy naive pts with clinical stage T2N0, T1–2N1, or T3N0–1 received either preoperatively cisplatin (75 mg/m2, day 1) and gemcitabine (1,250 mg/m2, days 1&8), q3week followed by surgery (C+S) or surgery alone (S). In 2004 the enrollment was closed early after the inclusion of 270 out of 700 planned pts because investigators felt it unethical to complete the study treating patients with surgery alone due to positive adjuvant studies. Results: From September 2000 to December 2004, 141 pts were randomized to S and 129 to C+S. Median age was 63/61 years, and most of pts were male (89%/78%). Stage IB/IIA disease was reported in 55% and 46%, respectively. The commonest histology was squamous cell carcinoma (45%/37%) followed by adenocarcinoma (30%/33%). In C+S arm, 86% of patients received all 3 cycles of chemotherapy. Surgery was performed in 96% of pts in the S arm and in 85% of C+S arm. Response rate to chemotherapy was 35% (95%CI 26–44). Progression of neoplastic disease during chemotherapy was reported in 5.5% of pts. As of November 2007, 55% of the progressions occurred. The 3-yr progression-free survival (PFS) rate was 48% in S (95%CI: 38% - 56%) and 53% in C+S (95%CI: 43% - 61%) (p= 0.11, log-rank test). The overall 3-year survival rate was 60% in S (95% CI: 51% - 68%) and 67% in C+S (95% CI 58% - 75%) (p= 0.053). Eight deaths related to study drug or procedure were observed during the study (6 in S, 2 in C+S). Conclusions: This prematurely closed phase III study in early-stage NSCLC indicates the efficacy outcome estimates in the range of those reported from other neoadjuvant trials in the same setting of patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly AstraZeneca, Bayer, Eli Lilly, Roche, sanofi-aventis Eli Lilly
Assessment of the tumor inflammatory cell infiltrate in preoperative colonoscopic biopsies of patients with primary operable colorectal cancer.
Authors: James Hugh Park, David Mansouri, Clare Orange, Paul G. Horgan, Donald C. Mcmillan, Campbell S.D. Roxburgh
Journal: Journal of Clinical Oncology (2015)

637 Background: The tumor inflammatory cell infiltrate is an important and potentially modifiable determinant of outcome in colorectal cancer (CRC). Although a weak inflammatory infiltrate is associated with poor prognosis independent of TNM stage, identifying such patients prior to surgery is problematic. The aim of the present study was to compare the tumor inflammatory cell infiltrate in matched preoperative colonoscopic tumor biopsies and resected tumor specimens from patients undergoing primary elective resection of CRC. Methods: Using an automated scoring system (nuclear h-score) CD3 + T-lymphocyte density was quantified in preoperative tumor biopsies of 76 patients undergoing elective resection of stage I-III CRC and compared to pathological characteristics and manual semi-quantitative (high vs. low) scoring of CD3 + density within the invasive margin (IM) intraepithelial (IE) and cancer stroma (CS) compartments of resected tumor specimens. Results: The median h-score was 41 (range 14-85). Patients with a high tumor resection IM, IE and CS CD3 + density had a higher biopsy CD3 + density than patients with a low IM, IE and CS CD3 + density (median h-score: IM – 47 vs. 37, p=0.011; IE – 50 vs. 38, p=0.014, CS – 46 vs. 37, p=0.014). Patients with mismatch repair deficient tumors showed a trend towards a higher biopsy CD3 + density (57 vs. 40, p=0.169). No other pathological factors were associated with biopsy CD3 + density. When biopsy CD3 + density was categorised as high (h-score ≥41) or low (h-score&lt;41), high biopsy CD3 + density was associated with CD3 + density within the IM, IE (both p≤0.05) and CS (p&lt;0.01) and showed a trend towards greater 5-year survival (high – 80% (SE 7), low – 67% (SE 8), p=0.122). Conclusions: The results of the present study suggest that assessment of the inflammatory cell infiltrate in preoperative colonoscopic biopsies may provide reliable assessment of the inflammatory cell infiltrate within resected CRC tumors. Although requiring validation in an independent cohort, this has significant implications for the provision of neoadjuvant therapy, particularly targeting the inflammatory cell infiltrate, in patients with primary operable CRC.
COMBI-d: A randomized, double-blinded, Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF<sup>V600E/K </sup>mutation-positive cutaneous melanoma
Authors: Georgina V. Long, Daniil L. Stroyakovsky, Helen Gogas, Eugeny Levchenko, Filippo de Braud, James M. G. Larkin, Claus Garbe, Thomas Jouary, Axel Hauschild, Jean Jacques Grob, Vanna Chiarion-Sileni, Celeste Lebbe, Mario Mandalà, Michael Millward, Douglas James DeMarini, Jhangir G Irani, Ngocdiep Le, Michelle Casey, Kiran Patel, Keith Flaherty
Journal: Journal of Clinical Oncology (2014)

9011^ Background: As monotherapies, the BRAF inhibitor dabrafenib (D) and the MEK inhibitor trametinib (T) demonstrated superior progression-free survival (PFS) v chemotherapy in pts with BRAFV600 mutant, metastatic melanoma (MM). Resistance develops in most pts, and oncogenic toxicities (e.g., cutaneous squamous carcinoma (cuSCC)) are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects in the Phase I/II study of D+T v D (NCT01072175), with an improvement in overall response rate (ORR), PFS and reduced frequency of cuSCC. This Phase III study (NCT01584648) was conducted to confirm the superiority of D+T over D in pts with BRAFV600E/K mutant MM. Methods: Pts were randomized 1:1 to receive D (150 mg twice daily) + T (2 mg once daily) or D+ placebo (P) as first-line therapy. Eligible pts were ≥18 years and ECOG performance status ≤1, with histologically confirmed unresectable stage IIIC or IV, BRAFV600E/K mutant cutaneous melanoma. The primary endpoint was investigator-assessed PFS; secondary endpoints were overall survival (OS), ORR, duration of response, and safety. Cross over was prohibited. The study has 95% power and a one-sided α=0.025 to detect a PFS hazard ratio (HR) of 0.59. Results: From May 2012 to Jan 2013, 423 pts were randomized (211 to D+T, 212 to D+P). Median follow up was 9 mo (0-16 mo). HR for investigator-assessed PFS was 0.75 (95% CI: 0.57, 0.99; p=0.035), in favor of D+T with a median PFS of 9.3 v 8.8 mo with D+P. The confirmed ORR was 67% (complete response [CR] 10%) for D+T and 51% (CR 9%) for D+P (p=0.0015). HR for interim OS was 0.63 (95% CI 0.42, 0.94; p=0.023), in favor of D+T (40 v 55 deaths). Rates of AEs were similar for both arms. More pts had AEs leading to dose modifications with D+T v D+P. Increased incidence (51% v 28%) and severity (grade 3, 6% v 2%) of pyrexia occurred with D+T v D+P. Fewer cutaneous hyperproliferative events occurred with D+T v D+P (CuSCC 2% v 9%; hyperkeratosis 3% v 32%). Conclusions: D+T demonstrated a significant improvement in PFS compared to D+P in pts with BRAFV600E/K mutant MM. Clinical trial information: NCT01072175.
Infrequent alterations of the RAR alpha gene in acute myelogenous leukemias, retinoic acid-resistant acute promyelocytic leukemias, myelodysplastic syndromes, and cell lines
Authors: R Morosetti, F Grignani, C Liberatore, PG Pelicci, GJ Schiller, M Kizaki, CR Bartram, CW Miller, HP Koeffler
Journal: Blood (1996)
Hematologic toxicities before and during bevacizumab chemotherapy in women with gynecologic malignancy
Authors: J. N. Bottsford-Miller, A. Shafer, A. Deal, L. Filip, W. Fowler
Journal: Journal of Clinical Oncology (2009)

e16565 Background: Many women undergoing chemotherapy for gynecologic malignancy experience hematologic toxicity that delays therapy or requires supportive intervention. In animal models anti-VEGF antibodies increase erythropoietin levels. We examined the hematologic toxicities experienced by patients prior to (PR) and during bevacizumab (BR) treatment. Methods: Retrospective, single-institution study of women with gynecologic malignancy treated at the University of North Carolina with bevacizumab as part of their therapy from January 2005 to June 2007. Data collected included prior therapies, blood product and growth factor use, and interruptions in therapy. Comparisons were made between individual patients’ hematologic parameters during the PR and BR. Median differences between hematologic nadirs were compared using Wilcoxon Signed Rank Tests. Differences in proportions were compared by Chi-Square or Fisher's Exact tests. Results: 43 patients ware identified, 40 with complete data. Most women were Caucasian (88%) and had ovarian or primary peritoneal carcinoma (77%); median (range) age was 53 (23–73). 32 (74%) received three or more different chemotherapy drugs before starting bevacizumab. The median difference in HCT nadir (31.2 vs. 33, p = 0.01) and ANC nadir (1.2 vs. 1.4, p = 0.04) during the PR and BR were significant in favor of the bevacizumab regimens. The median nadir differences for WBC (2.7 vs. 3.1, p = 0.1) and PLT (129 vs. 150, p = 0.07) were non-significant favoring BR. For HCT toxicity grades, 22 (55%) had the same grade during their PR and BR, 15 (38%) had a lower grade during BR, and 3 (7%) had a higher grade during BR (p = 0.001). Similar trends were seen for WBC (p = 0.27), ANC (p = 0.1), and PLT (p = 0.15). During BR there was a trend toward fewer patients receiving darbepoetin (66% vs. 44%, p = 0.07) and filgastrim (29% vs. 14%, p = 0.1). Conclusions: Patients receiving bevacizumab had no worse hematologic toxicity compared to their prior regimens and may have had less severe anemia. While not statistically significant, there were trends toward less growth factor use with bevacizumab. Patients who have had prior hematologic toxicity should be considered for bevacizumab. The effect of bevacizumab on hematologic toxicity should be evaluated with prospective data. No significant financial relationships to disclose.
Intrinsic Genomic Differences Between African American and White Patients With Clear Cell Renal Cell Carcinoma
Authors: Bhavani Krishnan, Tracy L. Rose, Jordan Kardos, Matthew I. Milowsky, William Y. Kim
Journal: JAMA Oncology (2016)

There are well-documented racial disparities in outcomes for African American patients with clear cell renal cell carcinoma (ccRCC). Despite a dramatic improvement in overall survival in white patients since the advent of targeted therapy, survival for African Americans with advanced ccRCC has not changed. There is little known about potential racial differences in tumor biology of ccRCC.To determine if there are racial differences in the somatic mutation rate and gene expression of ccRCC tumors from white and African American patients.Overall, 438 patients with ccRCC were identified through The Cancer Genome Atlas (TCGA) clear cell kidney (KIRC) dataset (419 white and 19 African American patients). The GSE25540 dataset containing 135 patients (125 white and 10 African American patients) was used for validation. Tumor samples were collected from numerous cancer centers and were examined for racial differences in somatic mutation rates and RNA expression. Racial differences in somatic mutation rates and RNA expression were examined.The comparison of somatic mutation rates and differences in RNA expression in white and African American patients with ccRCC.Overall, 419 ccRCC tumor data sets from non-Hispanic white patients and 19 from non-Hispanic African American patients were identified through the publically available TCGA KIRC data set, and a validation set of 125 white and 10 African American ccRCC patient tumors was identified from the publicly available GSE25540 data set. African American patients were significantly less likely than white patients to have VHL mutations (2 of 12 [17%] vs 175 of 351 [50%], respectively; P = .04) and were enriched in the ccB molecular subtype (79% in African American vs 45% in white patients ; P = .005), a molecular subtype that carries a worse prognosis. It was found that RNA expression analysis revealed relative down-regulation of hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF)-associated pathways in African American patients compared with white patients.African American patients have less frequent VHL inactivation, are enriched in the ccB molecular subtype, and have decreased up-regulation of HIF-associated gene signatures than white patients. These genomic differences would predict decreased responsiveness to VEGF-targeted therapy and are a biologically plausible contributing factor to the worse survival of African American patients with ccRCC, even in the targeted therapy era.
Complement-Dependent Cytotoxic Antitumor Antibody. I. Immunoglobulin Class Determined by Interaction With Protein A or Concanavalin
Authors: John J. Langone, Michael D. P. Boyle, Tibor Borsos
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Complement-Dependent Cytotoxic Antitumor Antibody. I. Immunoglobulin Class Determined by Interaction With Protein A or Concanavalin Get access John J. Langone, John J. Langone Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael D. P. Boyle, Michael D. P. Boyle Search for other works by this author on: Oxford Academic PubMed Google Scholar Tibor Borsos Tibor Borsos Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 60, Issue 2, February 1978, Pages 411–418, https://doi.org/10.1093/jnci/60.2.411 Published: 01 February 1978 Article history Received: 23 June 1977 Accepted: 16 September 1977 Published: 01 February 1978
The State of Lung Cancer Research: A Global Analysis
Authors: Ajay Aggarwal, Grant Lewison, Saliha Idir, Matthew Peters, Carolyn Aldige, Win Boerckel, Peter Boyle, Edward L. Trimble, Philip Roe, Tariq Sethi, Jesme Fox, Richard Sullivan
Journal: Journal of Thoracic Oncology (2016)

IntroductionLung cancer is the leading cause of years of life lost because of cancer and is associated with the highest economic burden relative to other tumor types. Research remains at the cornerstone of achieving improved outcomes of lung cancer. We present the results of a comprehensive analysis of global lung cancer research between 2004 and 2013 (10 years).MethodsThe study used bibliometrics to undertake a quantitative analysis of research output in the 24 leading countries in cancer research internationally on the basis of articles and reviews in the Web of Science (WoS) database.ResultsA total of 32,161 lung cancer research articles from 2085 different journals were analyzed. Lung cancer research represented only 5.6% of overall cancer research in 2013, a 1.2% increase since 2004. The commitment to lung cancer research has fallen in most countries apart from China and shows no correlation with lung cancer burden. A review of key research types demonstrated that diagnostics, screening, and quality of life research represent 4.3%, 1.8%, and 0.3% of total lung cancer research, respectively. The leading research types were genetics (20%), systemic therapies (17%), and prognostic biomarkers (16%). Research output is increasingly basic science, with a decrease in clinical translational research output during this period.ConclusionsOur findings have established that relative to the huge health, social, and economic burden associated with lung cancer, the level of world research output lags significantly behind that of research on other malignancies. Commitment to diagnostics, screening, and quality of life research is much lower than to basic science and medical research. The study findings are expected to provide the requisite knowledge to guide future cancer research programs in lung cancer.
Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000
Authors: Anja Möricke, Martin Zimmermann, Maria Grazia Valsecchi, Martin Stanulla, Andrea Biondi, Georg Mann, Franco Locatelli, Giovanni Cazzaniga, Felix Niggli, Maurizio Aricò, Claus R. Bartram, Andishe Attarbaschi, Daniela Silvestri, Rita Beier, Giuseppe Basso, Richard Ratei, Andreas E. Kulozik, Luca Lo Nigro, Bernhard Kremens, Jeanette Greiner, Rosanna Parasole, Jochen Harbott, Roberta Caruso, Arend von Stackelberg, Elena Barisone, Claudia Rössig, Valentino Conter, Martin Schrappe
Journal: Blood (2016)
Prediction of performance of psychiatric residents: A three-year follow- up study
Authors: H Kandler, R Plutchik, H Conte, B Siegel
Journal: American Journal of Psychiatry (1975)

The authors compared supervisors' global and specific item ratings of psychiatric residents' performance in each of three years of training with ratings of these applicants prior to their admission to the program. Although preadmission ratings had almost no predictive power, there were certain items that consistently discriminated between residents rated high and those rated low by supervisors in each year of training. The authors conclude that initial interviews of those selected cannot predict their subsequent performance. They therefore recommend that a major portion of these interviews be devoted to an exchange of information between the applicant and the department.