tbuckley/cabot-search huggingface dataset:
Treatment and prognosis of breast cancer patients with brain metastases according to intrinsic subtype.
Authors: Sayaka Kuba, Mayumi Ishida, Yoshiaki Nakamura, Kenji Taguchi, Kosho Yamanouchi, Shigeki Minami, Susumu Eguchi, Shinji Ohno
Journal: Journal of Clinical Oncology (2014)

1087 Background: It is still unclear how breast cancer (BC) subtype should affect treatment decisions for BC patients with brain metastases (BRM). This study analyzed extent and type of local BRM treatments and their outcomes according to BC subtype in patients with BC and BRM. Methods: We reviewed records and database information for women who were treated at the National Kyushu Cancer Center between 2001 and 2010. Patients’ BC was divided into three subtypes: luminal (ER+ and/or PgR+, but HER2−); HER2 (HER2+) and TNBC (ER−, PgR− and HER2−). Results: Of 524 patients with advanced BC, we reviewed the 65 patients who had BRM and whose records showed ER, PgR and HER2 status, and outcome dates. Of these 65 patients, there were 26 (40%) with luminal BC, 26 (40%) with HER2 BC, and 13 (20%) with TNBC. Symptomatic BRM rates were similar across subtypes (HER2: 81%; luminal: 85%; TNBC: 77%). Percentages of patients with ≤ 4 BRMs did not significantly differ by subtype (HER2: 73%; luminal: 54%; TNBC: 46%; P=0.22). For local BRM treatments, 40 underwent stereotactic radiosurgery (SRS) or surgery, 21 received whole brain radiation therapy, and 4 had no local brain treatment. Rates of SRS or surgery for BRMs significantly differed among BC subtypes (HER2: 81%; luminal: 42%; TNBC: 47%; P=0.03). Median survival after BRMs also varied significantly by subtype (HER2: 22 months; luminal: 10 months; TNBC: 6 months; P=0.02). Having the HER2 subtype, performance status ≤ 1, ≤ 4 BRMs, undergoing systemic therapy after brain metastasis and undergoing SRS or surgery predicted longer overall survival after BRMs appeared. Multivariate analysis demonstrated that without systemic therapy and without having the HER2 subtype were independent factors associated with increased risk of death (HR 2.4, 95 % CI 1.01-5.6; p = 0.05 and HR 2.9, 95 % CI 1.5-5.8; p = 0.003 and respectively). Discussion: The number of BRMs is an important prognostic factor, as local brain treatment can be given for patients with BRMs. Patients with HER2 BC had more chance to receive SRS or surgery and better prognosis, as anti-HER2 treatment might be able to control systemic disease. Conclusions: Local brain treatments and prognosis differed with subtype in patients with BRM.
Comparison of Methods for Detection of Fulvestrant-Induced Changes in Breast Tumor Estrogen and Progesterone Receptor Expression in a Neoadjuvant Trial (NEWEST).
Authors: I. Kuter, E. Anderson, U. Emeribe, P. Finlay, R. Nicholson, J. Gee
Journal: Cancer Research (2009)

Abstract Background: Fulvestrant downregulates breast tumor estrogen and progesterone receptor (ER and PgR) levels in a dose-dependent manner. Using an Automated Cellular Imaging System (ACIS), NEWEST (NCT00093002) reported that 4-wks' treatment with fulvestrant high-dose (HD, 500mg/month+500mg on Day 14 of Month 1) significantly reduced ER levels in primary breast tumors v approved-dose (AD, 250mg/month). However, no significant difference was detected between the two doses on PgR levels. To allow comparison with previous studies, a non-automated H-score assessment was performed and compared with ACIS.Methods: ER and PgR H-scores were derived by manual assessment of % tumor cells in each of 5 staining categories (negative, very weak, weak, moderate, strong) in the same sections scored by ACIS. This microscopic assessment was performed by 2 experienced observers blind to ACIS and clinical data. Mean % changes in H-scores were then calculated (table).Results: Both scoring methods showed a greater effect for fulvestrant HD v AD on ER expression at Wk 4, but H-score provided better dose discrimination. ACIS showed no difference between fulvestrant HD v AD on PgR expression at Wk 4, however, a significantly greater reduction in PgR expression was detected with fulvestrant HD using H-score.Wk 4Mean % change from baseline ACISH-score HDADHDADER-25.0%-13.5%-50.3%-13.7% n=60(n=63)(n=58)(n=60) p=0.0002 p&amp;lt;0.0001 PgR-22.7%-17.6%-80.5%-46.3% (n=43)(n=45)(n=31)(n=34) NS p=0.0018 Baseline mean H-score for HD and AD: 151.6 and 157.7 for ER; 103.8 and 122.9 for PgR.Conclusion: The choice of scoring method for determining ER and PgR expression in pharmacodynamic studies such as NEWEST is critical. Compared with H-scores, ACIS has a narrower dynamic range and reduced ability to discriminate fulvestrant HD v AD, particularly on PgR expression. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1087.
Actigraphy findings and cancer-related fatigue (CRF) in advanced cancer patients treated with methylphenidate (MP) and nursing telephone intervention (NTI).
Authors: Eduardo Bruera, Sriram Yennurajalingam, Dave Balachandran, Nikhil S Padhye, Janet L. Williams, Susan Frisbee-Hume
Journal: Journal of Clinical Oncology (2013)

e20528 Background: There are limited studies about actigraphic sleep, wakefulness, activity and fatigue and treatment in advanced cancer patients. The objective of this study was to evaluate the changes in the nocturnal sleep/rest, and daytime wake/activity and subjective measures of fatigue before and after treatment with MP+/- NTI. Methods: A subset of patients from a previous reported placebo and control telephone intervention (CTI) controlled RCT of MP and/or NTI for CRF were reviewed. Subjective and objective assessments were analyzed at Day-8 and Day-15 as a result of treatment with MP and/or NTI or their control arms. Actigraphic sleep measures assessed were total sleep time (TST), sleep efficiency, and wake after sleep onset (WASO). Additionally, activity (mean day-time activity), and fatigue (FACIT-F, ESAS-Fatigue item) were included in the multivariate analysis. Results: A total of 60 (MP=30, Placebo=30; NTI=35; CTI=25) patients were evaluated. The median age was 56, 62% were female; most common cancer type was breast 13/60(22%). The baseline mean FACIT-F subscale, ESAS Fatigue item, TST, WASO, sleep efficiency and day-time activity were 22.4 (9.33), 6.5(1.74), 437(162.4), 139(121.4), 71(16.4), 202(438). Multivariate outcomes at Day-8 showed significant change from baseline (η 2 =0.38, p&lt;0.001) and interaction effect between MP and NTI (η 2 =0.26, p=0.015). WASO had an interaction effect (β=-101.4, p=0.009), an MP effect (β=80.4, p=0.002) and reduction in time (β=-52.1, p=0.003). FACIT-F and ESAS-Fatigue item showed improvement in time (β=6.9, p=0.010; β=-2.4, p&lt;0.001). Conclusions: WASO was significantly lower in patients receiving methylphenidate and nursing telephone intervention. Further larger studies are needed to validate these findings.
Outcomes in patients with unresected glioblastoma including assessment of treatment with bevacizumab as a component of initial therapy.
Authors: Stuart Burri, Ashley Love Sumrall, Renee P Kelly, Peggy O Boltes, Daniel Ernest Haggstrom, Roshan Sudhir Prabhu, Mark D Smith, William E Ballinger, James Thomas Symanowski, Robert W. Fraser, Anthony L. Asher
Journal: Journal of Clinical Oncology (2014)

2069 Background: Radiation therapy (RT) and concurrent temozolomide (CRT) is the accepted standard for newly diagnosed glioblastoma (GBM). Despite promising results in recurrent settings, addition of bevacizumab (BEV) to CRT did not improve survival in prospective trials where the majority of patients underwent surgery with gross total resection. The biologic mechanism of BEV, however, suggests increased efficacy in tumors with intact blood supply, such as unresected GBM (UGB). Given the dismal prognosis of UGB, we have incorporated use of BEV into the management of select patients with UGB. We performed a retrospective analysis of our UGB patient population to assess outcomes and evaluate effectiveness of BEV in addition to CRT. Methods: Retrospective review for all UGB patients (stereotactic biopsy only) treated 2005-2012 was performed. 67 patients were identified. Treatment was categorized by treatment intent : hospice referral (group 1)-24%, palliative RT (group 2)-7%, definitive CRT (group 3)-55%, and CRT+BEV (group 4)-12%. Median age was 65; median ECOG PS 2. Results: Median overall survival (OS) was 4.8 months. Survival was similar for PS 1 and 2 and inferior for PS 3-4. Patient’s <65 OS was superior at 8.3 months vs. 3.7 months (p=.005) versus >65. OS for patients <75 was 6.0 versus 2.3 months (p=.002). Median OS for groups 1-4 were 1.0, 1.7, 7.9 and 15.9 months, respectively. In Cox multivariate analysis adjusted for age and PS CRT+BEV patients survival was superior to group 1 (p<.001) and group 2 (p=.002) with a trend compared to CRT (p=.108). 7 patients survived > 24 mos. 3 (43%) were in the CRT+BEV group (representing only 12% of all treated patients). 4.5% of the patients suffered hemorrhage at biopsy and expired in < 1 month. Conclusions: Patients treated with CRT+BEV had median OS > three times the group median and twice that of patients treated with CRT. The median survival of 15.9 months in UGB treated with CRT+BEV is numerically similar to patients treated with resection followed by CRT in other series. Adjusting for age and PS there remained a statistical trend to superior OS for CRT+BEV versus standard CRT. Further study regarding the benefit of BEV in patients with UGB is warranted.
APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases
Authors: Hélène-Marie Lanoiselée, Gaël Nicolas, David Wallon, Anne Rovelet-Lecrux, Morgane Lacour, Stéphane Rousseau, Anne-Claire Richard, Florence Pasquier, Adeline Rollin-Sillaire, Olivier Martinaud, Muriel Quillard-Muraine, Vincent de la Sayette, Claire Boutoleau-Bretonniere, Frédérique Etcharry-Bouyx, Valérie Chauviré, Marie Sarazin, Isabelle le Ber, Stéphane Epelbaum, Thérèse Jonveaux, Olivier Rouaud, Mathieu Ceccaldi, Olivier Félician, Olivier Godefroy, Maite Formaglio, Bernard Croisile, Sophie Auriacombe, Ludivine Chamard, Jean-Louis Vincent, Mathilde Sauvée, Cecilia Marelli-Tosi, Audrey Gabelle, Canan Ozsancak, Jérémie Pariente, Claire Paquet, Didier Hannequin, Dominique Campion
Journal: PLoS Medicine (2017)

Background Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. Methods and findings We report here a novel update (2012–2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers—total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42—in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. Conclusions Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.
Impact of multidisciplinary therapy on high-grade appendiceal adenocarcinoma (AA).
Authors: Karen A. Beaty, Richard E. Royal, Keith F. Fournier, Melissa W. Taggart, Michael J. Overman, Jonathan Phillips, Safia Rafeeq, Paul F. Mansfield, Robert A. Wolff, Cathy Eng
Journal: Journal of Clinical Oncology (2013)

4134 Background: AA is a rare malignancy ranging from well-differentiated to poorly differentiated carcinoma, including those with signet ring cells. Optimal therapy for low grade peritoneal disease is cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC). However, some patients (pts) are suboptimal for CRS/HIPEC, and are considered for systemic chemotherapy (SC) alone, or SC + CRS. In light of our previously reported overall survival (OS) benefits for the role of SC in metastatic AA, here we explore the impact of surgical intervention on OS in these pts. Our aim was to clarify the OS benefit of multidisciplinary therapy (SC + CRS + HIPEC) in those pts with aggressive tumor biology. Methods: A retrospective chart review of AA pts registered in our tumor registry between Jan. 2005 to Dec. 2009 was undertaken to identify patients with AA who received SC. Electronic medical records (EMR) were reviewed for CRS, HIPEC, histology, SC, and OS. The K-M method and Log-Rank test were used for statistical analysis. Results: Of 143 AA pts, 52 (36%) pts were high grade with 33 (23%) having signet ring cells. After a median follow-up of 35M, high grade tumors were noted to have worse OS overall (24M vs 56M, p&lt;.001). When comparing treatment received, and adjusting for tumor biology, those pts with high grade disease again fared worse, and experienced comparatively worse OS. However, those treated with SC + CRS + HIPEC experienced the longest median survival. Conclusions: Pts with peritoneal disease from high grade AA who completed SC with CRS + HIPEC experienced prolonged OS compared to those treated by SC +/- CRS. Our data suggest that SC + palliative CRS offers minimal benefit for high grade disease. Selection bias influences these results heavily; as those who do well proceed to complete all components of therapy. A treatment plan that includes SC + CRS + HIPEC can result in durable survival, and is a strategy that warrants further study emphasizing the importance of multidisciplinary management. [Table: see text]
Detection of ROS1 translocations in triple-negative lung adenocarcinomas.
Authors: Anne McLeer Florin, Lenaig Mescam-Mancini, Denis Moro-Sibilot, Clarisse Audigier-Valette, Chantal Decroisette, Jean-Christophe Sabourin, Pierre Jean Souquet, Sylvie Lantuejoul
Journal: Journal of Clinical Oncology (2013)

8099 Background: After ALK (anaplastic lymphoma kinase) rearrangements, ROS1 (c-ros oncogene 1, located at 6q22) translocations were recently shown to define a new molecular subgroup in non-small cell lung cancers (NSCLC). These translocations, activating a proto-oncogene with a tyrosine kinase domain, are also targeted by the MET and ALK crizotinib. ROS1 rearrangements are found in only 1.2-1.7% NSCLCs, but seemingly only in triple negative (EGFR and KRAS non-mutated and ALK non-rearranged) adenocarcinomas and preferentially in non- or light smokers. Methods: 60 triple negative non- or light-smoking patients with lung adenocarcinoma were screened for ROS1 rearrangements by fluorescent in situ hybridization (FISH). Two commercially available break-apart FISH probe kits containing a mixture of two probes hybridizing on each side of the ROS1 locus, one located in a centromeric (3’) position, and the other one in a telomeric (5’) position relative to the ROS1 gene were used. ROS1 fusions were therefore detected without any preconception on the fusion partner, as multiple fusion partners have been described. At least 100 nuclei were screened, and a tumor was considered positive if it contained more than 15% rearranged nuclei. Results: Forty-nine of the 60 tumors were interpretable. Four (8.2%) of theses 49 tumors were ROS1 rearranged by FISH. Only one of the positive cases showed a “classical” split rearrangement pattern (one fusion, one green and one red signal in more than 15% of nuclei), whereas the three other tumors showed a variant pattern, with a deletion of the telomeric probe, located in a 5’ position relative to the ROS1 gene locus, indicating the presence of a fusion partner upstream of the ROS1 gene. The four positive cases were all at an advanced stage (3 or 4), but did not display any common architectural feature. Conclusions: The prevalence of ROS1 positivity in our selected population was far superior (8.2%) to that of a non-selected NSCLC population, suggesting that this type of screening may be more effective (faster and more cost-worthy) to detect ROS1 positive tumors.
The PACE continuous innovation Indicators: A flexible tool to evaluate progress in cancer treatments.
Authors: Silvia Paddock, Lauren Brum, Kathleen Sorrow, Samuel Thomas, Susan Spence, Catharina Maulbecker-Armstrong, Clifford Goodman, David Grainger, Michael Peake, Corina Ramers-Verhoeven, Gary Geipel, Rose Li
Journal: Journal of Clinical Oncology (2015)

e17783 Background: Measuring progress in cancer treatment research is complicated by the reality that various stakeholders judge achievements differently, because they have diverse priorities and values. A single approach that harmonizes these values may be neither possible nor desirable. Instead, we need tools to visualize differences in values and to track progress accordingly. Lilly Oncology’s Patient Access to Cancer care Excellence (PACE) initiative developed a flexible platform, the PACE Continuous Innovation Indicators, to address this need. Methods: The Indicators employ a value model that allows users to identify their priorities on a matrix of disease states and therapeutic goals. The assigned values then function as weights in the computation of Evidence Scores (E-Scores), a novel measure of progress against different cancers over time. E-Scores represent the sum of discrete pieces of evidence derived from the literature. Each piece contains outcome measures (e.g., p-values, hazard ratios) for one treatment in a specified context. Because evidence supporting or contesting treatments constantly evolves, the Indicators utilize an innovative data management approach that expedites the integration of new evidence and data sources. Results: The PACE Continuous Innovation Indicators provide a platform to explore the relative pace of innovation across areas of cancer treatments. Visual outputs help identify areas of unmet need and potentially misaligned incentives that concentrate research efforts on a limited set of treatment goals. Conclusions: Learning from past progress and having a better understanding of unmet needs may help users to identify incentives that will drive the development of promising therapies in multiple treatment contexts. We envision partnerships and collaborations to support efforts in education, research, and policy. We will not make this tool available to individuals or organizations for the purpose of deriving treatment recommendations. Funding: For the time and effort in contributing to the development of the PACE Continuous Innovation Indicators program, all co-authors received remuneration from Eli Lilly and Company.
Sown the seeds: An analysis of published trials in clinical oncology.
Authors: Natalie M. Spradlin, David H. Johnson, Leora Horn
Journal: Journal of Clinical Oncology (2012)

6068 Background: Competition in the pharmaceutical marketplace has resulted in “seeding trials” which appear to serve little scientific purpose other than to gain a financial hold in the marketplace. Hallmarks of “seeding” clinical trials [Kessler, et al N Eng J Med 1994] include trial design that does not support stated research goals, industry sponsorship without novel findings or poor scientific rationale, and drugs introduced into an already crowded therapeutic class, i.e. “me too” drugs. We evaluated clinical trials published in high impact oncology journals to ascertain the prevalence of trials bearing the characteristics of a seeding trial. Methods: We conducted a PubMed search using “clinical trial”, “oncology”, published 2/2005 – 2/2010, in Ann Oncol, J Clin Oncol, Lancet, Lancet Oncol, or the N Engl J Med. All phase I/II, II and III studies were included. Phase I, hematology, radiation oncology, and pediatric studies were excluded. Data collected included disease site, phase, funding source, journal, and whether the trial fit criteria for “seeding” as previously defined. Results: 1781 articles have been evaluated to date. 528 met criteria for analysis. 130 were considered seed studies. Seed studies per journal were Ann Oncol 26 of 128, J Clin Oncol 88 of 340, Lancet 8 of 22, Lancet Oncol 5 of 16, and N Engl J Med 3 of 22. Studies published per disease site and percent seed studies were melanoma 19 and 31.6%, breast 106 and 30.2%, GI 126 and 20.6%, lung 101 and 29.7%, GU 65 and 24.6%, gynecology 40 and 30%, head and neck 24 and 12.5%, CNS 24 and 12.5%, sarcoma 11 and 18.2%, and advanced cancer 12 with zero seeds. Overall phase totals were phase I/II 16, phase II 272, and phase III 240. Seed studies per phase were phase II 28.7%, phase III 21.7% and zero for phase I/II. 210 studies were solely industry sponsored, and of these, 37.1% were seed studies. Funding was not listed for 73 studies. Conclusions: The integrity of clinical trials is challenged in the race to claim major market share. Our analysis of clinical trials published in high impact oncology journals found seeding trials account for 24.6% of publications. 37.1% of industry sponsored trials are seed studies. Seed studies are more common among the major disease sites or sites for which targeted therapies exist.