tbuckley/cabot-search huggingface dataset:
A phase 1 trial of a human thymus-expressed apoptosis factor in patients with advanced solid tumors: Interim report.
Authors: Salomon M Stemmer1, Ofer Benjaminov4, Michael H. Silverman3, Uziel Sandler2, Ofer Purim, Naomi Sender1, Tamar Segal1, Chen Meir1, Pnina Oren2, Joel Ohana2, Yoram Devary
Journal: Journal of Clinical Oncology (2015)

e14018 Background: This apoptosis factor (NEROFE) is a 14-a.a. modified form of a hormone-like peptide present in the human thymus, which plays a key role in immune system regulation. In preclinical evaluation, it induced apoptosis in cancer cells, inhibited angiogenesis/metastasis, and showed in vivo efficacy with no toxicity. Methods: This ongoing, single-center, first-in-human, 3+3 dose-escalation study of this factor given I.V. at 6 mg/m2-96 mg/m2over 5 3-pt cohorts (3 times a week; 28-day cycle) examines the MTD, safety, PK profile, and anti-tumor activity in pts with advanced solid tumors. Pts undergo tumor assessments every other cycle. Samples for PK are taken on days 1 of cycles 1 and 2. Results: To date, 14 previously treated (57% ≥ 3 lines) and 1 first line pts (M = 8, F = 7, median age: 63) with advanced/metastatic solid tumors have been enrolled. MTD has not been reached. Treatment was well-tolerated with no cumulative toxicity. The most frequently observed AEs (G < 2) in the first 4 cohorts were: hypertension (21%) and increased bilirubin (14%); 5 of 15 evaluable pts continued therapy beyond cycle 2. SD was noted in 2 pts: colorectal cancer (6M) and spinal cord neoplasia (+10M). PK was dose-dependent and approximately linear (Table). Factor administration was associated with orders of magnitude decreases in plasma levels of VEGF A, PDGF AA, PDGF BB, VEGF D, bFGF, aFGF and Angiopoeitin-1 in all pts in cohorts 3 and 4. Also, in 3 pts with elevated plasma EGF levels, it decreased the levels to below normal levels. In the 2 pts that achieved SD, tumor biopsies stained positive to ST2 receptor, had increased plasma TNF-alpha and IL-2. Conclusions: This factor administered at doses up to 96 mg/m2is safe, well-tolerated, and demonstrates interesting anti-angiogenic activity in combination with increased immune cytokines. Tumor ST2 expression may be a biomarker for sensitivity to this factor. Dose-escalation continues in this trial. Clinical trial information: NCT01690741. PK Parameters Dose (mg/m2) Auc0-t (ng h/mL) Cmax (ng/ml) T1/2 (hrs) Cycle 1 Day 1 Cycle 2 Day 1 Cycle 1 Day 1 Cycle 2 Day 1 Cycle 1 Day 1 Cycle 2 Day 1 Cohort 1 6 3813 9719 1209 1536 2.3 2.8 Cohort 2 12 12905 11452 6048 6048 2.1 2.0 Cohort 3 24 49630 57069 14609 14609 3.2 3.7 Cohort 4 48 79935 100093 18267 22113 4.9 4.6
Survival at sea.
Authors: E C Lee
Journal: BMJ (1976)

neither can be compare the UK in 1946, when there were 3 million motors, and in 1974, when there were 17 million.We must have some comparative rate, and if this is improving we are entitled to claim that we are making progress.The large number of deaths is at least partly due to the enormous number of motors.It is also remarkable that your profession, who are in the best position to know, should neglect the large saving in lives made by the motor in enabling you to get to your patients more quickly and to get them to hospital promptly, in enabling the fire brigade to reach fires early, and so on.This mistake has been made twice, if not three times, with tragic results, Between 1946 and 1956 the number of deaths rose slightly, although the "Smeed rate"-which allows for the population and number of motors-and the deaths per 100 million vehicle-kilometres both fell markedly.The rise in deaths, slight though it was, was blamed wholly on the drivers, though the number of motors had risen from 3 million to 61 million.An Act increasing penalties was passed, the trend of the deaths rose sharply, and both rates rose.This was again blamed on the drivers and another Act, much increasing penalties, was passed in 1962.The deaths then rocketed upwards to the highest
Disruption of the protein C inhibitor (PCI) gene does not result in hemostatic abnormalities but in impaired spermatogenesis and infertility in male PCI-/- mice
Authors: P Uhrin, Mieke Dewerchin, M Hilpert, P Chrenek, C Schoefer, M Zechmeister-Machart, G Kroenke, A Vales, Peter Carmeliet, BR Binder, M Geiger
Journal: Blood (2000)
Frontline azacitidine (AZA) or intensive chemotherapy (ICTx) in older AML patients.
Authors: C. Gardin, R. Itzykson, S. Thépot, C. Recher, A. Marfaing, O. Beyne-Rauzy, S. Boehrer, F. Dreyfus, P. Fenaux, H. Dombret
Journal: Journal of Clinical Oncology (2010)

6530 Background: AZA is approved in the EU and USA to treat high-risk MDS and AML with < 30% marrow blasts. As its off- label use is increasing, its role in management of older AML patients, especially those with > 30% marrow blasts, must be evaluated. Methods: We compared 124 AML patients (aged 65y+) treated upfront with AZA in the French patient named program (Thepot, ASH 2009) to 403 non CBF-AML patients from the ICTx ALFA-9803 trial (Gardin, Blood 2007). Risk factors including PS, age, WBC, prior MDS, and cytogenetics were analyzed, with overall survival (OS) and 3-month death rate as endpoints. Results: As expected, patients selected to receive AZA had highermedian age (75 vs. 71 years) (p < 0.001), lower median WBC count (3.1 vs 5.0 G/L, p = 0.02), more frequent prior MDS (43% vs. 16%, p < 0.001) and adverse cytogenetics (43% vs. 19%, p < 0.001), than patients who received ICTx, but similar PS (72% 0-1). Despite these differences, our ICTx- derived risk index, based on adverse cytogenetics, PS, WBC count, and age (Malfuson, Haematologica 2008) was also a powerful predictor of OS after AZA (p < 0.001). In patients with a poor-risk index, the 3-month death rate was 38% in both cohorts, compared to only 18% and 14 % in AZA and ICTx patients with a low-risk index, respectively. AZA patients with PS > 1, WBC > 15 G/L (best cut-off for AZA), and adverse cytogenetics did poorly, while post- MDS AML and age had no prognostic impact in this cohort. After restricting the comparison to patients with WBC ≤ 15 G/L, 18 m-OS was 31% (20-43) in the AZA vs. 40% (33-47) in the ICTx cohort (p = 0.22), with similar early death rates (27% vs 23%). No differences in outcome appeared between AZA and ICTx cohorts when focusing on post-MDS AML, normal cytogenetics (18-m OS, 64% [35-82] vs. 49% [39-59], p = 0.27), or in patients with adverse cytogenetics, including those with isolated +8, abn(5q) or-7/del7q (18-m OS, 10% [3-23] vs. 15% [6-28], p = 0.69). Conclusions: This comparison suggests that usual AML and host risk factors defined for ICTx have similar impact after AZA. If one excludes patients with WBC > 15 G/L who did poorly with AZA, outcomes seem equivalent, even in cytogenetically normal AML. A controlled trialis thus warranted to compare AZA and ICTx in those older patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene Celgene
ZIC5 Drives Melanoma Aggressiveness by PDGFD-Mediated Activation of FAK and STAT3
Authors: Reiko Satow, Tomomi Nakamura, Chiaki Kato, Miku Endo, Mana Tamura, Ryosuke Batori, Shiori Tomura, Yumi Murayama, Kiyoko Fukami
Journal: Cancer Research (2016)

Insights into mechanisms of drug resistance could extend the efficacy of cancer therapy. To probe mechanisms in melanoma, we performed siRNA screening of genes that mediate the development of neural crest cells, from which melanocytes are derived. Here, we report the identification of ZIC5 as a mediator of melanoma drug resistance. ZIC5 is a transcriptional suppressor of E-cadherin expressed highly in human melanoma. ZIC5 enhanced melanoma cell proliferation, survival, drug resistance, in vivo growth and metastasis. Microarray analysis revealed that ZIC5 downstream signaling included PDGFD and FAK activation, which contributes to drug resistance by enhancing STAT3 activation. Silencing of ZIC5 or PDGFD enhanced the apoptotic effects of BRAF inhibition and blocked survival of melanoma cells resistant to BRAF inhibitors. Furthermore, inhibition of FAK or STAT3 suppressed expression of ZIC5, which was positively regulated by PDGFD, FAK, and STAT3 in a positive feedback loop. Taken together, our results identify ZIC5 and PDGFD as candidate therapeutic targets to overcome drug resistance in melanoma. Cancer Res; 77(2); 366-77. ©2016 AACR.
Neuroendocrine tumor of the pancreas with cystic appearance mimicking a progressive intraductal papillary mucinous neoplasm: pitfall in medical imaging
Authors: Francesco Vitali, Deike Strobel, Lukas Pfeifer, Marc Heinrich, David Wachter, Markus Neurath, Dane Wildner
Journal: Endoscopy (2016)

Pancreatic cystic lesions are increasingly being recognized on imaging studies. Among these, intraductal papillary mucinous neoplasms (IPMNs) frequently exhibit a spectrum of neoplastic transformation and follow-up is recommended according to the Sendai [1] and Fukuoka criteria [2], with the preference being for magnetic resonance imaging (MRI) [3]. Endoscopic ultrasound (EUS) can help to verify the absence of thickened walls or mural nodules [2].
Body mass index and response to neoadjuvant chemotherapy in breast cancer patients
Authors: J. K. Litton, A. M. Gonzalez, C. L. Warneke, S. Kau, A. U. Buzdar, M. Bondy, S. Mahabir, G. N. Hortobagyi, A. Brewster
Journal: Journal of Clinical Oncology (2007)

531 Background: Obesity in breast cancer patients is associated with increased risk of poor outcome. One possible mechanism is that obesity may affect metabolism of chemotherapeutic agents, influencing tumor response to chemotherapy. To test this hypothesis, we evaluated the relationship between body mass index (BMI, weight kg/height m 2 ) and response to neoadjuvant chemotherapy in women diagnosed with operable breast cancer. Methods: From May 1990 - July 2004, 1169 patients diagnosed with invasive breast cancer at our institution, received neoadjuvant chemotherapy (anthracycline and/or taxane) followed by definitive surgery. Based on BMI, patients were categorized as obese (BMI ≥30), overweight (BMI 25 to &lt;30), normal weight (18.5 to &lt;25) and underweight (BMI &lt;18.5). We used logistic regression to examine associations between BMI and pathologic response to therapy (complete= no invasive carcinoma, and partial) as well as tumor characteristics. Kaplan-Meier survival curves for BMI groups were compared using the log-rank test. Results: Median patient age was 50 (range 23 - 84) years; 30% were obese, 32% overweight, 36% normal weight and 1% underweight. BMI was not significantly associated with pathologic response to neoadjuvant chemotherapy even after adjusting for relevant clinical factors (OR 1.00; 95% CI 0.96–1.03, p = 0.8). Compared to patients not overweight, obese patients had higher odds of having ER negative tumors (OR 1.5; 95% CI 1.1–2.0; p = 0.01) and T3 or T4 lesions (OR 1.7; 95% CI 1.3–2.4, p &lt; 0.001) adjusting for age, race and menopausal status. At a median follow up of 4.1 (range 0.2–14.3) years, obesity was significantly associated with poorer overall survival (p = 0.006) but not progression-free survival. Conclusions: Obese patients presented with more aggressive tumor characteristics and had worse overall survival compared to patients not overweight. However, BMI was not related to lower tumor response to anthracycline and/or taxane based neoadjuvant chemotherapy suggesting a role for other co-morbidities in influencing outcome. Understanding specific components through which overweight and obesity contribute to breast cancer outcome is essential to individualize and improve care of overweight/obese breast cancer patients. No significant financial relationships to disclose.
The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA center dot CER) Trial
Authors: Kenneth W Mahaffey, Pierluigi Tricoci, Yuliya Lokhnygina, Paul W Armstrong, Philip Aylward, Edmond Chen, Claes Held, Sergio Leonardi, Ann M Kilian, David J Moliterno, Tyrus L Rorick, John Strony, Frans Van de Werf, Lars Wallentin, Harvey D Wite, Robert A Harrington
Journal: Circulation (2011)
Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study
Authors: Maxime Dougados, Désirée van der Heijde, Ying-Chou Chen, Maria Greenwald, Edit Drescher, Jiajun Liu, Scott Beattie, Sarah Witt, Inmaculada de la Torre, Carol Gaich, Terence Rooney, Douglas Schlichting, Stephanie de Bono, Paul Emery
Journal: Annals of the Rheumatic Diseases (2016)

Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3.More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein.In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.NCT01721057; Results.
Advance Directives
Authors: Thomas E. Finucane
Journal: Annals of Internal Medicine (1992)

Letters15 February 1992Advance DirectivesThomas E. Finucane, MDThomas E. Finucane, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-116-4-348 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editors:I would like to report three kinds of unexpected problems that patients have encountered in trying to complete advance directives. Some elderly patients lead very isolated lives and are unable to identify a trusted confidante whom they are willing to designate with a durable power of attorney. The second is a bit more puzzling. Several patients have been unwilling, apparently due to embarrassment, to ask their neighbors simply to witness either a living will or a durable power of attorney. They seem to feel that discussing plans for their dying with neighbors and friends would be an...Reference1. GrecoSchulmanLavizzo-MoureyHansel-Flaschen PKRJ. The Patient Self-Determination Act and the future of advance directives. Ann Intern Med. 1991;115:639-43. LinkGoogle Scholar1. GrecoSchulmanLavizzo-MoureyHansen-Flaschen PKRJ. The Patient Self-Determination Act and the future of advance directives. Ann Intern Med. 1991;115:639-43. LinkGoogle Scholar1. . Handbook of Living Will Laws. New York: Society for the Right to Die; 1987:31-134. Google Scholar2. GrecoSchulmanLavizzo-MoureyHansen-Flaschen PKRJ. The Patient Self-Determination Act and the future of advance directives. Ann Intern Med. 1991;115:639-43. LinkGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: The Johns Hopkins University Baltimore, MA 21205 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByAdvance directives and cancer decision making near the end of life.The Use of Advance Directives in End-of-life Decision Making 15 February 1992Volume 116, Issue 4Page: 348-349KeywordsElderlyLiving wills Issue Published: 15 February 1992 PDF DownloadLoading ...
Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms
Authors: M Ruella, S S Kenderian, O Shestova, M Klichinsky, J J Melenhorst, M A Wasik, S F Lacey, C H June, S Gill
Journal: Leukemia (2016)
Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab
Authors: A.M. Menzies, D.B. Johnson, S. Ramanujam, V.G. Atkinson, A.N.M. Wong, J.J. Park, J.L. McQuade, A.N. Shoushtari, K.K. Tsai, Z. Eroglu, O. Klein, J.C. Hassel, J.A. Sosman, A. Guminski, R.J. Sullivan, A. Ribas, M.S. Carlino, M.A. Davies, S.K. Sandhu, G.V. Long
Journal: Annals of Oncology (2016)
Predictive value of chemotherapy-induced neutropenia for drug efficacy in advanced gastric carcinoma: Analysis of prospective nationwide survey
Authors: T. Yamanaka, S. Matsumoto, S. Teramukai, R. Ishiwata, Y. Nagai, M. Fukushima
Journal: Journal of Clinical Oncology (2007)

15075 Background: Myelosuppression that occurs during chemotherapy has been reported to be a predictor of better survival in patients with breast or lung carcinomas. We evaluated the prognostic implications of chemotherapy-induced neutropenia in advanced gastric cancer. Methods: Data obtained from a prospective nationwide survey of oral fluoropyrimidine S-1, performed in Japan between 1999 and 2000, were reviewed. Advanced gastric cancer patients with both adequate bone marrow function and no prior history of chemotherapy within 6 months before starting S-1 therapy were analyzed (N=1055). Chemotherapy-induced neutropenia was treated as a time-dependent covariate, and the hazard ratios [HRs] of death for experiencing neutropenia, compared with no such toxicity, were estimated using Cox regression model. Results: During treatment with S-1, a total of 293 (28%) patients had grade 1 or higher neutropenia. The adjusted HRs from a multivariate Cox model were 0.72 for patients with grade 1 neutropenia (95% confidence interval [CI] 0.54–0.95; P=0.0189), 0.63 for those with grade 2 neutropenia (95% CI 0.50–0.78; P&lt;0.0001), and 0.71 for those with grade 3–4 neutropenia (95% CI 0.51–0.98; P=0.0388). Conclusions: The results of this study suggest that occurrence of neutropenia during chemotherapy is an independent predictor of better survival for advanced gastric cancer, while the absence of such toxicity indicates that the dosages of drugs are pharmacologically inadequate. Monitoring of neutropenia in patients who receive chemotherapy may contribute to improved drug efficacy and patient survival. No significant financial relationships to disclose.
Adjuvant chemotherapy (ACT) in stage II colon cancer (CC) in patients with Lynch syndrome.
Authors: Karsten Schulmann, Sven Koepnick, Christoph Engel, Christiane Bernhardt, Verena Steinke, Brigitte Royer-Pokora, Hans K. Schackert, Magnus von Knebel Doeberitz, Elke Holinski-Feder, Reinhard Büttner, Wolff H. Schmiegel
Journal: Journal of Clinical Oncology (2012)

3550 Background: Previous studies showed conflicting results regarding the value of ACT in MSI-H CC. A recent study reported differential benefits from 5-FU-based ACT comparing suspected sporadic vs suspected hereditary MSI-H CC. We sought to evaluate the prognostic impact of ACT in a large cohort of Lynch syndrome (LS) patients (pts) with stage II CC. Methods: To minimize selection bias diagnoses &gt;2 years prior to registration in the database of the German HNPCC consortium were excluded. 278 patients (61% male, mean age 42.9y, 13% stage IIB, 51% with MMR gene mutation) were eligible. Overall Survival (OS), CC-specific Survival (CSS), and Disease Free Survival (DFS) were analyzed using Kaplan-Meier and Cox Regression analyses. Results: 5y OS, CSS and DFS were 95%, 95% and 93% respectively. Right-sided CC was independently associated with lower DFS in stage II and IIA. Increasing age was associated with lower OS, CSS and DFS in stage IIA, however we observed only trends in the multivariate analysis. Surgery alone (without ACT) was associated with a slightly lower OS in stage IIA (univariate HR 3,659; 95% CI 0,81-16,5; P=0.092); but not with lower DFS and CSS. Prognosis was not different comparing FOLFOX vs. 5-FU-based ACT. Conclusions: Our data suggest that LS pts with stage II CC do not benefit from ACT. FOLFOX was not superior to 5-FU-based ACT. If our results are confirmed, LS pts with stage IIA CC should not receive ACT. The group of stage IIB CC was too small to make definite conclusions. [Table: see text]
Five-year results of preoperative concurrent paclitaxel with radiation in locally advanced breast cancer (LABC).
Authors: S. Formenti, S. Adams, A. B. Chakravarthy, S. C. Lymberis, D. V. Spicer, J. A. Bauer, M. Volm, D. Roses, J. D. Goldberg, J. A. Pietenpol
Journal: Journal of Clinical Oncology (2010)

567 Background: Prospective trials of preoperative concurrent paclitaxel (P) and radiation (RT) for LABC were conducted at three academic institutions. Rates of pathologic response, DFS and OS are reported. Methods: 105 LABC patients were treated between March 1997 and August 2009; 33 at University of Southern California, 36 at New York University and 36 at Vanderbilt University. P was given at 30 mg/m2 intravenously twice a week for 10-12 weeks. RT was delivered daily at 1.8 Gy to the breast, axillary and supraclavicular lymph nodes (LN) during weeks 2-7, to a total dose of 45 Gy followed by a tumor boost of 14 Gy at 2 Gy/fraction. Weekly trastuzumab (2 mg/kg) was added for 8 recent patients whose tumor over-expressed Her-2/neu. At one institution three cycles of P (175 mg/m2 q 3 weeks) were given prior to chemo-radiation. Pathologic response was defined as absence of invasive cancer in breast and LN (pCR) or less than 10 microscopic foci of invasive cancer in breast or LN (pPR). After surgery additional systemic therapy was left to the discretion of the treating physician. Results: Pathologic response (pCR and pPR) after concurrent P-RT was achieved in 34% (36/105) of patients. At a median follow-up of 60 months, the median survival has not been reached. The estimated 5-year DFS is 82.3% (95% CI: 71.6-89.3%), the 5-year OS is 71.6% (95% CI: 60.5-80.1%). The 5-year estimated OS for patients achieving a pathological response was 87.9% compared with 61.6% for nonresponders (Log-Rank = 8.61, p-value = 0.003). Local recurrence was only observed in 4/105 patients (3.8%): in 3 of 4 patients synchronously with or following systemic recurrence. Patients with a pathologic response had a lower risk of recurrence or death compared to patients who did not have a pathologic response (hazard ratio = 0.35, 95% CI: 0.15-0.80, logrank p-value = 0.009); similarly, responders were 0.23 times less likely to die over the time period than non-responders (95% CI: 0.08, 0.68). Conclusions: This series of 105 LABC patients treated with concurrent paclitaxel and radiation demonstrated a 71.6% 5-year OS and 96% local control. Pathologic response to concurrent paclitaxel and radiation was associated with a significantly better 5-year survival. No significant financial relationships to disclose.
Detection of Acquired Uniparental Disomy (aUPD) with HLA Typing and Microarray Analysis after T Cell-Containing Haploidentical (HI) Hematopoietic Stem Cell Transplantation (HSCT)
Authors: Dolores Grosso, Beth Colombe, Zi-Xuan Wang, Matthew Carabasi, Onder Alpdogan, Joanne E. Filicko-O'Hara, Margaret Kasner, Thomas R. Klumpp, Ubaldo Martinez-Outschoorn, Manish Sharma, John L. Wagner, Mark Weiss, Neal Flomenberg
Journal: Blood (2015)