tbuckley/cabot-search huggingface dataset:
Phase I Trials in Pediatric Oncology: Perceptions of Pediatricians From the United Kingdom Children’s Cancer Study Group and the Pediatric Oncology Group
Authors: E.J. Estlin, S. Cotterill, C.B. Pratt, A.D. J. Pearson, M. Bernstein
Journal: Journal of Clinical Oncology (2000)

To identify areas of concern regarding the conduct of phase I trials, the perceived expectations and motivations of the parents of children entered, the expectations of toxicity and benefit, and the ethical concerns of pediatric hematologists and oncologists in the United Kingdom and North America.A survey instrument consisting of 19 open- and closed-ended questions was sent to United Kingdom Children's Cancer Study Group (UKCCSG)- and Pediatric Oncology Group (POG)-affiliated pediatricians.Fifty-three UKCCSG- and 78 POG-affiliated pediatricians responded. Thirty-two UKCCSG and 51 POG respondents had previously entered at least one child into a phase I study. Overall, respondents believed that parents entered their children for medical benefit, altruism, and hope of cure. Although many respondents believed that children could benefit from medical improvement, feelings of altruism, and maintenance of hope, the chance of cure or complete remission was thought to be small. Similarly, parents were thought to potentially benefit through altruism and maintenance of hope. Whereas 83% of UKCCSG respondents indicated that phase I trials were associated with ethical difficulties, this was a concern for 48% of POG respondents. The main ethical concerns of respondents were risk of toxicity, consent of the child, unrealistic hope, and coercion.The respondents in this survey expressed mainly ethical concerns regarding the conduct of phase I trials and had realistic expectations of the potential for toxicity and benefit for those children who participate in these studies.
Measurement of circulating tumor DNA as a cancer biomarker in gastrointestinal malignancies using a novel next-generation sequencing method.
Authors: Edward Samuel James, Azeet Narayan, Stacey Stein, Jill Lacy, Abhijit Patel, Howard S. Hochster
Journal: Journal of Clinical Oncology (2014)

217 Background: Circulating tumor DNA (ctDNA) holds promise as a highly specific cancer biomarker. The presence of mutant tumor-derived DNA fragments in the blood provides an opportunity to non-invasively assess tumor mutation profiles and to quantify changes in tumor DNA levels over time. Methods: After obtaining informed consent, plasma samples were collected prospectively at multiple time points in a cohort of patients (pts) with various gastrointestinal (GI) malignancies in the locally advanced, metastatic and adjuvant settings. Hotspot regions of genes known to be commonly mutated in GI tumors were amplified by multiplexed PCR, and the resultant amplicons were subjected to next-generation ultra-deep sequencing. Suppression of sequencer and PCR errors allowed mutations to be identified and quantified with a sensitivity of approximately 1 variant in 5,000 molecules. Sample-specific barcoding allowed simultaneous analysis of up to 96 samples. Results: 29 out of 74 available samples from 17 pts were analyzed for the presence of ctDNA. 3 pts had KRAS mutations exclusively. 2 pts had mutations in two of the evaluated genes: KRAS plus PIK3CA and KRAS plus TP53. 2 pts with measurable mutant ctDNA had samples analyzed at multiple time points. One of these patients with locally advanced pancreatic cancer initially had a KRAS G12D mutation which disappeared after treatment with chemo-radiation therapy, but then he developed significantly rising levels of a different KRAS G12L mutation just preceding the diagnosis of liver metastases by imaging. A second pt with metastatic colon cancer had high levels of ctDNA prior to treatment that decreased dramatically after initiation of mFOLFOX and bevacizumab therapy. Conclusions: Our initial analysis indicates that our technique is able to quantify multiple mutations at very low copy numbers accurately in this cohort of pts with GI cancers. Moreover, we were able to monitor changes in mutation type and quantity using this non-invasive “liquid biopsy” approach. Analysis of remaining samples is ongoing, and additional longitudinal data will be presented.
Erotomania revisited: from Kraepelin to DSM-III-R
Authors: J H Segal
Journal: American Journal of Psychiatry (1989)

Erotomania, the persistent delusion of being loved from afar by another person, has defied easy categorization for years. Kraepelin and de Clérambault both discussed the syndrome in detail, but it has recently appeared officially for the first time, in DSM-III-R, as a subtype of delusional (paranoid) disorder, in a return to the original Kraepelinian formulation. The author reviews the history, theories of etiology, course, and treatment of erotomania. He concludes that the DSM-III-R classification is correct and that neuroleptics and enforced separation, although only moderately effective, are the best treatments for troublesome cases.
A multinational assessment of gastric and esophageal cancer burden by age, gender, and disease characteristics.
Authors: Kimberly A Lowe, Aaron Katz, Michael A. Kelsh, Thomas L. Vaughan
Journal: Journal of Clinical Oncology (2015)

29 Background: Gastric and esophageal cancers are the fourth and eighth most common cancers worldwide, with an estimated 1.5 million new cases combined in 2008. A comprehensive, international comparison of the descriptive epidemiology of these diseases is lacking. The objectives of this study are to (1) characterize the current and projected incidence rates and the current case fatality of these cancer types by age and gender within countries in Europe, Asia, the Americas, Oceania, and Africa; (2) describe the temporal variation in cardia and non-cardia gastric cancer and squamous and adenocarcinoma esophageal cancer in the U.S. by age and gender. Methods: Data from GLOBOCAN were used to calculate country-specific incidence rates (per 100,000) for 2012, 2015, and 2025, and the country-specific case fatality (%) in 2012. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program in the U.S. were used to estimate gastric cancer incidence rates from 2004-2011 (per 100,000) and 12-month survival (%) stratified by gender, age (0-64/65+), stage at diagnosis, gastric cancer subtype, and esophageal cancer histology. Joinpoint regression was used to quantify changes in the Average Annual Percent Change (AAPC) in these outcomes. Results: GLOBOCAN results showed wide geographic variation in gastric and esophageal cancer incidence rates. In most countries, the case-fatality among males and females 65+ years was &gt; 60%. In the U.S., the annual incidence of all gastric cancer subtypes decreased significantly among males and females 65+ (AAPC= -2.4% &amp; -1.6%, respectively). Esophageal cancer incidence decreased in both genders and age groups, with a significant decline observed among females 65+ with squamous histology (-3.5%). Twelve-month survival in esophageal cancer showed modest improvements, with a significant increase observed among males 65+ with adenocarcinoma histology (2.0%). Conclusions: The worldwide burden of gastric and esophageal cancers is substantial. In the U.S., declines in incidence and modest improvements in survival of these cancers were observed.
Irrinotecan hydrochloride (CPT-11) and mitomycin C in ovarian clear cell adenocarcinoma
Authors: Y. Aoki, T. Yahata, K. Fujita, T. Amikura, H. Obata, M. Sekine, K. Tanaka
Journal: Journal of Clinical Oncology (2004)

5129 Background:The purpose of this study was to report the results of adjuvant CPT-11 and MMC combination chemotherapy (CPT-M) for ovarian clear cell adenocarcinoma (OCCA). Methods:Between 1996 and 2001, patients with OCCA underwent primary debulking surgery and received two cycles of CPT-11 (140 mg/m2) in combination with MMC (7 mg/m2) on days 1, 15, 29 in adjuvant setting. Overall survival was compared with our historical control, in which 14 patients with OCCA treated with an initial optimal standard surgery and postoperative adjuvant CAP (cyclophosphmide, doxorubicin, cisplatin). Results:Median age was 52 year-old (range, 29–74). Twelve patients were in stage Ic, 1 in stage IIa, 5 in stage IIc, 1 in stage IIIb, and 1 in stage IV. Optimal cytoreduction with standard surgery was obtained in all 20 patients. The major toxicity with this regimen was neutropenia, which was brief and reversible. The incidences of grade 3 and 4 neutropenia were 38% and 15%, respectively. The non-hematological toxicities were generally mild and well tolerated. One patient with stage Ic refused chemotherapy after the first cycle of CPT-M, and died of her disease 8 months after initial surgery. Five-year survival rate was 94.1% for CPT-M group, and 63.4% for CAP group (p=0.128). Survival was better for patients treated with CPT-M. Conclusions:This preliminary study shows that the combination of CPT-M appears to be safe and useful in patients with OCCA. Prospective randomized trials should be conducted to assess this regimen appropriate for women with OCCA. No significant financial relationships to disclose.
Phase I study of AV-412, a novel, irreversible EGFR inhibitor, administered intermittently in patients with advanced solid tumors.
Authors: K. Kelly, J. J. Hwang, G. Shapiro, S. Mani, M. M. Cotreau, M. Credi, M. Al-Adhami, P. Bhargava
Journal: Journal of Clinical Oncology (2010)

3103 Background: AV-412, an irreversible EGFR TKI, has demonstrated activity in chimeric mouse models bearing the L858R/T790M mutation. A daily dosing study identified a maximally tolerated dose (MTD) of 150 mg/day [AACR-NCI-EORTC 2009]. The goals of this study were to determine the MTD, safety, dose limiting toxicity (DLT), pharmacokinetics (PK), and activity of AV-412 administered on two intermittent dosing schedules. Methods: Patients (pts) with incurable solid tumors were enrolled and administered AV-412 orally three times a week (TIW). Once the MTD was identified, a once weekly (OW) schedule was evaluated. Doses ranged from 100-200 mg TIW to 200-500 mg OW. Results: 36 patients were treated: 26 males/10 females, median age 60 years (range 27-80). ECOG PS 0/1 (21/15 pts). Tumor types were colorectal (17), pancreatic (4), appendiceal (3), esophageal (2), NSCLC (2), and other (8). Median number of prior treatments were 4 (range 0-14). Twenty-four pts (66.7%) received a prior EGFR inhibitor. The median duration of treatment was 49 days (range 1- 99). Two pts experienced DLT in cycle 1 at 200 mg TIW (grade 3 nausea and vomiting, and grade 3 diarrhea), therefore the MTD was 100 mg. In the OW schedule, two pts experienced DLT in cycle 1 at 500 mg (grade 3 acute renal failure, and grade 3 diarrhea) and 400 mg OW was declared the MTD. Common treatment-related adverse events (all grades) were nausea (69.4%), diarrhea (55.6%), vomiting (41.7%), and fatigue (27.8%). Treatment-related skin rash was rare (2.7%). Preliminary PK data showed less than dose proportional exposure and high interpatient variability. Preliminary efficacy data revealed 8 pts had stable disease with a median duration of 7.7 weeks. Conclusions: AV-412 is well tolerated at 400 mg once weekly. The OW schedule was able to achieve a higher MTD and Cmax when compared to daily dosing. Additional studies are under discussion. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AVEO AVEO
Antitumor efficacy of APO866 against Myla-2059, a model of cutaneous t-cell lymphoma
Authors: Christopher Ireson, Yvan Varisco, Antoine Attinger, Isabelle Bassi, Stephane Germain, Benard Sordat, Keith Dawson, Udo Dobbeling, Reinhard Dummer, Marc Dupuis
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5610 

APO866 (formerly FK866), an inhibitor of the enzyme nicotinamide phosphoribosyltransferase (NMPRTase), has been shown to inhibit the growth of an array of cancer cell lines in vitro and human tumor xenografts in vivo. The mechanism of action involves depletion of intracellular NAD+, resulting in apoptosis. During an in vitro screen of cancer cell lines to identify potential clinical targets, Myla-2059 cells, derived from a cutaneous T-cell lymphoma (CTCL), were found to be particularly sensitive to this agent (IC50=5.6 nM, n=3) as determined by FACS analysis with annexin/PI staining. In order to compare the efficacy of this agent with other agents shown to be active against CTCL in vivo, recipient female Balb/c nude mice were implanted subcutaneously with a Myla-2059 tumor fragment (approximately 50 mm3). When tumors reached treatment size (200 mm3), mice were treated with APO866 (20 mg/kg i.p., twice daily on days 1, 2, 3, 4, 8, 9, 10 and 11), methotrexate (0.3 mg/kg, i.v. on days 1 and 8), gemcitabine (120 mg/kg, i.v. on days 1, 4, 7 and 10) or with vehicle alone. Futhermore, the effect of combining APO866 with gemcitabine was investigated in vitro and in vivo. Both APO866 and the combination of APO866 with gemcitabine significantly reduced tumour growth compared to the control (p<0.01, one way anova) and in 3/9 animals in the APO866 and combination treatment groups, no regrowth of tumors was observed 45 days after start of treatment. Treatment with methotrexate and gemcitabine alone did not affect tumor growth. In summary we have shown that (i) Myla-2059 cells are sensitive to APO866 both in vitro and in vivo and (ii) this agent is more effective than other agents know to be active against CTCL. In conclusion these data support the clinical evaluation of APO866 in the treatment of CTCL.
Risks of recurrence and survival after relapse in patients with Ewing tumor
Authors: H. Jürgens, A. Ranft, U. Dirksen, V. Vieth, M. Paulussen, C. Franzius, T. Bölling, A. Craft
Journal: Journal of Clinical Oncology (2007)

10012 Background: Ewing tumor treatment has resulted in long term survival rates of approx. 70% in localized, and 30% in metastatic disease. Survival following relapse has remained poor with survival rates well below 30%. Methods: All histological proven Ewing tumor patients from three consecutive GPOH trials since 1981 (CESS81 &amp; CESS86 &amp; EICESS92; N=1,549) were included to conduct a meta-analyses of time to and type of recurrence. The follow up has been recently updated in 2006 resulting in a maximum observation period of 25 years. The cumulative incidences of the types of first relapse excluding progress under therapy were computed with competing risk analysis. Multivariate stepwise regression analyses according to the Cox proportional hazard model researched the influences of time to and type of relapse on survival after relapse. Results: More than 70% of first recurrences occurred within 2 years, and 85% within 3 years from initial diagnosis. Most common relapses were systemic with a 3-year cumulative incidence of approx. 0.10 each for lung metastases, bone metastases and multisystem metastases including other sites, followed by local and combined relapses both with a 3-year cumulative incidence of approx. 0.05. Multivariate analyses identified both early (&lt;2 years after diagnosis) and combined relapses as most unfavorable prognostic factors for survival after relapse, with hazard ratios &gt;2.5 (p&lt;.001). Comparing relapse types, patients with local relapses, and pulmonary metastases only, had a better prognosis. Conclusions: The risk of relapse is markedly reduced 2–3 years after diagnosis. The treatment strategies should take the time at risk for relapse into consideration. New strategies for treatment of relapses are needed in particular for the most unfavorable bone, multisystem and combined relapses. Supported by Deutsche Krebshilfe Grants DKH M43/92/Jü2, DKH 70–2551 Jü3, and EU BIOMED Grants BMH1-CT92–1341 and BMH4–983956 No significant financial relationships to disclose.
Sunitinib monotherapy in patients with advanced hepatocellular carcinoma (HCC): Insights from a multidisciplinary phase II study
Authors: A. X. Zhu, D. V. Sahani, E. di Tomaso, D. G. Duda, O. A. Catalano, M. Ancukiewicz, L. S. Blaszkowsky, T. A. Abrams, D. P. Ryan, R. K. Jain
Journal: Journal of Clinical Oncology (2008)

4521 Background: HCC is a highly vascular tumor and angiogenic pathways such as VEGF and IL-6 play a key role in proliferation and angiogenesis. Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor with significant activity against VEGFR2. This phase II study evaluated the efficacy, toxicity, and changes in angiogenic parameters following SU administration in pts with advanced HCC. Methods: Eligibility criteria included unresectable or metastatic measurable HCC, 0/1 prior chemotherapy regimens, ECOG PS ≤1, CLIP score ≤3, and adequate organ function. Pts received SU at 37.5 mg po qd on a standard 4 wks on, 2 wks off regimen (6- wk cycle). The primary endpoint was PFS. Exploratory studies included serial analyses using DCE-MRI (for permeability measurements), multiplex protein array (for plasma angiogenic markers evaluation) and flow cytometry (for circulating endothelial and progenitor cell [CEC/CPC] evaluation). Results: The targeted 34 pts have been enrolled: median age=64 (range 30–82), M/F=29/5, ECOG 0/1=15/19, CLIP 1/2/3=13/12/9. One pt had a partial response and 16 pts had stable disease ≥12 weeks; 5 remain on study. The median number of cycles received was 2 (range 1–14). Median PFS = 4.0 months (95% CI: 2.6–5.9) and median OS = 9.9 months (95% CI: 7.5–11.7). SU was generally well tolerated. Grade 3/4 toxicities included SGOT (18%), lymphopenia (15%), neutropenia, thrombocytopenia and fatigue (12%), SGPT (9%), and hand-foot syndrome, rash, hyperbilirubinemia and hypertension (6%). SU treatment significantly decreased tumor vascular permeability (Ktrans, p<0.01), plasma sVEGFR2 (p<0.01) and CPC (p<0.05) levels, and significantly increased plasma P1GF and VEGF levels (p<0.01, all by Wilcoxon test). Interim analyses showed that time-dependent IL-6 and CPC levels significantly correlated with survival (p<0.05, Wald test in proportional hazards model). Conclusions: SU 37.5 mg/d on a 4/2 schedule shows modest antitumor activity and acceptable safety in HCC pts. SU induces significant changes in vascular permeability and blood angiogenic markers. IL- 6 and CPC levels on treatment appear to correlate with survival. Complete data on 12 plasma angiogenic markers and their correlation with clinical outcome will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Bayer, Dyax, Genentech, Pfizer Oncology, Takeda AstraZeneca Oncology
Dyskinesia and psychosis in a patient following baclofen withdrawal
Authors: V Kirubakaran, D Mayfield, S Rengachary
Journal: American Journal of Psychiatry (1984)

A paraplegic man with no history of psychiatric illness developed psychosis and dyskinesia following abrupt withdrawal of baclofen; the symptoms resolved 72 hours after resumption of the drug. The psychosis and dyskinesia may have been a manifestation of baclofen's alteration of cerebral dopaminergic mechanisms.
Oral tyrosine kinase inhibitor masitinib in combination with gemcitabine in patients with advanced pancreatic cancer: A multicenter phase II study
Authors: P. Hammel, F. Mornex, G. Deplanque, E. Mitry, P. Levy, J. Seitz, A. Moussy, O. Hermine, P. Rougier, E. Raymond
Journal: Journal of Clinical Oncology (2009)

4617 Background: Masitinib, a tyrosine kinase inhibitor targeting c-Kit, PDGFR, FGFR3 and affecting the FAK pathway, can enhance the antiproliferative effects of gemcitabine (GEM) in human pancreatic cancer cells. This multicenter phase 2 study aimed to determine the efficacy and safety of masitinib in combination with GEM in the first-line treatment of patients with locally advanced (LAPC) or metastatic (MPC) pancreatic cancer. Methods: Patients received oral masitinib (9 mg/kg/d) and standard weekly infusion of GEM (1,000 mg/m2). Primary endpoint was time-to-progression (TTP). Our hypothesis for efficacy was a TTP over 2.1 months. Secondary endpoints included survival rates, tumor response (RECIST) and clinical benefit. Results: 22 patients, with LAPC (n=9) or MPC (n=13), KPS[80–100]/[70] (18/4) were enrolled and treated with masitinib plus GEM. Median TTP was 6.4 months, well beyond our threshold for efficacy (LAPC: 8.3 months, MPC: 2.7 months, KPS[80–100]: 6.4 months, KPS[70]: 0.8 months). At 12 months, 17% of LAPC and 14% of KPS[80–100] were progression-free; all MPC and KPS[70] patients had progressed. The disease control rate was 73% (LAPC: 89%, MPC: 62%, KPS[80–100]: 89%; KPS[70] patients progressed immediately). Median OS was 7.1 months (LAPC: 8.4 months, MPC: 6.8 months, KPS[80–100]: 8.0 months, KPS[70]: 4.4 months). At 18 months, the survival rate was 23%. However, when considering KPS[80–100] alone, it reached 28%. The 18-months survival rates were similar for LAPC (22%) and MPC (23%). 16% of the 19 patients evaluated experienced clinical benefit (LAPC: 38%, KPS[80–100]: 18%). One patient (5%) presented suspected grade 4 neutropenia. Main suspected grade 3 toxicity were anemia, lymphopenia (23%), leucopenia, neutropenia (18%), asthenia (14%), diarrhea, cytolytic hepatitis, and skin rash (9%). Altogether, the combination masitinib plus GEM did not seem to increase the toxicity commonly reported with GEM alone. Conclusions: The antitumor activity of the combination masitinib plus GEM is very promising and does not present limiting toxicities. Based on those encouraging data, a randomized phase III trial comparing masitinib plus GEM with GEM alone is now actively recruiting patients in the US and in Europe. [Table: see text]
The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies.
Authors: J W Smith, W J Urba, B D Curti, L J Elwood, R G Steis, J E Janik, W H Sharfman, L L Miller, R G Fenton, K C Conlon
Journal: Journal of Clinical Oncology (1992)

A phase I trial was undertaken because interleukin-1 alpha (IL-1 alpha) possesses antiproliferative, immunostimulatory, antiinfection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment.In this phase I trial, IL-1 alpha was administered intravenously (IV) during a 15-minute period daily for 7 days to patients with advanced solid malignancies.The maximum-tolerated dose (MTD) of IL-1 alpha alone was 0.3 microgram/kg. A second group of patients received indomethacin plus IL-1 alpha based on preclinical studies, which indicated that indomethacin could abrogate IL-1 alpha-induced hypotension; however, the MTD of IL-1 alpha plus indomethacin was 0.1 microgram/kg lower than IL-1 alpha alone. Fever, chills, headache, nausea, vomiting, and myalgia were common but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 micrograms/kg IL-1 alpha. Dose-limiting toxicities included hypotension, myocardial infarction, confusion, severe abdominal pain, and renal insufficiency. IL-1 alpha treatment caused a significant, dose-related increase in the total WBC count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased because of enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts decreased during therapy but were significantly elevated above baseline values 1 to 2 weeks posttreatment; this may have been an effect of IL-6 that was shown to be induced by IL-1 alpha treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid-stimulating hormone and decreases in cholesterol, testosterone, and protein-C were observed with treatment.We conclude that at doses of IL-1 alpha that can be given safely to cancer patients, significant, potentially beneficial hematopoietic effects occur.