tbuckley/cabot-search huggingface dataset:
Lower than standard doses of irinotecan (cpt-11) in the treatment of metastatic colorectal carcinoma (MCC)
Authors: Z. Nikolic-Tomasevic, S. Jelic, Z. M. Tomasevic, S. Radulovic, D. Radosavljevic, I. Popov
Journal: Journal of Clinical Oncology (2005)

3738 Background: Rate of objective responses and disease stabilization seems to be similar in MCC, irrespective of cpt-11 dose (120–180-250–350mg/m2) and schedule. Although dose lower than 80mg/m2 is rarely recommended, actually there are no data about “minimal effective” dose of cpt-11 in the treatment of MCC. Methods: Twenty nine patients (m/f: 16/13) median 55 yrs. (28–72), with non-resectable MCC, were treated with lower than standard doses of cpt-11, with continuous 5-FU infusion (AIO/de Gramont). 41% were older than 65 yrs (median 68, 5) and 6/29 pts (20, 6%) had PS 3. Due to limited drug supplies, individual absolute doses were adjusted to 100 mg (treatment A) i.e. 200mg (treatment B) per infusion Treatment A (N=10) was considered for patients with at least one of the following characteristics: >70 yrs, bulky tumors and metastases.>10 cm, poor performance status. Median cpt-11 dose was 65mg/m2, range 45–75mg/m2. Treatment B (N=19) was considered for patients with following characteristics: <70 yrs, non bulky disease, PS 0–2. Median cpt-11 dose was 100mg/m2, range 80–120mg/m2. Results: Response was: Treatment A: PR 4/10; SD 4/10; PD 2/10: Treatment B: PR 6/19: SD 7/19: PD 6/19. Median treatment duration was 4 months, (treatment A 2–17m+; treatment B 2–11 m+). Two patients (1 per each treatment arm) undergo liver resection after 2, and 6 months of treatment. Five patients (17%) had hematological toxicity grade 3, (4 neutropenia, 1 thrombocytopenia) but only patient with prolonged thrombocytopenia grade 3 had to stop treatment after 11 months of treatment and good disease control. No diarrhea > grade 2 was registered. Conclusions: Limited resources have negative impact on treatment options in MCC and consequently often negatively reflects treatment outcome. However, the rate of PR/SD and treatment duration, is similar in both presented groups (Fisher, p= 0,88), and are comparable with published data with higher doses of cpt-11. Also, patients with poor PS or bulky disease, who usually are not considered for cpt-11, had similar benefit with manageable toxicity. No significant financial relationships to disclose.
Bisphosphonate use and osteonecrosis of the jaw: Pharmacovigilance and reporting of this serious adverse event from the Research on Adverse Drug Events and Reports (RADAR) project
Authors: B. J. Edwards, M. Gounder, J. McKoy, D. Raisch, M. Farrugia, M. Cesar, R. Marx, S. Ruggiero, M. Dimopoulos, C. Bennett
Journal: Journal of Clinical Oncology (2007)

6519 Background: Two years after zoledronate, received FDA approval, four dental professionals treated 107 cases of osteonecrosis of the jaw (ONJ). We review the timeline and source for initial recognition of ONJ and the comprehensiveness of dissemination of information on this adverse drug event. Methods: Data sources included primary case series from dental professionals; published case reports, clinical trials, and cases reported to the manufacturers or the FDA. Exposure adjusted incidence rates estimates were derived from manufacturer sponsored and investigator initiated review of claims data from large cancer centers. Safety notifications were disseminated by the manufacturers, regulatory authorities, and academic investigators. Results: Between 2001 and 2003, 107 patients with ONJ received care from dental professionals. In late 2003, and 2004 peer-reviewed case series were published. By 2006, safety databases maintained by the FDA, the manufacturer, and the RADAR project included information on 2,270, 1,178, and 368 cases of ONJ, respectively. In 2004 and 2005, incidence estimates of 0.8 and 22 ONJ cases per 1,000 person-years of intravenous bisphosphonate therapy were reported by the manufacturer and academic investigators. From 2003 to 2006, safety information from manufacturers, national regulatory authorities, case series, and clinical guidelines were disseminated. Conclusions: Recognition and reporting of ONJ occurred two years after FDA approval of zoledronate, dissemination of safety information occurred in the third year, and publications were disseminated from year three to year five. The life-cycle for identification and information dissemination for this serious adverse drug reaction was short and comprehensive. [Table: see text] [Table: see text]
Vascular effects of the vascular targeting agent NGR-hTNF in patients (pts) with advanced solid cancer: A dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) EORTC study.
Authors: H. Van Laarhoven, I. Desar, J. Asten, W. M. Fiedler, S. Marreaud, J. N. Timmer-Bonte, E. Teroert, C. Bordignon, A. Heerschap, C. Van Herpen
Journal: Journal of Clinical Oncology (2010)

e13525 Background: Vascular targeted TNF (NGR-hTNF) has antivascular properties. In a recent phase I study (EORTC 16041) it was not possible to select an optimal biological dose of NGR-hTNF from DCE-MRI measurements. We hypothesized this could be due to: (1) insufficient reproducibility of DCE-MRI; (2) non-specific vascular targeting of NGR-hTNF; (3) interference of vessel maturation with anti-vascular effects of NGR-hTNF (4) interference of pharmacodynamic (PD) effects with anti-vascular effects of NGR-hTNF. Methods: DCE-MRI analyses were performed at baseline and two hours after the first administration of NGR-hTNF in 31 cancer pts treated in the phase I study. Reproducibility was determined in 5 non-treated pts with liver metastases. Mean values of kep and Ktrans were calculated and histogram analyses were performed for metastases and healthy liver tissue. Specificity of vascular targeting was assessed by comparing results in metastases and healthy liver tissue. As a surrogate measure of vascular maturation, we assessed pretreatment tumor sizes and correlated these with DCE-MRI results. PD effects of NGR-hTNF were measured by the kinetics of soluble TNF receptors (sTNF-R). Results: Reproducibility of DCE-MRI was adequate, although superior in metastases compared to healthy liver tissue. Mean DCE-MRI parameters did not significantly change after NGR-hTNF administration, but histogram analyses showed significant changes in metastases and healthy liver tissue in some pts. The antivascular effect of NGR-hTNF was larger in smaller tumors, which have less mature vasculature. sTNF-R increased in a dose-dependent manner which could partly explain the failure of DCE-MRI to predict the optimal biological dose. Conclusions: The inability of DCE-MRI to determine the optimal biological dose of NGR-hTNF was not due to inadequate reproducibility, but most likely due to a combination of: (i) different profiles of vascular effects of NGR-hTNF in tumors and healthy liver tissue, (ii) dependency of the antivascular effect of NGR-hTNF on tumor vessel maturation and (iii) the shedding kinetics of soluble TNFα− R. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MolMed
Testing the cultural group selection hypothesis in Northern Ghana and Oaxaca
Authors: Cristina Acedo-Carmona, Antoni Gomila
Journal: Behavioral and Brain Sciences (2016)

Abstract We examine the cultural group selection (CGS) hypothesis in light of our fieldwork in Northern Ghana and Oaxaca, highly multi-ethnic regions. Our evidence fails to corroborate two central predictions of the hypothesis: that the cultural group is the unit of evolution, and that cultural homogenization is to be expected as the outcome of a selective process.
Progranulin promotes peripheral nerve regeneration and reinnervation: role of notch signaling
Authors: Christine Altmann, Verica Vasic, Stefanie Hardt, Juliana Heidler, Annett Häussler, Ilka Wittig, Mirko H. H. Schmidt, Irmgard Tegeder
Journal: Molecular Neurodegeneration (2016)

Peripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain. Although peripheral nerves are capable of regrowth they often fail to re-innervate target tissues. Using newly generated transgenic mice with inducible neuronal progranulin overexpression we show that progranulin accelerates axonal regrowth, restoration of neuromuscular synapses and recovery of sensory and motor functions after injury of the sciatic nerve. Oppositely, progranulin deficient mice have long-lasting deficits in motor function tests after nerve injury due to enhanced losses of motor neurons and stronger microglia activation in the ventral horn of the spinal cord. Deep proteome and gene ontology (GO) enrichment analysis revealed that the proteins upregulated in progranulin overexpressing mice were involved in 'regulation of transcription' and 'response to insulin' (GO terms). Transcription factor prediction pointed to activation of Notch signaling and indeed, co-immunoprecipitation studies revealed that progranulin bound to the extracellular domain of Notch receptors, and this was functionally associated with higher expression of Notch target genes in the dorsal root ganglia of transgenic mice with neuronal progranulin overexpression. Functionally, these transgenic mice recovered normal gait and running, which was not achieved by controls and was stronger impaired in progranulin deficient mice. We infer that progranulin activates Notch signaling pathways, enhancing thereby the regenerative capacity of partially injured neurons, which leads to improved motor function recovery.
Systemic and Tumor Th1 and Th2 Inflammatory Profile and Macrophages in Lung Cancer: Influence of Underlying Chronic Respiratory Disease
Authors: Mercè Mateu-Jimenez, Víctor Curull, Lara Pijuan, Albert Sánchez-Font, Hugo Rivera-Ramos, Alberto Rodríguez-Fuster, Rafael Aguiló, Joaquim Gea, Esther Barreiro
Journal: Journal of Thoracic Oncology (2016)
External beam radiotherapy for laryngeal cancer and risk for second primary thyroid carcinoma: A SEER database analysis
Authors: P. H. Ahn, S. Kalnicki, M. K. Garg
Journal: Journal of Clinical Oncology (2008)

17003 Background: Low radiation doses lead to increased rates of second primary cancers of the thyroid. It is unclear whether higher, definitive doses of radiotherapy would have a similar effect on induction of second primary thyroid cancers. We compare the risks of second primary thyroid cancers after treatment for localized laryngeal cancer. Method: The 17-registry Surveillance, Epidemiology, and End Results database was searched for patients with Historic Stage A in situ or localized squamous cell carcinoma of the larynx (T1–2, some T3, N0 M0). Radiotherapy technique for this site and stage would involve a definitive dose to the thyroid immediately adjacent to the larynx. For patients who underwent definitive external beam radiotherapy or definitive resection, the incidence of a new primary thyroid cancer were compared. Results: There were 23,091 cases with in situ or localized disease of the larynx. Of these, 7,988 underwent surgical resection while 15,103 underwent radiotherapy. 30 pathologically confirmed cases of a new thyroid primary occurred at least 2 months after diagnosis of laryngeal carcinoma. 13 of these were originally treated with laryngeal resection only (0.16%), while 17 were originally treated with laryngeal radiation (0.11%). No statistically significant correlation existed between laryngeal radiation and second thyroid cancers. In the group <40 years of age on initial laryngeal cancer diagnosis, 228 patients had been treated with radiation versus 181 treated surgically. Of these, 4 cases in the radiation arm versus no cases in the surgery cohort experienced a second primary thyroid cancer. This was not statistically significant. Of patients who received primary radiotherapy to the larynx, there was a correlation between age <60 and the likelihood of a second thyroid primary (p=.02). Conclusion: There is no overall association between definitive-dose radiotherapy to the larynx and formation of a second primary thyroid cancer. The low overall incidence of such cases and small probability of second primary cancer in the thyroid after radiotherapy to the larynx suggests that this should not determine the ultimate choice regarding radiation versus surgery for early-stage laryngeal cancer. No significant financial relationships to disclose.
Mortality burden of melanoma: Metastatic site-specific and temporal trends
Authors: R. P. Scheri, J. E. Herndon, J. Marcello, J. Wheeler, D. S. Tyler, A. P. Abernethy
Journal: Journal of Clinical Oncology (2008)

9076 Background: Metastatic melanoma has high disease-specific mortality burden, as measured by Years of Life Lost (YLL). Has mortality burden shifted over time? Methods: This was a retrospective analysis of a prospective database of 14,029 melanoma cases treated at Duke between 1970–2004. Metastatic analyses focused on cases that developed recurrences after initial diagnosis. YLL was calculated by subtracting the survival since diagnosis from the individual’s life expectancy without cancer at an equivalent time of diagnosis, based on U.S. Life Tables, 2003. Average YLL (AYLL) was calculated by group. Survival was calculated by Kaplan Meier method. Results: Of 14,029 cases, 6,810 (49%) had metastases, and of metastatic cases 4,636 (68%) developed recurrences after initial diagnosis; metastatic cases were mean age 49 (SD 15), 60% male, and 99% white. First metastatic sites were lymph nodes 55%, skin 23%, lung 10%, brain 5%, liver 3%, bone 2%, and other 3%. Lymph nodes as first site of metastasis increased in frequency over time (1970s: 51%, 1980s: 54%, and 1990s: 61%). Among metastatic cases, AYLL increased by decade of diagnosis and differed by site of first metastasis (Table). Conclusions: Although a retrospective analysis of a US referral melanoma population, this large-scale analysis suggests that the mortality burden of metastatic melanoma may be increasing over time. This could be due to several factors, including later diagnosis, higher risk of death with initial recurrence in lymph nodes and brain, and lack of available treatments that extend survival. This analysis highlights the continued unmet need to improve survival outcomes in metastatic melanoma. AYLL for fatal cases of metastatic melanoma by decade of diagnosis and site of first metastasis AYLL (SD) Decade of Diagnosis 1970s 21.8 (14.1) 1980s 23.9 (13.1) 1990s 25.4 (12.4) All cases 1970–2004 23.6 (13.3) Site of first metastasis Nodes 25.2 (13.4) Skin 19.9 (13.2) Lung 23.4 (12.4) Brain 25.1 (13.0) Liver 20.1 (12.5) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
Activity and Induction of Apoptosis of the Specific Tyrosine Kinase Inhibitor AMN 107 in bcr-abl + Cell Lines and in Imatinib Resistant Primary Cells from CML Patients.
Authors: Philipp Le Coutre, Gökben Baskaynak, Ingo Tamm, Jörg Westermann, Justus Duyster, Malte v. Bonin, Stefan Pursche, Petra Mayer, Paul Manley, Jürgen Mestan, Eberhard Schleyer, Bernd Dorken
Journal: Blood (2004)
Lymphocyte reconstitution in multiple myeloma patients after allogeneic G-CSF-mobilized hematopoietic progenitor cells transplantation from HLA-identical siblings
Authors: M. Martino, R. Fedele, G. Irrera, G. Messina, M. Cuzzola, C. Gareffa, G. Console, A. Dattola, P. Iacopino
Journal: Journal of Clinical Oncology (2009)

7098 Background: Allogeneic transplantation of G-CSF-mobilized hematopoietic progenitor cells (HPC) results in rapid and complete engraftment in a large proportion of patients and in relatively fast immune recovery. Methods : We have analyzed by flow cytometry the immune reconstitution in 19 patients (pts) affected by multiple myeloma undergone to allogeneic HPC transplant from HLA-identical related donors after nonmyeloablative conditioning regimen with fludarabine 90 mg/m 2 and cyclophosphamide 900 mg/m 2 . In each patient a comparable number of mononuclear cells, CD3+ T lymphocytes and CD34+ progenitor cells was infused. To evaluate the kinetics of the immune reconstitution, the overall number of total lymphocytes, T, B and NK cells of each patient were assessed before and 1, 2, 3, 6, 12, 18, 24, 30, 36 months after allogeneic HPC transplant. Results: Overall T cell reconstitution was in all the pts at 3 months, since at that time the CD3+ T cell median number was 880 cells/microl (r. 589–1,357). However, in all pts high numbers of CD3+ T cells were achieved at 12 months after transplant (median 1,326 cells/microl, r. 850–2,309). The CD4+ T cell median number was 281 cells/microl (r. 185–433) at 6 months, 391 cells/microl (r. 303–505) at 12 months, 603 cells/microl (r. 433–736) at 18 months. The CD8+ T cell median number was increased from the transplant to 18 months in which it was 1,489 cells/microl (r. 760–1,976). The decrease of CD8+ T cells with the normalization of CD4+/CD8+ ratio was observed at 30 months when CD4+ T cells were 650 cells/microl (r. 370–989) and CD8+ T cells were 690 cells/microl (r. 445–1,743). B cells recovery was observed at 18 months with a median number of 194 cells/microl (r. 40–404). The faster reconstitution was documented for NK cells with a median number of 314 cells/microl (r. 61–647) at 2 months. Conclusions: the complete immune reconstitution in our pts was achieved at 30 months after transplant. Our objective is to evaluate if this slow immune recovery is associated with a high incidence of infectious diseases and a low incidence of chronic GVHD. No significant financial relationships to disclose.
The Role of Her2/Neu in ALL: Long Term Clinical Follow-up of Surface-Positive Patients and Induction of NK Cell ADCC by Trastuzumab in Vitro
Authors: Sebastian P. Haen, Benjamin J Schmiedel, Nora Roth, Christoph Faul, Robert Möhle, Marc Schmalzing, Lothar Kanz, Wichard Vogel, Helmut R Salih
Journal: Blood (2012)
GW26-e4709 Epigallocatechin-3-Gallate Protects HUVECs from PM2.5-Induced Oxidative Stress Injury by Activating Nrf2/HO-1 Pathways
Authors: Guangzhao Yang, Zhao-Jun Wang, Feng Bai, Xiao-Jiang Qin, Jing Cao, Ming-Sheng Zhang, Ji-Yuan Lv
Journal: Journal of the American College of Cardiology (2015)
GW26-e1295 Hypertensive Left Ventricular Hypertrophy is a Major Cause of Acquired Long QT Syndrome
Authors: Yanli Zhang, Ying Liu, Yunlong Xia, Haixu Yu, Yuyu Sun, Yifan Tie, Yinong Jiang, Yanzong Yang, Li Zhang
Journal: Journal of the American College of Cardiology (2015)
Baseline Symptoms, Female Sex, and Younger Age Are Correlated with Higher Levels of Peri-Collection Pain, Symptoms, and Persistent Discomfort One Year after Related Donor BM and PBSC Donation: An Analysis of the Related Donor Safety Study (RDSafe)
Authors: Michael A. Pulsipher, Brent R. Logan, Deidre M. Kiefer, Pintip Chitphakdithai, Galen E. Switzer, Marcie L Riches, J. Douglas Rizzo, Paolo Anderlini, Susan F. Leitman, James W Varni, Amy Hays, Hati Kobusingye, RaeAnne M. Besser, John P. Miller, Rebecca J. Drexler, Roberta J. King, Mary M. Horowitz, Willis H. Navarro, Dennis L. Confer
Journal: Blood (2014)
Escalating weekly doses of cetuximab: A phase I trial in advanced solid tumors
Authors: C. Ho, D. Eisen, L. A. Beckett, P. Luciw, P. H. Gumerlock, D. R. Gandara, A. M. Davies
Journal: Journal of Clinical Oncology (2006)

13012 Background: Cetuximab, an IgG1 monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is FDA-approved at a 400 mg/m 2 loading dose, followed by 250 mg/m 2 weekly maintenance. Clinical activity of cetuximab has been reported to correlate with grade of skin toxicity, and skin toxicity is reported to increase with increasing dose. We therefore examined the safety and feasibility of escalating weekly cetuximab doses. We hypothesized that increased dose would correlate with rash severity as a surrogate for tumor response. Methods: Four dose levels were tested: cetuximab loading 400 mg/m 2 and 250,300,350,400 mg/m 2 weekly maintenance. Dose limiting toxicity (DLT) was defined as: grade 4 platelets, grade 3 platelets with bleeding, febrile neutropenia, grade 4 cutaneous toxicity, grade 3 cutaneous toxicity necessitating holding cetuximab for &gt; 4 weeks or any other grade ≥ 3 non-hematologic toxicity. Rash was evaluated using two additional validated dermatology methods: acne lesion counting and global acne grading scale (Int J Derml.1997;36:416–18, J Am Acad Derm.1996;35:559–65, Arch Derm.1982;118:23–25). Results: Twelve patients with advanced solid tumors were treated, including 3 H&amp;N, 2 pancreas, 2 breast, 2 lung, 2 colorectal and 1 bladder. Patient characteristics: age range 44–84, median 62; gender: 10 M; KPS ≥80/&lt;80=7/5; prior chemo ≤1:&gt;1=5:7; median cycles 2 (1–8). Treatment was generally well tolerated. There were no DLTs. The most common grade 3/4 toxicities were acneiform rash (1) and lymphopenia (2). The majority of patients (6) had a Grade 2 rash. In 10 evaluable patients, there were no responses; 3 patients had stable disease. Correlative science studies are ongoing evaluating EGFR expression and polymorphisms, pEGFR, pMAPK, pAKT, Ki67, p27 levels and K-ras mutations. Conclusions: 1) Cetuximab 400 mg/m 2 loading dose and 400 mg/m 2 weekly maintenance is feasible and well tolerated. Doses up to 400 mg/m2 did not portend increased toxicity and a MTD was not reached on this schedule. 2) Grade of rash did not increase with increasing doses of weekly cetuximab in this limited population. 3) To date, cetuximab has not demonstrated RECIST response in this cohort of pretreated patients with solid tumors. 20 additional patients are being evaluated at the highest dose level. No significant financial relationships to disclose.
Expression and function of CTLA4 in melanoma.
Authors: Barbara Seliger, Michele Maio, Ornella Cuaia, Luana Calabro
Journal: Journal of Clinical Oncology (2013)

e20040 Background: The definition of co-inhibitory molecules negatively interfering with immune responses has provided novel targets for therapeutic intervention. These include CTLA4, which directly binds to CD80 and CD86 on T cells leading to a down-regulation of immune responses. Recently, anti-CTLA4 antibodies have been established, which were able to stimulate T cell responses and anti-tumour immunity in vitro and cause objective responses in melanoma patients even months later after clinical progression. Since CTLA4 was found to be expressed on tumour cells, which might explain the distinct anti-tumour immunity of CTLA4 in tumour patients, the aim of this study was determine the expression and function of CTLA4 in 60 human tumour cells of distinct origin. Methods: qPCR, Western blot, cytometry and/or immunohistochemistry was performed to determine the expression of CTLA4. Cell proliferation and anchorage-independent growth of CTLA4 + tumor cells was determined by XTT and soft agar colony formation, while CTL-mediated lysis was determined by standard chromium release assay. Results: Expression analysis revealed n extremely heterogeneous and tumour-specific CTLA4 mRNA expression in the tumour cell lines tested with the highest frequency (85 %) and expression levels in melanoma. In contrast, only low constitutive CTLA4 surface expression levels, but high levels of intracellular CTLA4 protein were found. Immunohistochemical analyses with seven distinct anti-CTLA4 antibodies showed a heterogeneous staining pattern in selected melanoma cell lines analysed. In order to understand the molecular mechanisms of CTLA4 expression different CTLA4 expression models were established in melanoma and subjected to functional analysis. High levels of CTLA4 expression caused a down-regulation of their cell proliferation as well as a reduced anchorage independent growth. However, CTLA4 expression did not affect the immunogenicity of tumour cells as determined using co-culture assays of CTLA4 + tumour cells with either HLA-matched PBMCs or melanoma antigen-specific CTL. Conclusions: In conclusion, CTLA4 is expressed in melanoma cells and reveals non-immunogenic functions by modulating the growth properties, rather than inhibiting T cell responses.