tbuckley/cabot-search huggingface dataset:
Combination of targeted therapy (imatinib) with immunotherapy (peginterferon α-2b) to overcome drug resistance and tumor stem cells in gastrointestinal stromal tumors (GIST).
Authors: L. L. Chen, X. Chen, L. G. Gouw, R. I. Andtbacka, K. A. Jones, J. H. Ward, R. Randall, J. C. Trent, S. Patel, R. S. Benjamin
Journal: Journal of Clinical Oncology (2010)

10035 Background: Major barriers to durable remission in cancer are drug-resistant clones and tumor stem cells. We sought to harness and enhance endogenous antitumor immunity by combining imatinib with peginterferon α-2b (PegIntron; PegIFNa2b) in GIST. Methods: Patients (pts) with primary tumor ≥6 cm or metastatic imatinib-sensitive GIST were enrolled. Patients received imatinib at 400mg/d for KIT exon 11 mutation GIST and 800 mg/d for the rest, started 3–5 d before PegIFNa2b. The first cohort (3 pts) received PegIFNa2b at 4 mcg/kg/wk and developed granulocytopenia, so the dose was reduced to 3 mcg/kg/wk × 4 doses then 1.5 mcg/kg/wk × 18. Partial response (PR) is judged by ≥25% decrease in SUV (PET-CT criteria), ≥10% decrease in size or ≥15% decrease in density (HU) (Choi criteria), and RECIST. Progression-free survival (PFS) was assessed. Genotyping, cytokine panel, and flow cytometry phenotyping of peripheral lymphocytes at specific time points were performed. This is a case report from chart review. Results: 8 pts were enrolled (age: 42–89 years). The combination treatment was well tolerated; grade 3 skin rash/dermatitis occurred in 2 pts. All 8 pts showed PR by Choi and RECIST criteria, and 7 pts showed PR and 1 inevaluable (not FDG avid) by PET-CT. The oldest pt died of unrelated causes while in remission. PFS of 7 evaluable pts ranges from 365 to >900 days, 6 pts exceeded historical controls and 1 will reach it in 1 month (PFS of historical control of KIT exon 11 mutation GIST is 687 days, KIT exon 9 mutation 200 days, and wild type 82 days). A pt with wild type GIST initially achieving a PR, later progressed (day 365). When PegIFNa2b was restarted, a second PR was induced, with 1 target lesion showing SUV reduction from 22.8 to 9.5, and another from 28 to 18.2. PegIFNa2b resulted in a surge of CD45RO+CD4+ and CD45RO+CD8+ memory T cell subsets and induction of interferon γ producing lymphocytes. Conclusions: Combination of imatinib and PegIFNa2b showed promising efficacy in 8 GIST pts. Induction of a second PR after progression (due to imatinib resistance) by re-initiation of PegIFNa2b is unprecedented. The trial was closed early in anticipation of a larger future study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck
Validity of predictions of residual retroperitoneal mass histology in nonseminomatous testicular cancer.
Authors: E W Steyerberg, A Gerl, S D Fossá, D T Sleijfer, R de Wit, W J Kirkels, N Schmeller, C Clemm, J D Habbema, H J Keizer
Journal: Journal of Clinical Oncology (1998)

To validate predictions of the histology (necrosis, mature teratoma, or cancer) of residual retroperitoneal masses in patients treated with chemotherapy for metastatic nonseminomatous testicular germ cell tumor.We studied 172 testicular cancer patients who underwent resection while tumor markers were normal. Predictive characteristics for the residual histology were registered, including the presence of teratoma elements in the primary tumor, the prechemotherapy level of tumor markers (alpha-fetaprotein [AFP], human chorionic gonadotropin [HCG], lactate dehydrogenase [LDH]), the size of the residual mass, and the percentage of shrinkage in mass diameter. We calculated the predicted probability of necrosis and the ratio of cancer and mature teratoma with previously published logistic regression formulas.The distribution of the residual histology was necrosis in 77 (45%), mature teratoma in 72 (42%), and cancer in 23 (13%). Necrosis could be well distinguished from other tissue, with an area under the receiver operating characteristic (ROC) curve of 82%. No tumor was found in 15 patients with a predicted probability of necrosis over 90%. The predicted probabilities corresponded reliably with the observed probabilities (goodness-of-fit tests, P > .20), although a somewhat higher probability of necrosis was observed in patients treated with chemotherapy containing etoposide. Conversely, cancer could not reliably be predicted or adequately discriminated from mature teratoma.The predicted probabilities of necrosis have adequate reliability and discriminative power. These predictions may validly support the decision-making process regarding the need and extent of retroperitoneal lymph node dissection.
Clinical impact on time to progression (TTP) of acneiform skin lesions in cetuximab-based regimens in colorectal cancer
Authors: J. Bosch, L. Abella, A. Viudez, A. Chopitea, J. Rodriguez, J. Rodriguez, J. Aristu, L. Arbea, L. Arbea, C. Reyna, J. García-Foncillas
Journal: Journal of Clinical Oncology (2008)

15096 Background: Cetuximab, a chimeric IgG1 (immunoglobulin G1) monoclonal antibody that binds to the extracellular domain of EGFR, inhibits its activation and modulate tumor-cell growth. The presence of acneiform rash has been associated with improved survival in some studies. Methods: A retrospective review of 62 patients with metastatic colorectal cancer treated with cetuximab-based regimens in our center from July 2004 to August 2007 has been performed. Results: Oxaliplatin and irinotecan- based regimens were included. Overall median time to progression was 6.6 months (CI 95%: 5.4–7.9). No significant differences were observed in time to progression (TTP) between the regimens considered. Rash grade was: 0 (n=17), 1 (n=16), 2 (n=20) and 3 (n=5). Statistical differences were found in TTP when patients that did not develop rash (4.88, CI 95%: 2.7–7.0) were compared to patients with any grade of rash (7.38, CI: 5.9–8.8) (p<0,05). Comparisons among subgroups of rash did not show statistical differences. No differences were observed between rash grade 1 and 2 or more subgroups. Conclusions: The presence of rash whatever its grade is associated with a significant improvement on time to progression in cetuximab-based regimens in metastatic colorectal cancer. No significant financial relationships to disclose.
Recent Advances in Active Immunization
Authors: H. J. Parish
Journal: BMJ (1952)

MEDIuLJOULsystem of government and who had somewhat unusual views on the preservation of the health of the body politic.This same doctor, having noted that those in power are often troubled with short and weak memories, proposed that " who- ever attended a first minister, after having told his business with the utmost brevity, and in the plainest words, should, at his departure, give the said minister a tweak by the nose, or a kick in the belly, or tread on his corns, or lug him thrice by both ears, or run a pin into his body,, or pinch his arms black and blue, to prevent forgetfulness."REFERENCES
Sex Hormones as Novel Risk Biomarkers for Atherosclerosis in Peripheral Vascular Disease⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Peter P. Liu, Masahiro Fukuoka
Journal: Journal of the American College of Cardiology (2007)
ES-285, a novel marine anticancer agent: Investigation of mechanism of action using gene expression microarrays
Authors: Richard Baird, Paul Clarke, Paul Workman
Journal: Cancer Research (2005)

4111    Introduction:  ES-285 is a novel anti-cancer agent originally isolated from the North Atlantic Clam,  Spisula polynyma . Previous studies have shown that ES-285 has antiproliferative activity in a unique pattern across the NCI 60 cell line panel. Although the mechanism of this cellular response is unclear, ES-285 induces changes in cell morphology and the actin cytoskeleton, possibly though Rho signalling (Cuadros et al., Cancer Lett. 152 (1); 23-29). We have used cDNA gene expression microarrays to further investigate the mechanism of action of ES-285. .  Methods:  We have compared the cellular and molecular response to ES-285 with those of structurally-related compounds (safingol, sphingosine and ES-427, an inactive analogue of ES-285) together with compounds known to modulate Rho/ROCK signalling (FTI-277, GGTI-298 and Y-27632). Antiproliferative activity was assessed by MTT assay. Membrane integrity was investigated by following the release of LDH into culture medium after drug treatment. Effects on cell morphology and the actin cytoskeleton were visualized with confocal microscopy. Drug-induced changes in gene expression were measured using 22k cDNA microarrays (www.crukdmf.icr.ac.uk). .  Results:  ES-285 has antiproliferative activity against a panel of 10 cancer cell lines  in vitro  with IC50s 20-200nM. ES-285 causes minimal LDH release at 24 hours, but marked LDH release at 72 hours, when apoptotic cells are present. These effects are not seen with equimolar doses of ES-427. There was no correlation between constitutive actin stress fibre density of the different cell lines and their sensitivity to ES-285. However, in HT29 cells a concentration-dependent loss of stress fibres was seen, with abrogation of most fibres by 4 hours at a dose of 100nM (5xIC50). Loss of actin stress fibres was also seen with Y-27632 and GGTI-298 at 24 hours. No effect on stress fibres was seen with safingol, sphingosine or FTI-277. cDNA microarrays revealed that ES-285 treatment significantly alters the expression of a large number of genes at timepoints as early as 2 hours. This transcriptional response to ES-285 includes genes involved in apoptosis, cell cycle, signal transduction and the actin cytoskeleton. .  Conclusions:  ES-285 inhibits the proliferation of cancer cell lines  in vitro  at nanomolar concentrations. In HT29 colon cancer cells, treatment with ES-285 is associated with loss of actin stress fibres. The transcriptional response to ES-285 is distinct from, but overlaps with, that induced by structurally-related compounds and inhibitors of Rho/ROCK signalling. Further analysis and validation of these gene expression changes is being used to generate further hypotheses about the mechanism of action of ES-285 and to identify pharmacodynamic markers for use in a phase 1 clinical trial of ES-285 which is underway. .  Acknowledgement:  ES-285 and ES-427 were kindly supplied by PharmaMar S.A., Madrid, Spain.
Low-molecular-weight heparin and the survival of patients with advanced malignancy
Authors: C. P. W. Klerk, S. Smorenburg, H.-M. Otten, D. Richel, G. Van Tienhoven, A. Lensing, H. Büller, P. Prandoni, M. Bos, M. Prins
Journal: Journal of Clinical Oncology (2004)

8018 Background: Studies on the treatment of venous tromboembolism (VTE) have found a better survival in cancer patients treated with low-molecular-weight heparin (LMWH) when compared to unfractionated heparin.Methods: In a double-blind randomized controlled study we investigated the effect of LMWH on the survival of patients with advanced solid cancer without VTE. Patients received a weight-adjusted therapeutic dose of LMWH for two weeks and half this dose for another six weeks. Primary study outcome was cumulative mortality of all causes. Primary safety endpoint was major hemorrhage during study treatment. All analyses were on an intention-to-treat basis. Results: A total of 302 patients was included. 148 were randomized to LMWH and 154 to placebo. The overall hazard ratio was 0.75 (95% confidence interval 0.59–0.96) in favor of LMWH. Median survival was 8.0 and 6.6 months in the LMWH and placebogroup, respectively. A statistically significant treatment effect remained even after adjustment for potential confounders. Five of the LMWH-treated patients (3%) versus one of the placebo-recipients (1%) had a major hemorrhage during study treatement (p=0.12). An a priori defined subgroup analysis of patients with a life expectancy of 6 months or more at enrollment found a hazard ratio of 0.64 (95% CI 0.45–0.90) in favor of LMWH with a median survival of 15.4 months versus 9.4 months in the placebo group. In patients with a life expectancy of less than 6 months, the hazard ratio was 0.88 (NS). Conclusions: LMWH appears to increase the median survival of patients with an advanced solid malignancy and further clinical evaluation seems warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo Sanofi-Synthelabo
Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment
Authors: Steve Turner, Ben Francis, Susanne Vijverberg, Maria Pino-Yanes, Anke H. Maitland-van der Zee, Kaninika Basu, Lauren Bignell, Somnath Mukhopadhyay, Roger Tavendale, Colin Palmer, Daniel Hawcutt, Munir Pirmohamed, Esteban G. Burchard, Brian Lipworth
Journal: Journal of Allergy and Clinical Immunology (2016)
Delay in diagnosis of childhood sarcoma
Authors: M. Jofe, I. Hanif
Journal: Journal of Clinical Oncology (2005)

9073 Background: Recent advances have improved sarcoma evaluation in children, frequently allowing earlier diagnosis. Rapid detection should improve outcome since delay may lead to metastatic spread or more extensive disease precluding limb salvage. Hence, factors leading to earlier diagnoses of these malignant tumors are crucial for improved outcome. We reviewed the histories of our sarcoma patients who had symptoms for greater than six months at presentation to identify common diagnostic factors, reasons for diagnostic failure and prognostic implications of diagnostic delay. Methods: Our data bank of the Section of Pediatric Orthopaedic Oncology was reviewed identifying patients with a biopsy confirmed diagnosis of bone or soft tissue sarcoma made six months or longer after initial presentation. Results: There were 20 patients, (8 boys, 12 girls), average age 11yrs. 9 months (range 2years 2 months to 18 years) with an average delay in diagnosis of 8 ½ months from initial presentation. Seven children had Ewing’s sarcoma, 10 osteosarcoma, 2 fibrosarcoma and one undifferentiated sarcoma. All children had pain unrelieved by rest and either abnormal physical exams, radiographs or both. Thirteen children had enlarging masses that were followed without biopsy. Four children had radiographs that were interpreted as normal despite showing findings consistent with sarcoma One patient underwent arthroscopy and an additional patient had an arthroscopy scheduled but sustained a pathologic femur fracture prior to surgery. Two additional patients presented with pathologic fractures. Nine children presented with metastatic disease. Excluding 6 spine sarcomas, only 3/14 patients were candidates for conventional limb salvage. Fourteen children (70%) are either dead of disease or have a dismal prognosis. Conclusions: This current study emphazizes that a careful history, physical examination and radiographs remain the mainstay for the diagnosis of sarcoma and when diagnosis is delayed the consequences can be devastating. Therefore when unrelenting pain persists longer than four weeks, careful evaluation is required. Similarly enlarging masses should be biopsied in a timely fashion. No significant financial relationships to disclose.
Abstract #4: Sulforaphane destabilizes the androgen receptor in prostate cancer cells by inactivating HDAC6
Authors: Angela Gibbs, Jacob Schwartzman, Vivianne Deng, Alex Perepechaev, Joshi Alumkal
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Background: Sulforaphane is an isothiocyanate compound found in broccoli, the consumption of which is associated with reduced rates of prostate cancer development. Sulforaphane, itself, prevents and induces regression of prostate and other malignancies in pre-clinical models, but the full mechanisms by which it exerts these effects remain unclear. Recent reports show that sulforaphane inhibits histone deacetylation and impairs the growth of prostate cancer cells. However, it remains quite possible that this agent may inhibit deacetylation of non-histone proteins, too. We therefore tested the hypothesis that sulforaphane treatment inhibits deacetylation of key regulatory proteins in prostate cancer cells. Specifically, we focused on the acetylation state of HSP90, a chaperone protein that stabilizes the androgen receptor (AR). We hypothesized that hyperacetylation of HSP90 using this agent would lead to AR destabilization and attenuated AR signaling. Methods: LNCaP and VCaP prostate cancer cells were used to assess the effects of treatment with sulforaphane. Co-immunoprecipitation studies were performed to assess changes in acetylation of HSP90 and its interaction with AR after sulforaphane treatment. Western blots were performed to assess the effect of increasing doses of sulforaphane on AR protein expression and the effect of proteasome inhibition on sulforaphane treatment effects. QRTPCR was performed to determine whether sulforaphane resulted in reduced AR target gene expression, and ChIP was performed to assess whether enrichment of AR was decreased at its target genes. Sulforaphane\#8217;s effects on HDAC6 enzymatic activity were assessed in an in vitro assay, and the consequences of over-expressing HDAC6, an HSP90 deacetylase, on sulforaphane treatment effects were also determined. Small interfering RNA against HDAC6 was transfected in order to compare this effect with sulforaphane treatment. Results: Sulforaphane treatment increases the acetylation of HSP90, dissociating it from AR, and consequently leads to AR protein degradation, which is reversed by proteasome inhibition, diminished AR target gene expression and reduced AR enrichment at its target genes. Sulforaphane also inhibits HDAC6 deacetylase enzymatic activity, and over-expression of HDAC6 attenuates sulforaphane-mediated AR protein depletion while small interfering RNA to HDAC6 recapitulates the sulforaphane treatment effects. Conclusions: We conclude that sulforaphane inactivation of HDAC6-mediated HSP90 deacetylation and consequent AR degradation and attenuated AR signaling may represent a principal mechanism by which this agent demonstrates activity as a chemopreventive and therapeutic agent in prostate cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4.
Reduced-intensity conditioning regimen and allogeneic stem cell transplantation from related or unrelated HLA identical donor in high-risk neuroblastoma.
Authors: A. Prete
Journal: Journal of Clinical Oncology (2010)

9562 Background: To evaluate the feasibility and efficacy of a reduced intensity conditioning regimen (RIC) followed by allogeneic haemopoietic stem cell transplantation (HSCT) from related or unrelated HLA identical donor (UD) in neuroblastoma (NB) poor responder to front line therapy or relapsed after a previous autologous stem cell transplantation. Methods: 21 patients (pts), aged 2-13 years, affected by resistant (5) or relapsed (16) NB were submitted to an SCT after a RIC consisting of Thiotepa 15 mg/kg and Melphalan 140 mg/sqm. The donor was an identical sibling in 11 cases or a UD in 10. At time of transplant 14 pts were in partial remission (PR), and 7 in stable disease. Graft versus host disease (GVHD) prophylaxis consisting of cyclosporin A ± anti-lymphocytic serum and short term methotrexate in UD setting. SC sources were bone marrow in 17 cases and peripheral blood in 4. Results: All the 21 pts showed a recovery of bone marrow function after a median time of 12 and 17 days for PMN and PLT respectively in sibling setting, and 14 and 17 days in UD setting. Grade II-IV GVHD occurred in 11 pts. After a median follow-up of 26 (8-52) months, 12 pts relapsed, 8 dead for progressive disease and 8 are alive and well. The median time of relapse from SCT was 11 (4-25) months. The 2 years probability of OS and EFS were respectively 0.53 (0.13) and 0.26 (0.13), with a better EFS for pts who developed grade II-III acute GVHD (0.33 vs 0.18), were in PR (0.32 vs 0) and received a sibling donor (0.34 vs 0.20) Conclusions: TT-PAM and HSCT, from either related and unrelated donors, was well tolerated. TRM was negligible (<5%), even in pts with previous autoHSCT. Some children with refractory or relapsed disease achieved long-term remission and a proportion (≤ 25%) of them might eventually be cured. As smaller is the amount of disease at transplant, as better is the outcome. No evident GVHD-effect on relapse probability. Best outcome observed in the small subset of patients who received front-line HSCT. These data compare favorably with other “salvage” strategies, but prognosis is still very poor. No significant financial relationships to disclose.
Squamous Cell Carcinoma “Transformation” Concurrent with Secondary T790M Mutation in Resistant EGFR -Mutated Adenocarcinomas
Authors: Agita Jukna, Gloria Montanari, Maria Cecilia Mengoli, Alberto Cavazza, Marisa Covi, Fausto Barbieri, Federica Bertolini, Giulio Rossi
Journal: Journal of Thoracic Oncology (2015)
Ocular relapse in the anterior chamber in childhood acute lymphoblastic leukemia.
Authors: N Bunin, G Rivera, F Goode, H O Hustu
Journal: Journal of Clinical Oncology (1987)

We reviewed 11 cases of ocular relapse in the anterior chamber in children with acute lymphoblastic leukemia (ALL), representing 0.5% of all primary relapses seen at this center. Nine patients had hypopyon, and two had iris involvement only. Concomitant testicular relapse was present in two children and hematologic relapse in one. Ocular relapse occurred at 12 to 74 months (median, 36 months) from the data of initial diagnosis. Children who relapsed after therapy was discontinued did so within 1 year of completing therapy. Topical steroids and systemic chemotherapy were administered to all patients with ocular relapse; four also received radiation to the involved eye (600 to 1,050 cGy). Four children, each with a prolonged initial complete remission, remain free of disease for 15+, 32+, 34+, and 145+ months following anterior chamber relapse; three had received radiation therapy. Five patients died of recurrent leukemia, and two of infection while in remission. Aggressive retreatment appears warranted in cases of anterior chamber relapse of ALL, as some of these children may attain prolonged new remissions.