tbuckley/cabot-search huggingface dataset:
Phase I trial of a histone deacetylase inhibitor (HDACI) and retinoid acid (RA) in patients (pts) with advanced solid tumor malignancies
Authors: D. M. Atieh, M. I. Milowsky, M. Cobham, J. Kaplan, C. Smith, L. J. Gudas, D. M. Nanus
Journal: Journal of Clinical Oncology (2006)

13114 Background: Transcription of RA responsive genes is inhibited by co-repressor complexes which have HDAC activity. Pre-clinical data demonstrates that addition of an HDACI to RA enhances transcription of genes that augment anti-tumor and differentiation response, and results in tumor inhibition in a RCC model (Clin Cancer Res. 2005;11:3558). Valproic Acid (VPA) has potent HDCAI activity and ATRA-IV is a liposomal RA with excellent bioavailability. The objective of this trial is to determine safety, pharmacokinetics (PK) of combination therapy, as well as correlative studies of RA receptor expression and histone acetylation status. Methods: Adults with a refractory metastatic solid tumor malignancy, KPS &gt;60%, adequate organ function, life expectancy &gt;3 months are eligible. 3-pt cohorts in a 2-step dose escalation: Oral VPA (Abbott Pharmaceutical) is dosed (starting at 10 mg/kg/d every 8 hrs) until trough VPA serum concentration of 50–80; 80–100 and 100–120 μg/ml. IV ATRA (Antigenics) is then administered at 60mg/m 2 IV weekly. Once VPA MTD is determined, ATRA-IV is then escalated to 90, 120 and 140 mg/m 2 unless DLT’s are seen. Dose levels are escalated in cohorts of 3–6 pts and cycle length is 4 weeks. Results: 9 pts have been enrolled and 5 are evaluable for toxicity of both drugs (renal cell, prostate, GE junction, bladder and small blue cell tumor). 4 pts withdrew from VPA toxicity prior to ATRA-IV. Median age 67 (range 26–79), pts received between 1–4 prior therapies (non-palliative surgery, chemotherapy, radiation, PBSCT). VPA did not alter ATRA-IV pharmacokinetics. The MTD of VPA has not yet been reached and the ATRA escalation phase has not yet been initiated. Most common toxicities observed were pain, dyspnea, gastrointestinal and neurologic. One grade 3 neurotoxic event occurred related to POD. 1 pt had a transient decline in PSA. Correlative studies are ongoing. Conclusions: Epigenetic modifications induced by HDACIs may allow the anti-tumor effects of retinoids to be realized. Toxicity of VPA has limited the addition of RA to this HDACI. HDACI + RA is a rationale approach to treat progressive RCC and future studies will incorporate more potent and less toxic HDACI + RA to treat RCC. No significant financial relationships to disclose.
Abstract 16742: Determinants of Mortality And Neurological Outcome Following Treatment of Acute Type A Dissections Using Different Cerebral Protection Methods
Authors: Dominik Wiedemann, Marion Dorfmeister, Gottfried Sodeck, Claudia Herbst, Alfred Kocher, Stephane Mahr, Günther Laufer, Marek Ehrlich
Journal: Circulation (2011)

Objective: To assess the efficacy and midterm results of different cerebral protection techniques in the treatment of acute type A aortic dissection. Methods and results: Between 1993 and 2010, 329 patients(220 male, median age 59)undergoing replacement of the ascending aorta/arch with an open distal anastomosis were analyzed. Either hypothermic circulatory arrest(HCA) alone at 18 Degrees(n=116;35%) or in combination with retrograde cerebral perfusion(RCP) (n=120;36%) or antegrade cerebral perfusion(ACP) at 25 Degrees(n=93;29%) were used. Median circulatory arrest time was 29 minutes(4-145). Overall in-hospital mortality was 19% (63/329); 28%(32 pts) in the HCA group(25pts), vs.17% in the RCP group(21pts) vs. 11%(10pts) in the ACP group(p=0.02). Permanent neurological dysfunction(PND) occurred in 53 patients(16%), with no statistically significantly differences between the 3 groups.(25% in HCA vs.13% in the RCP vs.12% in the ACP group;p=0.13) Transient neurological dysfunctions(TND) were observed in 14 of the other 266 patients(5 %) with a trend towards improved clinical outcome with the use of ACP(10% in HCA group, vs.6 % in the RCP vs.2% in the ACP group;p=0.14). Multivariate analysis revealed that preoperative hemodynamic instability was the only statistically significant independent predictor of in-hospital mortality(odds ratio [OR] 5.24; 95% CI 2.6 - 10.5;p&lt;0.001) and the only significant independent predictor of PND was the use of HCA alone(OR 2.52; 95% CI 1.35- 4.69;p=0.004). Overall long-term survival(mean follow up 65 months) was 76% at one year,68% at 5 years and 56% at 10 years with statistically significant differences between the three groups(p=0.03). ACP patients had 1,5 and 10 year survival rates of 86%, 81% and 74% respectively,in comparison to 74%, 66% and 52% in the RCP group and 68%, 65% and 55% in the HCA alone group. (Figure1) Conclusion: The use of ACP confers mostly a survival benefit in the treatment of acute type A aortic dissections.
Abstract 15480: Racial Differences in Heart Transplant Recipients Bridged with LVAD Support
Authors: Eugene C DePasquale, Khurram Nasir, Charisse Ward, Daniel L Jacoby
Journal: Circulation (2012)

Background:  Racial differences in long-term outcomes after heart transplant are well known. However, racial differences in outcomes among those bridged with LVAD support have not been characterized. We sought to examine the differences in mortality in this population.   Methods:  3011 HT recipients bridged with LVAD support (exclusions included age    Results:  There were 3011 patients of which 31.9% were non-white. Ischemic cardiomyopathy (48% & 25%, W & NW respectively) and dilated cardiomyopathies (45% & 69%, W & NW respectively) were the most prevalent diagnoses. There were more women in the NW group. In addition, the NW group was associated with higher mean PAP, higher PCWP and higher cardiovascular mortality. Survival (1, 3, 5y) was: white (89, 82, 74%) & non-white (85, 76, 70%) (Figure 1, log rank p=0.006). Unadjusted HR for all-cause mortality was 1.29 (CI 1.07-1.55, p    Conclusion:  Survival of NW heart transplant recipients bridged with LVAD support was diminished compared to W patients in this cohort. This was associated with higher filling pressures and cardiovascular mortality. In addition, LVAD utilization between groups remained unchanged during the study period. Further study is warranted to understand and diminish the disparities in these groups.
Bcr-Abl Exerts Its Antiapoptotic Effect Against Diverse Apoptotic Stimuli Through Blockage of Mitochondrial Release of Cytochrome C and Activation of Caspase-3
Authors: Gustavo P. Amarante-Mendes, Caryn Naekyung Kim, Linda Liu, Yue Huang, Charles L. Perkins, Douglas R. Green, Kapil Bhalla
Journal: Blood (1998)
CALGB 60104: Adherence with adjuvant capecitabine among women age 65 and older with early stage breast cancer treated on CALGB 49907
Authors: A. H. Partridge, L. E. Archer, A. B. Kornblith, J. R. Gralow, D. Grenier, E. A. Perez, A. C. Wolff, C. A. Hudis, E. P. Winer, H. Muss
Journal: Journal of Clinical Oncology (2008)

6542 Background: Patient adherence is critical in evaluating the efficacy of an oral therapy. Little is known about adherence with oral chemotherapy. CALGB49907 was a randomized clinical trial comparing standard chemotherapy versus capecitabine (X) in early-stage breast cancer patients aged > 65. We sought to measure adherence among women randomized to X. Methods: We used microelectronic monitoring (MEMS) caps on participants' X bottles to record each time a patient opened the bottle to take X. Adherence was calculated as the number of doses taken as measured by MEMS divided by the number of doses expected to be taken, taking into account toxicity-related dosing changes. Based on prior research, a participant was defined as non-adherent if fewer than 80% of doses expected were recorded by MEMS. Accrual goal was 184. Results: 161 patients had enrolled in this companion study when CALGB49907 closed to enrollment. Median age of participants was 71 (range 65–89); 85% of participants were white, 89% had a PS of 0–1, 51% underwent mastectomy, 69% tumors were HR-positive and 69% were node positive. Women with complete data (N=123) did not differ from those with incomplete data (N=38) by age, race/ethnicity, PS, type of surgery, T stage, nodal status, or HR status. Adherence was 85% across all cycles for all patients with complete data, and adherence was not significantly associated with cycle number (1–6) (p=0.39). In univariate analysis, age as a continuous variable was not associated with adherence. Overall, 24% of participants took fewer than 80% of expected doses (5% took 20–39%, 6% took 40- 59%, 14% took 60–79%) and were considered non-adherent. In a logistic regression model, participants with node-negative disease were more likely to be non-adherent (p=0.04). Non-significant covariates were age, type of surgery, T stage, HR status. Conclusions: 76% of older women with early stage breast cancer were adherent to short-term oral chemotherapy in a randomized clinical trial. Age was not significantly associated with adherence in this study. Further analyses to evaluate additional predictors of non-adherence, and the impact of non-adherence on disease and toxicity outcomes will be performed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche
A phase 2, single agent study of CI-1033 administered at two doses in ovarian cancer patients who failed platinum therapy
Authors: S. M. Campos, M. V. Seiden, A. Oza, M. Plante, R. Potkul, O. Hamid, P. Lenehan, E. Kaldjian, C. Jordan, H. Hirte
Journal: Journal of Clinical Oncology (2004)

5054 Background: Ovarian cancer that is refractory to platinum-based therapies is a therapeutic challenge, particularly in the setting of erbB-1 and -2 receptor over- expression. CI-1033 is an irreversible, 4-anilinoquinazoline pan-erbB tyrosine kinase inhibitor with activity in a wide variety of human tumor xenografts, particularly erbB+ tumors including ovarian SK-OV-3. Methods: This study evaluated 50- and 200mg doses of CI-1033, given daily for 21 days repeated every 28 until disease progression in pts with platinum-refractory ovarian cancer. Primary eligibility criteria included disease progression following platinum therapy, measurable disease, and Karnofsky Performance Status (KPS) of 60–100. Baseline tumor erbB receptor profiles were determined by IHC staining retrospectively in 56 of the 105 pts. Endpoints included 1-yr progression-free survival (PFS) and overall survival (OS). Results: Between January and May of 2002, 105 patients were enrolled. Baseline characteristics were balanced between both groups: overall median number of prior chemotherapy regimens was 4 (1–12); median KPS was 90. Fifty-three pts received 146 cycles in the 50-mg arm; 52 pts received 138 cycles in the 200-mg arm. Dose reductions were necessary in 59% of pts in the 200-mg arm predominantly due to gastrointestinal adverse effects (AEs); no pts required dose reductions in the 50-mg arm. The most common treatment-related AEs in the 50-mg arm were Grade 1–2 diarrhea (57%), asthenia (43%), and nausea (41%); AEs in the 200-mg arm were Grade 2–3 diarrhea (85%), stomatitis (69%), and rash (58%). There were no objective responders in either arm; stable disease (≥8 weeks) was achieved in 28% and 34% of pts in the 50- and 200-mg arms, respectively. One-yr PFS rates were 0% and 9%, and 1-year OS were 37% and 38% for 50- and 200-mg dose group, respectively. No associations were apparent between baseline tumor erbB expression profiles and PFS or OS. Conclusions: CI-1033 has minimal activity in this heavily pretreated, platinum-refractory population. The 50-mg dosing regimen was better tolerated than the 200-mg arm, with gastrointestinal AEs being most common toxicities. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Employed by Pfizer Eli-Lilly Pfizer Eli Lilly; GlaxoSmithKline
Quantitative and Ultrastructural Changes of Peritoneal Macro Phages in Immunized Rats After Intraperitoneal Injection of Novikoff Hepatoma&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;, &lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: A Nanci, F Babaï, A Dumont
Journal: JNCI Journal of the National Cancer Institute (1980)

The response of peritoneal cells to transplantable Novikoff hepatoma was studied in immunized and nonimmunized inbred male SD rats to elucidate the role of macrophages in syngeneic tumor rejection. Specific immunization was induced by double sc challenge with viable tumor cells. Peritoneal cells were harvested by lavage at intervals of 6 hours and 1, 2, 3, 4, and 9 days after ip tumor injection. Some of the lavage fluid was used to determine the total number of cells, and the remainder was prepared for ultrastructural study. Different counts were made at the electron microscope level, and the ultrastructures of macrophages and tumor cells were studied. The results indicated that during the early intervals after tumor injection, the numbers of macrophages and lymphocytes were significantly increased in immunized animals. The mononuclear cells accumulated more slowly in the peritoneal cavities of nonimmunized rats. Morphologic heterogeneity was observed in the macrophage population of immunized rats up to day 4. Concurrent with these changes in macrophages were the decreased mitotic activity and ultrastructural alterations in tumor cells followed by their complete disappearance. In nonimmunized animals tumor cells proliferated actively and by day 9 constituted 85% of the peritoneal population.
<i>EGFR</i> and <i>KRAS</i> mutation status of lung adenocarcinomas in African Americans
Authors: M. Reinersman, G. J. Riely, A. Nicastri, G. A. Soff, A. Getinet, A. G. Schwartz, M. F. Zakowski, V. W. Rusch, M. G. Kris, M. Ladanyi
Journal: Journal of Clinical Oncology (2009)

11065 Background: The 2004 discovery of the tyrosine kinase inhibitor-sensitizing mutations in the epidermal growth factor receptor (EGFR) represents a major advance in the study and management of non-small cell lung cancer. Conversely, KRAS mutations in these cancers confer resistance to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. EGFR mutations occur almost exclusively in adenocarcinoma, and are more common in never smokers, women, and people born in East Asian (compared to Whites). No comprehensive studies exist of EGFR and KRAS mutations in lung cancers from African-American patients. Methods: We collected formalin-fixed paraffin-embedded material from 121 resected lung adenocarcinomas from African-American patients for DNA extraction. EGFR exon 19 deletions and exon 21 L858R point mutations were detected by sensitive mutation-specific PCR-based methods. KRAS codon 12 and 13 mutation testing was performed by mass-spectrometry (Sequenom)-based genotyping and direct sequencing. These data were compared to Memorial Sloan-Kettering data for EGFR and KRAS mutations in all resected adenocarcinomas in white patients. Results: EGFR mutations were detected in 23 of 121 cases (19%), while KRAS mutations were found in 21 (17%). Exon 19 deletions accounted for 18 of 23 of the EGFR mutations compared to 5 EGFR L858R mutations. KRAS mutations were primarily the transversion type mutations (17 of 21). When compared to data from Memorial Sloan-Kettering for White patients (81/273, 30%), the 17% rate of KRAS mutations in lung adenocarcinomas from African-Americans was significantly lower (p=0.01). EGFR mutation status was similar between African-Americans and Whites (19% vs 18%, p=0.9) and the proportion of exon 19 deletions and L858R mutations was comparable as well. Conclusions: This is the first large series reporting results of mutation testing in lung adenocarcinoma specimens from African-Americans. African-American patients are less likely than Whites to harbor KRAS mutations in their lung adenocarcinomas. There was no significant difference in the prevalence of EGFR mutations. Since biological characteristics underlie clinical factors, these differences may help explain differences in outcomes comparing African-Americans to other groups. No significant financial relationships to disclose.
Herbal (Astragalus) saponins inhibit HepG2 cell growth and promote apoptosis through NF-κB and ERK signaling
Authors: Joshua Ko, Kathy Auyeung
Journal: Cancer Research (2008)

2276   We have recently reported that the total saponins of the Chinese medicinal herb  Astragalus membranaceus  (AST) possess promising anti-tumorigenic effects in human colon cancer cells and tumor xenograft through inhibition of cell proliferation and promotion of apoptosis ( Carcinogenesis  28:1347-1355, 2007). In the present study, the anti-carcinogenic effects of AST were further studied in HepG2 human hepatocellular carcinoma cells. We focused on the involvement of both extracellular signal-regulated kinases (ERK) and nuclear factor-kappa B (NF-κB) signaling pathways in AST-induced apoptosis. Our results have shown that AST could suppress HepG2 cell growth, while at the same time downregulate expression of the liver tumor marker α-fetoprotein. Furthermore, apoptosis was induced through caspase 3 activation and subsequent poly(ADP-ribose) polymerase (PARP) cleavage, leading to the appearance of nuclear chromatin condensation. Besides, downregulation of the anti-apoptotic proteins bcl-2 and bcl-x L  were also observed following AST treatment. In order to unveil the underlying mechanism of action, DNA binding activity of the transcription factor NF-κB was examined by electrophoretic mobility shift assay. Data have demonstrated that NF-κB DNA binding activity was significantly decreased after AST treatment. On the other hand, expression of the phosphorylated form of ERK was found to be prominently increased in a dose-dependent manner. Pretreatment of PD98059, a strong inhibitor of ERK, facilitated the cleavage of PARP, indicating an active involvement of the ERK signaling pathway in AST-induced apoptotic activity. Taken together, our findings suggest that AST has the potential to be developed as an effective chemotherapeutic agent in treating liver cancers, with known molecular targets and precise mechanism of action.
Primary and secondary prophylactic nipple-sparing subcutaneous mastectomy (NSSM): A retrospective single-center analysis.
Authors: Stefan Paepke, Svenja Allhorn, Marion Kiechle
Journal: Journal of Clinical Oncology (2012)

162 Background: Given a strict indication the NSSM is a oncologically safe surgical procedure and allows breast reconstructive interventions with a good cosmetic result. With regard to prophylactic mastectomy (PM) the (radical) ablatio mammae is so far regarded as the therapy of choice, since a maximal removement of the breast glandular tissue seems ensured. So far, it is unclear if NSSM is a oncologically safe treatment option also in the context of prophylactic surgery. The introduction of new materials for tissue extension in plastic-reconstructive interventions such as porcine acellular dermis (Strattice) or titanized polypropylene meshes (TiLoopBra ) permits the reconstruction of the natural breast shape and size and thus the preservation of the body integrity also in prophylactic operations. Methods: This is a retrospective analysis of the PM performed at the Department of OB/GYN of the TU München (Munich, Germany) between 01/2005 and 12/2011 (76 cases). Primary PM were done in 13 cases due to positive family history (n=3), BRCA mutations (n=9) or at the request of the patient (n=1). 63 breast cancer patients were operated (secondary contralateral mastectomies) because of a positive familiy history (n=21), BRCA mutations (n=17) or high need for security (n=25). 19 mastectomies and 57 NSSMs were performed. With all NSSMs an instant reconstruction was done (17x expander, 25x implants, 1x TRAM, 14x DIEP), in 42 patients using a tissue extension (titanized poylpropylene meshes or acellular dermis). 9 patients with ablatio mammae received a breast reconstruction. Results: There was a continuous increase in prophylactic operations and NSSMs over the past five years. In four patients there was a coincidental pathological finding diagnosed in the healthy breast (2x DCIS, 1x Ca, 1x CLIS). In the group of primary prophylactic operated patients there were no (pre-)cancerous lesions found. In the secondary PM patients there were no recurrences, secondary cancers or metastases. Conclusions: In conclusion there was no difference between both surgical techniques with regard to oncologic safety. As far as breast reconstructive possibilities are concerned there are clear advantages in NSSM.
Chemical Phototoxicity in Humans&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: John H. Epstein, M.D.
 4
Journal: JNCI Journal of the National Cancer Institute (1982)

Phototoxic reactions may be induced by endogenous or exogenous chemicals. Endogenous photosensitizers made by the body include porphyrin molecules which are responsible for the photocutaneous syndromes noted in the porphyrias. Exogenous photosensitizers may arrive on the skin through topical applications or may be distributed through the vasculature. Topical photosensitizers are found in cosmetics, medications, plants, and industrial and air pollutant emissions. Systemic photosensitizers consist primarily of therapeutic agents. Acute and chronic phototoxic reactions may occur. The acute response is generally characterized by erythema and edema followed by hyperpigmentation and desquamation. The end point of chronic damage may be cutaneous cancer formation. The mechanisms of these changes may well relate to nucleic acid injury, protein and membrane damage, and alterations in other nuclear and cytoplasmic molecular structures. However, translation of experimental information into human responses remains to be clarified. A great deal of investigation is still needed in developing assays for detecting phototoxic chemicals and for defining mechanisms involved in phototoxic events in human skin.
Disease and stimulus specific pro-inflammatory cytokine secretion by human fibroblast of asthma patients
Authors: Luigi Costa, Pieter Borger, Paola Casarosa, Michael Tamm, Michael Roth
Journal: European Respiratory Journal (2011)

It is well documented that the asthmatic lung contains increased levels of pro-inflammatory cytokines. We provide evidence that compared to healthy primary human fibroblasts isolated from medium size airways of asthma patients secrete significantly more pro-inflammatory cytokines in a stimulus and disease specific pattern. Bronchial fibroblasts from 5 asthma patients and 5 healthy controls were isolated and stimulated with PDGF-BB, TNF-alpha or IL-1beta (0.1, 1.0, 10 ng/ml), all of which are well known asthma-relevant factors. After 24 hours, secreted IL-6, IL-8, eotaxin and GM-CSF were determined in the cell culture medium. PDGF-BB dose dependently increased both IL-6 and eotaxin secretion by 3 and 6 fold, respectively, but with no difference between asthma and control. In contrast, IL-8 and GM-CSF levels were significantly increased in asthma. TNF-alpha increased IL-6, eotaxin and GM-CSF significantly stronger in asthma fibroblasts relative to control. IL-8 secretion dose-dependently increased after TNF-alpha treatment, but no difference between asthma and control was observed. IL-1beta dose-dependently increased the secretion of all 4 cytokines, however, with a disease specific increase of GM-CSF at 10 ng/ml. Our data suggest that bronchial fibroblasts contribute to chronic inflammation in asthma in a disease and stimulus specific pattern.  Supported by: Boehringer Ingelheim Pharma, SNF grant (320030_124905/1)