tbuckley/cabot-search huggingface dataset:
P3-17-06: Final Results of a Controlled, Randomized 3-Arm Phase II Trial of EndoTAG”-1, a Cationic Liposomal Formulation of Paclitaxel Targeting Tumor Endothelial Cells, in Advanced Triple-Negative Breast Cancer (TNBC).
Authors: A Awada, IN Bondarenko, O Tarasova, J Bonneterre, E Nowara, JM Ferrero, AV Bakshi, H Weidenthaler, C Wilke, MJ Piccart
Journal: Cancer Research (2011)

Abstract Background EndoTAG™-1 (ET) is an innovative therapy of paclitaxel (P) embedded in cationic liposomes displaying antitumor activity by targeting negatively charged activated endothelial cells of tumor vessels. Methods: 140 patients (pts) with locally relapsed (r) or metastatic (m) centrally verified TNBC were randomized to i.v. weekly ET (22mg/m2 ) plus P (70mg/m2) (ET+P), biweekly ET alone (44mg/m2) or weekly P (90mg/m2) in a 2:2:1 ratio. Pts had ≤ 1 prior chemotherapy (CT) for r or m disease and ≥ 6 months (mo) after taxane. A cycle (cy) comprised 3 weeks(w) of therapy and 1 w rest. Pts were treated for a minimum of 4 cy or until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS) rate at week 16 based on blinded central imaging and local assessment. Secondary endpoints included median overall survival (mOS), tumor response (RECIST), Quality of Life (QoL) and safety. The study was not powered for intergroup comparisons. Results: Pts baseline characteristics were overall well distributed. Appr. 80% of all pts were treated 1st line for r or m TNBC. Results of PFS rates at week 16 are shown in table. Based on central review, median PFS at week 16 was 4.2 mo for ET+P [95% CI: 3.5−9.1], 3.4 on ET [2.0−3.8] and 3.7 on P [1.9−6.7]. Antitumor activity was highest for ET+P with a clinical benefit rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥6 mo at data cut off date of week 41) of 53% (26/49 evaluable pts), 31% (15/49) on ET and 36% (9/25) on P. The best overall response (CR, PR, SD at any time) on ET+P was 80% (39/49), on ET 65% (32/49) and 68% (17/25) on P. Analysis of median OS is shown in table. Analysis of the not predefined subgroup (centrally TNBC + ECOG 0/1 + first line population) showed an impressive median OS of 17.8 mo for ET+P. No differences were reported for QoL. No additional toxicities to those known for ET and P were observed except uncomplicated grade 3/4 neutropenia in the ET + P arm. Conclusions: At cut-off date week 41, the final analysis demonstrated ET+P as a promising combination compared to single agent arms. ET+P was well tolerated. These data will be the basis for a confirmatory phase III study. Acknowlegments: B. Glasschroeder, U. Elsasser Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-06.
A Medical Treatment for Gallstones?
Authors: Kurt J. Isselbacher
Journal: New England Journal of Medicine (1972)

Four years ago in these pages the question was asked "Why can't gallstones make the first division in the research league?" Since that time considerable fundamental progress has been made, especially in the area of bile-salt metabolism, and the report by Danzinger and his co-workers in this issue of the Journal indicates that gallstones have finally made it! The investigators from the Mayo Clinic have demonstrated that chenodeoxycholic acid, when given to patients with cholesterol gallstones, can cause the dissolution of stones in situ. In the United States over 15 million people have cholesterol gallstones, of which over 1/3 are . . .
Abstract 349: Fascin expression in colorectal cancer metastases predicts survival after curative-intent surgery
Authors: Catherine Sullivan, Xiaojie Guo, Zuoheng Wang, Constantine Theoharis, David L. Rimm, Daniel J. Boffa
Journal: Cancer Research (2011)

Abstract Background: Patients with metastatic colorectal cancer that is limited to a few lesions in the lungs or liver may benefit from the complete surgical removal of all deposits of metastatic cancer (referred to as a curative metastasectomy). Although the outcome after this curative-intent surgery is considerably better than patients with more extensive metastatic cancer, only a third of the surgical patients are actually cured. As a result, there is a great need for a mechanism to predict outcome after surgery for limited metastatic cancer, in order to better match patients with effective therapy. Fascin is an actin bundling protein linked to epithelial to mesenchymal transformation and metastatic progression. Fascin expression has previously demonstrated prognostic potential in patients with extensive metastatic colorectal cancer. We hypothesized that Fascin expression within surgically removed colorectal cancer metastases would correlate with survival after curative-intent surgery. Methods: 82 paraffin embedded colorectal metastases collected after curative-intent surgery between 1990 and 2008 were incorporated into tissue microarrays (TMAs) in two fold redundancy. Fascin expression within the metastases was determined by quantitative immunofluorescence using Automated Quantitative Analysis (AQUA), and normalized based on a panel of cell lines (AQUA score range 0-72). The median follow up was 2.8 years and thus far 51 patients have died (62%). Results: The majority of colorectal cancer metastases had been removed from the liver (70 patients), while 12 represented pulmonary metastases. There were no differences in survival by location of metastases (p = .65). Survival was analyzed based on high (top quartile, n = 21) and low (bottom three quartiles, n = 61) expression of Fascin (AQUA score cut point of 3.4). High expression of Fascin correlated with a worse prognosis, HR 1.97; 95% CI 1.07-3.62 p = .009. Conclusions: Fascin expression within colorectal cancer metastases may be used to predict outcome after curative-intent surgery. Patients with high Fascin expression may be considered for additional therapy or may be advised against particularly high risk procedures. Further study is warranted to validate the role of Fascin expression analysis in this patient cohort. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 349. doi:10.1158/1538-7445.AM2011-349
NHS chief tells politicians to embrace hospital closures to improve services for patients
Authors: N. Hawkes
Journal: BMJ (2013)

Opposing changes to hospital services in England risked perpetuating mediocrity, the NHS’s medical director, Bruce Keogh, has warned.

Appealing to politicians to step above their local interests and think of the wider interests of the NHS, the man responsible for quality at the NHS Commissioning Board said that changes might mean local closures or reconfigurations but that the result would be that patients could be directed to specialist centres where their care would be better.

“Unless we can get to that place where people look at the greater good, which is sometimes in conflict with local interests, then professional, personal, and political interests will conspire to perpetuate mediocrity and inhibit the pursuit of excellence to the detriment of our NHS and ultimately our patients,” Keogh told the Guardian .1

Reconfigurations in at least 15 places …
Abstract 248: Control of prostate tumor growth and centriole amplification by antizyme and antizyme inhibitor
Authors: Rachelle R. Olsen, Ivy Chung, Bruce R. Zetter
Journal: Cancer Research (2011)

Abstract The endogenous antizyme inhibitor (AZI) is best characterized for its role in regulating polyamine homeostasis. Polyamines are organic cations synthesized by the enzyme ornithine decarboxylase (ODC), a protein which is negatively regulated and targeted for proteasomal degradation by antizyme (AZ). AZI is a potential oncogene which promotes cell growth not only by inhibiting antizyme (AZ) activity, but also by releasing ODC from AZ-mediated degradation. High levels of ODC and polyamines are associated with numerous types of neoplastic transformation, and the genomic region including AZI is frequently amplified in tumors of the ovary and prostate. To determine whether AZI functionally promotes prostate tumor growth, we made PC3M-LN4 (human) and AT6.1 (rat) cancer cell lines stably expressing AZI shRNA. AZI knockdown was confirmed by western blot and RT-PCR. To examine the ability of these cells to form tumors in vivo, 1×106 cells were injected subcutaneously into nude mice either with (PC3M-LN4) or without (AT6.1) Matrigel. Tumor growth was measured two times per week by caliper. Cells in which AZI levels had been knocked down by shRNA formed significantly smaller tumors in vivo, and had significantly smaller end tumor weights. These results suggest that not only does AZI promote tumor growth, but also that AZI may be a novel and valid therapeutic target for cancer treatment. In addition to their effects on cell proliferation, previous studies in our laboratory have shown that both AZI and AZ localize to centrosomes and are important for controlling centrosome duplication. Centrosome amplification is a frequent and early event in tumorigenesis. We found that overexpression of AZI and knockdown of AZ both result in cells with daughter centriole amplification due to abnormal centriole synthesis. To gain insight into the mechanism by which AZ and AZI modulate centriole synthesis, we are currently analyzing whether proteins that regulate centrosome duplication interact with either AZI or AZ. We are also using Tet-inducible overexpression vectors to monitor the effect of increased AZ or AZI levels on centriole amplification, and exploring how localization of these proteins to the centrosome contributes to the centrosome amplification phenotype. These studies provide a much greater understanding of AZI function, and suggest that high AZI levels may contribute to tumorigenesis both by promoting cell growth and inducing centrosome amplification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 248. doi:10.1158/1538-7445.AM2011-248
Phase I-II study of the histone deacetylase inhibitor (HDACi) vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer (MBC): New York Cancer Consortium trial P7703.
Authors: B Ramaswamy, K Bhalla, B Cohen, C Pellegrino, D Hershman, E Chuang, G Somlo, M Goetz, R Swaby, U Hopkins, P Christos, I Espinoza-Delgado, JA Sparano
Journal: Cancer Research (2009)

Abstract Abstract #404 Background: The oral HDACi vorinostat (V) sensitizes breast cancer cells to tubulin polymerizing agents and anti-VEGF directed therapies in vitro. We sought to determine the safety and efficacy of V plus paclitaxel (P) and bevacizumab (B) as first-line therapy for MBC.&amp;#x2028; Methods: Eligible patients (pts) with measurable disease, ECOG PS 0 or 1, and no prior chemotherapy for MBC, received P (90mg/m2) on days 1, 8, 15 and B (10mg/kg) on days 1,15 every 28 days, plus V 200 mg (N=3) or 300 mg (N=28) BID orally for 3 days given the day before, day of, and day after each P dose. Response was assessed after every 3 cycles (RECIST). The trial was designed to distinguish between a response rate of &amp;lt; 40% vs. &amp;gt; 60% (alpha=0.10, beta=0.10) using Simon's optimal 2-stage design. At least 12 responses were required in the first 28 evaluable pts in the 1st stage and 21 of 41 in the 2nd stage.&amp;#x2028; Results: There were no dose-limiting toxicities among the first 6 pts treated at the 1st (200 mg BID; N=3) and 2nd (300 mg BID; N=3) dose levels. Among the 26 evaluable pts treated at the recommended phase II dose of 300mg bid in the 1st stage, 14 patients had a partial response (PR-54%; 90% confidence interval [C.I.] 36%-71%), 6 had stable disease (SD) at 3 months and remain on treatment, 2 had SD as the best response with progressive disease (PD) at 11.8 and 15 months, and 4 had PD as their best response. Additionally, 2 of 3 pts treated at the first V dose level had a PR, indicating PR in 16 of 29 overall (55%, 90% C.I 38%-71%). Only 11 of 29 evaluable pts (38%) have progressed after a median followup of 10.5 months (R-2.3-14.9). Two pts had tumor biopsies and peripheral blood mononuclear cells (PBMC) collected before and 4 hours after the 3rd V dose (300 mg BID) which showed increased acetylation of K69 lysine residue of the chaperone protein Hsp 90, upregulation of Hsp70, and downregulation of AKT by Western Blot, providing evidence of Hsp90 inhibition in tumor and PBMC.&amp;#x2028; &amp;#x2028; Gr 3-4 toxicities included neutropenia (26%), neuropathy (23%), fatigue (16%), thrombosis (10%), vomiting (6%), hypertension (3%), and diarrhea (3%).&amp;#x2028; Conclusions: Our preliminary findings indicate that the HDACi V inhibits Hsp90 and downregulates AKT in breast cancer in vivo, and enhances the effectiveness of P plus B in MBC. Accrual is nearly complete and the final efficacy analysis will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 404.
AB0215 Experimental neuropsychiatric lupus induced by 16/6 idiotype antibodies
Authors: S. Kivity, A. Katzav, M. Teresa-Arango, M. Rabi, Y. Zafrir, N. Agmon-Levin, M. Blank, E. Mozes, J. Chapman, Y. Shoenfeld
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The 16/6 idiotype was shown to induce experimental lupus in naïve mice<sup>1</sup>. Its ability to induce brain specific disease was not evaluated before. <h3>Objectives</h3> We assessed the behavior and brain immunohistochemistry of naive mice injected intra-cerebra-ventricularly (ICV) with the 16/6 antibody. <h3>Methods</h3> Twenty one CH3 mice were injected ICV to the right hemisphere: 11 with human 16/6 idiotype antibodies and 10 with commercial human IgG antibodies (control). Depression was addressed by forced swimming test (FST), explorative activity was evaluated by the staircase test. Cognitive function was examined in the novel object recognition (NOR) and Y-maze tests at days 19 and 20 respectively. Fixated brain sections (50πl thick) were stained for activated microglia, neuronal nucleus, and astrocytes. <h3>Results</h3> In the NOR test there was a significant preference for the novel object in the control group (64% time spent near the novel object, p=0.01) and no difference in the preference was seen in the 16/6-injected mice. The preference for spatial novelty in the Y-maze test was significantly higher in the control group compared to the 16/6-injected mice (42% vs. 9% respectively, p=0.06). Depression–like and explorative behavior was not significantly different between 16/6-injected and control mice. Immunohistochemistry analysis revealed increased microglial activation in the hippocamppal, dentate and amygdale regions, in the 16/6 injected group, compared to the control ones. <h3>Conclusions</h3> Passive transfer of 16/6 antibodies to mice brain results in a cognitive impairment, and evidence of brain inflammatory changes. This finding may shed light on the pathophysiology of neuropsychiatric lupus. <h3>References</h3> Blank, M. and Y. Shoenfeld, The story of the 16/6 idiotype and systemic lupus erythematosus. Isr Med Assoc J 2008; 10(1): p. 37-9. <h3>Disclosure of Interest</h3> None Declared
Abstract 3456: Characterization of dibenzo[<i>a,l</i>]pyrene-<i>trans</i>-11,12-diol glucuronidation by UDP-glucuronosyltransferases
Authors: Kristine C. Olson, Dongxiao Sun, Gang Chen, Arun K. Sharma, Shantu Amin, Ira J. Ropson, Thomas E. Spratt, Philip Lazarus
Journal: Cancer Research (2010)

Abstract A procarcinogen found most notably in tobacco smoke is dibenzo[a,l]pyrene (DB[a,l]P), which can be further metabolized into its epoxide, diol, and carcinogenic diol-epoxide forms. DB[a,l]P metabolites are some of the most potent carcinogens of the polycyclic aromatic hydrocarbon (PAH) family of compounds due to a structural feature called the fjord region. The activated metabolites of DB[a,l]P bind mostly to deoxyadenosine in DNA to form stable adducts, which can potentially lead to DNA damage. UDP-glucuronosyltransferase (UGT) enzymes mediate the attachment of a UDP-glucuronic acid to a wide variety of endogenous and exogenous substrates including several carcinogens, resulting in increases in water solubility and elimination of the carcinogen from the body. The focus of the current study was to examine the detoxification of the carcinogenic diol form (DB[a,l]P-trans-11,12-diol) by glucuronidation. In order to understand the metabolism of this potent PAH by human UGT enzymes, HEK293 cell lines over-expressing individual UGTs were screened for glucuronidation activity toward DB[a,l]P-11,12-diol. Glucuronide products were quantified using an ultra-performance liquid chromatography (UPLC) method. Six UGTs (UGTs 1A1, 1A7, 1A8, 1A9, 1A10 and UGT2B7) were found to be highly active. Three glucuronide conjugates were observed in activity assays with UGT1A1 and 1A10, while only two glucuronides were formed with UGTs 1A7, 1A8, 1A9, and 2B7. Enzyme kinetic analysis indicated that UGT1A9 is the most active isoform among all the UGTs, exhibiting the highest Vmax/Km for the two glucuronide products it formed. These results suggest that multiple UGTs are involved in stereospecific glucuronidation of DB[a,l]P metabolites in humans. In addition to the further characterization of (DB[a,l]P-trans-11,12-diol) glucuronide conjugates, studies examining the role of polymorphisms in active UGTs on cancer risk are currently on-going. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3456.
Lymphoepithelial cyst of the upper esophagus
Authors: H. Noh, J. Koo, H. Oh, J. Yun, S. Jung, E. Lee, H. Yim, S. Lee, J. Choi
Journal: Endoscopy (2011)

A 61-year-old man underwent esophagogastroduodenoscopy as part of a general checkup at a private clinic, and was referred to our hospital with a suspected submucosal tumor of the esophagus. The patient had no symptoms and was in good health except that he was taking aspirin for angina pectoris, although he had not experienced any cardiac events in the past 6 years. On physical examination, the abdomen was flat and soft. Laboratory findings were within normal limits. The endoscopic examination showed a small submucosal tumor 22 cm from the incisors below the upper esophageal sphincter ([Fig. 1]). Endoscopic ultrasonography showed a low echoic tumor, 5 × 4 mm in size, in the submucosal layer of the esophagus ([Fig. 2]). The tumor was removed by endoscopic mucosal resection using a snare and sent for histological examination. The resected tumor was 9 × 7 × 4 mm in size. A unilocular cyst was found below the esophageal mucosa. The cyst was lined by stratified squamous epithelium surrounded by a florid lymphoid hyperplasia with germinal centers ([Fig. 3]). The histopathological examination confirmed the diagnosis of lymphoepithelial cyst. We plan to follow up the patient with gastroendoscopy in 1 year.
AB0700 Successful experience with tocilizumab in two patients with macrophage activation syndrome associated with juvenile idiopathic arthritis
Authors: S. Rodionovskaya, I. Nikishina
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile idiopathic arthritis (sJIA) often leading to multiple organ failure. Biological agents including tocilizumab are used extensively in the treatment of JIA, but can trigger MAS development in some patients and therefore MAS is often considered as a contraindication to tocilizumab. We have experience of successful use of tocilizumab in sJIA complicated by MAS. <h3>Objectives</h3> Clinical narrative of MAS in two sJIA patients. <h3>Results</h3> A 10 year old boy has suffered from sJIA for over 2 years, presents with fever, serositis, lymphadenopathy, hepatomegaly, polyarthritis, leukocytosis 22×10<sup>9</sup>, CRP 120 g/L, ESR 64 mm/hr. Treatment with glucocorticoids (GCs), methotrexate, and cyclosporine A was inadequately effective. While on intravenous administration of methotrexate 30 mg the patient presented with persistent febrile hyperthermia, hepatosplenomegaly, nephritis, rapid decrease in ESR - 2 mm/hr, cytopenia (platelet count 116×10<sup>12</sup>, WBC 5.4×10<sup>9</sup>, HB 90 g/L), ferritin – 905 µg/L, transaminase increases (LDH - 723 U/L, ALT), increase in triglycerides, and decrease in fibrinogen. The use of methylprednisolone 15 mg/kg for 3 days, GCs, cyclosporine and administration of tocilizumab 10 mg/kg every 12 weeks resulted in MAS resolution. Normalization of LDH and ferritin was observed after the second administration of tocilizumab. A 3 year old girl with sJIA and primary hyperinsulinism has been ill for 1 year. Following 2-month therapy with IL-1 receptor antagonist anakinra 2-4 mg/kg she developed sJIA relapse (fever, rash, polyserositis, arthritis) with symptoms of MAS (uncontrolled fever, CNS lesion, nephritis, splenomegaly +10 cm, hepatomegaly, lymphadenopathy, ESR 10 mm/hr, thrombocytopenia 115×10<sup>12</sup>, anaemia - HB 89 g/l, ferritin &gt;10000 µg/L, transaminase increases - LDH 1702 U/L, increase in triglycerides; coagulation disorders. Anakinra was discontinued, GCs were administered orally 1 mg/kg, following which the disease activity persisted but cytopenia resolved. After 2 weeks, tocilizumab 12 mg/kg iv once every 2 weeks was administered with favorable effect. Normalization of ferritin and LDH was achieved after the third administration of tocilizumab. No adverse events were observed. The both patients continue to receive tocilizumab infusions every 2 weeks with good therapeutic response corresponding to ACR70-90%. <h3>Conclusions</h3> Our experience with tocilizumab given in combination with GCs in patients with sJIA complicated by MAS showed its high efficacy and good tolerability superior to that of GCs alone. <h3>References</h3> <i>Journal of Rheumatology.2011;38</i> <i>Current Opinion inRheumatology. 2002;14</i> <h3>Disclosure of Interest</h3> None Declared