tbuckley/cabot-search huggingface dataset:
Activity of sequential therapies (txs) in patients (pts) with castration resistant prostate cancer (CRPC) previously treated with galeterone.
Authors: Rana R. McKay, Lillian Werner, Matthew Fiorillo, Kathryn Dumas, Jennifer Roberts, Khalid Mamlouk, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2015)

e16072 Background: Galeterone inhibits prostate cancer growth via: 1) irreversible and selective CYP17 inhibition, 2) competitive antagonism of the androgen receptor (AR), and 3) AR protein degradation. Developing a rational approach to sequential txs in CRPC is paramount to clinical decision making. The primary aim of this analysis is to evaluate clinical response and resistance to CRPC tx post galeterone. Methods: We conducted a retrospective analysis of men in ARMOR2 (NCT01709734), a phase II study designed to establish the dose of galeterone and assess safety and efficacy of the optimal dose (2550 mg daily). 39 men with treatment-naive CRPC from 6 sites are included in the post-galeterone tx analysis. We report on pts receiving galeterone at Partners Institutions (n=14). Subsequent analyses will include other sites. Results: For pts in the post-galeterone tx analysis (n=39), median age was 72 years (54 – 94) and median PSA was 16.8 ng/mL (3.3 – 634); 24 pts had metastases. Median time on galeterone was 119 days (11 – 392). Of the Partners pts (n=14), 9 discontinued tx: 3=AEs, 5=progression and 1=death. 8 pts received 1 and 2 received 2 post-galeterone txs. Median PSA at initiation of the first post-galeterone tx was 8.25 ng/mL (3.2 – 299). Median maximum percent PSA decline from initiation of first post-galeterone tx was 98% (range 100% decline, 33% increase, Table 1). Of the 2 pts who completed their first post-galeterone tx, duration of tx was 2 months (mos, enzalutamide) and 9 mos (docetaxel). Of the 6 pts still receiving their first post-galeterone tx, 3 have remained on tx for > 7 mos. Conclusions: Initial data indicates that pts may have favorable response to both hormonal tx and chemotherapy after galeterone with a lack of cross resistance. Additional analysis (available at ASCO) will expand these observations and provide useful insight for treating physicians. The predictive biomarker, AR-V7 is in Phase III development. Clinical trial information: NCT01709734.PSA response to post-galeterone txs. Tx* Pts Any PSA Decline N (%) ≥ 50% PSA Decline N (%) ≥ 90% PSA Decline N (%) Abiraterone 3 2 (67%) 2 (67%) 2 (67%) Enzalutamide 3 1 (33%) 1 (33%) 1 (33%) Docetaxel 3 2 (67%) 1 (33%) 1 (33%) *1 pt received nilutamide (not included).
Abstract 2865: Characterization of histone deacetylases in embryonal rhabdomyosarcoma
Authors: Michael Phelps, Terra Vleeshouwer-Neumann, Jenna Bailey, Nicole Hickman, Eleanor Chen
Journal: Cancer Research (2015)

Abstract Histone acetylation and deacetylation are key epigenetic modifications that influence gene expression in both normal and neoplastic cells. Histone deacetylases (HDACs) have been the target for cancer therapeutics due to their demonstrated role in modulating tumor onset and progression in a subset of cancers. We have shown that treatment with pan HDAC inhibitors leads to reduced tumor growth and increased tumor cell differentiation of cultured Embryonal Rhabdomyosarcoma (ERMS) cells. However, the role of specific HDACs in ERMS remains unknown. To determine the function specific to each HDAC in ERMS, we have employed the Clustered Regularly Interspersed Short Palindrome Repeats (CRISPR)/Cas9 nuclease-mediated genome editing technology to enable effective knockout of individual HDAC genes in ERMS. Our CRISPR/Cas9 system uses a transient and multiplex gene targeting approach that induces loss-of-function mutations with high efficiency and allows rapid phenotypic analysis. Combining this system with stable selection of mutant clones with null mutations, we have systematically targeted all class I HDAC genes in ERMS cells. Initial characterization reveals distinct functions of class I HDAC genes in ERMS tumorigenesis. HDAC1 loss-of-function in ERMS cells promotes tumor growth. By contrast, HDAC3 or HDAC8 loss-of-function reduces tumor cell viability. HDAC2 loss-of-function does not affect tumor growth but induces robust differentiation of ERMS cells. In future studies, candidate genes/pathways regulated by HDACs will be identified by an integrated approach of Chromatin Immunoprecipitation (ChIP) and gene expression profiling studies. To validate HDAC mutant phenotypes observed in vitro and assess pre-clinical efficacy of targeted HDAC therapies, CRISPR/Cas9 inducible ERMS lines are currently being developed to facilitate tumor xenograft studies in vivo. Overall, our initial gene targeting results reveal distinct roles of class I HDAC genes in modulating ERMS tumor growth and differentiation. Our results suggest that therapeutic efficacy of pan HDAC inhibitors may be compromised by simultaneously inhibiting tumor-promoting and tumor-suppressive functions of HDACs. Targeted HDAC therapies therefore, may have more potent therapeutic benefits. Citation Format: Michael Phelps, Terra Vleeshouwer-Neumann, Jenna Bailey, Nicole Hickman, Eleanor Chen. Characterization of histone deacetylases in embryonal rhabdomyosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2865. doi:10.1158/1538-7445.AM2015-2865
TROP2 is a major determinant of growth and metastatic spreading of human cancer
Authors: S. Alberti, M. Trerotola, G. Vacca, R. Zappacosta, C. Rossi, E. Guerra, V. Bonasera, R. Lasorda, R. Lattanzio, M. Piantelli
Journal: Journal of Clinical Oncology (2007)

10510 Background: The TROP2 gene encodes a transmembrane calcium signal transducer, involved in the regulation of cell- cell adhesion. Methods: To identify the role of Trop-2 in transformed cells, we studied its expression pattern and function by DNA array and SAGE analysis, Northern and Western blotting, flow cytometry, confocal microscopy and IHC in experimental systems and in man. Overexpression or down-regulation of Trop-2 and directed mutagenesis were used to identify its role in tumor growth and metastasis in vivo. Results: DNA microarray, EST, SAGE, RT-PCR and Northern blot analysis of human tumors revealed expression of the TROP2 gene in most cancers. IHC analysis of human tumors (1755 cases) revealed a corresponding overexpression of Trop-2 protein. Trop-2 potently stimulated the growth of tumor cells, whereas TROP2 siRNA inhibited it. Deletion of the cytoplasmic region of Trop-2 abolished the growth stimulatory capacity, as did mutagenesis of the S303 PKC phosphorylation site. Proteomic analysis showed that multiple PKC isoforms partecipate to the Trop-2 signaling network. In vivo imaging showed dynamic colocalization of PKCs and Trop-2 in vivo in membrane ruffles and podosomes. DN PKCs and siRNA abolished Trop-2-induced growth. Strikingly, comparative global gene expression analysis revealed that TROP2 was the only gene up-regulated across different metastatic models, tumor types and animal species. IHC analysis revealed a dramatic up-regulation in metastases from colon, stomach, breast and ovary tumors in man. To assess if Trop-2 may play a causal role in metastatic spreading, TROP2-transfected KM12SM colon cancer cells were orthotopically injected in nude mice. TROP2-overexpressing transfectants demonstrated increased metastatic potential to the liver. Deletion of the HIKE domain of Trop-2 severely diminished, whereas that of the whole cytoplasmic region vastly increased metastatic diffusion, indicating the existence of both metastatic enhancers and silencers in the Trop-2 cytoplasmic tail. Conclusions: Our findings demonstrate that Trop-2 is a novel, widespread, stimulator of human cancer growth and a unique marker and causal factor of metastatic cancer, and candidate Trop-2 as a target of novel diagnostic and therapeutic procedures. No significant financial relationships to disclose.
AB0823 Age at Disease Onset Helps to Further Characterize the Disease Phenotype in Psoriatic Arthritis
Authors: R. Queiro, I. Morante, I. Cabezas, B. Acasuso, P. Tejόn, M. Alperi, J.L. Riestra, L. Arboleya, J. Ballina
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> The age of onset of psoriasis has been used for decades as an appropriate descriptor to define two subpopulations of psoriatic patients (types I and II). Clinical features of both types of psoriasis have been clearly delineated. However, the importance of this distinction in patients with psoriatic arthritis (PsA) has not been studied in depth. <h3>Objectives</h3> To evaluate the importance of age of onset of both psoriasis and arthritis in dissecting the clinical features of PsA. <h3>Methods</h3> This cross-sectional study included 205 patients with PsA (CASPAR criteria) seen at a single university institution. Socio-demographic, clinical, radiographic, and laboratory variables were included and population was then stratified according to age at onset of psoriasis, as well as joint manifestations, in two groups: early-onset and late -onset, according to a cut off value of 40 years old. Uni and multivariate analysis were performed. All patients gave informed consent. This study was approved by an institutional ethics committee. <h3>Results</h3> Early-onset psoriasis (EOP) showed extensive skin involvement (OR 2.3, p=0.011), higher prevalence of axial pattern as disease onset (OR 4.6, p=0.009) and mixed pattern during evolution (OR 2.4, p=0.019), increased frequencies of family history of both psoriasis (OR 3.1, p=0.003) and PsA (OR 4.0, p=0.021), higher prevalence of HLA-C*06 (OR 2.03, p=0.03) and HLA-B*27 (OR 2.7, p=0.02). Early onset arthritis (EOA) patients presented more family history of PsA (OR 2.9, p=0.007), as well as HLA-B*27 positivity (OR 5.9, p&lt;0.0001). Patients with late-onset arthritis (LOA) had more DM (OR 4.0, p=0.009), hypertension (OR 2.5, p=0.004), dyslipidemia (OR 2.3, p=0.011), and obesity (OR 1.7, p=0.012). Late-onset psoriasis (LOP) showed more obesity (OR 1.9, p=0.035), DM (OR 9.4, p&lt;0.0001), hypertension (OR 4.1, p&lt;0.0001), and ischemic heart disease during follow-up (OR 5.9, p=0.021). In multivariate analysis, LOP predicted DM development (OR 12.1; CI: 2-73.1, p=0.006). Likewise, LOA was shown to be an independent risk factor for hypertension (OR 5.2; CI: 1.09-25.02, p=0.039). <h3>Conclusions</h3> Age at disease onset is a key stratification factor to better characterize the clinical and cardiovascular risk profile of psoriatic disease. In psoriatic disease, diabetes risk seems to be related to age at skin disease onset whereas hypertension development appears linked to age at joint disease onset. Both conditions are more prevalent in late disease. <h3>References</h3> Queiro R, Tejόn P, Alonso S, Coto P. Age at disease onset: a key factor for understanding psoriatic disease. Rheumatology (Oxford) 2014; 53:1178-85. <h3>Disclosure of Interest</h3> None declared
Hypoglycemia Associated with Carcinoma of the Cecum and Syndrome of Testicular Feminization
Authors: Robert E. Tranquada, Albert B. Bender, Paul M. Beigelman
Journal: New England Journal of Medicine (1962)

SINCE Doege's first description of a nonpancreatic tumor associated with hypoglycemia1 at least 58 further reports have appeared. Lowbeer2 has recently summarized 49 cases, and 10 other cases have been added since.3 4 5 6 7 8 9 10 11 12 Thirty-four of the reported cases represent hypoglycemia associated with tumors of mesodermal origin. Nearly all these tumors were very large, weighing 0.7 to 9.0 kg., and were located retroperitoneally, in the mediastinum, attached to the diaphragm or in the pelvis. The remaining cases include 5 carcinomas of the adrenal cortex, some of which were associated with metabolic and endocrine changes related to the type of steroid hormone produced . . .
Effects of Rous Sarcoma Virus on Chicken-Embryo Limb Buds Grafted Onto the Chorioallantoic Membrane2
Authors: Virginia C. Dunkel, Vincent Groupé
Journal: JNCI Journal of the National Cancer Institute (1965)

Leg buds in the 3d day of embryonic development were susceptible to infection with Rous sarcoma virus (RSV). RSV had no detectable effect on growth and differentiation as determined by gross examination 5 and 7 days after transplantation onto the chorioallantoic membrane (CAM). However, by the 9th day, such infected limbs were grossly enlarged due to hemorrhage, and cartilaginous structures were difficult to identify. Histological examination revealed tumor and hemorrhagic foci in all RSV-infected limbs 5 days after transplantation. Nine days after transplantation 50 to 70 percent of the transplanted limbs were dead. These limbs contained rudimentary cartilaginous structures surrounded by an amorphous, red-staining material containing numerous pyknotic nuclei. Limbs viable 9 days after transplantation appeared as masses of hemorrhage and tumor cells with rudiments of cartilage. Necrotic changes due to RSV were not observed until death of the limb due to massive hemorrhage. Hemorrhage was never found in the absence of tumor cells.
PWE-045 Full blood count does not have additional utility in predicting liver fibrosis in virus-related chronic liver disease in a UK hospital: Abstract PWE-045
Authors: M Oppenheimer, M L Cowan, M Gess, S J Thomson, S Clark, D M Forton, T M Rahman, S Krishna
Journal: Gut (2010)

<h3>Introduction</h3> Staging of liver fibrosis by liver biopsy informs prognosis and aids treatment decisions but is associated with morbidity. A recent publication validated a new non-invasive fibrosis index, P2/MS in Korean patients with chronic viral hepatitis.1 This model is novel in relying upon haematological parameters rather than the levels of serum proteins to predict the risk of cirrhosis. We sought to validate the predictive value of P2/MS in identifying liver cirrhosis and fibrosis in a cohort of patients with chronic viral hepatitis in a UK hospital outpatient clinic. <h3>Methods</h3> We used the full blood count of subjects with compensated chronic viral liver disease undergoing liver biopsy prospectively recruited into a study of serum markers of liver fibrosis to calculate P2/MS. The ability of P2/MS to predict fibrosis and cirrhosis was compared to other validated models using the χ<sup>2</sup> test for equality of area under the ROC curve. <h3>Results</h3> Results were available for 181 patients, of whom 145 had HCV and 36 HBV. The median age was 46 years, 62% were male and 52% Caucasian. Significant fibrosis (Ishak stage &gt;2) was present in 81 (45%), of whom 35 had cirrhosis (19%). P2/MS was superior to AST/ALT ratio at predicting fibrosis and cirrhosis. It was inferior to hyaluronic acid in the diagnosis of cirrhosis and to APRI in detecting bridging fibrosis (Abstract 045). P2/MS diagnosed cirrhosis with a sensitivity of 57% (P2/MS&lt;45) and excluded bridging fibrosis with a specificity of 33% (P2/MS&gt;115). When the individual components of the P2/MS score were considered in isolation, liver fibrosis was not associated with monocyte or neutrophil fraction. The predictive ability of the P2/MS was due to the reduction in platelets in advanced liver disease. <h3>Conclusion</h3> P2/MS has a modest ability to detect bridging fibrosis and cirrhosis in a cohort of patients with chronic viral liver disease in a UK clinic. We have not validated the association between altered leucocyte populations and liver fibrosis. This may be secondary to ethnic differences, or to the lower incidence of cirrhosis in our population relative to the index study. The utility of P2/MS in different populations should be investigated in further studies.
Lectin ATL-104 in amelioration of intestinal damage caused by 5-fluorouracil in rats
Authors: G. Grant, M. Duncan, N. Fish
Journal: Journal of Clinical Oncology (2008)

20513 Background: Chemotherapy and radiotherapy can damage normal cells in the alimentary tract, leading to epithelial loss and ulceration (mucositis). In vivo, plant lectins stimulate gut epithelial growth. The potential of lectin ATL-104 to ameliorate gut damage caused by chemotherapy was investigated in a rat model. Methods: Rats (3–5/group) were given ATL-104 orally (200 mg/kg) or saline once daily for 1, 2 or 3d, then 5-fluorouracil (5FU, 150 mg/kg, once, ip) on day 4. At 1, 2, 3 and 4d post-5FU, animals were euthanased and small intestine samples collected for histological evaluation. Results were analysed using ANOVA and multiple comparison tests. Results: 5FU: In saline-treated controls, 5FU caused rapid loss of crypt epithelial cells and collapse of villi. Few dividing cells were detectable at 2d. The intestinal sub-epithelial myofibroblast sheath (ISEMF) was also disrupted. The dividing cell population re-established by 4d, but ISEMF did not. Regenerating crypts and villi remained disorganised. Villus heights (151± 8μm, [p≤0.001]) and intestinal mass (791± 49mg, [p≤0.001]) were well below those in non-treated controls (523±67μm; 1142±41mg). ATL-104/5FU: Pre-treatment for 3d with ATL-104 ameliorated the effects of 5FU. Crypt cell loss occurred as with saline/5FU, but was less marked. At 2d post-5FU, micro-crypts (clusters of dividing, goblet and Paneth cells enclosed in a myofibroblast sheath) were present throughout the gut. These were sites of organised re-growth. At 4d, villus height (372±27μm, [p≤0.01]), structure and intestinal mass (1064±42mg, [p≤0.03]) were returning to normal (523±67μm, 1142±41mg). ATL-104 given for only 1 or 2d also ameliorated the effects of 5FU on the gut, although less effectively than 3d of treatment. ATL-104 had to be given at 1d prior to 5FU. Little or no protection was evident if this dose was omitted. Conclusions: Pre-treatment of rats with ATL-104 limited intestinal damage caused by 5FU and aided restoration of gut structure. ATL-104 is thus a possible treatment for mucositis. Acknowledgement: MD supported by Alizyme TL, GG by Scottish Government Rural and Environmental Research and Analysis Directorate. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Alizyme Therapeutics Alizyme Therapeutics Ltd Alizyme Therapeutics Alizyme Therapeutics Ltd, Alzyme Therapeutics Ltd
66P Highly exhausted PD-1hi T cell subsets in human NSCLC are co-defined by the predominant expression of distinct inhibitory receptors and correlate with clinical outcome
Authors: D. Thommen, F. Uhlenbrock, P. Herzig, S. Savic Prince, W. Moersig, D. Lardinois, A. Zippelius
Journal: Journal of Thoracic Oncology (2016)
Aromatase inhibition and very low dose estradiol add-back: A pilot study for novel breast cancer prevention
Authors: A. Kendall, I. Smith, E. Folkerd, M. Dowsett
Journal: Journal of Clinical Oncology (2006)

1014 Background: Aromatase inhibitors (AIs) are important agents for the treatment of hormone receptor positive breast cancer in post menopausal women. They are being assessed as chemopreventives of breast cancer in large clinical trials, but there are known issues of tolerability notably affecting bone. It is possible that decreasing, but not abolishing, circulating estradiol levels may reduce breast cancer risk without such side effects. We have undertaken a novel pilot study to establish whether healthy volunteers on an AI could be delivered very low dose estradiol replacement to a predictable serum level of 10–20 pmol/L using a transdermal patch, and whether this would reverse changes in the bone resorption biomarker CTx. Methods: Ten healthy postmenopausal women with normal estradiol levels received letrozole 2.5mg/day for 16 weeks. From weeks 6–16 they were also given a quarter of Estraderm MX25 transdermal patch (6.25 μg of estradiol) replaced, twice weekly. Fasting blood samples were taken at baseline, 6, 10, 12, 14 and 16 weeks for estradiol, FSH, LH, SHBG and CTx. Results: Serum estradiol levels fell to &lt;3pmol/L at 6 weeks consistent with AI therapy. The quarter patch successfully replaced estradiol levels to a median of 12pmol/L although there was marked inter and intrasubject variability. FSH rose significantly with AI therapy with no appreciable change in SHBG or LH. There is encouraging evidence that CTx levels which increased with AI (p=0.076) can be corrected with low dose estradiol replacement although this did not reach statistical significance in this initial group. We continue to collect data on a further 8 subjects already recruited into the study. Conclusions: A quarter of Estraderm MX25 transdermal patch can be used to provide a serum estradiol level of 10–20 pmol/l in postmenopausal women given an AI. Further data will confirm whether this novel approach to chemoprevention can reverse the negative impact of AIs on bone metabolism and be suitable for extending to a full chemoprevention trial. [Table: see text] No significant financial relationships to disclose.
Prenatal Screening for Open Neural-Tube Defects in Maine
Authors: Glenn E. Palomaki, Josephine R. Williams, James E. Haddow
Journal: New England Journal of Medicine (1999)

To the Editor: In the United States, screening for open neural-tube defects is now part of routine prenatal care.1 The two most common defects (anencephaly and open spina bifida) are important caus...
Evaluation of the Quality of Life Associated with Zidovudine Treatment in Asymptomatic Human Immunodeficiency Virus Infection
Authors: William R. Lenderking, Richard D. Gelber, Deborah J. Cotton, Bernard F. Cole, Aron Goldhirsch, Paul A. Volberding, Marcia A. Testa
Journal: New England Journal of Medicine (1994)

Zidovudine therapy is recommended for asymptomatic patients infected with the human immunodeficiency virus (HIV) who have fewer than 500 CD4+ cells per cubic millimeter. An analysis of the quality of life associated with therapy that integrated both the effects of adverse events and the benefits of delayed disease progression might influence this recommendation.