tbuckley/cabot-search huggingface dataset:
Identification of an androgen withdrawal responsive phenotype in castrate resistant prostate cancer (CRPC) patients (pts) treated with abiraterone acetate (AA)
Authors: C. J. Logothetis, S. Wen, A. Molina, N. Chieffo, L. A. Smith, P. Troncoso, E. Efstathiou
Journal: Journal of Clinical Oncology (2008)

5017 Background: Responses to the CYP 17 inhibitor, AA, confirm the therapeutic significance of persistent androgen signaling in CRPC. Elucidating the source of residual androgens and validation of predictive markers will lead to individualized androgen deprivation therapy in CRPC. Methods: We performed an exploratory study to screen for associations between serum (endocrine) and microenvironment (paracrine) androgen concentration and response to AA. Study pts had bone metastases and a BM biopsy. Pts received oral AA 1,000mg QD and prednisone 10mg QD and had to have baseline <50ng/dl serum testosterone (S-T). Results: Seventeen CRPC pts were enrolled. Median PSA concentration: 192.3 (range, 5.6–1971). Median age: 73 (range, 52–84), median performance status (PS-ECOG) 2 (range 0–2).Prior therapy: secondary hormonal treatment 13 (76%) ,chemotherapy 14(82.3%). No correlation between baseline S-T levels (median 28 ng/dl range <10–41) and bone marrow testosterone (BM-T) levels (median 13.17ng/dl, range <10–81) was noted (p value 0.28 Spearman’s test). Eleven of 17 (58.8%) pts had a PSA decline and 7/17(41.1%) had a greater than 50% decline following 8 weeks of treatment. One pt has progressed. Improvement in PS occurred in 8/17 (47%). No ≥ grade 3 treatment related toxicity occured. Two of 17 pts experienced grade 1 hypokalemia and hypertension respectively. Decline below detectable levels (<10ng/ml) in S-T occurred in all study pts (17/17) and in BM-T in 9/9 evaluable pts. Higher baseline BM- T correlated with >50 % PSA decline (p value: 0.05 t test, p value: 0.06 Wilcoxon test,). Median Baseline BM-T of these pts was 24.45 (range <10–81ng/dl). Heterogeneous CYP17 expression was observed in all BM metastatic lesions. (20–100% tumor involvement). Conclusions: CYP17 blockade results in PSA decline in select pts with advanced CRPC without significant toxicity. The observed correlation between baseline BM -T level and PSA decline suggest that BM-T may serve as a predictive marker. CYP 17 expression in bone metastases suggests that CYP17 is an adaptive response to castration Significance: The ongoing study of androgen signaling in CRPC may lead to markers that will predict for PSA decline with CYP 17 inhibition. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cougar Biotechnology Cougar Biotechnology
Lung on Chip: In vitro HGF effects on injured alveolar A549 epithelial cells in microfluidic system
Authors: Marcel Felder, Pauline Sallin, Laurent Barbe, Amiq Gazdhar, Thomas Geiser, Olivier Thierry Guenat
Journal: European Respiratory Journal (2011)

Microfluidic systems have become competitive tools in the invitro modelling of diseases and promising alternatives to animal studies. They allow obtaining more invivo like conditions for cellular assays. Research in idiopathic pulmonary fibrosis could benefit from this novel methodological approach to understand the pathophysiology of the disease & develop efficient therapies. The use of hepatocyte growth factor (HGF) for alveolar reepithelisation is a promising approach. In this study, we show a new microfluidic system to analyse the effects of HGF on injured alveolar epithelial cells. Microfluidic systems in polydimethylsiloxane were fabricated by soft lithography. The alveolar A549 epithelial cells (10,000 cells) were seeded and studied in these microfluidic systems with media perfusion (1μl/30min). Injury tests were made on the cells by the perfusion with media containing H2O2 or bleomycin. The degree of injury was then assessed by a metabolic and an apoptotic assays. Wound assays were also performed with a central laminar flow of trypsin. Monitoring of wound closure with HGF vs control media was assessed. The alveolar A549 epithelial cells grew and proliferated in the microfluidic system. In the wound closure assay, the degree of wound closure after 5 hours was (53.3±1.3%) with HGF compared to (9.8±2.4%) without HGF (P <0.001). We present a novel microfluidic model that allows culture, injury and wounding of A549 epithelial cells and represents the first step towards the development of an invitro reconstitution of the alveolar-capillary interface. We were also able to confirm that HGF increased alveolar epithelial repair in this system.
Who benefits from taxanes?
Authors: M. J. Piccart-Gebhart, P. L. Bedard
Journal: Journal of Clinical Oncology (2009)

e11503 Over the last fifteen years, 21 clinical trials randomized nearly 36,000 women with early-stage breast cancer to taxane-based versus non-taxane-based adjuvant chemotherapy regimens to establish the role of taxanes in early breast cancer therapy. Preliminary results from the Oxford Overview –pooling individual patient data from some of these studies –suggest that the inclusion of a taxane to an anthracycline-based regimen reduces 10-year breast cancer related mortality by an absolute value of 5% over anthracycline therapy alone. In spite of this enormous global research effort, there remains considerable uncertainty regarding which patients benefit from taxane therapy. Three recent meta-analyses indicate that taxanes are beneficial irrespective of age, lymph node involvement, and hormonal receptor expression. Unfortunately, differences in trial design, pathological evaluation, and outcome reporting limit the robustness of these findings. Individual studies have suggested that patients with HER-2 positive disease derive greater benefit from taxane therapy, although the methods used to assess HER-2 status have been heterogeneous and there is no clear biological rationale to account for differential benefit in this subset. A number of promising predictive molecular markers related to taxane metabolism, microtubule dynamics, and intracellular signaling warrant further evaluation using biospecimens collected from the first-generation taxane trials. Future clinical trials should account for the molecular heterogeneity of breast cancer, by excluding the chemotherapy insensitive luminal A subset and mandating upfront central pathological assessment to further optimize the role of taxane therapy in early-stage disease. No significant financial relationships to disclose.
Positron emission tomography (PET) and estrogen receptor (ER) ligand in patients with invasive breast cancer.
Authors: M. Gemignani, S. Patil, E. Brogi, S. M. Larson, M. Morrow, N. Pandit-Taskar
Journal: Journal of Clinical Oncology (2010)

617 Background: The presence of ER in breast cancer is a prognostic indicator for both disease-free and overall survival. Data from others have found that F-18 labeled estradiol (FES) with PET allows for successful identification of ER in breast cancers and may provide a noninvasive test for evaluation of ER expression. The purpose of the study is to evaluate FES PET in predicting the hormone-receptor status of patients (pts) with operative breast cancer. Methods: A pilot study to evaluate the sensitivity and specificity of the FES-PET scan using surgical pathology as the gold standard in a Simon optimal two-stage design is ongoing. Currently 38 pts have been prospectively enrolled in an IRB approved protocol. All pts had FES PET preoperatively, and pathologic evaluation of the tumor for ER and PR expression. If FDG PET was also performed, it was compared to the FES PET. A positive FES PET was defined as one with standard uptake value (SUV) of the tumor of ≥ 1.5. Pathologic expression for ER was quantified with ≥ 5% considered positive. Results: 38 pts have been enrolled to date. Median tumor size was 1.2 cm (range 1.0- 6.7). Ten pts had positive nodes at time of surgery (3.6%). Two pts did not undergo surgery as bone metastases were identified on preoperative FES PET. The sensitivity and specificity of the FES PET for the breast lesion were 83.0% and 62.5%, respectively. Using the Wilcoxon two sample test, we did not find a statistical difference between size of tumor and FES PET uptake. Comparison of FDG PET and FES PET was available in 5 pts. The breast lesion was identified in 4 of the 5 FDG, with 3 of these also seen on FES; 2 had ER+ tumors. Conclusions: FES PET is a sensitive predictor of ER+ in primary tumors of the breast. It is highly predictive for metastatic disease and has helped in the identification of pts with metastatic disease in a preoperative surgical setting. Based on these results, we anticipate FES PET will be a promising agent for evaluating response in a pilot clinical trial in pts with recurrent/metastatic breast cancer scheduled to be treated with endocrine therapy. Pathology (n) FES + (n) FES - (n) ER+ (30) 25 5 ER- (8) 3 5 No significant financial relationships to disclose.
Axillary staging for breast cancer in the octogenarian population
Authors: K. E. Kilbride, T. M. Breslin, M. S. Sabel, V. M. Cimmino, L. A. Newman, A. E. Chang, K. M. Diehl
Journal: Journal of Clinical Oncology (2008)

20596 Background: Current data suggests that older patients are less likely to receive standard therapy for breast cancer than their younger counterparts, especially with use of axillary staging and adjuvant modalities. The purpose of this study is to review the experience of axillary staging in the octogenarian population at our institution. Methods: A prospectively-collected, IRB-approved database of patients treated by a multidisciplinary approach was queried for all patients age 80 or greater with a new diagnosis of invasive breast cancer. Clinicopathologic data was obtained and the patients were divided into 2 groups based on year of diagnosis. Results: During the period 1999–2007, 82 patients age 80 or greater were diagnosed with breast cancer, with median follow-up 27.2 months (1–86 months). Median age at diagnosis was 84 years (80–95 years); mean tumor size was 18.2 mm (2–60 mm). Seventy-eight (95.1%) patients had no evidence of distant metastasis at presentation. Axillary staging was performed in 48 cases over the course of the study. When grouped by year of diagnosis, those treated earlier were less likely to undergo axillary staging than those later in the cohort (42.2% vs 74.4%, p = 0.004). The use of sentinel lymph node biopsy increased in the later period (24.4% vs 64.1%, p = 0.0001). The likelihood of finding nodal disease also increased from 4.4% to 30.8% (p = 0.002). However, this did not translate into increased use of adjuvant therapies or risk of recurrence. Of the 9 patients with recurrences (11.9%), 2 recurred locally and 2 in the axilla. Median time to recurrence was 17 months (12–40 months). Hormone receptor negativity (p < 0.001), her-2/neu positivity (p < 0.001), and axillary nodal involvement (p = 0.026) were associated with increased risk of recurrence. Use of hormonal therapy decreased recurrence (p = 0.009). Overall, 3 patients died in the study, 2 with distant metastasis. Conclusions: Both the recognition of the special needs of geriatric cancer patients and the advent of sentinel lymph node biopsy have resulted in increased use of axillary staging and upstaging of patients with nodal disease. Further evaluation regarding the use of adjuvant therapy in this population is warranted; at this time, it is best served by a multidisciplinary approach considering risk of recurrence and patient factors. No significant financial relationships to disclose.
Isolation of Human Diploid Cell Variants With Enhanced Colony-Forming Efficiency in Semisolid Medium After a Single-Step Chemical Mutagenesis: Brief Communication 2
Authors: Victoria H. Freedman, Seung-il Shin
Journal: JNCI Journal of the National Cancer Institute (1977)

To examine the role of somatic mutation in malignant transformation, we studied the induction of anchorage-independent variants from normal human diploid fibroblasts by single-step mutagenesis in vitro. Primary cell strains from normal human embryo and newborn (foreskin) tissues were treated with N-methyi-N′-nitro-N-nitrosoguanidine and plated in methylcellulose. Growing colonies were obtained at a frequency of about 10-5 per mutagenized cell. In untreated controls, the frequency of colony-forming cells was less than 10-8. In many of the colonies isolated from methylcellulose, the enhanced ability to form colonies in the semisolid medium was maintained as a stable property. These “anchorage-transformed” clones were unchanged in morphology but formed multilayered foci in confluent monolayer culture. In chromosome composition, ability to plate in 1% serum, and susceptibility to cellular senescence, they were not distinguishable from the parental cells. When injected into nude mice, the variants did not produce tumors. These results indicated that human diploid cell variants specifically transformed with respect to anchorage regulation of growth can be induced by a single-step mutagenesis in vitro, and that other transformed phenotypes are not necessarily expressed in such variant.
Phase I and Pharmacokinetic Study of the Novel MDR1 and MRP1 Inhibitor Biricodar Administered Alone and in Combination With Doxorubicin
Authors: Ronald A. Peck, Jan Hewett, Matthew W. Harding, Yow-Ming Wang, Pravin R. Chaturvedi, Anish Bhatnagar, Harvey Ziessman, Frank Atkins, Michael J. Hawkins
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance–associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of 99m Tc-sestamibi, a P-gp and MRP1 substrate, was also evaluated. PATIENTS AND METHODS: Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m 2 /h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m 2 was administered. Cycles were repeated every 21 to 28 days. 99m Tc-sestamibi scans were performed before and during administration of VX-710 alone. RESULTS: Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m 2 /h or less. Among seven patients receiving VX-710 160 mg/m 2 /h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m 2 /h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of 99m Tc-sestamibi in all patients. CONCLUSION: A 96-hour infusion of VX-710 at 120 mg/m 2 /h plus doxorubicin 45 mg/m 2 has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.
NI-51 * STEREOTACTIC ROBOT-GUIDED BIOPSIES OF BRAIN LESIONS: EXPERIENCE WITH 4 CASES
Authors: A. Lary, A. Alzahrani, A. Alahmari, M. Alshardan
Journal: Neuro-Oncology (2014)

BACKGROUND AND PURPOSE: Biopsies of brain lesions are useful for histopathological analysis, which guide appropriate treatment. For the past few years, a frameless stereotactic robot, the NeuroMate robot (Renishaw, UK) has also been used for brain biopsies. We report a retrospective study of 4 patients who underwent NeuroMate robot-guided biopsies of brain lesions to evaluate the efficiency and safety of the system. METHODS: From January 2014 to March 2014, 4 adult patients underwent 4 biopsies of supratentorial brain lesions. The biopsy procedure comprised four stages: image acquisition, preoperative planning, patient-to-image registration, and operative procedure. A single burr hole was the entry point of each patient. RESULTS: All biopsies were positive for histopathological diagnosis from the first trial. All biopsies correlated precisely to preoperative biopsy planning. There was no operative mortality or morbidity. CONCLUSIONS: The frameless NeuroMate robot is an efficient and safe instrument for biopsies of brain lesions. We believe that the use of frameless stereotactic techniques for brain biopsies could increase the number of biopsies and therefore improve the diagnostic yield and accuracy of the technique.
Acanthocytosis associated with myelodysplasia.
Authors: D C Doll, A F List, D A Dayhoff, T S Loy, Q S Ringenberg, J W Yarbro
Journal: Journal of Clinical Oncology (1989)

Dysplastic hematopoiesis associated with erythrocyte macrocytosis is a morphologic hallmark of myelodysplasia. We report the cases of six patients with myelodysplasia in which acanthocytosis was the predominant red blood cell (RBC) abnormality. In each case acanthocytes represented 5% to 10% of circulating RBC forms and was the primary reason for referral in two cases. None of the patients had comorbid conditions known to be associated with acanthocyte formation. Myelodysplasia should be considered in the differential diagnosis of acanthocytosis, particularly in the anemic, elderly individual. Acanthocytosis may be a harbinger of an unrecognized, hematologic stem-cell disorder.
Weekly combination chemotherapy of docetaxel and carboplatin and 5-FU in recurrent cervix cancer
Authors: Y. M. Elkerm, A. Elsaid, M. Elnemr
Journal: Journal of Clinical Oncology (2007)

16038 Background: The current phase II study assessed docetaxel/carboplatin/5FU given weekly for 24 weeks, for recurrent uterine cervix cancer. Methods: Fourty patients with histologically confirmed, recurrent uterine cervix cancer were enrolled. The patients eligible for this study had histologically confirmed, recurrent uterine cervix cancer. . Patients received weekly docetaxel 20 mg/m2 and carboplatin area under the curve (AUC) 2 weekly with bolus 5FU 500 mg/m2. The response status of the patients was assessed using the common ECOG response criteria. Results: 40 patients were entered in this study. The distribution of intial stage at first presentation was IB, 6 ; IIB, 16; IIIB, 10; IVB, 8. There were 30 squamous cell carcinomas, 6 adenocarcinomas, 4 adenosquamous cell carcinoma. : All patients were evaluable, and completed all planned therapy. The most frequent maximum toxicities during chemotherapy were Grade 2 mucositis with neutopenia. Nonhematological toxicity was generally mild, except for ubiquitous complete alopecia. Responses after 6 months included 6 patients with complete responses, 22 patients with PR and 12 patients with SD. No progression of disease was observed. Conclusions: This regimen was feasible, safe, and particularly well tolerated. Early Phase II outcomes revealed promising activity in patients completing all treatment. No significant financial relationships to disclose.
Bevacizumab (BV) induced hypertension (HT): A manageable toxicity
Authors: A. U. Pande, J. C. Lombardo, M. Fakih, M. K. Wong, R. V. Iyer, B. W. Kuvshinoff, M. M. Javle
Journal: Journal of Clinical Oncology (2006)

13539 Background: BV inhibits angiogenesis by targeting vascular endothelial growth factor (VEGF). Anti-VEGF therapy blocks nitric oxide and causes relative vasoconstriction leading to HT in some patients (pts). Guidelines for anti-hypertensive (anti-HT) therapy in this setting are not well-established. Methods: Medical records of pts treated with BV from Oct. 2003 to Sep. 2005 were reviewed to document the incidence and treatment outcomes of BV induced HT. Grading of HT was as per CTC version 3.0. Institutional review board approval was obtained for this investigation. Results: One hundred fifty-four pts were treated with BV during study period. Fifty-five (35%) pts with colon (n=44), pancreatic (n=8), renal cell (n=2) and small cell lung cancer (n=1) had HT: 11 developed new-onset HT, 41 experienced exacerbation of pre-existing HT &amp; 3 with prior HT became normotensive. BV was given with FOLFOX (n=38), FOLFIRI (n=5), gemcitabine &amp; capecitabine (n=8) or interferon (n=4). Median dose of BV was 10 mg/kg (range=5–15 mg/kg). HT occurred after a median of 11 weeks after BV therapy (range=3–33 weeks). HT grading: grade 1 (n=1), grade 2 (n=29) &amp; grade 3 (n=22). HT was controlled (BP≤140/90) in 44 (80%) and BP was &gt;140/90 in 8 pts (BV was discontinued in 3). Complications of HT were chest tightness (n=1) and TIA (n=1). Anti-HT therapies are described in table 1 . Quinapril was commonly used (n=31): median dose of 20mg qd (range 5–40 mg). Renal function abnormalities occurred in 13 pts (creatinine 1.3–3.3), and proteinuria occurred in 7/27 pts. Conclusion: Exacerbation or new onset HT occurred in 35% of BV-treated pts after a median of 11 weeks. BV-induced HT is controllable in most cases with standard anti-HT therapy such as ACE-I. BV interruption and serious complications from HT are uncommon. [Table: see text] [Table: see text]
Abstract 181: Myozap Deficiency Promotes Adverse Remodeling And Cardiomyopathy In Response To Biomechanical Stress
Authors: Ashraf Y Rangrez, Derk Frank, Reza Poyanmehr, Alexander Bernt, Norbert Frey
Journal: Circulation Research (2014)

Background: Myozap is a new addition to the list of intercalated disc (ID) proteins, which we previously identified using a bioinformatics screen. In vitro characterization of Myozap revealed that it activates Rho-dependent SRF signaling. Moreover, cardiac restricted overexpression of Myozap in mice resulted in protein aggregate-associated cardiomyopathy, whereas, knockdown of its ortholog in Zebrafish led to severe contractile dysfunction and cardiomyopathy. The objective of the current study was to elucidate the cardiac consequences of targeted deletion of Myozap in mice. Methods and Results: We generated a Myozap null mutant (MZP-ko) by global deletion of Myozap in mice. Unchallenged MZP-ko mice did not exhibit a baseline cardiac phenotype. However, upon biomechanical stress due to TAC (transverse aortic constriction), deficiency for Myozap led to accelerated cardiac hypertrophy (significant increases in the heart to body weight, left ventricular to body weight ratios) and fibrosis, accompanied by “super”-induction of the hypertrophic gene program (ANF/BNP). Moreover, MZP-ko mice revealed a severe reduction of fractional shortening and signs heart failure (increased lung/body weights) as well as a markedly increased mortality in response to TAC). Additional molecular data exhibited a significant decrease in the levels of native and phosphorylated Connexin 43 after transverse aortic constriction (TAC) in MZP-ko mice compared to wildtype animals. Finally, we observed a downregulation of dysbindin, a novel interaction partner of Myozap and known inducer of ERK1/2 signaling in TAC operated MZP-ko mice. Consistently, activation of ERK1/2 in response to TAC was blunted compared to wild-type littermates. Conclusions: We here show that myozap deficiency in vivo leads to a maladaptative response to increased biomechanical stress associated with cardiomyopathy, heart failure and cardiac death. Mechanistically, this phenotype can at least in part be explained by the interruption of the interaction between myozap and dysbindin with subsequent loss of ERK1/2 activation. Taken into a larger perspective, our data imply an essential role of the ID and its associated proteins in cardiac remodeling.