tbuckley/cabot-search huggingface dataset:
Baseline predictors of response to treatment with darbepoetin-alpha (DA) in anemic patients with low-risk myelodysplastic syndrome (MDS)
Authors: J. Gabrilove, R. Paquette, R. Lyons, C. Mushtaq, M. Sekeres, D. Tomita, T. Lillie
Journal: Journal of Clinical Oncology (2007)

7081 Background: Patients (pts) with MDS often develop anemia, resulting in fatigue and an increased requirement for transfusions. The erythropoiesis-stimulating agent (ESA) DA can raise hemoglobin (Hb) levels in low-risk MDS pts. Previous analyses suggest that baseline (BL) endogenous erythropoietin (eEPO) levels and French-American-British (FAB) disease category are predictors of response to ESAs. Methods: This was a phase 2, open-label, 52-week (wk) study of DA administered 500 mcg every 3 wks (Q3W) to anemic (Hb=11g/dL), low- or intermediate-risk MDS pts. Pts received 500 mcg DA Q2W if they did not respond by wk 7. The last DA dose was at wk 52; end of study was wk 53 or 55 for pts receiving DA Q2W or Q3W, respectively. The primary endpoint was % pts with an erythroid response (International Working Group criteria) by wk 13. Other endpoints included change from BL in Hb and FACT-F score. Exploratory analyses examined the incidence of erythroid responses adjusted by FAB category (refractory anemia [RA], RA with ringed sideroblasts [RARS], or RA with excess blasts [RAEB]). Results: Final 53/55 wk data will be presented. Results were stratified by whether pts received an ESA before enrollment (ESA-naive [ESA-N] vs ESA-treated [ESA-T]). ESA-T pts are a heterogeneous group and their data are difficult to interpret; thus, predictors of response will be presented for ESA-N pts only. Of 144 ESA-N pts, 56% had RA, 37% had RARS, and 7% had RAEB. Most ESA-N pts achieved the target Hb and had a major erythroid response ( Table ). Pts with RA were more likely to achieve a major erythroid response than pts with RARS or RAEB. For ESA-T pts, demographics and type/length of ESA treatment will be presented. Of all pts, serious adverse events (SAEs) were reported in 62 (30%) pts and treatment-related SAEs in 2 (1%) pts. Conclusions: FAB category may affect response to DA in MDS pts. Additional data will be presented on the effect of BL eEPO, transfusion needs, and previous ESA treatment on response and duration of response. [Table: see text]
Phase I trial of metronomic cyclophosphamide (CTX) and lenalidomide (LEN) in patients with castration-resistant prostate cancer (CRPC).
Authors: Jue Wang, Timothy R. McGuire, James K. Schwarz, Jane L Meza, James E E Talmadge
Journal: Journal of Clinical Oncology (2012)

164 Background: Angiogenesis and suboptimal antitumor immune response are important in the progression of CRPC. Both LEN and metronomic CTX have known anti-angiogenic and immunomodulatory activities. A phase I study of a novel combination of metronomic CTX with LEN in patients with CRPC who have failed prior docetaxel therapy was initiated to assess safety and effects on potential biomarkers. Methods: CTX was given 50 mg PO QD(day 1-28) and LEN 10-25 mg PO QD(day 1-21) on a 28 day cycle. Dose limiting toxicity was defined as any treatment-related grade 4 hematologic event or grade 3 / 4 non-hematologic event during cycles one. Quantification of circulating tumor cells (CTC), plasma cytokines, analgesic consumption and quality of life assessments were performed. Measurement of Treg and MDSCs were performed in some patients. Results: 17 patients with CRPC have been enrolled in L0-4; all patients are evaluable for toxicity. Patient characteristics include: ECOG performance status 0/1= 4/13; median age=77 (range 50–86); median PSA=36.7 (range 1.36–2287). Dose level 1 (CTX 50 mg/d, LEN 10 mg/d) was expanded to 6 patients after one out of three initial patients was removed from the study for Gr 3 gastrointestinal bleeding (in cycle 1). Dose level 1 (CTX 25 mg/d, LEN 10 mg/d) had no DLT’s. The maximum tolerated dose has not yet been reached. Other Grade 3/4 toxicities observed after cycle 1 included grade 3 pain (N=1), grade 3 neutropenia (N=4), grade 3 thrombocytopenia (N=2), grade 4 neutropenia (N=2). Most frequent grade 1 and 2 toxicities included anemia, fatigue, neutropenia, and hypocalcemia. Overall, 9 of 14 patients (64%) have experienced a reduction in PSA. One patient had partial response after one cycle. Stable disease was documented in 5 of 14 (36%) evaluable patients. Two inflammatory cytokines, IL-6 (N = 19; r = 0.64; p = 0.0035) and IL-8 (N = 9; r = 0.86; p = 0.0028), were found to significantly correlated with PSA. Conclusions: The combination of metronomic CTX and LEN can be safely administered. Preliminary clinical activity was observed in this heavily-pretreated patient population. Enrollment to this study continues and clinical and biomarker studies are ongoing.
IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia
Authors: Yuliya Pylayeva-Gupta, Shipra Das, Jesse S. Handler, Cristina H. Hajdu, Maryaline Coffre, Sergei B. Koralov, Dafna Bar-Sagi
Journal: Cancer Discovery (2015)

A salient feature of pancreatic ductal adenocarcinoma (PDAC) is an abundant fibroinflammatory response characterized by the recruitment of immune and mesenchymal cells and the consequent establishment of a protumorigenic microenvironment. Here, we report the prominent presence of B cells in human pancreatic intraepithelial neoplasia and PDAC lesions as well as in oncogenic Kras-driven pancreatic neoplasms in the mouse. The growth of orthotopic pancreatic neoplasms harboring oncogenic Kras was significantly compromised in B-cell-deficient mice (μMT), and this growth deficiency could be rescued by the reconstitution of a CD1d(hi)CD5(+) B-cell subset. The protumorigenic effect of B cells was mediated by their expression of IL35 through a mechanism involving IL35-mediated stimulation of tumor cell proliferation. Our results identify a previously unrecognized role for IL35-producing CD1d(hi)CD5(+) B cells in the pathogenesis of pancreatic cancer and underscore the potential significance of a B-cell/IL35 axis as a therapeutic target.This study identifies a B-cell subpopulation that accumulates in the pancreatic parenchyma during early neoplasia and is required to support tumor cell growth. Our findings provide a rationale for exploring B-cell-based targeting approaches for the treatment of pancreatic cancer.
Retinal Cavernous Hemangioma
Authors: Edward Bloch, Jamil Hakim
Journal: Ophthalmology (2015)

An asymptomatic 14-year-old boy was incidentally found to have a “bunch-of-grapes”−like retinal lesion, consistent with a retinal cavernous hemangioma. Although typically sporadic and unilateral, these lesions can be familial and associated with cutaneous, hepatic, or intracranial hemangiomas. Vitreous hemorrhage may result from epiretinal membrane contraction and vitreous traction. Fundus photograph showing the retinal cavernous haemangioma (Fig A). Near-infrared spectroscopy (Fig B) and spectral-domain optical coherence tomography (Fig C) demonstrating the epiretinal membrane and vitreous traction.
Corrigendum to ‘Elaboration of a consensual definition of de-escalation allowing a ranking of β-lactams’ [Clin Microbiol Infec 21 (2015) 649.e1–649.e10]
Authors: E. Weiss, J.-R. Zahar, P. Lesprit, E. Ruppe, M. Leone, J. Chastre, J.-C. Lucet, C. Paugam-Burtz, C. Brun-Buisson, J.-F. Timsit, C. Brun-Buisson, F. Bruneel, J. Chastre, S. Lasocki, M. Leone, P. Montravers, S. Nseir, C. Paugam-Burtz, S. Pease, J.-F. Timsit, E. Weiss, M. Wolff, S. Alfandari, B. Fantin, B. Gachot, P. Lesprit, J.-C. Lucet, G. Potel, C. Pulcini, C. Rabaud, P. Tattevin, L. Armand-Lefevre, J.-D. Cavallo, V. Jarlier, O. Joint-Lambert, J. Robert, E. Ruppé, P.L. Woerther
Journal: Clinical Microbiology and Infection (2015)
Phase 1 pharmacokinetic and pharmacodynamic trial of docetaxel and 17AAG (17-allylamino-17-demethoxygeldanamycin)
Authors: D. B. Solit, M. Egorin, G. Valentin, A. Delacruz, Q. Ye, L. Schwartz, S. Larson, N. Rosen, H. I. Scher
Journal: Journal of Clinical Oncology (2004)

3032 Background: 17AAG is an ansamycin antibiotic that binds to the Hsp90 chaperone protein and inhibits its function. Hsp90 is required for the refolding of proteins during cellular stress and the conformational maturation of a subset of signaling proteins. Treatment of cancer cells with 17AAG causes the proteasomal degradation of Hsp90 client proteins, which include HER2, steroid receptors, Raf, cdk4, and Akt. The combination of 17AAG and taxanes is synergistic in cell culture and animal model systems. Methods: We initiated a phase 1 study of docetaxel and 17AAG to define the maximally tolerated dose, toxicity profile, and pharmacodynamics of these agents when administered in combination to patients (pts) with advanced solid tumors. Pts were treated with docetaxel (55 and 70 mg/m2) and 17AAG (80 to 300 mg/m2) in 6 cohorts. Docetaxel and 17AAG were administered sequentially (each over 1 hour) without delay on day 1 of each 21 day cycle. Results: To date, we have enrolled 16 pts (median age 61, range: 32–78) with cancers of the prostate (5), H&N (4), renal (2), melanoma (1) and others (4 pts). Pts have received a median of 3 cycles (range: 2–6). No dose limiting toxicities have been observed to date. Three pts had Grade 4 neutropenia of less than 7 days duration. No objective responses have been seen. Three pts had stable disease of at least 3 cycles duration and one pt with prostate cancer had a decline in PSA. Plasma serum levels of docetaxel and 17AAG were not altered by co-administration at the dose levels studied. Peripheral blood lymphocytes (PBL) were collected to study changes in Hsp90-dependent client proteins following therapy as a function of dose. Post-treatment increases in Hsp70 in PBL have been observed in all pts treated with 17-AAG at or above 110 mg/m2. Declines in Raf and Akt in PBL have been seen in some but not all pts treated at doses of 17-AAG above 160 mg/m2. Conclusions: The combination of docetaxel and 17AAG is well tolerated at the dose levels studied to date. Accrual continues at the 17AAG 300 mg/m2 dose level and at the time of the meeting updated accrual, response and correlative data will be reported. Supported by NIH P50-CA92629 and CaPCURE. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Conforma Aventis
Evelina's legacy
Authors: Ruth Richardson
Journal: The Lancet (2015)

The Evelina London Children's Hospital stands beside St Thomas's Hospital close to the River Thames, and serves sick children from the whole of south London. The current building was opened in 2005. It succeeds the original hospital on Southwark Bridge Road, founded in 1869 in a district notorious for its poverty, by one of the richest men in the UK. Baron Ferdinand de Rothschild (1839–98) established the hospital after the death of his wife Evelina (1839–66) and their only child, in childbirth.
A new serologic staging system for large-cell lymphomas based on initial beta 2-microglobulin and lactate dehydrogenase levels.
Authors: F Swan, W S Velasquez, S Tucker, J R Redman, M A Rodriguez, P McLaughlin, F B Hagemeister, F Cabanillas
Journal: Journal of Clinical Oncology (1989)

We report results of our investigation of prognostic factors for patients with large-cell lymphoma who were entered on the same treatment protocol and who had known pretreatment serum beta 2-microglobulin (beta 2M) and lactate dehydrogenase (LDH) levels. beta 2M and LDH levels were the most significant and independent variables for predicting time to treatment failure (TTF) and survival. The serum level of beta 2M correlated with tumor burden. These two serum markers defined three significantly different prognostic groups. All 27 patients in the low-risk group remain alive and in remission; in contrast, 22 of the 27 patients (81%) in the high-risk group have failed treatment, and only seven (26%) remain alive. In comparison with the Ann Arbor staging system, serum levels of beta 2M and LDH may provide a more precise system for defining risk groups and thereby allow a more rational approach to the development and analysis of treatment strategies.
Characterization of tumor infiltrated cells in mouse model
Authors: Yae-Huei Liou, Nan-Shih Liao, Shih-Wen Huang
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Solid tumors show a trend to develop immunosuppressive microenvironment and a dynamic cell composition along tumor progression. Various types of non-immune and immune cells constitute solid tumor. Understanding the change of cellular constituents and their function is pertinent to
Nifedipine for tocolysis
Authors: William Stones
Journal: The Lancet Global Health (2015)

The release of the new WHO recommendations (October, 2015)1Vogel JP Oladapo OT Manu A Gülmezoglu AM Bahl R New WHO recommendations to improve the outcomes of preterm birth.Lancet Glob Health. 2015; 3: e589-e590Summary Full Text Full Text PDF Scopus (50) Google Scholar for preterm birth interventions is welcome. With regard to the place of tocolysis, the guidelines present a balanced view of the current uncertainties and indicate a preference for nifedipine as the drug of choice when tocolysis is considered, while emphasising the need for further research. However, an important issue in the availability and prescription of nifedipine is not covered in the WHO recommendations:2WHOWHO recommendations on interventions to improve preterm birth outcomes. World Health Organization, Geneva/New York2015http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/preterm-birth-guidelineGoogle Scholar that of the appropriate formulation for use in this indication. Although the evidence on nifedipine for tocolysis relates to immediate-release formulations, in low-resource countries only sustained-release formulations, indicated for hypertension, are typically available. Thus clinicians may all too easily find themselves using the wrong formulation for tocolysis. There is no evidence to suggest that sustained-release nifedipine might have efficacy for tocolysis and there is notable potential for harm: normotensive patients who are exposed to 30 mg of a sustained-release formulation could become hypotensive over several hours. The immediate release formulation is appropriately specified in the WHO Model List of Essential Medicines3WHO19th WHO model list of essential medicines (April 2015). World Health Organization, Adelaide2015http://www.who.int/medicines/publications/essentialmedicines/en/Google Scholar but making this available in clinical settings globally may be problematic. It does not have other therapeutic uses and might be approaching the status of an orphan drug. Should research confirm the usefulness of nifedipine as part of the package of interventions to improve the outcomes of preterm birth in low-resource settings, close attention will be required to drug procurement, supply-chain logistics, and methods to make the formulations clearly distinguishable at the point of care. I declare no competing interests.
CELLS INVOLVED IN THE IMMUNE RESPONSE
Authors: M. Richter, N. I. Abdou
Journal: The Journal of Experimental Medicine (1969)

Bone marrow cells obtained from rabbits of one allotype were injected into irradiated rabbits of a different allotype. The recipients were also injected with sheep red blood cells, and their spleen cells were tested for plaque-forming capacity 7 days later. Spleen cells of all recipients gave large numbers of plaques as did spleen cells incubated with antiserum, directed toward donor allotype. However, incubation of the recipient spleen cells with antiserum directed toward recipient allotype completely suppressed plaque formation. These results demonstrate that antibody-formation in irradiated recipients of transferred lymphoid cells is a property of the recipient animal and that the antibody-forming cell is relatively irradiation-resistant. It was also demonstrated that only viable normal bone marrow cells are capable of transferring antibody-forming capacity to irradiated recipient rabbits. Neither sonicates nor heat-killed preparations of normal rabbit bone marrow cells possessed this capacity.
Abstract 3553: xCT is a new cancer stem cell immunotherapeutic target for breast cancer
Authors: Marco Macagno, Stefania Lanzardo, Laura Conti, Roberto Ruiu, Raffaele A. Calogero, Federica Cavallo
Journal: Cancer Research (2015)

Abstract The several unsuccessful treatments in metastatic cancers might miss cancer stem cells (CSC), a sub-population of cells with a critical role in cancer. By contrast, a vaccine-elicited immune response against CSC might be particularly effective. The identification of oncoantigens (OA) expressed by CSC may provide new targets for effective anticancer vaccines. To this purpose, the transcription profile of the ErbB2+ TUBO mammary cancer cell line was compared with that of TUBO cells grown under specific conditions to generate CSC-enriched mammospheres. Integrating the data obtained with meta-analyses of seven independent human breast tumor data sets we identified new CSC mammary OA that were validated both in vitro and in vivo. Among the identified OA, we focused on xCT, a channel that supports glutathione synthesis regulating the intracellular redox balance. We observed that xCT expression increases in TUBO and 4T1 derived mammospheres; its silencing, obtained with specific siRNA, or incubating mammospheres with its inhibitor sulfasalazine (2), significantly reduces TUBO cells ability to generate mammospheres. In vivo xCT inhibition impaired CSC ability to generate lung metastases derived both from an intravenous injection of TUBO-derived mammospheres and from subcutaneous 4T1 tumors; furthermore, this effect was improved when combined with the cytotoxic drug doxorubicin. Moreover, the anti xCT vaccination of mice bearing mammosphere-derived tumors both from TUBO and 4T1 cells reduced the speed of tumor growth. In conclusion, this study provides a genomic characterization of mammary CSC and identifies fresh target for new and potentially effective anticancer vaccines, thus providing a new tool for the design of combined therapeutic approaches that efficaciously target both CSC and more differentiated cells in breast cancers, leading to both cancer treatment and prevention of metastases and recurrence. BIBLIOGRAPHY 1. Nagano O et al., Oncogene 2013. 2. Chen RS et al., Oncogene 2009. Citation Format: Marco Macagno, Stefania Lanzardo, Laura Conti, Roberto Ruiu, Raffaele A. Calogero, Federica Cavallo. xCT is a new cancer stem cell immunotherapeutic target for breast cancer. [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 3553. doi:10.1158/1538-7445.AM2015-3553
Polymorphisms of the Repeated Sequences in the Enhancer Region of the Thymidylate Synthase Gene Promoter May Predict Downstaging After Preoperative Chemoradiation in Rectal Cancer
Authors: Elena Villafranca, Yury Okruzhnov, Miguel A. Dominguez, Jesús García-Foncillas, Ignacio Azinovic, Enrique Martínez, Jose J. Illarramendi, Fernando Arias, Rafael Martínez-Monge, Esteban Salgado, Silvia Angeletti, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2001)

Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)-based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival.Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU-based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival.Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P =.036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P =.17).This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU-based chemoradiation.
Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALL-protocols: results of the German Cooperative Study
Authors: R Dopfer, G Henze, C Bender-Gotze, W Ebell, G Ehninger, W Friedrich, H Gadner, T Klingebiel, C Peters, H Riehm
Journal: Blood (1991)
Phase III trial of infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment in advanced colorectal carcinoma (ACRC): Results of an interim safety analysis
Authors: H.-T. Arkenau, H. Schmoll, S. Kubicka, T. Seufferlein, P. Reichardt, W. Freier, U. Graeven, A. Grothey, R. Porschen
Journal: Journal of Clinical Oncology (2004)

3546 Background: In a previous phase III study, the FUFOX regimen has shown superior response rates and progression-free survival compared with bolus 5-FU/FA (Mayo Clinic protocol) in patients with ACRC (Grothey, ASCO 2002). The combination of capecitabine (CAP) and oxaliplatin (OX) has demonstrated good efficacy and safety results in recent phase II studies. In August 2002 we initiated a phase III trial to compare FUFOX and CAPOX as first line therapy in patients with ACRC. Here, we present the results of a planned interim safety analysis. Patients and methods: From August 2002 to October 2003 275 (of target 420) patients (m:f = 176:99; median age 66 (range 32–85)) have been randomized to receive either FUFOX (135 pts. arm A: 5-fluorouracil 2000mg/m2 24h infusion, folinic acid 500mg/m2, oxaliplatin 50mg/m2 d1,8,15,22; q5 wks) or CAPOX (140 pts. arm B: capecitabine 1000mg/m2 bid d1–14, oxaliplatin 70mg/m2 d1 and 8; q3 wks). All patients had measurable metastatic disease, ECOG performance status 0–2, normal renal and hepatic function. Results: To date 783 treatment cycles (320 FUFOX, 463 CAPOX) are evaluable (median number of cycles per patient: arm A: 4, range 1–8; arm B: 4, range 1–12. Seven deaths occured within the first 60 days (3 (2.2%) in arm A : 1x bowel obstruction, 1x severe diarrhea, 1x unknown cause) and 4 (2.8%) in arm B : 1x stroke, 1x bowel obstruction, 1x severe diarrhea and sepsis, 1x unknown cause). Major toxicities grade 2–4 (NCI-CTC) are listed in the table below. Conclusions: These data show that both FUFOX and CAPOX have a comparable toxicity profile as first line therapy in ACRC and are both well tolerated. Updated toxicity results will be reported at the meeting. At that time, the planned enrollment of 420 patients will have been completed. No significant financial relationships to disclose.