tbuckley/cabot-search huggingface dataset:
Safety, efficacy, and pharmacodynamics of the investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer (mCRPC): Updated data from a phase I/II study.
Authors: David B. Agus, Walter Michael Stadler, Daniel H. Shevrin, Lowell Hart, Gary R. MacVicar, Omid Hamid, John D. Hainsworth, Mitchell E. Gross, Jingyuan Wang, Iain James Webb, David MacLean, Robert Dreicer
Journal: Journal of Clinical Oncology (2012)

98 Background: The investigational agent orteronel (TAK-700) is a selective 17,20 lyase inhibitor that down regulates androgenic steroid production in vitro and in vivo. Since phase 1 data in patients (pts) with mCRPC were promising, this open-label, multicenter study was expanded to gather additional data on safety and antitumor activity. Methods: The phase 2 portion of this study included four additional dose cohorts. Pts had no prior chemotherapy, and had baseline testosterone &lt;50 ng/dL and prostate-specific antigen (PSA) ≥5 ng/mL. Results: 97 pts received orteronel 300 mg BID (n=23), 400 mg BID + prednisone 5 mg BID (n=24), 600 mg BID + prednisone (n=26), or 600 mg QD (n=24). At data cut-off (23 May 2011), 62% of pts had withdrawn (including 19% due to AEs and 19% for disease progression [PD]). Most common AEs were fatigue (76%), nausea (47%), and constipation (38%); most common grade ≥3 AEs were fatigue (12%) and hypokalaemia (8%). PSA response rates (≥50% decrease) at 12 wks were 63%, 50%, 41%, and 60% in the 300 mg BID, 400 and 600 mg BID + prednisone, and 600 mg QD groups. Of 51 RECIST-evaluable pts, 10 had partial responses (of which 5 confirmed), 22 stable disease, and 15 PD. At 12 wks, median testosterone decreased from baseline in all groups: (ng/dL, 12 wks/baseline) 0.98/8.50 (300 mg BID), 0.30/9.90 (400 mg BID +prednisone), 0.07/7.33 (600 mg BID + prednisone), 0.49/6.31 (600 mg QD). Similarly, at 12 wks, median dehydroepiandrosterone sulfate (DHEA-S) decreased from baseline in all groups: (µg/dL, 12 wks/baseline) 8.65/53.0 (300 mg BID), 0.10/36.3 (400 mg BID + prednisone), 0.10/51.7 (600 mg BID + prednisone), 5.30/31.5 (600 mg QD). Overall, mean circulating tumor cell numbers decreased from 16.6 (per 7.5mL blood) at baseline to 3.9 at 12 wks. Conclusions: Orteronel ≥300 mg BID appears active and well tolerated in pts with mCRPC, with similar efficacy ± prednisone. PSA response rates suggest that testosterone, rather than DHEA, may be a more reliable marker of lyase inhibition efficacy. Preclinical data and changes in pharmacodynamic parameters in this study suggest partially selective 17,20 lyase inhibition. Final data will be reported.
Phase II study of sorafenib plus tegafur/uracil (UFT) in patients with advanced hepatocellular carcinoma (HCC)
Authors: Y. Shen, Y. Shao, C. Hsu, C. Hsu, Z. Lin, P. Chen, Y. Ding, A. Cheng
Journal: Journal of Clinical Oncology (2008)

15664 Background: Sorafenib, a multikinase inhibitor with anti-angiogenic and pro-apoptotic activities, has recently been approved for the treatment of advanced HCC. Combination of sorafenib with metronomic chemotherapy has theoretic advantage in improving anti-tumor activity without increasing treatment-related toxicities. UFT (tegafur: uracil = 4:1 in molar ratio) is an oral fluoropyrimidine which is active against various gastrointestinal cancers. We conducted this study to evaluate the efficacy and safety of sorafenib plus low-dose UFT in advanced HCC patients (pts). Methods: Pts with histologically or cytologically proven unresectable/metastatic HCC, ECOG PS 0–2, Child-Puch class A, platelets ≥ 100 K/μl, transaminases ≤ 5 × ULN, bilirubin ≤ 3 mg/dl, INR ≤ 2.3 and creatinine ≤ 1.5 × ULN were enrolled. Prior local treatment for HCC was allowed. Sorafenib (400 mg bid) and UFT (125 mg/m2 based on tegafur bid) were taken per os continuously. Tumor assessment was performed q8w by RECIST criteria. Primary endpoint is progression-free survival (PFS). Results: Between Apr. and Nov. of 2007, 40 pts were enrolled. 24 pts were evaluable at this interim analysis. The baseline pt characteristics were: male/female 22/2; median age 57 (range, 31–83); TNM stage IIIA/IIIC/IV 11/2/11; CLIP score all ≤3; extrahepatic metastasis 50%; major hepatic vessel/main portal vein involvement 50%/21%; prior local treatment 67%; HBsAg(+)/anti-HCV(+)/both(+) 18/6/1. Pts received a median of 15.5 (range 4–32+) weeks of treatment. Grade 3 hematologic toxicities occurred in 1 pt. Most common grade 3 non-hematologic toxicities included hand-foot skin reactions, malaise and diarrhea in 3, 4 and 2 pts, respectively. No grade 4 toxicities or any ≥ grade 3 hypertension, bleeding or thromboembolic events were noted. There were 3 (12.5%) PR and 11 (45.8%) SD, with a median PFS of 3.7 months (95% C.I., 1.7–5.7). Conclusions: The result of this interim analysis suggests that combination of sorafenib and UFT is potentially an effective regimen for pts with advanced HCC. The toxicities observed were manageable. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Bayer
Corrected area under serum PSA curve as a predictor of survival after chemotherapy for hormone-refractory prostate cancer (HRPC) patients
Authors: S. Oudard, E. Banu, N. Thiounn, M. Zerbib, T. Flam, B. Debré, A. Banu, F. Scotté, J.-M. M. Andrieu
Journal: Journal of Clinical Oncology (2004)

9579 Background: The rate of serum prostate-specific antigen (PSA) decline during chemotherapy can be used to predict overall survival probability among HRPC patients (pts). Using a pharmacokinetic principle, we were able to define a new potential predictive factor: Corrected Area Under Serum PSA Curve. Methods: We conducted a retrospective analysis to validate the PSA c-AUC concept, defined as total Area Under serum PSA Curve (PSA AUC) value per unit of time, on all known PSA values. The trapezoidal and Simpson's rules were used to calculate the PSA AUC. Patients had regular PSA evaluations from primary diagnosis until death or last evaluation. Based on their PSA c-AUC values, patients were analysed according to the overall survival as primary endpoint. Results: Two hundred twenty HRPC patients treated with docetaxel or mitoxantrone based chemotherapy were included in this analysis. Patients characteristics: median age 69 years (range 51–91 years), median PSA follow-up duration of 19.9 months (range 1–169 months). Median PSA c-AUC was 63 ng/mL (range 0.2–2985 ng/mL). The median survival for the entire group was 18.4 months (95% C.I 15.7–21.1 months); 120 pts (57%) have died. There was an significant difference in overall survival in favour of the low PSA c-AUC level (< 60 ng/mL) group compared with the high PSA c-AUC level (≥ 60 ng/mL) group. The median survival were 21.6 months (95% C.I 18.2–25.1 months) vs. 13.7 months (95% C.I. 10.7–16.8 months), (p=0.0005), respectively. In a univariate analysis significant interactions with survival was identified after adjustment according to treatment arm, for Gleason score (p=0.04), PSA c-AUC (p=0.01) and hormono-sensitivity duration (p=0.04). Only PSA c-AUC variable remained significant in the multivariate analysis. Conclusions: The PSA c-AUC value is a potent predictive factor for overall survival independent of treatment regimen. This parameter may play a significant role in the treatment management of HRPC patients and could be used in prospective clinical trials. No significant financial relationships to disclose.
The relationship between Bordetella pertussis genotype and clinical severity in Australian children with pertussis
Authors: Michelle Clarke, Peter B. McIntyre, Christopher C. Blyth, Nick Wood, Sophie Octavia, Vitali Sintchenko, Lynne Giles, Helen Quinn, Verity Hill, Gabrielle Hanly, Ruiting Lan, Helen S. Marshall
Journal: Journal of Infection (2015)
Vanderbilt Head and Neck Symptom Survey Version 2.0 (VHNSS 2.0): A tool for the study of long-term oral health consequences of therapy for head and neck cancer (HNC).
Authors: E. Cooperstein, J. B. Epstein, B. A. Murphy, M. S. Dietrich, J. Gilbert
Journal: Journal of Clinical Oncology (2010)

9055 Background: HNC therapy causes adverse late oral health outcomes (LOHO), the prevalence, severity, and functional implications of which are largely unknown. VHNSS 1.0 was developed to measure treatment-related symptom burden, but common LOHO were not included. We report the development of a LOHO subscale. Methods: Questions were developed by an expert panel and review of oral health measures for the general population. Final tool included 50 items which scored symptoms or functional manifestations from 0 (none) to 10 (severe). It was administered to 70 subjects who completed radiation ± chemotherapy. Results: Completion time <10 minutes. To focus on late effects, we report on 48 participants ≥ 6 months post-treatment. 60% reported moderate/severe (M/S) xerostomia which impacted chewing/swallowing (54%), speaking (39%), and sleeping (30%). 44% reported M/S thick mucous resulting in choking/gagging (22%), difficulty swallowing (22%), and altered sleep (15%). 28% reported M/S voice changes with hoarseness (20%) and trouble being understood (29%). M/S dental complaints included difficulty chewing (22%), tooth sensitivity (28%), loose teeth (8%), tooth cracking/chipping (19%), and denture problems (6%). 39% reported M/S taste changes affecting desire to eat (28%), type (34%) and amount of food eaten (28%). 17% reported M/S mucosal sensitivity. 45% reported sensitivity to hot, spicy, or acidic foods. 51% reported sensitivity to dryness. Mucosal sensitivity altered food choices (34%) but did not affect tooth brushing. Many patients reported M/S limitation in jaw (46%) and neck/shoulder (29%) movement. Conclusions: The VHNSS 2.0 incorporates important LOHO in HNC patients. Validation studies are planned in HNC survivors. Preliminary data indicates that LOHO cause significant symptom burden and function loss. No significant financial relationships to disclose.
Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII
Authors: Brittney L Gurda, Adrien De Guilhem De Lataillade, Peter Bell, Yanqing Zhu, Hongwei Yu, Ping Wang, Jessica Bagel, Charles H Vite, Tracey Sikora, Christian Hinderer, Roberto Calcedo, Alexander D Yox, Richard A Steet, Therese Ruane, Patricia O'Donnell, Guangping Gao, James M Wilson, Margret Casal, Katherine P Ponder, Mark E Haskins
Journal: Molecular Therapy (2015)

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.
A phase 1 trial of PT-100 in patients receiving myelosuppressive chemotherapy
Authors: J. J. Nemunaitis, C. C. Cunningham, N. N. Senzer, E. Haltom, B. Jones, S. J. Vukelja, D. A. Richards, M. J. Uprichard
Journal: Journal of Clinical Oncology (2004)

2572 Background: PT-100 is a small molecule which competitively inhibits dipeptidyl peptidase activity of fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV). It rapidly increases cytokine (G-CSF, IL-8) production, accelerates neutrophil and erythrocyte regeneration, and causes tumor regression in mice via inhibition of FAP and DPP-IV. This dose-escalation study was conducted to evaluate the safety of PT-100 in patients receiving myelosuppressive chemotherapy (a doxorubicin or taxane based regimen) and to assess its effects on neutrophil recovery. Methods: Patients received 2 cycles of chemotherapy: the first cycle (C1) served as each patient's individual control. PT-100 was administered orally for 7 days in cycle 2 (C2) as a 200, 400, 800, and 1200mcg total daily dose (divided twice daily) to 6, 6, 13, and 4 patients, respectively. Most patients received PT-100 on Days 2–8 of chemotherapy in C2, except at 800mcg where one cohort was treated on a Day 5–11 schedule. Patients had to have Grade 3/4 neutropenia in C1 to receive PT-100 in C2. Results: Five of 13 patients receiving PT-100 800mcg experienced a ≥ 2-day improvement in ≥ Grade 3 neutropenia, and a 62% improvement in median AUC in C2 vs. C1 was observed in patients treated on the Day 2–8 schedule. A corresponding upregulation in G-CSF, IL-6, and IL-8 was observed in most patients. Overall, PT-100 was well-tolerated. Edema/peripheral swelling, hypotension, and hypovolemia were the most common non-hematologic AEs considered related to PT-100. Two Grade 3 AEs were considered related to PT-100: syncope (1200mcg) and orthostatic hypotension (800mcg). An MTD was not reached. Conclusions: Given the accelerated neutrophil recovery, strong preclinical evidence of antitumor activity, and tolerable toxicities of PT-100, studies using a longer PT-100 dosing schedule are warranted to investigate its antitumor and neutrostatic effects. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Point Therapeutics Point Therapeutics Point Therapeutics Cell Genesys; ONYX Pharmaceuticals Corixa
Functional components of surface membranes: potential targets for pharmacological manipulation.
Authors: V T Marchesi
Journal: Pharmacological Reviews (1978)

This short survey of three major developments in membrane studies should serve to convince pharmacologists that biochemical approaches to the study of cell membranes have finally borne fruit. A reasonable model of cell membrane architecture is now in hand, and it should be possible to use these findings to design and interpret new pharmacological approaches to the manipulation of cells via their surface membranes.
National Kidney Foundation Practice Guidelines for Chronic Kidney Disease
Authors: Andrew S. Levey, Josef Coresh, Ethan Balk, Annamaria T. Kausz, Adeera Levin, Michael W Steffes, Ronald J. Hogg, Ronald D. Perrone, Joseph Lau, Garabed Eknoyan, Kerry Willis
Journal: Annals of Internal Medicine (2003)
Abstract P6-17-02: Inhibition of osteolytic tumor growth by 5-FdU-alendronate, a bisphosphonate conjugate that maintains bone formation: Implications for treatment of osteolytic bone lesions
Authors: Christian Schem, Rob J Tower, Philipp Kneissl, Anna C Rambow, Graeme M Campbell, Thorsten Heilmann, Anna Trauzold, Walter Jonat, Claus C Glüer, Sarah Schott, Sanjay Tiwari
Journal: Cancer Research (2015)

Abstract Patients with breast cancer bone metastases suffer significant morbity from skeletal-related events but an effective agent that inhibits bone resorption while maintaining bone formation has not been identified. In this study we tested the therapeutic efficacy of a novel drug, 5-FdU-ale, a conjugate between the anti-metabolite 5-FdU and the bisphosphonate alendronate, in a mouse model of breast cancer bone metastases. Administration of 5-FdU-ale in vitro induces cell cycle arrest similar to treatment with unconjugated 5-FdU. In vivo, mice harboring bone lesions treated with 5-FdU-ale showed a reduction in tumor size not observed with administration of either Alendronate or 5-FdU. Since osteolysis mediated release of growth factors from bone contribute to tumor growth, we show 5-FdU-ale treatment significantly reduces bone resorption, although uniquely, the inhibition of osteoclast activity is not mediated through inhibition of prenylation of small GTPases. Furthermore, and in contrast to Alendronate, there is no concomitant decrease in bone formation activity, as determined by serum osteocaclin levels. This finding is supported by micro-CT analyses which reveal significantly higher bone volume and histologically, pockets of tumor cells are observed largely confined to regions of marrow space between endochondral and trabecular bone. Taken together, we conclude that 5-FdU-ale has potent anti-tumor efficacy in osteolytic bone lesions mediated uniquely through bone formation activity of osteoblasts and inhibition of bone resorption. The study identifies the important role of osteoblast in not only preventing the osteolytic metastatic phenotype but as a means of harnessing the therapeutic potential of bone formation to treat osteolytic lesions. Citation Format: Christian Schem, Rob J Tower, Philipp Kneissl, Anna C Rambow, Graeme M Campbell, Thorsten Heilmann, Anna Trauzold, Walter Jonat, Claus C Glüer, Sarah Schott, Sanjay Tiwari. Inhibition of osteolytic tumor growth by 5-FdU-alendronate, a bisphosphonate conjugate that maintains bone formation: Implications for treatment of osteolytic bone lesions [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-17-02.
Renal function among cancer patients with bone metastases treated with zoledronic acid in a real world setting
Authors: B. L. Nordstrom, C. Langer, A. Hussain, V. Barghout, D. Modi, L. Lacerna, J. R. Gralow
Journal: Journal of Clinical Oncology (2007)

19540 Background: Zoledronic acid (ZA) is a bisphosphonate that reduces skeletal related events (SREs) in cancer patients (pts) with bone metastases but can impact renal function in some pts. This retrospective study examined serum creatinine (sCr) elevations and subsequent treatment changes among pts receiving ZA in community based medical practices. Methods: Data were obtained from the Varian Medical Oncology database of electronic medical records from 17 US oncology practices. Cancer pts with bone metastases and at least one ZA infusion in 2002–06 were followed; all available sCr levels were examined. SCr measurements ≤4 weeks after a ZA infusion were considered levels while on ZA. Elevated sCr was defined as an increase over baseline of ≥0.5 mg/dL or a doubling from baseline for pts with baseline levels &lt;1.4 mg/dL (or ≥1.0 mg/dL for higher baseline levels). Pts with a sCr elevation on ZA were followed to observe changes in ZA dosing and sCr. Results: The study included 875 pts (318 with breast cancer, 131 lung, 154 prostate, 23 multiple myeloma, and 249 other or unknown cancer) with ≥1 sCr level during baseline and ≥1 (median 6) while on ZA. Median age was 66, 41% were male, and 90% had baseline sCr under 1.4 mg/dL. Pts received a median of 6 ZA infusions. SCr elevations occurred in 87 pts (10%), at a median of 19 weeks (range 0.6–126) after the start of ZA. Pts with baseline sCr over 2.0 mg/dL were more likely to experience an elevation (11 pts, 33%). Following the elevated sCr, 37 pts (43%) discontinued ZA; dose reductions and delays were infrequent. Among 49 pts who remained on ZA after elevated sCr and had further sCr while on ZA, 20 (41%) returned to within 10% of baseline, at a median of 7 weeks (range 0.3–31) after the first measured elevation. The proportion returning to normal is a conservative estimate given limited follow-up sCr data. Conclusions: The observed incidence of elevated sCr of 10% in this community based study is similar to clinical trials. Most pts either discontinued ZA or returned to baseline levels despite continued ZA treatment. Few practitioners adhered to recommendations to withhold ZA until levels return to within 10% of baseline. No significant financial relationships to disclose.
Prospective Weekly Surveillance Of Respiratory Viruses Using Viral Culture In First 100 Days After Allogeneic Stem Cell Transplantation
Authors: Masanori Tsuji, Satsuki Kakiuchi, Hidekazu Nishimura, Hikari Ota, Aya Nishida, Kazuya Ishiwata, Hideki Araoka, Hisashi Yamamoto, Yuki Asano-Mori, Naoyuki Uchida, Koji Izutsu, Atsushi Wake, Shigeyoshi Makino, Akiko Yoneyama, Chang-Kweng Lim, Masayuki Saijo, Shuichi Taniguchi
Journal: Blood (2013)
Prophylactic Cranial Irradiation in Locally Advanced Non–Small-Cell Lung Cancer After Multimodality Treatment: Long-Term Follow-Up and Investigations of Late Neuropsychologic Effects
Authors: M. Stuschke, W. Eberhardt, C. Pöttgen, G. Stamatis, H. Wilke, G. Stüben, F. Stöblen, H. H. Wilhelm, H. Menker, H. Teschler, R.-D. Müller, V. Budach, S. Seeber, H. Sack
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle. RESULTS: Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P = .005) and that of overall brain relapse from 54% to 13% (P &lt; .0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P = .01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not. CONCLUSION: PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.