tbuckley/cabot-search huggingface dataset:
Phase II study of the A-ICOX regimen [bevacizumab (Bev), weekly intermittent capecitabine (Cap) and oxaliplatin (Ox)] for untreated advanced colorectal cancer (CRC)
Authors: R. K. Ramanathan, K. Rajasenan, T. Crandall, E. P. Balaban, R. A. Pinkerton, P. Kane, D. M. Potter, S. Dranko, A. Schmotzer, B. C. Lembersky
Journal: Journal of Clinical Oncology (2007)

4092 Background: FOLFOX in combination with Bev is a standard regimen for treating advanced CRC. Cap on a d 1–14 schedule every 3 weeks is now being substituted for 5-flurouracil (CapOx); however optimal doses and schedules of Cap in combination with Ox and Bev needs continued evaluation. Intermittent weekly Cap (3,500 mg/m 2 , d 1–7) with Ox (85 mg/m 2 ) every 2 weeks compared to the standard CapOx regimen in untreated advanced CRC has shown superior response and time-to-progression in Europe (Scheithauer W et al. J Clin Oncol. 21,1307; 2003). Methods: This phase II trial is designed to evaluate the A-ICOX regimen in US patients with CRC. The primary endpoint is to detect a 50% improvement in median progression free survival (PFS) from 8 to 12 months. With a sample of 40 patients, a 1-sided level 0.1 log-rank test has 81% power to detect this difference. Patients with advanced untreated CRC are eligible for study. Cap is administered at the dose of 2,500 mg/m 2 in two divided doses on d 1–7 (n=11) and has been increased to 3000 mg/m 2 dose (n=26), based on tolerability of the lower dose. The dose of Ox is 85 mg/m 2 and Bev is 5 mg/kg. Cycles are repeated every 2 weeks. Results: Thirty-seven of 40 pts have been enrolled, with 30 evaluable for toxicity and response. Patient characteristics: Male (n=19); ECOG performance status 0 (n=18), 1 (n=12); median age 63 (range 38–80 years). Median cycles administered 4 (range 1–17). Partial responses were seen in 10 pts (33%), and metastasectomy was performed in 8 pts (27%). The PFS analysis is premature at this point. Gr 3/4 hematological toxicity occurred in only 2 pts (7 %). Other gr 3/4 adverse events have included: diarrhea (10 %), hand-foot syndrome (7 %), peripheral neuropathy (7%), nausea (7%) and vomiting (7 %). Conclusions: The first US experience of the A-ICOX regimen shows it to be very well tolerated, and Cap (3,000 mg/m 2 , d 1–7) in combination with Ox and Bev therapy can be safely administered. The incidence of subsequent metastasectomy, a marker of activity, is encouraging. A phase III trial of the A-ICOX regimen is now being conducted against standard Q-3 weekly CapOx/Bev. (Study supported by Genentech and Roche Pharmaceuticals) [Table: see text]
Phase I study of plerixafor and bevacizumab in recurrent high-grade glioma.
Authors: Eudocia Quant Lee, Alona Muzikansky, Elizabeth Robins Gerstner, John G. Kuhn, David A. Reardon, Lakshmi Nayak, Andrew David Norden, Lisa M. Doherty, Jennifer Rifenburg, Debra C. LaFrankie, Julee Pulverenti, Trupti Vardam-Kaur, Deirdre Stokes, Katrina Howard Smith, Christine Sceppa McCluskey, Sarah C. Gaffey, Tracy Batchelor, Dan G. Duda, Rakesh K. Jain, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2015)

TPS2080 Background: Although anti-angiogenic therapy for high-grade glioma is promising, responses are not durable. The SDF-1/CXCR4 axis may help mediate resistance to VEGFR inhibition. Plerixafor is a reversible CXCR4 inhibitor that has demonstrated growth inhibition in glioblastoma xenografts. Methods: We are conducting a Phase I study to determine the safety and tolerability of plerixafor in combination with bevacizumab in patients with recurrent HGG. In Part 1 of the study, a 3 x 3 dose escalation design to a maximum planned dose level of plerixafor 320 µg/kg on Days 1-21 and bevacizumab 10 mg/kg on Days 1 and 15 of each 28 day cycle was used. DLTs were determined during the initial 4 weeks of therapy and included drug-related Grade ≥ 3 non-hematologic toxicities and Grade ≥ 4 hematologic toxicities. Part 2 of the study is a surgical study to determine if plerixafor penetrates tumor tissue. Results: Part 1 of the study has been completed with 23 patients enrolled. Part 2 of the study is now open with 3 patients enrolled to date. For all 26 patients, the median age is 59 (23-72), median KPS 90 (70-100), 11 women (42.3%). In Part 1, no DLTs were seen at the maximum planned dose level of plerixafor 320 µg/kg + bevacizumb. Treatment has been well tolerated to date with one grade 3 hypophosphatemia and one grade 3 rectal fistula. Preliminary pharmacokinetic data on plerixafor from the first two cohorts compares well with historical PK data. Conclusions: Combination treatment with bevacizumab and plerixafor is well tolerated in HGG patients. No DLTs were encountered at the maximum planned dose level. To date, 3 of 10 planned patients have enrolled in the surgical cohort to examine tumor tissue penetration. Updated results as well as preliminary circulating biomarker analysis will be presented. Clinical trial information: NCT01339039.
Efficacy and safety according to age subgroups in AVEX, a randomized phase III trial of bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer.
Authors: Mark P. Saunders, Istvan Lang, Eugenio Marcuello, Vito Lorusso, Janja Ocvirk, Dongbok Shin, Derek J. Jonker, Stuart Osborne, Markus Loeffler, Daniel Waterkamp, David Cunningham
Journal: Journal of Clinical Oncology (2013)

3521 Background: Elderly patients (pts) are underrepresented in clinical trials. The open-label phase III trial AVEX evaluated the benefit of adding bevacizumab (BEV) to capecitabine (cape) in elderly pts with previously untreated metastatic colorectal cancer (mCRC). This analysis explores clinical outcomes by age subgroup. Methods: In AVEX, 280 pts ≥70 y with mCRC for whom single-agent chemotherapy was deemed appropriate, were randomized to first-line cape (1000 mg/m 2 bid days 1–14) alone (n=140) or with BEV (7.5 mg/kg) q3w (n=140). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), overall response rate, and safety. The study was powered to show a difference in PFS but not OS. A post hoc analysis was conducted to assess PFS, OS, and safety in pts 70–74 y, 75–79 y, and ≥80 y. Results: Median age was 76 y (range, 70–87). In the overall population, BEV + cape significantly prolonged PFS compared with cape (median 9.1 vs 5.1 mo; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41–0.69; p&lt;.001). Differences in OS did not reach statistical significance in the overall population (HR, 0.79; 95% CI, 0.57–1.09; p=.182). Treatment was well tolerated. Results according to age are shown (Table). Conclusions: The addition of BEV to cape was associated with significant improvements in PFS in the overall elderly mCRC population and within age subgroups. The safety profile of BEV + cape was consistent across age groups. Clinical trial information: NCT00484939. [Table: see text]
Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology
Authors: Marco Pirazzini, Ornella Rossetto, Roberto Eleopra, Cesare Montecucco
Journal: Pharmacological Reviews (2017)

The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology.
Sensory innervation of perivascular adipose tissue: a crucial role in artery vasodilatation and leptin release
Authors: Hamidah Abu Bakar, William Robert Dunn, Craig Daly, Vera Ralevic
Journal: Cardiovascular Research (2017)

Electrical field stimulation (EFS) elicits robust sensory neurogenic relaxation responses in the rat isolated mesenteric arterial bed but these responses are absent or difficult to demonstrate in isolated arteries. We believe that this mismatch is due to the absence of perivascular adipose tissue (PVAT) as it is conventionally removed in studies on isolated vessels. We aimed to determine whether sensory nerves are expressed in PVAT, their physiological roles and their possible interactions with PVAT-derived adipokines.Using confocal imaging, enzyme immunoassay (EIA), myography, vascular perfusion, and multiplex analysis of rat mesenteric arteries, we show that PVAT is crucial for the roles of sensory nerves in control of vasomotor tone and adipokine release. Immunofluorescence double staining showed co-expression of calcitonin gene-related peptide (CGRP; sensory neurotransmitter) and PGP9.5 (neuronal marker) in PVAT of mesenteric arteries. CGRP release from dissected PVAT, measured using EIA, was increased by capsaicin which activates sensory nerves. EFS in both mesenteric arteries and perfused mesenteric arterial beds, with and without PVAT, demonstrated neurogenic relaxation in the presence of PVAT, which was greatly attenuated in preparations without PVAT. Neurogenic relaxation due to EFS was associated with release of leptin in PVAT-intact mesenteric arterial beds, which was abolished in preparations without PVAT. Exposure to low oxygen was associated with an attenuated leptin and adiponectin release, but an increase in IL-6 release, from mesenteric arterial beds. Exogenous leptin augmented relaxation to CGRP in mesenteric arteries.These data show, for the first time, expression of sensory nerves within PVAT and that PVAT is crucial for sensory neurogenic vasorelaxation and crosstalk with adipocytes leading to leptin release, which may augment CGRP-mediated relaxation; leptin release is abolished after exposure to conditions of reduced oxygenation.
Contrast-enhanced T1-weighted digital subtraction maps combined with diffusion MRI to identify recurrent glioblastoma patients that benefit from bevacizumab therapy.
Authors: Benjamin M. Ellingson, Hyun J. Kim, Davis C. Woodworth, Timothy Francis Cloughesy
Journal: Journal of Clinical Oncology (2014)

2008^ Background: Bevacizumab is an anti-angiogenic therapy approved for recurrent glioblastoma (GBM); however, use of bevacizumab remains controversial. In the current study we demonstrate that recurrent GBM patients with a particular imaging phenotype identified on diffusion MRI who also show an early response on contast-enhanced T1-weighted digital subtraction maps (delta T1) have a significant survival advantage when treated with bevacizumab. Methods: A total of 105 patients with recurrent GBM enrolled in a multicenter clinical trial (BRAIN Trial, AVF3708g) with apparent diffusion coefficient (ADC) data from diffusion MRI available were included. Delta T1 maps were calculated by subtracting post-contrast from pre-contrast T1-weighted images, leaving only areas of enhancement visible. ADC histogram analysis was performed prior to therapy by fitting a double mixed Gaussian model to ADC histograms in contrast-enhancing areas. Patients were stratified into three groups based on their imaging phenotype: (1) Pro-Bev – patients with a high pre-treatment ADC in the lower Gaussian curve who show more than a 25% reduction in enhancement after therapy; (2) Anti-Bev – a low pre-treatment ADC who also do not show a change in contrast enhancement after therapy; and (3) Mixed Response – patients with only a single prognostic factor, either by diffusion MRI or delta T1. Results: Patients with both a favorable pre-treatment diffusion MRI phenotype and an early response after bevacizumab therapy demonstrated a significantly longer PFS (Cox, P=0.01; c-index = 0.61) and OS (P=0.001; c=index=0.60) compared with the other groups. Patients with an unfavorable pre-treatment diffusion MRI phenotype who do not have an early response were more likely to progress and expire early. Conclusions: A combination of pre-treatment diffusion MRI analysis and response assessment using delta T1 maps can be used as an early indicator of GBM patients that will benefit from bevacizumab therapy at recurrence. Such a combination technique may be useful for patient stratification for clinical trials involving bevacizumab combination therapies. Clinical trial information: NCT00345163.
Oral adjuvant chemotherapy using uracil-tegafur (UFT) with leucovorin (LV) after resection of colorectal cancer liver metastases: Long-term survival results of the phase III UFT/LV study.
Authors: Kiyoshi Hasegawa, Akio Saiura, Tadatoshi Takayama, Shinichi Miyagawa, Junji Yamamoto, Yasutsugu Bandai, Masanori Teruya, Fuyo Yoshimi, Seiji Kawasaki, Hiroto Koyama, Masaru Oba, Michiro Takahashi, Suguru Yamashita, Nobuyuki Mizunuma, Yutaka Matsuyama, Toshiaki Watanabe, Masatoshi Makuuchi, Norihiro Kokudo
Journal: Journal of Clinical Oncology (2017)

672 Background: Surgical resection has been accepted as the standard therapy for colorectal cancer liver metastases (CRLM), however, high recurrence incidence even after curative resection remains a severe problem. The 1 st analysis of the UFT/LV trial showed that oral UFT/LV for 6 months significantly prolonged relapse-free survival (RFS) after resection for CRLM (Kobayashi A et al. ASCO 2014, Hasegawa K et al. PlosOne 2016 E-pub). To further evaluate the impact of the UFT/LV therapy on overall survival (OS), we performed the 2 nd analysis under longer follow-up period, as have been scheduled by the protocol. Methods: Patients undergoing curative resection of CRLM were randomly assigned to either UFT/LV or surgery alone (control) group. In the UFT/LV group, 5 cycles of adjuvant UFT/LV (UFT 300mg/m 2 and LV 75 mg/day for 28 days followed by 7 days rest in one cycle) were administered. Results: Between 2004 and 2010, a total of 180 patients were enrolled to this trial, among whom 3 patients were ineligible for analysis. Median follow-up of the 2 nd analysis was 6 years. The 5y-OS rate in the UFT/LV group was 65.3%, which was slightly better than the control group (62.2%) without statistical significance. The hazard ratio for death in the UFT/LV relative to the control was 0.86 (95% confidence interval: 0.54-1.38, P = 0.54). The OS curves of the 2 groups were identical within 4 years after resection, however, the OS curve of the UFT/LV group seemed to go higher than the control group. The 5y-RFS rate in the UFT/LV group was 36.2%, which was significantly better than that in the control group (32.3%), as have been shown by the 1 st analysis. Conclusions: The results of the 2 nd analysis suggested that oral UFT/LV adjuvant chemotherapy might be also useful to prolong OS, as have been confirmed for RFS. This regimen can be recommended as an alternative choice after hepatic resection for CRLM. Clinical trial information: C000000013.
Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors
Authors: Debu Tripathy, Aditya Bardia, William R Sellers
Journal: Clinical Cancer Research (2017)

The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which received FDA approval in March 2017 and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib. Here, we describe the mechanism of action of ribociclib and review preclinical and clinical data from phase I, II, and III trials of ribociclib across different tumor types, within the context of other selective CDK4/6 inhibitors. The pharmacokinetics, pharmacodynamics, safety, tolerability, and clinical responses with ribociclib as a single agent or in combination with other therapies are discussed, and an overview of the broad portfolio of ongoing clinical trials with ribociclib across a wide range of indications is presented. On the basis of the available data, ribociclib has a manageable tolerability profile and therapeutic potential for a variety of cancer types. Its high selectivity makes it an important partner drug for other targeted therapies, and it has been shown to enhance the clinical activity of existing anticancer therapies and delay the development of treatment resistance, without markedly increasing toxicity. Ongoing trials of doublet and triplet targeted therapies containing ribociclib seek to identify optimal CDK4/6-based targeted combination regimens for various tumor types and advance the field of precision therapeutics in oncology.
Smoking affects treatment outcome in patients with advanced non-small cell lung cancer
Authors: A. S. Tsao, D. D. Liu, J. J. Lee, M. R. Spitz, W. K. Hong
Journal: Journal of Clinical Oncology (2004)

7182 Background: Patients with small cell lung cancer and head and neck cancers who smoke during radiotherapy but not chemotherapy have an adverse prognostic outcome. We sought to determine whether this effect occurs in patients with non-small cell lung cancer (NSCLC). Methods: A retrospective review was performed of the smoking status and response and survival rates among patients with NSCLC who were treated with front-line therapy at M.D. Anderson Cancer Center (1993–2002). Results: Of 905 patients, 595 received chemotherapy and 310 received chemoradiation. In the chemotherapy group, 15% of patients were never smokers, 43% were former and 42% were current smokers; 85% were stage 4, 12% were stage 3B, and 3% were stage 3A; 61% were men, 86% had a performance status (PS) 0–1, and 78% received a platinum-based chemotherapy regimen. Never smokers had higher response rates (20% vs. 8% vs. 12%, P=0.01) and lower progressive disease rates (51% vs. 65% vs. 66%, P=0.03) compared to former and current smokers, respectively. Overall survival rates were better among never-smokers (P=0.01), women (P=0.0002), patients with bronchioloalveolar or neuroendocrine histology (P=0.02), and patients with a PS 0–1 (P=0.002). Adjusted for gender, the hazard ratio was 1.35 for former smokers (P=0.051) and 1.34 for current smokers (P=0.051). Survival rates did not correlate with the number of cigarette packs per day, total smoking years, or whether a patient received a platinum-based regimen. In the chemoradiation group, 31% were stage 4, 62% were stage 3B, and 7% were stage 3A; 7% were never smokers, 41% were former, and 52% were current smokers. Univariate analysis showed an equivocal effect of smoking status on response and survival rates. Conclusions: Patients with advanced NSCLC treated with front-line chemotherapy who had no prior smoking histories had better treatment response and overall survival rates than former and current smokers. There was no difference in treatment outcome between current and former smokers who received chemotherapy or chemoradiation. Further details of the comparative analysis of patients who continued to smoke during therapy vs. those who did not will be presented. No significant financial relationships to disclose.
The Role of Titanium Surface Nanostructuring on Preosteoblast Morphology, Adhesion, and Migration
Authors: Yulia Zhukova, Christian Hiepen, Petra Knaus, Marc Osterland, Steffen Prohaska, John W. C. Dunlop, Peter Fratzl, Ekaterina V. Skorb
Journal: Advanced Healthcare Materials (2017)

Surface structuring of titanium-based implants is known to modulate the behavior of adherent cells, but the influence of different nanotopographies is poorly understood. The aim is to investigate preosteoblast proliferation, adhesion, morphology, and migration on surfaces with similar surface chemistry but distinct nanotopographical features. Sonochemical treatment and anodic oxidation are employed to fabricate disordered, mesoporous titania (TMS) and ordered titania nanotubular (TNT) topographies on titanium, respectively. Morphological evaluation reveals that cells are polygonal and well-spread on TMS, but display an elongated, fibroblast-like morphology on TNT surfaces, while they are much flatter on glass. Both nanostructured surfaces impair cell adhesion, but TMS is more favorable for cell growth due to its support of cell attachment and spreading in contrast to TNT. A quantitative wound healing assay in combination with live-cell imaging reveals that cell migration on TMS surfaces has a more collective character than on other surfaces, probably due to a closer proximity between neighboring migrating cells on TMS. The results indicate distinctly different cell adhesion and migration on ordered and disordered titania nanotopographies, providing important information that can be used in optimizing titanium-based scaffold design to foster bone tissue growth and repair while allowing for the encapsulation of drugs into porous titania layer.
Impairments of motor function among children with a familial risk of schizophrenia or bipolar disorder at 7 years old in Denmark: an observational cohort study
Authors: Birgitte Klee Burton, Anne A E Thorup, Jens Richardt Jepsen, Gry Poulsen, Ditte Ellersgaard, Katrine S Spang, Camilla Jerlang Christiani, Nicoline Hemager, Ditte Gantriis, Aja Greve, Ole Mors, Merete Nordentoft, Kerstin Jessica Plessen
Journal: The Lancet Psychiatry (2017)