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Dose escalation

Richard Baumgartner, William Cho, Alexandre Coimbra, Christopher Chen, Zaiqi Wang, Arie Struyk, Narayanaswamy Venketasubramanian, May Low, Cindy Gargano, Fuqiang Zhao, Donald Williams, Torsten Reese, Stephanie Seah, Dai Feng, Sonya Apreleva, Esben Petersen, Jeffrey L Evelhoch
PURPOSE: To present the testretest and contrast dose effect results of cerebral blood volume (CBV) functional MRI (fMRI) in healthy human volunteers using ferumoxytol (Feraheme), an ultrasmall-superparamagnetic iron oxide (USPIO) nanoparticle. MATERIALS AND METHODS: This was an open-label, two-period, fixed-sequence study in healthy young volunteers. In eight subjects, using a 3 Tesla field strength system, blood oxygen level dependent (BOLD) and CBV fMRI were acquired in response to a visual black-and-white checkboard stimulation paradigm using an escalating ferumoxytol dose design (250, 350, and 510 mg iron)...
October 24, 2016: Journal of Magnetic Resonance Imaging: JMRI
Sihem Ait-Oudhia, Donald E Mager
Cancer is a complex disease that is characterized by an uncontrolled growth and spread of abnormal cells. Drug development in oncology is particularly challenging and is associated with one of the highest attrition rates of compounds despite substantial investments in resources. Pharmacokinetic and pharmacodynamic (PK/PD) modeling seeks to couple experimental data with mathematical models to provide key insights into factors controlling cytotoxic effects of chemotherapeutics and cancer progression. PK/PD modeling of anti-cancer compounds is equally challenging, partly based on the complexity of biological and pharmacological systems...
October 22, 2016: Journal of Pharmacokinetics and Pharmacodynamics
Daniel E Spratt, Payal D Soni, Patrick W McLaughlin, Gregory S Merrick, Richard G Stock, John C Blasko, Michael J Zelefsky
PURPOSE: To review outcomes for high-risk prostate cancer treated with combined modality radiation therapy (CMRT) utilizing external beam radiation therapy (EBRT) with a brachytherapy boost. METHODS AND MATERIALS: The available literature for high-risk prostate cancer treated with combined modality radiation therapy was reviewed and summarized. RESULTS: At this time, the literature suggests that the majority of high-risk cancers are curable with multimodal treatment...
October 19, 2016: Brachytherapy
H Kumon, Y Ariyoshi, K Sasaki, T Sadahira, M Araki, S Ebara, H Yanai, M Watanabe, Y Nasu
As the First-In-Human study of in situ gene therapy using an adenovirus vector carrying the human REIC (reduced expression in immortalized cell)/Dkk-3 gene (Ad-REIC), we conducted neoadjuvant intraprostatic injections in patients with high-risk localized prostate cancer undergoing radical prostatectomy (RP). Patients with recurrence probability of 35% or more within 5 years following RP, as calculated by Kattan's nomogram, were enrolled. Patients received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection...
October 21, 2016: Cancer Gene Therapy
Antonella Conforti, Nadia Starc, Simone Biagini, Luigi Tomao, Angela Pitisci, Mattia Algeri, Pietro Sirleto, Antonio Novelli, Giulia Grisendi, Olivia Candini, Cintia Carella, Massimo Dominici, Franco Locatelli, Maria Ester Bernardo
The risk of malignant transformation of ex-vivo expanded human mesenchymal stromal cells (huMSCs) has been debated in the last years; however, the biosafety of these cells after exposure to supramaximal physical and chemical stress has never been systematically investigated.We established an experimental in vitro model to induce supramaximal physical (ionizing radiation, IR) and chemical (starvation) stress on ex-vivo expanded bone marrow (BM)-derived huMSCs and investigated their propensity to undergo malignant transformation...
October 15, 2016: Oncotarget
Si Yeol Song, Kyu-Pyo Kim, Seong-Yun Jeong, Jin Park, Jaesook Park, Joohee Jung, Hye Kyung Chung, Sa-Won Lee, Min Hyo Seo, Jung-Shin Lee, Kyung Hae Jung, Eun Kyung Choi
We assessed the efficacy of the polymeric nanoparticle containing docetaxel (PNP-DTX) in preclinical mouse models and determined the maximum tolerated dose (MTD) through clinical study. Subcutaneous and orthotopic mouse models were dedicated. Tumor growth delay in orthotopic model and quantification of in vivo imaging in orthotopic model were evaluated. Phase I clinical study was a single-center, prospective, open-label trial in advanced solid tumors. PNP-DTX was injected intravenously and the starting dose was 20 mg/m2 escalated to 35 mg/m2, 45 mg/m2, 60 mg/m2 and 75 mg/m2...
October 14, 2016: Oncotarget
Michelle Hook, Sarah Woller, Eric Bancroft, Miriam Aceves, Mary Katherine Funk, John Hartman, Sandra M Garraway
Opioids and NSAIDs are commonly used to manage pain in the early phase of spinal cord injury (SCI). Despite its analgesic efficacy, however, our studies suggest that intrathecal (i.t.) morphine undermines locomotor recovery and increases lesion size in a rodent model of SCI. Similarly, intravenous (i.v.) morphine attenuates locomotor recovery. The current study explores whether i.v. morphine also increases lesion size after a spinal contusion (T12) injury, and quantifies the cell types that are affected by early opioid administration...
October 20, 2016: Journal of Neurotrauma
Matthew D Hall, Timothy E Schultheiss, David D Smith, Marwan G Fakih, Jeffrey Y C Wong, Yi-Jen Chen
BACKGROUND: Neoadjuvant chemoradiation therapy (CRT) increases pathological complete response (pCR) rates compared to radiotherapy alone in patients with stage II-III rectal cancer. Limited evidence addresses whether radiotherapy dose escalation further improves pCR rates. Our purpose is to measure the effects of radiotherapy dose and other factors on post-therapy pathologic tumor (ypT) and nodal stage in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision...
October 20, 2016: Acta Oncologica
Corinna La Rosa, Jeff Longmate, Joy Martinez, Qiao Zhou, Teodora I Kaltcheva, Weimin Tsai, Jennifer Drake, Mary Carroll, Felix Wussow, Flavia Chiuppesi, Nicola Hardwick, Sanjeet Dadwal, Ibrahim Aldoss, Ryotaro Nakamura, John A Zaia, Don J Diamond
Attenuated poxvirus Modified vaccinia Ankara (MVA) is a useful viral-based vaccine for clinical investigation, because of its excellent safety profile and property of inducing potent immune responses against recombinant (r) antigens. We developed Triplex by constructing an rMVA encoding three immunodominant CMV antigens which stimulates a host anti-viral response: UL83 (pp65), UL123 (IE1-exon4), and UL122 (IE2-exon5). We completed the first clinical evaluation of the Triplex vaccine in 24 healthy adults, with or without immunity to CMV and vaccinia virus (previous DryVax smallpox vaccination)...
October 19, 2016: Blood
Firas El Chaer, Dimpy P Shah, Roy F Chemaly
Cytomegalovirus (CMV) infection is a significant complication in hematopoietic cell transplantation (HCT) recipients. Four antiviral drugs are used for preventing or treating CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. With prolonged and repeated use of these drugs, CMV can become resistant to standard therapy, resulting in increased morbidity and mortality, especially in HCT recipients. Antiviral drug resistance should be suspected when CMV viremia (DNAemia or antigenemia) fails to improve or continue to increase after 2 weeks of appropriately dosed and delivered antiviral therapy...
October 19, 2016: Blood
Wataru Obara, Takashi Karashima, Kazuyoshi Takeda, Renpei Kato, Yoichiro Kato, Mitsugu Kanehira, Ryo Takata, Keiji Inoue, Toyomasa Katagiri, Taro Shuin, Yusuke Nakamura, Tomoaki Fujioka
PURPOSE: Through genome-wide expression profile analysis, hypoxia-inducible protein 2 (HIG2) has previously been identified as an oncoprotein involved in development/progression of renal cell carcinoma (RCC). We subsequently identified a highly immunogenic HLA-A*0201/0206-restricted epitope peptide (HIG2-9-4) corresponding to a part of HIG2 and applied it as a therapeutic vaccine. We conducted a phase I clinical trial using the HIG2-9-4 peptide for patients with advanced RCC. MATERIALS AND METHODS: Nine patients having HLA-A*0201 or HLA-A*0206 with metastatic or unresectable RCC after failure of the cytokine and/or tyrosine kinase inhibitor therapies were enrolled in this study...
October 18, 2016: Cancer Immunology, Immunotherapy: CII
Neil H Segal, Theodore F Logan, F Stephen Hodi, David F McDermott, Ignacio Melero, Omid Hamid, Henrik Schmidt, Caroline Robert, Vanna Chiarion-Sileni, Paolo A Ascierto, Michele Maio, Walter J Urba, Tara C Gangadhar, Satyendra Suryawanshi, Jaclyn Neely, Maria Jure-Kunkel, Suba Krishnan, Holbrook E Kohrt, Mario Sznol, Ronald Levy
PURPOSE: Urelumab is an agonist antibody to CD137 with potential application as an immuno-oncology therapeutic. Data were analyzed to assess safety, tolerability, and pharmacodynamic activity of urelumab, including the dose selected for ongoing development in patients with advanced solid tumors and lymphoma. PATIENTS AND METHODS: Three hundred and forty-six patients with advanced cancers who had progressed after standard treatment received at least one dose of urelumab in one of three dose-escalation, monotherapy studies...
October 18, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Wei Yu, Wei Hu, Yongjie Shui, Xiaoyang Zhu, Chao Li, Xiaoqiu Ren, Xueli Bai, Risheng Yu, Li Shen, Tingbo Liang, Lei Zheng, Qichun Wei
OBJECTIVES: To explore the areas at highest risk for postoperative pancreatic cancer local recurrence according to the spatial location of local failures, with the aim to provide a precise target volume for pancreatic cancer adjuvant radiotherapy. METHODS: Patients with pancreatic cancer who had undergone surgery for the primary tumor in pancreas at our institution from January 2010 to August 2015 were retrospectively analyzed. All local recurrences were plotted on the computed tomography (CT) image of a representative patient according to their relative coordinates to superior mesenteric artery (SMA) or celiac axis (CA)...
October 19, 2016: Radiation Oncology
Perparim Limani, Michael Linecker, Philipp Kron, Panagiotis Samaras, Bernhard Pestalozzi, Roger Stupp, Alexander Jetter, Philipp Dutkowski, Beat Müllhaupt, Andrea Schlegel, Claude Nicolau, Jean-Marie Lehn, Henrik Petrowsky, Bostjan Humar, Rolf Graf, Pierre-Alain Clavien
BACKGROUND: Solid tumors, such as hepato-pancreato-biliary cancer, develop tumor hypoxia with tumor growth. Despite advances in surgery, a majority of these patients are in an unresectable condition. At this stage standard cytotoxic chemotherapy regimens are applied with limited success. Novel biological treatment options based on an antiangiogenic mechanism of action neglect other hypoxia mediated mechanisms (e.g. epithelial-mesenchymal transition, Warburg effect, and immunological response) leading to an increased invasiveness with a poor outcome...
October 19, 2016: BMC Cancer
Jacqueline R Kelly, Zain A Husain, Barbara Burtness
Increasingly, squamous cell carcinoma of the oropharynx (OPSCC) is attributable to transformation resulting from high-risk human papillomavirus (HPV) infection. Such cancers are significantly more responsive to treatment than traditional tobacco- and alcohol-associated squamous cell cancers of the head and neck. Conventional management with definitive chemoradiation, surgery and adjuvant radiation, or radiation given with altered fractionation schemes, while effective, incurs long-term morbidity that escalates with treatment intensity and significantly impairs quality of life...
October 15, 2016: European Journal of Cancer
Sameer Bakhshi, Sainath Bhethanabhotla, Rakesh Kumar, Krishankant Agarwal, Punit Sharma, Sanjay Thulkar, Arun Malhotra, Deepa Dhawan, Sreenivas Vishnubhatla
BACKGROUND: Data about significance of (18)F-FDG positron emission tomography (PET) at interim assessment and end of treatment in pediatric Hodgkin lymphoma (HL) are limited. METHODS: Patients (≤18 years) with HL were prospectively evaluated with contrast-enhanced computed tomography (CECT) and PET combined with low-dose CT(PET-CT) at baseline, post 2 cycles of chemotherapy and post completion of treatment. Revised international working group criteria (RIW) and Deauville (DA) five point-scale for response assessment by PET-CT were used...
October 6, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Nazanin Ebrahimiadib, Bobeck S Modjtahedi, Samaneh Davoudi, C Stephen Foster
PURPOSE: To evaluate the efficacy of chlorambucil in the treatment of serpiginous choroiditis. METHODS: Patient records from the Massachusetts Eye Research and Surgery Institution (MERSI) were reviewed from over the past 10 years. In total, 17 patients with the diagnosis of serpiginous choroiditis treated with chlorambucil were identified. QuantiFERON gold was negative in all of them. Chlorambucil was started at 0.15 mg/kg and dosage was titrated up using weekly white blood cell (WBC) count to achieve a target cell number of 3...
October 18, 2016: Ocular Immunology and Inflammation
Julie M Waldfogel, Suzanne Nesbit, Steven P Cohen, Sydney M Dy
Opioids remain the mainstay of treatment for severe cancer pain, but up to 20% of patients have persistent or refractory pain despite rapid and aggressive opioid titration, or develop refractory pain after long-term opioid use. In these scenarios, alternative agents and mechanisms for analgesia should be considered. This case report describes a 28-year-old man with metastatic pancreatic neuroendocrine cancer with severe, intractable pain despite high-dose opioids including methadone and a hydromorphone patient-controlled analgesia (PCA)...
October 18, 2016: Journal of Pain & Palliative Care Pharmacotherapy
Francesco Cappuccio
The evidence. Salt (i.e. sodium chloride) is causally related to blood pressure (BP). The higher the salt intake, the higher the BP, an effect seen since birth. A small and sustained reduction in salt intake causes a fall in BP. The evidence from controlled studies, small and large, short and long, all agree on the following: (1) salt intake is one of the major determinants of BP in populations and individuals; (2) a reduction in salt intake causes a dose-dependent reduction in BP - the lower the salt the lower the BP; (3) the effect is seen in both sexes, in people of all ages and ethnic groups, and with all starting BPs...
September 2016: Journal of Hypertension
Kawsar R Talaat, Ruth D Ellis, Janet Hurd, Autumn Hentrich, Erin Gabriel, Noreen A Hynes, Kelly M Rausch, Daming Zhu, Olga Muratova, Raul Herrera, Charles Anderson, David Jones, Joan Aebig, Sarah Brockley, Nicholas J MacDonald, Xiaowei Wang, Michael P Fay, Sara A Healy, Anna P Durbin, David L Narum, Yimin Wu, Patrick E Duffy
Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa. In this report, we describe results of an open-label, dose-escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel®...
2016: PloS One
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