Rectal cancer: An evidence-based update for primary care providers

PubMed Central

Gaertner, Wolfgang B; Kwaan, Mary R; Madoff, Robert D; Melton, Genevieve B

2015-01-01

Rectal adenocarcinoma is an important cause of cancer-related deaths worldwide, and key anatomic differences between the rectum and the colon have significant implications for management of rectal cancer. Many advances have been made in the diagnosis and management of rectal cancer. These include clinical staging with imaging studies such as endorectal ultrasound and pelvic magnetic resonance imaging, operative approaches such as transanal endoscopic microsurgery and laparoscopic and robotic assisted proctectomy, as well as refined neoadjuvant and adjuvant therapies. For stage II and III rectal cancers, combined chemoradiotherapy offers the lowest rates of local and distant relapse, and is delivered neoadjuvantly to improve tolerability and optimize surgical outcomes, particularly when sphincter-sparing surgery is an endpoint. The goal in rectal cancer treatment is to optimize disease-free and overall survival while minimizing the risk of local recurrence and toxicity from both radiation and systemic therapy. Optimal patient outcomes depend on multidisciplinary involvement for tailored therapy. The successful management of rectal cancer requires a multidisciplinary approach, with the involvement of enterostomal nurses, gastroenterologists, medical and radiation oncologists, radiologists, pathologists and surgeons. The identification of patients who are candidates for combined modality treatment is particularly useful to optimize outcomes. This article provides an overview of the diagnosis, staging and multimodal therapy of patients with rectal cancer for primary care providers. PMID:26167068

Combination therapeutics of Nilotinib and radiation in acute lymphoblastic leukemia as an effective method against drug-resistance.

PubMed

Kaveh, Kamran; Takahashi, Yutaka; Farrar, Michael A; Storme, Guy; Guido, Marcucci; Piepenburg, Jamie; Penning, Jackson; Foo, Jasmine; Leder, Kevin Z; Hui, Susanta K

2017-07-01

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis and a high likelihood of acquired chemo-resistance. Although tyrosine kinase inhibitor (TKI) therapy has improved clinical outcome, most ALL patients relapse following treatment with TKI due to the development of resistance. We developed an in vitro model of Nilotinib-resistant Ph+ leukemia cells to investigate whether low dose radiation (LDR) in combination with TKI therapy overcome chemo-resistance. Additionally, we developed a mathematical model, parameterized by cell viability experiments under Nilotinib treatment and LDR, to explain the cellular response to combination therapy. The addition of LDR significantly reduced drug resistance both in vitro and in computational model. Decreased expression level of phosphorylated AKT suggests that the combination treatment plays an important role in overcoming resistance through the AKT pathway. Model-predicted cellular responses to the combined therapy provide good agreement with experimental results. Augmentation of LDR and Nilotinib therapy seems to be beneficial to control Ph+ leukemia resistance and the quantitative model can determine optimal dosing schedule to enhance the effectiveness of the combination therapy.

Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD.

PubMed

Amin, Jaimin; Huang, Brian; Yoon, Jessica; Shih, David Q

2015-02-01

The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of these drugs lead to individual variation in thiopurine metabolite levels that can determine its therapeutic efficacy and development of adverse reactions. In this update, we will review thiopurine metabolic pathway along with the up-to-date approaches in administering thiopurine medications based on the current literature. A search of the PubMed database by 2 independent reviewers identifying 98 articles evaluating thiopurine metabolism and IBD management. Monitoring thiopurine metabolites can assist physicians in optimizing 6-MP and AZA therapy in treating patients with IBD. Of the dosing strategies reviewed, we found evidence for monitoring thiopurine metabolite level, use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of AZA or 6-MP to optimize thiopurine therapy and minimize adverse effects in IBD. Based on the currently available literature, various dosing strategies to improve therapeutic response and reduce adverse reactions can be considered, including use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of thiopurine.

Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C.

PubMed

Mulhall, Brian P; Younossi, Zobair

2005-01-01

Nearly 4 million people in the United States have evidence of hepatitis C infection (HCV), representing a significant cause of cirrhosis and liver cancer as well a major burden to our healthcare systems and society. Antiviral therapy can successfully eradicate HCV over the long term, potentially reducing the risk of progression and improving patients' quality of life. The currently preferred HCV treatment is a combination of pegylated interferon alfa and ribavirin, which can achieve an overall sustained viral eradication rate of 55%. The duration of this treatment is typically determined by HCV genotype and the patient's early virologic response to the antiviral regimen. Evidence has accumulated over the past few years to indicate that close adherence to the optimal antiviral regimen can enhance sustained virologic response. But optimal treatment outcomes require diligence and careful management of side effects related to combination therapy. Although reducing the dose of pegylated interferon alfa, ribavirin, or both can effectively treat side effects, suboptimal doses of this regimen, especially ribavirin, may negatively affect virologic response. An alternative strategy is to use growth factors to treat cytopenias. This strategy can obviate dose reductions while potentially improving patients' quality of life. Patient support seems especially important early after the initiation of antiviral therapy. Encouraging study findings involving the growth factors, epoetin alfa and darbepoetin alfa, suggest improved anemia and quality of life while maintaining the optimal ribavirin dose. Future work should be aimed at providing stronger evidence for the use of these "supportive products" during anti-HCV therapy. As we strive to develop better treatment options for our HCV patients, the importance of adhering to the treatment regimen continues to play a central role. Effective side effect management is crucial for the success of this treatment because adherence is negatively affected by side effects related to the antiviral regimen. By identifying and addressing the important side effects of combination therapy for HCV, adherence to treatment can be improved and optimal outcomes can be achieved.

Current and future management of treatment failure in low- and middle-income countries.

PubMed

Boyd, Mark A

2010-01-01

Access to second-line therapy in low- and middle-income countries has been limited to date. The WHO predicts that between 500 000 and 800 000 HIV-infected people on first-line combination antiretroviral therapy will require switch to second-line therapy by 2010. This paper aims to describe and review access to second-line therapy in low- and middle-income countries at present and examine future possibilities. The majority of HIV-infected patients failing first-line combination antiretroviral therapy is identified by way of routine monitoring of clinical and immunological status as a surrogate for virological monitoring. Evidence suggests that immunological and clinical monitoring lack both sensitivity and specificity for virological failure. Consequently, at treatment failure, patients have often selected a degree of resistance within the nucleoside/nucleotide reverse transcriptase inhibitor class that questions the efficacy of using nucleoside/nucleotide reverse transcriptase inhibitors in a second-line regimen. There is a paucity of good-quality evidence on which to base guidelines and policy. Optimally, a second-line regimen would be simple, potent, tolerable and lend itself to provision according to the successful 'public health' approach. Provision of second-line therapy to HIV-infected individuals failing first-line therapy is a major challenge to the ongoing success of access to HIV care programmes in low- and middle-income countries. The optimal second-line combination antiretroviral therapies are unknown. Research trials to help define best practice are in advanced stages of development and implementation.

Antithrombotic therapy in patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention: should we change our practice after the PIONEER AF-PCI and RE-DUAL PCI trials?

PubMed

Duerschmied, D; Brachmann, J; Darius, H; Frey, N; Katus, H A; Rottbauer, W; Schäfer, A; Thiele, H; Bode, C; Zeymer, Uwe

2018-04-20

The number of patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) is increasing. Since these patients have a CHA 2 DS 2 -VASc score of 1 or higher, they should be treated with oral anticoagulation to prevent stroke. However, combination therapy with oral anticoagulation for prevention of embolic stroke and dual platelet inhibition for prevention of coronary thrombosis significantly increases bleeding complications. The optimal combination, intensity and duration of antithrombotic combination therapy is still not known. In the rather small randomized WOEST trial, the combination of a vitamin K antagonist (VKA) and clopidogrel decreased bleeding compared to the conventional triple therapy with VKA, clopidogrel and aspirin. In the PIONEER AF-PCI trial, two rivaroxaban-based treatment regimens significantly reduced bleeding complications compared to conventional triple therapy without increasing embolic or ischemic complications following PCI. Dual therapy with rivaroxaban and clopidogrel appeared to provide an optimal risk-benefit ratio. In the RE-DUAL PCI trial, dual therapy with dabigatran also reduced bleeding complications compared to conventional triple therapy. With respect to the composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization dabigatran-based dual therapy was non-inferior to VKA-based triple therapy. The upcoming trials AUGUSTUS with apixaban and ENTRUST-PCI with edoxaban will further examine the use of NOACs in this setting. While recent guidelines recommend NOAC-based dual therapy in only a subset of patients (those who are at increased risk of bleeding), the available data now suggest that this should be the preferred choice for the majority of patients. Adding aspirin to this primary choice for up to 4 weeks in patients at especially high ischemic risk would likely prevent atherothrombotic events, but this needs further investigation. Taken together, it is time to adjust our practice and move to dual therapy consisting of a NOAC plus clopidogrel in most patients.

Optimizing management of actinic keratosis and photodamaged skin: utilizing a stepwise approach.

PubMed

Lee, Andrew D; Jorizzo, Joseph L

2009-09-01

The incidence of photodamaged skin and skin lesions of all degrees of severity, from actinic keratosis (AK) to skin cancers, has dramatically increased. Actinic keratoses are pathologic, reflecting damage of essential skin cell functions and potentially progressing to invasive squamous cell carcinoma (SCC). The rate of progression is uncertain but may be as high as 10%. Because it is impossible to predict which AKs will progress to SCC, all lesions should be treated. Options include topical therapies, cryotherapy, curettage, and photodynamic therapy. Unfortunately, many individuals do not seek treatment or avoid it because of irritation, discomfort, and concern for scarring. Combining field-directed therapy and cryotherapy has been more effective than cryotherapy alone. Incorporating patient education with treatment may optimize outcomes. We propose a comprehensive 5-step approach for managing AK lesions and photodamaged skin that includes periodic clinical skin examinations; treating AK lesions with a combination of field- and lesion-directed therapy; and patient education regarding sun-protective measures and regular skin self-examinations.

Personalizing initial therapy in acute myeloid leukemia: incorporating novel agents into clinical practice

PubMed Central

DeStefano, Christin B.; Hourigan, Christopher S.

2018-01-01

While the past decade has seen a revolution in understanding of the genetic and molecular etiology of the disease, in clinical practice, initial therapy for acute myeloid leukemia (AML) patients has been a relatively straightforward choice between intensive combination cytotoxic induction therapy as used for decades or less-intensive hypomethylating therapy. The year 2017, however, witnessed US Food and Drug Administration approvals of midostaurin, enasidenib, gemtuzumab ozogamicin and CPX-351 for AML patients, with many other promising agents currently in clinical trials. This review discusses these options, highlights unanswered questions regarding optimal combinations and proposes some suggested approaches for the personalization of initial therapy for AML patients. PMID:29713444

A randomised controlled trial of combined EEG feedback and methylphenidate therapy for the treatment of ADHD.

PubMed

Li, Li; Yang, Li; Zhuo, Chuan-jun; Wang, Yu-Feng

2013-08-22

To evaluate the efficacy of combined methylphenidate and EEG feedback treatment for children with ADHD. Forty patients with ADHD were randomly assigned to the combination group (methylphenidate therapy and EEG feedback training) or control group (methylphenidate therapy and non-feedback attention training) in a 1:1 ratio using the double-blind method. These patients, who met the DSM-IV diagnostic criteria and were aged between 7 and 16 years, had obtained optimal therapeutic effects by titrating the methylphenidate dose prior to the trial. The patients were assessed using multiple parameters at baseline, after 20 treatment sessions, after 40 treatment sessions, and in 6-month follow-up studies. Compared to the control group, patients in the combination group had reduced ADHD symptoms and improved in related behavioural and brain functions. The combination of EEG feedback and methylphenidate treatment is more effective than methylphenidate alone. The combined therapy is especially suitable for children and adolescents with ADHD who insufficiently respond to single drug treatment or experience drug side effects.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update.

PubMed

Denduluri, Neelima; Chavez-MacGregor, Mariana; Telli, Melinda L; Eisen, Andrea; Graff, Stephanie L; Hassett, Michael J; Holloway, Jamie N; Hurria, Arti; King, Tari A; Lyman, Gary H; Partridge, Ann H; Somerfield, Mark R; Trudeau, Maureen E; Wolff, Antonio C; Giordano, Sharon H

2018-05-22

Purpose To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Methods An Expert Panel conducted targeted systematic literature reviews guided by a signals approach to identify new, potentially practice-changing data that might translate to revised practice recommendations. Results The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for patients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer. Recommendations Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Additional information can be found at www.asco.org/breast-cancer-guidelines .

Optimization of personalized therapies for anticancer treatment.

PubMed

Vazquez, Alexei

2013-04-12

As today, there are hundreds of targeted therapies for the treatment of cancer, many of which have companion biomarkers that are in use to inform treatment decisions. If we would consider this whole arsenal of targeted therapies as a treatment option for every patient, very soon we will reach a scenario where each patient is positive for several markers suggesting their treatment with several targeted therapies. Given the documented side effects of anticancer drugs, it is clear that such a strategy is unfeasible. Here, we propose a strategy that optimizes the design of combinatorial therapies to achieve the best response rates with the minimal toxicity. In this methodology markers are assigned to drugs such that we achieve a high overall response rate while using personalized combinations of minimal size. We tested this methodology in an in silico cancer patient cohort, constructed from in vitro data for 714 cell lines and 138 drugs reported by the Sanger Institute. Our analysis indicates that, even in the context of personalized medicine, combinations of three or more drugs are required to achieve high response rates. Furthermore, patient-to-patient variations in pharmacokinetics have a significant impact in the overall response rate. A 10 fold increase in the pharmacokinetics variations resulted in a significant drop the overall response rate. The design of optimal combinatorial therapy for anticancer treatment requires a transition from the one-drug/one-biomarker approach to global strategies that simultaneously assign makers to a catalog of drugs. The methodology reported here provides a framework to achieve this transition.

EGFR Targeted Therapies and Radiation: Optimizing Efficacy by Appropriate Drug Scheduling and Patient Selection

PubMed Central

Cuneo, Kyle C.; Nyati, Mukesh K.; Ray, Dipankar; Lawrence, Theodore S.

2015-01-01

The epidermal growth factor receptor (EGFR) plays an important role in tumor progression and treatment resistance for many types of malignancies including head and neck, colorectal, and nonsmall cell lung cancer. Several EGFR targeted therapies are efficacious as single agents or in combination with chemotherapy. Given the toxicity associated with chemoradiation and poor outcomes seen in several types of cancers, combinations of EGFR targeted agents with or without chemotherapy have been tested in patients receiving radiation. To date, the only FDA approved use of an anti-EGFR therapy in combination with radiation therapy is for locally advanced head and neck cancer. Given the important role EGFR plays in lung and colorectal cancer and the benefit of EGFR inhibition combined with chemotherapy in these disease sites, it is perplexing why EGFR targeted therapies in combination with radiation or chemoradiation have not been more successful. In this review we summarize the clinical findings of EGFR targeted therapies combined with radiation and chemoradiation regimens. We then discuss the interaction between EGFR and radiation including radiation induced EGFR signaling, the effect of EGFR on DNA damage repair, and potential mechanisms of radiosensitization. Finally, we examine the potential pitfalls with scheduling EGFR targeted therapies with chemoradiation and the use of predictive biomarkers to improve patient selection. PMID:26205191

Impact of Matrix-Assisted Laser Desorption and Ionization Time-of-Flight and Antimicrobial Stewardship Intervention on Treatment of Bloodstream Infections in Hospitalized Children.

PubMed

Malcolmson, Caroline; Ng, Karen; Hughes, Shevaun; Kissoon, Niranjan; Schina, Jillian; Tilley, Peter A; Roberts, Ashley

2017-06-01

Early definitive identification of infectious pathogens coupled with antimicrobial stewardship interventions allow for targeted and timely administration of antimicrobials. We investigated the combined impact of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) technology and an antimicrobial stewardship program (ASP) in pediatric patients with blood stream infections (BSIs). This is a single-center study comparing a control group of patients from October 2009 to July 2010 with BSIs to a cohort of patients postimplementation of MALDI-TOF and an ASP, from October 2013 to July 2014. Primary outcome was time to optimal therapy. Secondary outcomes included time to effective therapy, 30-day all-cause mortality, 30-day readmission rate, hospital length of stay, and intensive care admission. One hundred episodes of BSIs were identified in the preintervention period, and 121 episodes were identified in the postintervention period. Time from blood culture collection to organism identification was significantly reduced in the prospective cohort compared with historical controls (18.8 vs 43.7 hours, respectively). A total of 73 ASP interventions were made on the treatment of BSIs in the postintervention period. Combined use of MALDI-TOF and ASP significantly reduced time to optimal therapy (77.0 to 54.2 hours, P < .001). In the subgroup analysis of Gram-negative bacteremia, time to effective and optimal therapy were significantly reduced (2.0 vs 0.7 hours and 146.8 vs 48.0 hours, respectively). There were no significant differences in clinical outcomes. The combined use of MALDI-TOF and ASP allows early optimization of antimicrobial therapy in pediatric inpatients with BSIs. © The Author 2016. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Output-driven feedback system control platform optimizes combinatorial therapy of tuberculosis using a macrophage cell culture model.

PubMed

Silva, Aleidy; Lee, Bai-Yu; Clemens, Daniel L; Kee, Theodore; Ding, Xianting; Ho, Chih-Ming; Horwitz, Marcus A

2016-04-12

Tuberculosis (TB) remains a major global public health problem, and improved treatments are needed to shorten duration of therapy, decrease disease burden, improve compliance, and combat emergence of drug resistance. Ideally, the most effective regimen would be identified by a systematic and comprehensive combinatorial search of large numbers of TB drugs. However, optimization of regimens by standard methods is challenging, especially as the number of drugs increases, because of the extremely large number of drug-dose combinations requiring testing. Herein, we used an optimization platform, feedback system control (FSC) methodology, to identify improved drug-dose combinations for TB treatment using a fluorescence-based human macrophage cell culture model of TB, in which macrophages are infected with isopropyl β-D-1-thiogalactopyranoside (IPTG)-inducible green fluorescent protein (GFP)-expressing Mycobacterium tuberculosis (Mtb). On the basis of only a single screening test and three iterations, we identified highly efficacious three- and four-drug combinations. To verify the efficacy of these combinations, we further evaluated them using a methodologically independent assay for intramacrophage killing of Mtb; the optimized combinations showed greater efficacy than the current standard TB drug regimen. Surprisingly, all top three- and four-drug optimized regimens included the third-line drug clofazimine, and none included the first-line drugs isoniazid and rifampin, which had insignificant or antagonistic impacts on efficacy. Because top regimens also did not include a fluoroquinolone or aminoglycoside, they are potentially of use for treating many cases of multidrug- and extensively drug-resistant TB. Our study shows the power of an FSC platform to identify promising previously unidentified drug-dose combinations for treatment of TB.

[The optimization of an early rehabilitation program for cerebral stroke patients: the use of different methods of magneto- and laser therapy].

PubMed

Kochetkov, A V; Gorbunov, F E; Minenkov, A A; Strel'tsova, E N; Filina, T F; Krupennikov, A I

2000-01-01

Magnetotherapy and laser therapy were used in complex and complex-combined regimens in 75 patients after cerebral ischemic or hemorrhagic stroke starting on the poststroke week 4-5. Clinico-neurologic, neurophysiological and cerebrohemodynamic findings evidence for the highest effectiveness of neurorehabilitation including complex magneto-laser therapy in hemispheric ischemic and hemorrhagic stroke of subcortical location in the absence of marked clinico-tomographic signs of dyscirculatory encephalopathy. Complex-combined magneto-laser therapy is more effective for correction of spastic dystonia. Mutual potentiation of magnetotherapy and laser therapy results in maximal development of collateral circulation and cerebral hemodynamic reserve (84% of the patients). Complex effects manifest in arteriodilating and venotonic effects. Complex magneto-laser therapy is accompanied by reduction of hyperthrombocythemia and hyperfibrinogenemia.

Combination of ultrasound and rtPA enhances fibrinolysis in an In Vitro clot system

PubMed Central

Winter, Philipp; Müller-Werkmeister, Hendrik; Strand, Susanne; König, Jochem; Kempski, Oliver; Ringel, Florian; Kantelhardt, Sven R.; Keric, Naureen

2017-01-01

Background Catheter-based lysis with recombinant tissue plasminogen activator (rtPA) is a well-established therapy for spontaneous intracerebral hemorrhage (ICH). The effectiveness of this therapy can be increased with ultrasound, but the optimal conditions are not yet clearly established. Using a novel in vitro system of blood clots previously developed by our group, we investigated various parameters of intralesional sonothrombolysis using an endosonography catheter in combination with rtPA. Methods Standardized human blood clots were equipped with a drainage catheter and weighed before and after 4 treatments: control (drainage only), rtPA only, ultrasound only and the combination of rtPA+ultrasound. The effectiveness of ultrasound was further analysed in terms of optimal frequency, duration and distance to the probe. Temperature and acoustic peak rarefaction pressure (APRP) were assessed to analyse potential adverse effects and quantify lysis. Histo-morphological analysis of the treated clots was performed by H&E staining and confocal laser scanning microscopy using fluorescent fibrinogen. Results The combined treatment rtPA+ultrasound achieved the highest lysis rates with a relative weight of 30.3%±5.5% (p≤0.0001) compared to all other groups. Similar results were observed when treating aged clots. Confocal fluorescent microscopy of the treated clots revealed a rarefied fibrin mesh without cavitations. No relevant temperature increase occurred (0.53±0.75°C). The optimal insonation treatment time was 1 hour. APRP measurements showed a lysis threshold of 515.5±113.4 kPa. Application of 10 MHz achieved optimal lysis and lysis radius, while simultaneously proving to be the best frequency for morphologic imaging of the clot and surrounding tissue. Conclusions These promising data provide the basis for an individualized minimal invasive ICH therapy by rtPA and sonothrombolysis independent of ICH age. PMID:29145482

A modular approach to intensity-modulated arc therapy optimization with noncoplanar trajectories

NASA Astrophysics Data System (ADS)

Papp, Dávid; Bortfeld, Thomas; Unkelbach, Jan

2015-07-01

Utilizing noncoplanar beam angles in volumetric modulated arc therapy (VMAT) has the potential to combine the benefits of arc therapy, such as short treatment times, with the benefits of noncoplanar intensity modulated radiotherapy (IMRT) plans, such as improved organ sparing. Recently, vendors introduced treatment machines that allow for simultaneous couch and gantry motion during beam delivery to make noncoplanar VMAT treatments possible. Our aim is to provide a reliable optimization method for noncoplanar isocentric arc therapy plan optimization. The proposed solution is modular in the sense that it can incorporate different existing beam angle selection and coplanar arc therapy optimization methods. Treatment planning is performed in three steps. First, a number of promising noncoplanar beam directions are selected using an iterative beam selection heuristic; these beams serve as anchor points of the arc therapy trajectory. In the second step, continuous gantry/couch angle trajectories are optimized using a simple combinatorial optimization model to define a beam trajectory that efficiently visits each of the anchor points. Treatment time is controlled by limiting the time the beam needs to trace the prescribed trajectory. In the third and final step, an optimal arc therapy plan is found along the prescribed beam trajectory. In principle any existing arc therapy optimization method could be incorporated into this step; for this work we use a sliding window VMAT algorithm. The approach is demonstrated using two particularly challenging cases. The first one is a lung SBRT patient whose planning goals could not be satisfied with fewer than nine noncoplanar IMRT fields when the patient was treated in the clinic. The second one is a brain tumor patient, where the target volume overlaps with the optic nerves and the chiasm and it is directly adjacent to the brainstem. Both cases illustrate that the large number of angles utilized by isocentric noncoplanar VMAT plans can help improve dose conformity, homogeneity, and organ sparing simultaneously using the same beam trajectory length and delivery time as a coplanar VMAT plan.

Antimicrobial photodynamic therapy combined with conventional endodontic treatment to eliminate root canal biofilm infection.

PubMed

Garcez, Aguinaldo S; Ribeiro, Martha S; Tegos, George P; Núñez, Silvia C; Jorge, Antonio O C; Hamblin, Michael R

2007-01-01

To compare the effectiveness of antimicrobial photodynamic therapy (PDT), standard endodontic treatment and the combined treatment to eliminate bacterial biofilms present in infected root canals. Ten single-rooted freshly extracted human teeth were inoculated with stable bioluminescent Gram-negative bacteria, Proteus mirabilis and Pseudomonas aeruginosa to form 3-day biofilms in prepared root canals. Bioluminescence imaging was used to serially quantify bacterial burdens. PDT employed a conjugate between polyethylenimine and chlorin(e6) as the photosensitizer (PS) and 660-nm diode laser light delivered into the root canal via a 200-micro fiber, and this was compared and combined with standard endodontic treatment using mechanical debridement and antiseptic irrigation. Endodontic therapy alone reduced bacterial bioluminescence by 90% while PDT alone reduced bioluminescence by 95%. The combination reduced bioluminescence by >98%, and importantly the bacterial regrowth observed 24 hours after treatment was much less for the combination (P<0.0005) than for either single treatment. Bioluminescence imaging is an efficient way to monitor endodontic therapy. Antimicrobial PDT may have a role to play in optimized endodontic therapy. (c) 2006 Wiley-Liss, Inc.

Design of clinical trials involving multiple hypothesis tests with a common control.

PubMed

Schou, I Manjula; Marschner, Ian C

2017-07-01

Randomized clinical trials comparing several treatments to a common control are often reported in the medical literature. For example, multiple experimental treatments may be compared with placebo, or in combination therapy trials, a combination therapy may be compared with each of its constituent monotherapies. Such trials are typically designed using a balanced approach in which equal numbers of individuals are randomized to each arm, however, this can result in an inefficient use of resources. We provide a unified framework and new theoretical results for optimal design of such single-control multiple-comparator studies. We consider variance optimal designs based on D-, A-, and E-optimality criteria, using a general model that allows for heteroscedasticity and a range of effect measures that include both continuous and binary outcomes. We demonstrate the sensitivity of these designs to the type of optimality criterion by showing that the optimal allocation ratios are systematically ordered according to the optimality criterion. Given this sensitivity to the optimality criterion, we argue that power optimality is a more suitable approach when designing clinical trials where testing is the objective. Weighted variance optimal designs are also discussed, which, like power optimal designs, allow the treatment difference to play a major role in determining allocation ratios. We illustrate our methods using two real clinical trial examples taken from the medical literature. Some recommendations on the use of optimal designs in single-control multiple-comparator trials are also provided. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Artificial intelligence in drug combination therapy.

PubMed

Tsigelny, Igor F

2018-02-09

Currently, the development of medicines for complex diseases requires the development of combination drug therapies. It is necessary because in many cases, one drug cannot target all necessary points of intervention. For example, in cancer therapy, a physician often meets a patient having a genomic profile including more than five molecular aberrations. Drug combination therapy has been an area of interest for a while, for example the classical work of Loewe devoted to the synergism of drugs was published in 1928-and it is still used in calculations for optimal drug combinations. More recently, over the past several years, there has been an explosion in the available information related to the properties of drugs and the biomedical parameters of patients. For the drugs, hundreds of 2D and 3D molecular descriptors for medicines are now available, while for patients, large data sets related to genetic/proteomic and metabolomics profiles of the patients are now available, as well as the more traditional data relating to the histology, history of treatments, pretreatment state of the organism, etc. Moreover, during disease progression, the genetic profile can change. Thus, the ability to optimize drug combinations for each patient is rapidly moving beyond the comprehension and capabilities of an individual physician. This is the reason, that biomedical informatics methods have been developed and one of the more promising directions in this field is the application of artificial intelligence (AI). In this review, we discuss several AI methods that have been successfully implemented in several instances of combination drug therapy from HIV, hypertension, infectious diseases to cancer. The data clearly show that the combination of rule-based expert systems with machine learning algorithms may be promising direction in this field. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Integrative Therapies for Low Back Pain That Include Complementary and Alternative Medicine Care: A Systematic Review

PubMed Central

Rose, Kevin; Kadar, Gena E.

2014-01-01

Study Design: Systematic review of the literature. Objective: To evaluate whether an integrated approach that includes different Complementary and Alternative Medicine (CAM) therapies combined or CAM therapies combined with conventional medical care is more effective for the management of low back pain (LBP) than single modalities alone. Summary of Background Data: LBP is one of the leading causes of disability worldwide, yet its optimal management is still unresolved. Methods: The PRISMA Statement guidelines were followed. The Cochrane Back Review Group scale was used to rate the quality of the studies found. Results: Twenty-one studies were found that met the inclusion criteria. The CAM modalities used in the studies included spinal manipulative therapy, acupuncture, exercise therapy, physiotherapy, massage therapy, and a topical ointment. Twenty studies included acupuncture and/or spinal manipulative therapy. Nine high quality studies showed that integrative care was clinically effective for the management of LBP. Spinal manipulative therapy combined with exercise therapy and acupuncture combined with conventional medical care or with exercise therapy appears to be promising approaches to the management of chronic cases of LBP. Conclusions: There is support in the literature for integrated CAM and conventional medical therapy for the management of chronic LBP. Further research into the integrated management of LBP is clearly needed to provide better guidance for patients and clinicians. PMID:25568825

Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone.

PubMed

Jovanovic, Lois; Hassman, David R; Gooch, Brent; Jain, Rajeev; Greco, Susan; Khutoryansky, Naum; Hale, Paula M

2004-02-01

The efficacy and safety of combination therapy (repaglinide plus pioglitazone) was compared to repaglinide or pioglitazone in 24-week treatment of type 2 diabetes. This randomized, multicenter, open-label, parallel-group study enrolled 246 adults (age 24-85) who had shown inadequate response in previous sulfonylurea or metformin monotherapy (HbA(1c) > 7%). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, pioglitazone, or repaglinide/pioglitazone. In the first 12 weeks of treatment, repaglinide doses were optimized, followed by 12 weeks of maintenance therapy. Pioglitazone dosage was fixed at 30 mg per day. Baseline HbA(1c) values were comparable (9.0% for repaglinide, 9.1% for pioglitazone, 9.3% for combination). Mean changes in HbA(1c) values at the end of treatment were -1.76% for repaglinide/pioglitazone, -0.18% for repaglinide, +0.32% for pioglitazone. Fasting plasma glucose reductions were -82 mg/dl for combination therapy, -34 mg/dl for repaglinide, -18 mg/dl for pioglitazone. Minor hypoglycemia occurred in 5% of patients for the combination, 8% for repaglinide, and 3% for pioglitazone. Weight gains for combination therapy were correlated to individual HbA(1c) reductions. In summary, for patients who had previously failed oral antidiabetic monotherapy, the combination repaglinide/pioglitazone had acceptable safety, with greater reductions of glycemic parameters than therapy using either agent alone.

An Effective Solution to Discover Synergistic Drugs for Anti-Cerebral Ischemia from Traditional Chinese Medicinal Formulae

PubMed Central

Lu, Peng; Chen, Chang; Fu, Meihong; Fang, Jing; Gao, Jian; Zhu, Li; Liang, Rixin; Shen, Xin; Yang, Hongjun

2013-01-01

Recently, the pharmaceutical industry has shifted to pursuing combination therapies that comprise more than one active ingredient. Interestingly, combination therapies have been used for more than 2500 years in traditional Chinese medicine (TCM). Understanding optimal proportions and synergistic mechanisms of multi-component drugs are critical for developing novel strategies to combat complex diseases. A new multi-objective optimization algorithm based on least angle regression-partial least squares was proposed to construct the predictive model to evaluate the synergistic effect of the three components of a novel combination drug Yi-qi-jie-du formula (YJ), which came from clinical TCM prescription for the treatment of encephalopathy. Optimal proportion of the three components, ginsenosides (G), berberine (B) and jasminoidin (J) was determined via particle swarm optimum. Furthermore, the combination mechanisms were interpreted using PLS VIP and principal components analysis. The results showed that YJ had optimal proportion 3(G): 2(B): 0.5(J), and it yielded synergy in the treatment of rats impaired by middle cerebral artery occlusion induced focal cerebral ischemia. YJ with optimal proportion had good pharmacological effects on acute ischemic stroke. The mechanisms study demonstrated that the combination of G, B and J could exhibit the strongest synergistic effect. J might play an indispensable role in the formula, especially when combined with B for the acute stage of stroke. All these data in this study suggested that in the treatment of acute ischemic stroke, besides restoring blood supply and protecting easily damaged cells in the area of the ischemic penumbra as early as possible, we should pay more attention to the removal of the toxic metabolites at the same time. Mathematical system modeling may be an essential tool for the analysis of the complex pharmacological effects of multi-component drug. The powerful mathematical analysis method could greatly improve the efficiency in finding new combination drug from TCM. PMID:24236065

Comparison of efficacy and tolerance between combination therapy and monotherapy as first-line chemotherapy in elderly patients with advanced gastric cancer: Study protocol for a randomized controlled trial.

PubMed

Lee, Keun-Wook; Zang, Dae Young; Ryu, Min-Hee; Kim, Ki Hyang; Kim, Mi-Jung; Han, Hye Sook; Koh, Sung Ae; Park, Jin Hyun; Kim, Jin Won; Nam, Byung-Ho; Choi, In Sil

2017-12-01

The combination of a fluoropyrimidine [5-fluorouracil (5-FU), capecitabine, or S-1] with a platinum analog (cisplatin or oxaliplatin) is the most widely accepted first-line chemotherapy regimen for metastatic or recurrent advanced gastric cancer (AGC), based on the results of clinical trials. However, there is little evidence to guide chemotherapy for elderly patients with AGC because of under-representation of this age group in clinical trials. Thus, the aim of this study is to determine the optimal chemotherapy regimen for elderly patients with AGC by comparing the efficacies and safeties of combination therapy versus monotherapy as first-line chemotherapy. This study is a randomized, controlled, multicenter, phase III trial. A total of 246 elderly patients (≥70 years old) with metastatic or recurrent AGC who have not received previous palliative chemotherapy will be randomly allocated to a combination therapy group or a monotherapy group. Patients randomized to the combination therapy group will receive fluoropyrimidine plus platinum combination chemotherapy (capecitabine/cisplatin, S-1/cisplatin, capecitabine/oxaliplatin, or 5-FU/oxaliplatin), and those randomized to the monotherapy group will receive fluoropyrimidine monotherapy (capecitabine, S-1, or 5-FU). The primary outcome is the overall survival of patients in each treatment group. The secondary outcomes include progression-free survival, response rate, quality of life, and safety. We are conducting this pragmatic trial to determine whether elderly patients with AGC will obtain the same benefit from chemotherapy as younger patients. We expect that this study will help guide decision-making for the optimal treatment of elderly patients with AGC.

Negative pressure wound therapy combined with acoustic pressure wound therapy for infected post surgery wounds: a case series.

PubMed

Howell-Taylor, Melania; Hall, Macy G; Brownlee Iii, William J; Taylor, Mary

2008-09-01

Acute infection of surgical incision sites often requires specialized wound care in preparation for surgical closure. Optimal therapy for preparing such wounds for a secondary closure procedure remains uncertain. The authors report wound outcomes after administering acoustic pressure wound therapy in conjunction with negative pressure wound therapy with reticulated open-cell foam dressing changes to assist with bacteria removal from open, infected surgical-incision sites in preparation for secondary surgical closure in three patients. Before incorporating acoustic pressure wound therapy at the authors' facility, the average negative pressure wound therapy with reticulated open-cell foam dressing course prior to secondary surgical closure was 30 days; with its addition, two of three patients underwent successful surgical closure with no postoperative complications after 21 and 14 days, respectively; one patient succumbed to nonwound-related complications before wound closure. Larger, prospective studies are needed to evaluate combining negative pressure wound therapy with reticulated open-cell foam dressing and acoustic pressure wound therapy for infected, acute post surgery wounds.

Combination antibiotic therapy for the treatment of infective endocarditis due to enterococci.

PubMed

Leone, Sebastiano; Noviello, Silvana; Esposito, Silvano

2016-06-01

Enterococci are common causes of infective endocarditis (IE) in both health care and community-based setting. Enterococcal IE requires bactericidal therapy for an optimal outcome. For decades, cell-wall-active antimicrobial agents (penicillins or vancomycin) in combination with aminoglycosides were the cornerstone of the treatment; however, the emergence of antibiotic resistance has significantly reduced the efficacy of these regimens. Data for this review were identified by searches of MEDLINE and references from relevant articles on antibiotic combination regimens for the treatment of enterococcal IE. Abstracts presented in scientific conferences were not searched for. New effective and safe combination treatments, including double-β-lactam and daptomycin/β-lactam combination, are proving useful for the management of IE due to enterococci.

Antimicrobial Photodynamic Therapy Combined With Conventional Endodontic Treatment to Eliminate Root Canal Biofilm Infection

PubMed Central

Garcez, Aguinaldo S.; Ribeiro, Martha S.; Tegos, George P.; Núñez, Silvia C.; Jorge, Antonio O.C.; Hamblin, Michael R.

2011-01-01

Background and Objective To compare the effectiveness of antimicrobial photodynamic therapy (PDT), standard endodontic treatment and the combined treatment to eliminate bacterial biofilms present in infected root canals. Study Design/Materials and Methods Ten single-rooted freshly extracted human teeth were inoculated with stable bioluminescent Gram-negative bacteria, Proteus mirabilis and Pseudomonas aeruginosa to form 3-day biofilms in prepared root canals. Bioluminescence imaging was used to serially quantify bacterial burdens. PDT employed a conjugate between polyethylenimine and chlorin(e6) as the photosensitizer (PS) and 660-nm diode laser light delivered into the root canal via a 200-µ fiber, and this was compared and combined with standard endodontic treatment using mechanical debridement and antiseptic irrigation. Results Endodontic therapy alone reduced bacterial bioluminescence by 90% while PDT alone reduced bioluminescence by 95%. The combination reduced bioluminescence by >98%, and importantly the bacterial regrowth observed 24 hours after treatment was much less for the combination (P<0.0005) than for either single treatment. Conclusions Bioluminescence imaging is an efficient way to monitor endodontic therapy. Antimicrobial PDT may have a role to play in optimized endodontic therapy. PMID:17066481

[Antibiotics in the critically ill].

PubMed

Kolak, Radmila R

2010-01-01

Antibiotics are one the most common therapies administered in the intensive care unit setting. This review outlines the strategy for optimal use of antimicrobial agents in the critically ill. In severely ill patients, empirical antimicrobial therapy should be used when a suspected infection may impair the outcome. It is necessary to collect microbiological documentation before initiating empirical antimicrobial therapy. In addition to antimicrobial therapy, it is recommended to control a focus of infection and to modify factors that promote microbial growth or impair the host's antimicrobial defence. A judicious choice of antimicrobial therapy should be based on the host characteristics, the site of injection, the local ecology, and the pharmacokinetics/pharmacodynamics of antibiotics. This means treating empirically with broad-spectrum antimicrobials as soon as possible and narrowing the spectrum once the organism is identified (de-escalation), and limiting duration of therapy to the minimum effective period. Despite theoretical advantages, a combined antibiotic therapy is nor more effective than a mono-therapy in curing infections in most clinical trials involving intensive care patients. Nevertheless, textbooks and guidelines recommend a combination for specific pathogens and for infections commonly caused by these pathogens. Avoiding unnecessary antibiotic use and optimizing the administration of antimicrobial agents will improve patient outcomes while minimizing risks for the development of bacterial resistance. It is important to note that each intensive care unit should have a program in place which monitors antibiotic utilisation and its effectiveness. Only in this way can the impact of interventions aimed at improving antibiotic use be evaluated at the local level.

Cost-utility Analysis: Thiopurines Plus Endoscopy-guided Biological Step-up Therapy is the Optimal Management of Postoperative Crohn's Disease.

PubMed

Candia, Roberto; Naimark, David; Sander, Beate; Nguyen, Geoffrey C

2017-11-01

Postoperative recurrence of Crohn's disease is common. This study sought to assess whether the postoperative management should be based on biological therapy alone or combined with thiopurines and whether the therapy should be started immediately after surgery or guided by either endoscopic or clinical recurrence. A Markov model was developed to estimate expected health outcomes in quality-adjusted life years (QALYs) and costs in Canadian dollars (CAD$) accrued by hypothetical patients with high recurrence risk after ileocolic resection. Eight strategies of postoperative management were evaluated. A lifetime time horizon, an annual discount rate of 5%, a societal perspective, and a cost-effectiveness threshold of 50,000 CAD$/QALY were assumed. Deterministic and probabilistic sensitivity analyses were conducted. The model was validated against randomized trials and historical cohorts. Three strategies dominated the others: endoscopy-guided full step-up therapy (14.80 QALYs, CAD$ 462,180), thiopurines immediately post-surgery plus endoscopy-guided biological step-up therapy (14.89 QALYs, CAD$ 464,099) and combination therapy immediately post-surgery (14.94 QALYs, CAD$ 483,685). The second strategy was the most cost-effective, assuming a cost-effectiveness threshold of 50,000 CAD$/QALY. Probabilistic sensitivity analysis showed that the second strategy has the highest probability of being the optimal alternative in all comparisons at cost-effectiveness thresholds from 30,000 to 100,000 CAD$/QALY. The strategies guided only by clinical recurrence and those using biologics alone were dominated. According to this decision analysis, thiopurines immediately after surgery and addition of biologics guided by endoscopic recurrence is the optimal strategy of postoperative management in patients with Crohn's disease with high risk of recurrence (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B654).

Can magneto-plasmonic nanohybrids efficiently combine photothermia with magnetic hyperthermia?

NASA Astrophysics Data System (ADS)

Espinosa, Ana; Bugnet, Mathieu; Radtke, Guillaume; Neveu, Sophie; Botton, Gianluigi A.; Wilhelm, Claire; Abou-Hassan, Ali

2015-11-01

Multifunctional hybrid-design nanomaterials appear to be a promising route to meet the current therapeutics needs required for efficient cancer treatment. Herein, two efficient heat nano-generators were combined into a multifunctional single nanohybrid (a multi-core iron oxide nanoparticle optimized for magnetic hyperthermia, and a gold branched shell with tunable plasmonic properties in the NIR region, for photothermal therapy) which impressively enhanced heat generation, in suspension or in vivo in tumours, opening up exciting new therapeutic perspectives.Multifunctional hybrid-design nanomaterials appear to be a promising route to meet the current therapeutics needs required for efficient cancer treatment. Herein, two efficient heat nano-generators were combined into a multifunctional single nanohybrid (a multi-core iron oxide nanoparticle optimized for magnetic hyperthermia, and a gold branched shell with tunable plasmonic properties in the NIR region, for photothermal therapy) which impressively enhanced heat generation, in suspension or in vivo in tumours, opening up exciting new therapeutic perspectives. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06168g

Combined Treatment Effects of Radiation and Immunotherapy: Studies in an Autochthonous Prostate Cancer Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wada, Satoshi; Harris, Timothy J.; Tryggestad, Erik

2013-11-15

Purpose: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. Methods and Materials: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. Results: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evidentmore » with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. Conclusions: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.« less

Towards an optimal treatment algorithm for metastatic pancreatic ductal adenocarcinoma (PDA)

PubMed Central

Uccello, M.; Moschetta, M.; Mak, G.; Alam, T.; Henriquez, C. Murias; Arkenau, H.-T.

2018-01-01

Chemotherapy remains the mainstay of treatment for advanced pancreatic ductal adenocarcinoma (pda). Two randomized trials have demonstrated superiority of the combination regimens folfirinox (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) and gemcitabine plus nab-paclitaxel over gemcitabine monotherapy as a first-line treatment in adequately fit subjects. Selected pda patients progressing to first-line therapy can receive secondline treatment with moderate clinical benefit. Nevertheless, the optimal algorithm and the role of combination therapy in second-line are still unclear. Published second-line pda clinical trials enrolled patients progressing to gemcitabine-based therapies in use before the approval of nab-paclitaxel and folfirinox. The evolving scenario in second-line may affect the choice of the first-line treatment. For example, nanoliposomal irinotecan plus 5-fluouracil and leucovorin is a novel second-line option which will be suitable only for patients progressing to gemcitabine-based therapy. Therefore, clinical judgement and appropriate patient selection remain key elements in treatment decision. In this review, we aim to illustrate currently available options and define a possible algorithm to guide treatment choice. Future clinical trials taking into account sequential treatment as a new paradigm in pda will help define a standard algorithm. PMID:29507500

Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens.

PubMed

Wu, Lan; Leng, Donglei; Cun, Dongmei; Foged, Camilla; Yang, Mingshi

2017-08-28

Lung cancer is a complex disease caused by a multitude of genetic and environmental factors. The progression of lung cancer involves dynamic changes in the genome and a complex network of interactions between cancer cells with multiple, distinct cell types that form tumors. Combination therapy using different pharmaceuticals has been proven highly effective due to the ability to affect multiple cellular pathways involved in the disease progression. However, the currently used drug combination designs are primarily based on empirical clinical studies, and little attention has been given to dosage regimens, i.e. how administration routes, onsets, and durations of the combinations influence the therapeutic outcome. This is partly because combination therapy is challenged by distinct physicochemical properties and in vivo pharmacokinetics/pharmacodynamics of the individual pharmaceuticals, including small molecule drugs and biopharmaceuticals, which make the optimization of dosing and administration schedule challenging. This article reviews the recent advances in the design and development of combinations of pharmaceuticals for the treatment of lung cancer. Focus is primarily on rationales for the selection of specific combination therapies for lung cancer treatment, and state of the art of delivery technologies and dosage regimens for the combinations, tested in preclinical and clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Combination decongestion therapy in hospitalized heart failure: loop diuretics, mineralocorticoid receptor antagonists and vasopressin antagonists.

PubMed

Vaduganathan, Muthiah; Mentz, Robert J; Greene, Stephen J; Senni, Michele; Sato, Naoki; Nodari, Savina; Butler, Javed; Gheorghiade, Mihai

2015-01-01

Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality.

Updated Review: Improved Glycemic Control with Repaglinide-Metformin in Fixed Combination for Patients with Type 2 Diabetes

PubMed Central

Richard, John W.; Raskin, Philip

2011-01-01

As the prevalence of type 2 diabetes continues to rise, new drug therapies will need to be explored to prevent morbidity and mortality associated with diabetes as well as growing health care costs. Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. Numerous oral medications are currently approved for the treatment of type 2 diabetes. A treat-to-failure approach has traditionally been adopted with step-wise additions of oral medications; however, a growing frequency of treatment failures with monotherapy has led to the use of combination therapies earlier in the treatment of type 2 diabetes. One such combination regimen is repaglinide (a prandial glucose optimizer that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output and increases peripheral glucose uptake while minimizing weight gain). Findings from several clinical trials have shown repaglinide plus metformin combination therapy to be superior to either monotherapy with significant reductions in hemoglobin A1C and fasting glucose values. Repaglinide used in combination also has shown less incidence of hypoglycemia compared with other combination therapies such as sulphonylureas plus metformin. Repaglinide plus metformin combination therapy appears to be a valuable therapeutic option for type 2 diabetic patients seeking a less complex drug regimen while potentially achieving better glucose control if currently inadequately controlled on monotherapy. PMID:22879792

Updated review: improved glycemic control with repaglinide-metformin in fixed combination for patients with type 2 diabetes.

PubMed

Richard, John W; Raskin, Philip

2011-01-01

As the prevalence of type 2 diabetes continues to rise, new drug therapies will need to be explored to prevent morbidity and mortality associated with diabetes as well as growing health care costs. Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. Numerous oral medications are currently approved for the treatment of type 2 diabetes. A treat-to-failure approach has traditionally been adopted with step-wise additions of oral medications; however, a growing frequency of treatment failures with monotherapy has led to the use of combination therapies earlier in the treatment of type 2 diabetes. One such combination regimen is repaglinide (a prandial glucose optimizer that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output and increases peripheral glucose uptake while minimizing weight gain). Findings from several clinical trials have shown repaglinide plus metformin combination therapy to be superior to either monotherapy with significant reductions in hemoglobin A1C and fasting glucose values. Repaglinide used in combination also has shown less incidence of hypoglycemia compared with other combination therapies such as sulphonylureas plus metformin. Repaglinide plus metformin combination therapy appears to be a valuable therapeutic option for type 2 diabetic patients seeking a less complex drug regimen while potentially achieving better glucose control if currently inadequately controlled on monotherapy.

Cisplatin Cross-Linked Multifunctional Nanodrugplexes for Combination Therapy.

PubMed

Zhang, Weiqi; Tung, Ching-Hsuan

2017-03-15

Combination therapy efficiently tackles cancer by hitting multiple action mechanisms. However, drugs administered, simultaneously or sequentially, may not reach the targeted sites with the desired dose and ratio. The outcomes of combination therapy could be improved with a polymeric nanoparticle, which can simultaneously transport an optimal combination of drugs. We have demonstrated a simple one-pot strategy to formulate nanomedicines based on platinum coordination and the noncovalent interactions of the drugs. A naturally occurring polymer, hyaluronan (HA), was chosen as the building scaffold to form a nanodrugplex with cisplatin and aromatic-cationic drugs. The platinum coordination between cisplatin and HA induces the formation of a nanocomplex. The aromatic-cationic drugs are tightly packed by an electrostatic interaction and π-π stacking. The nanodrugplex bears excellent flexibility in drug combination and size control. It is stable in storage and has favorable release kinetics and targeting capabilities toward CD44, a receptor for HA that is highly expressed on many types of cancer cells.

Optimal simulations of ultrasonic fields produced by large thermal therapy arrays using the angular spectrum approach

PubMed Central

Zeng, Xiaozheng; McGough, Robert J.

2009-01-01

The angular spectrum approach is evaluated for the simulation of focused ultrasound fields produced by large thermal therapy arrays. For an input pressure or normal particle velocity distribution in a plane, the angular spectrum approach rapidly computes the output pressure field in a three dimensional volume. To determine the optimal combination of simulation parameters for angular spectrum calculations, the effect of the size, location, and the numerical accuracy of the input plane on the computed output pressure is evaluated. Simulation results demonstrate that angular spectrum calculations performed with an input pressure plane are more accurate than calculations with an input velocity plane. Results also indicate that when the input pressure plane is slightly larger than the array aperture and is located approximately one wavelength from the array, angular spectrum simulations have very small numerical errors for two dimensional planar arrays. Furthermore, the root mean squared error from angular spectrum simulations asymptotically approaches a nonzero lower limit as the error in the input plane decreases. Overall, the angular spectrum approach is an accurate and robust method for thermal therapy simulations of large ultrasound phased arrays when the input pressure plane is computed with the fast nearfield method and an optimal combination of input parameters. PMID:19425640

[Effect of ginseng rare ginsenoside components combined with paclitaxel on A549 lung cancer].

PubMed

Yang, Lei; Zhang, Zhen-Hai; Jia, Xiao-Bin

2018-04-01

Traditional Chinese medicine combined with anticancer drugs is a new direction of clinical cancer therapy in recent years. In this study, the optimal ratio of ginseng rare ginsenoside components and paclitaxel was optimized by MTT method, and the proliferative, apoptotic and anti-tumor effects of lung cancer A549 cells were investigated. It was found that the inhibitory effect on the proliferation of lung cancer A549 cells was the same as that on paclitaxel when the ratio of rare ginseng rare ginsenoside components to paclitaxel was 4∶6. Further studies showed that the combined therapy significantly increased the inductive effect of apoptosis in A549 cells, and up-regulated the expression of caspase-3 protein and down-regulated the ratio of Bcl-2/Bax. The tumor-bearing mice model showed that the combination therapy of ginseng rare ginsenoside components and paclitaxel could significantly inhibit the growth of tumor and alleviate the toxic and side effects of paclitaxel on liver. A multi-component system of ginseng rare ginsenoside components-paclitaxel was established in this paper. The proliferation and growth of lung cancer A549 cells were inhibited by paclitaxel-induced apoptosis, the dosage of paclitaxel and the toxicity of paclitaxel were reduced, and the effect of anti-lung cancer was enhanced, which provided a theoretical basis for later studies and clinical application. Copyright© by the Chinese Pharmaceutical Association.

EUD-based biological optimization for carbon ion therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brüningk, Sarah C., E-mail: sarah.brueningk@icr.ac.uk; Kamp, Florian; Wilkens, Jan J.

2015-11-15

Purpose: Treatment planning for carbon ion therapy requires an accurate modeling of the biological response of each tissue to estimate the clinical outcome of a treatment. The relative biological effectiveness (RBE) accounts for this biological response on a cellular level but does not refer to the actual impact on the organ as a whole. For photon therapy, the concept of equivalent uniform dose (EUD) represents a simple model to take the organ response into account, yet so far no formulation of EUD has been reported that is suitable to carbon ion therapy. The authors introduce the concept of an equivalentmore » uniform effect (EUE) that is directly applicable to both ion and photon therapies and exemplarily implemented it as a basis for biological treatment plan optimization for carbon ion therapy. Methods: In addition to a classical EUD concept, which calculates a generalized mean over the RBE-weighted dose distribution, the authors propose the EUE to simplify the optimization process of carbon ion therapy plans. The EUE is defined as the biologically equivalent uniform effect that yields the same probability of injury as the inhomogeneous effect distribution in an organ. Its mathematical formulation is based on the generalized mean effect using an effect-volume parameter to account for different organ architectures and is thus independent of a reference radiation. For both EUD concepts, quadratic and logistic objective functions are implemented into a research treatment planning system. A flexible implementation allows choosing for each structure between biological effect constraints per voxel and EUD constraints per structure. Exemplary treatment plans are calculated for a head-and-neck patient for multiple combinations of objective functions and optimization parameters. Results: Treatment plans optimized using an EUE-based objective function were comparable to those optimized with an RBE-weighted EUD-based approach. In agreement with previous results from photon therapy, the optimization by biological objective functions resulted in slightly superior treatment plans in terms of final EUD for the organs at risk (OARs) compared to voxel-based optimization approaches. This observation was made independent of the underlying objective function metric. An absolute gain in OAR sparing was observed for quadratic objective functions, whereas intersecting DVHs were found for logistic approaches. Even for considerable under- or overestimations of the used effect- or dose–volume parameters during the optimization, treatment plans were obtained that were of similar quality as the results of a voxel-based optimization. Conclusions: EUD-based optimization with either of the presented concepts can successfully be applied to treatment plan optimization. This makes EUE-based optimization for carbon ion therapy a useful tool to optimize more specifically in the sense of biological outcome while voxel-to-voxel variations of the biological effectiveness are still properly accounted for. This may be advantageous in terms of computational cost during treatment plan optimization but also enables a straight forward comparison of different fractionation schemes or treatment modalities.« less

Search Algorithms as a Framework for the Optimization of Drug Combinations

PubMed Central

Coquin, Laurence; Schofield, Jennifer; Feala, Jacob D.; Reed, John C.; McCulloch, Andrew D.; Paternostro, Giovanni

2008-01-01

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms—originally developed for digital communication—modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs using only one-third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6–9 interventions in 80–90% of tests, compared with 15–30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution. PMID:19112483

[Changes of twenty-four-hour profile blood pressure and its correction of patients with arterial hypertension on the background of combined antihypertensive therapy application].

PubMed

Solomennchuk, T M; Slaba, N A; Prots'ko, V V; Bedzaĭ, A O

2014-01-01

The aim of this research was the study of efficiency and endurance antihypertensive therapy on the basis of fixed combination of enalapril and hydrochlorothiazide (HCTZ) and enalapril and HCTZ in combination with amlodipine according to the twenty-four-hour (? day-and-night) monitoring of blood pressure (? 24H BPM) of patients with arterial hypertension (AH) 2-3 severity. The study included 33 patients with 2-3 grade of hypertension (average age--54,40 ± 3.45 years). All patients performed ? 24H BPM before treatment and after 12 weeks of therapy. The combination of enalapril and HCTZ allowed to achieve target levels of blood pressure in 79% of patients, amlodipine additional purpose--in 86% of patients. We found that this therapy has a corrective effect on daily blood pressure profile, significantly reducing the load pressure and blood pressure variability. During treatment with the combination of enalapril and HCTZ combination of enalapril, HCTZ with amlodipine optimal daily profile of blood pressure after 12 weeks of reaching respectively 63.1% and 71.4% of patients. The treatment with combination of enalapril and HCTZ and adding of amlodipine is characterized by good endurance and high adherence to treatment.

[The laser therapy of rheumatoid arthritis].

PubMed

Soroka, N F

1989-01-01

About 300 patients with rheumatoid arthritis (RA) underwent multimodality treatment including laser radiation of varying wavelengths. Use was made of helium-neon, infrared, argon and helium-cadmium lasers. A new method of combined laser therapy by radiation of helium-cadmium and helium-neon lasers is described. A scheme of optimal parameters and types of laser radiation recommended for the treatment of different clinical varieties of RA is provided.

Functional hyper-IL-6 from vaccinia virus-colonized tumors triggers platelet formation and helps to alleviate toxicity of mitomycin C enhanced virus therapy

PubMed Central

2012-01-01

Background Combination of oncolytic vaccinia virus therapy with conventional chemotherapy has shown promise for tumor therapy. However, side effects of chemotherapy including thrombocytopenia, still remain problematic. Methods Here, we describe a novel approach to optimize combination therapy of oncolytic virus and chemotherapy utilizing virus-encoding hyper-IL-6, GLV-1h90, to reduce chemotherapy-associated side effects. Results We showed that the hyper-IL-6 cytokine was successfully produced by GLV-1h90 and was functional both in cell culture as well as in tumor-bearing animals, in which the cytokine-producing vaccinia virus strain was well tolerated. When combined with the chemotherapeutic mitomycin C, the anti-tumor effect of the oncolytic virotherapy was significantly enhanced. Moreover, hyper-IL-6 expression greatly reduced the time interval during which the mice suffered from chemotherapy-induced thrombocytopenia. Conclusion Therefore, future clinical application would benefit from careful investigation of additional cytokine treatment to reduce chemotherapy-induced side effects. PMID:22236378

New Therapies in Head and Neck Cancer.

PubMed

Santuray, Rodell T; Johnson, Daniel E; Grandis, Jennifer R

2018-05-01

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high rates of mortality and morbidity. Beginning with cetuximab, investigators continue to optimize antibody technology to target cell-surface receptors that promote HNSCC growth. Small molecules and oligonucleotides have also emerged as therapeutic inhibitors of key receptor-mediated signaling pathways. Although many such therapies have been disappointing in clinical trials as single agents, they continue to be studied in combination with standard therapies. Approvals of pembrolizumab and nivolumab opened a new era of immunotherapy that aims to stimulate antitumor immunity in the tumor microenvironment. Immunotherapies are being intensively investigated in new HNSCC clinical trials, with the goal of optimizing the therapeutic potential of this new class of anticancer agent. Copyright © 2018 Elsevier Inc. All rights reserved.

Mutation testing for directing upfront targeted therapy and post-progression combination therapy strategies in lung adenocarcinoma

PubMed Central

Salgia, Ravi

2016-01-01

ABSTRACT Introduction: Advances in the biology of non-small-cell lung cancer, especially adenocarcinoma, reveal multiple molecular subtypes driving oncogenesis. Accordingly, individualized targeted therapeutics are based on mutational diagnostics. Areas covered: Advances in strategies and techniques for individualized treatment, particularly of adenocarcinoma, are described through literature review. Approved therapies are established for some molecular subsets, with new driver mutations emerging that represent increasing proportions of patients. Actionable mutations are de novo oncogenic drivers or acquired resistance mediators, and mutational profiling is important for directing therapy. Patients should be monitored for emerging actionable resistance mutations. Liquid biopsy and associated multiplex diagnostics will be important means to monitor patients during treatment. Expert commentary: Outcomes with targeted agents may be improved by integrating mutation screens during treatment to optimize subsequent therapy. In order for this to be translated into impactful patient benefit, appropriate platforms and strategies need to be optimized and then implemented universally. PMID:27139190

Modeling and Control of a Delayed Hepatitis B Virus Model with Incubation Period and Combination Treatment.

PubMed

Sun, Deshun; Liu, Fei

2018-06-01

In this paper, a hepatitis B virus (HBV) model with an incubation period and delayed state and control variables is firstly proposed. Furthermore, the combination treatment is adopted to have a longer-lasting effect than mono-therapy. The equilibrium points and basic reproduction number are calculated, and then the local stability is analyzed on this model. We then present optimal control strategies based on the Pontryagin's minimum principle with an objective function not only to reduce the levels of exposed cells, infected cells and free viruses nearly to zero at the end of therapy, but also to minimize the drug side-effect and the cost of treatment. What's more, we develop a numerical simulation algorithm for solving our HBV model based on the combination of forward and backward difference approximations. The state dynamics of uninfected cells, exposed cells, infected cells, free viruses, CTL and ALT are simulated with or without optimal control, which show that HBV is reduced nearly to zero based on the time-varying optimal control strategies whereas the disease would break out without control. At last, by the simulations, we prove that strategy A is the best among the three kinds of strategies we adopt and further comparisons have been done between model (1) and model (2).

Interventions for Detrusor Overactivity: The Case for Multimodal Therapy

PubMed Central

Dmochowski, Roger

2002-01-01

Viable therapeutic alternatives for the management of overactive bladder (OAB) have recently evolved that provide satisfactory symptomatic control for the majority of patients. However, the presupposition that interventions exist as stand-alone entities is not representative of experience in unique populations with the therapeutic benefit of combination therapy, using components drawn from behavioral, physiotherapeutic, neuromodulatory, and, if necessary, surgical alternatives. Even in populations relatively refractory to therapy, the use of multimodal therapy yields additive benefits for patients with OAB symptoms. Herein is detailed the evidence supporting the concept that multimodal therapy provides optimal benefit to patients suffering from this symptom complex. PMID:16986017

Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy

PubMed Central

Goins, Beth; Phillips, William T.; Bao, Ande

2016-01-01

Introduction A major limitation of current liposomal cancer therapies is the inability of liposome therapeutics to penetrate throughout the entire tumor mass. This inhomogeneous distribution of liposome therapeutics within the tumor has been linked to treatment failure and drug resistance. Both liposome particle transport properties and tumor microenvironment characteristics contribute to this challenge in cancer therapy. This limitation is relevant to both intravenously and intratumorally administered liposome therapeutics. Areas covered Strategies to improve the intratumoral distribution of liposome therapeutics are described. Combination therapies of intravenous liposome therapeutics with pharmacologic agents modulating abnormal tumor vasculature, interstitial fluid pressure, extracellular matrix components, and tumor associated macrophages are discussed. Combination therapies using external stimuli (hyperthermia, radiofrequency ablation, magnetic field, radiation, and ultrasound) with intravenous liposome therapeutics are discussed. Intratumoral convection-enhanced delivery (CED) of liposomal therapeutics is reviewed. Expert opinion Optimization of the combination therapies and drug delivery protocols are necessary. Further research should be conducted in appropriate cancer types with consideration of physiochemical features of liposomes and their timing sequence. More investigation of the role of tumor associated macrophages in intratumoral distribution is warranted. Intratumoral infusion of liposomes using CED is a promising approach to improve their distribution within the tumor mass. PMID:26981891

Physical Therapy for an Adult with Chronic Stroke after Botulinum Toxin Injection for Spasticity: A Case Report

PubMed Central

Phadke, Chetan P.; Ismail, Farooq; Boulias, Chris

2015-01-01

ABSTRACT Purpose: In this case report, we describe the type and duration of a physical therapy and botulinum toxin type A (BoNTA) intervention directed at lower limb spasticity and the gait and balance improvement in a patient post-stroke. Treatment of focal spasticity with BoNTA intramuscular injections combined with physical therapy is recommended by rehabilitation experts. However, the optimal type and duration of physical therapy intervention to optimize any functional gains that follow chemodenervation induced by BoNTA has not been established. Method: One individual with chronic stroke who received BoNTA injections for upper and lower extremity spasticity was included. Physical therapy intervention consisted of 45- to 60-min sessions twice weekly for 12 weeks, based on the Bobath–neurodevelopmental therapy approach, and an activity-based home program. Results: After BoNTA injections and physical therapy, the patient made clinically significant improvements in balance and gait speed and became more independent with his ambulation. Conclusions: This case report demonstrates that physical therapy after BoNTA injections can result in significant functional improvements for individuals with spasticity after chronic stroke that may not be possible with BoNTA injections alone. PMID:25931655

Promises and Dangers of Combination Therapy.

PubMed

Kruis, Wolfgang; Nguyen, Phuong G; Morgenstern, Julia

2017-01-01

The efficiency of the existing methods of treating inflammatory bowel disease (IBD) is limited. There are 2 ways to address this problem - either create new treatment modalities or optimize current therapies. Optimisation may be accomplished by using combinations of established therapeutic strategies. With regard to topically acting compounds such as 5-aminosalicylic acid, combining oral and rectal preparations is a commonly used method. Another commonly used combination is anti-tumor necrosis factor (TNF)-α antibody modalities together with immunosuppressants (thiopurines, methotrexate). Several aspects favour those combinations such as increased effectivity, prevention of immunogenicity and perhaps less adverse events. Currently, discussion on directly additive therapeutic effects is in progress, which have been demonstrated in some clinical trials. As on date, the combination of infliximab with azathioprine is most likely the most effective treatment of Crohn's disease. On the other hand, a combination therapy with both compounds affecting the immune system has, of course, risks. For sure, the frequency with which serious infectious complications are arising is increasing. Furthermore, the number of patients experiencing malignancies such as hepato-splenic lymphoma or melanoma is strongly suspected to be on the rise. In summary, combinations of current treatments for IBD are widely established. Various strategies have been studied and significant improvements of therapeutic effects have been demonstrated. Unfortunately, some of those proven combinations increase therapeutic risks, for example, increase the frequency of serious infections and also of some malignancies. Therefore, great caution has to be exercised when applying combination therapies. © 2017 S. Karger AG, Basel.

4-1BB Aptamer-Based Immunomodulation Enhances the Therapeutic Index of Radiation Therapy in Murine Tumor Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Benaduce, Ana Paula; Brenneman, Randall; Schrand, Brett

Purpose: To report a novel strategy using oligonucleotide aptamers to 4-1BB as an alternate method for costimulation, and show that combinatorial therapy with radiation improves the therapeutic ratio over equivalent monoclonal antibodies. Methods and Materials: Subcutaneous 4T1 (mouse mammary carcinoma) tumors were established (approximately 100 mm{sup 3}), and a radiation therapy (RT) dose/fractionation schedule that optimally synergizes with 4-1BB monoclonal antibody (mAb) was identified. Comparable tumor control and animal survival was observed when either 4-1BB antibody or aptamer were combined with RT using models of breast cancer and melanoma (4T1 and B16-F10). Off-target CD8{sup +} T-cell toxicity was evaluated by quantification ofmore » CD8{sup +} T cells in livers and spleens of treated animals. Results: When combined with 4-1BB mAb, significant differences in tumor control were observed by varying RT dose and fractionation schedules. Optimal synergy between RT and 4-1BB mAb was observed at 5 Gy × 6. Testing 4-1BB mAb and aptamer independently using the optimal RT (5 Gy × 6 for 4T1/Balb/c and 12 Gy × 1 for B16/C57BL6J mouse models) revealed equivalent tumor control using 4-1BB aptamer and 4-1BB mAb. 4-1BB mAb, but not 4-1BB aptamer-treated animals, exhibited increased lymphocytic liver infiltrates and increased splenic and liver CD8{sup +} T cells. Conclusions: Radiation therapy synergizes with 4-1BB mAb, and this effect is dependent on RT dose and fractionation. Tumor control by 4-1BB aptamer is equivalent to 4-1BB mAb when combined with optimal RT dose, without eliciting off-target liver and spleen CD8{sup +} expansion. 4-1BB aptamer-based costimulation affords a comparable and less toxic strategy to augment RT-mediated tumor control.« less

Anthrax prevention and treatment: utility of therapy combining antibiotic plus vaccine.

PubMed

Klinman, Dennis M; Yamamoto, Masaki; Tross, Debra; Tomaru, Koji

2009-12-01

The intentional release of anthrax spores in 2001 confirmed this pathogen's ability to cause widespread panic, morbidity and mortality. While individuals exposed to anthrax can be successfully treated with antibiotics, pre-exposure vaccination can reduce susceptibility to infection-induced illness. Concern over the safety and immunogenicity of the licensed US vaccine (Anthrax Vaccine Adsorbed (AVA)) has fueled research into alternatives. Second-generation anthrax vaccines based on purified recombinant protective antigen (rPA) have entered clinical trials. These rPA vaccines induce neutralizing antibodies that prevent illness, but the magnitude and duration of the resultant protective response is modest. Efforts are underway to bolster the immunogenicity of rPA by combining it with adjuvants and other immunostimulatory agents. Third generation vaccines are under development that utilize a wide variety of immunization platforms, antigens, adjuvants, delivery methods and routes of delivery to optimize the induction of a protective immunity. For the foreseeable future, vaccination will rely on first and second generation vaccines co-administered with immune adjuvants. Optimal post-exposure treatment of immunologically naive individuals should include a combination of vaccine plus antibiotic therapy.

FusionArc optimization: a hybrid volumetric modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) planning strategy.

PubMed

Matuszak, Martha M; Steers, Jennifer M; Long, Troy; McShan, Daniel L; Fraass, Benedick A; Romeijn, H Edwin; Ten Haken, Randall K

2013-07-01

To introduce a hybrid volumetric modulated arc therapy/intensity modulated radiation therapy (VMAT/IMRT) optimization strategy called FusionArc that combines the delivery efficiency of single-arc VMAT with the potentially desirable intensity modulation possible with IMRT. A beamlet-based inverse planning system was enhanced to combine the advantages of VMAT and IMRT into one comprehensive technique. In the hybrid strategy, baseline single-arc VMAT plans are optimized and then the current cost function gradients with respect to the beamlets are used to define a metric for predicting which beam angles would benefit from further intensity modulation. Beams with the highest metric values (called the gradient factor) are converted from VMAT apertures to IMRT fluence, and the optimization proceeds with the mixed variable set until convergence or until additional beams are selected for conversion. One phantom and two clinical cases were used to validate the gradient factor and characterize the FusionArc strategy. Comparisons were made between standard IMRT, single-arc VMAT, and FusionArc plans with one to five IMRT∕hybrid beams. The gradient factor was found to be highly predictive of the VMAT angles that would benefit plan quality the most from beam modulation. Over the three cases studied, a FusionArc plan with three converted beams achieved superior dosimetric quality with reductions in final cost ranging from 26.4% to 48.1% compared to single-arc VMAT. Additionally, the three beam FusionArc plans required 22.4%-43.7% fewer MU∕Gy than a seven beam IMRT plan. While the FusionArc plans with five converted beams offer larger reductions in final cost--32.9%-55.2% compared to single-arc VMAT--the decrease in MU∕Gy compared to IMRT was noticeably smaller at 12.2%-18.5%, when compared to IMRT. A hybrid VMAT∕IMRT strategy was implemented to find a high quality compromise between gantry-angle and intensity-based degrees of freedom. This optimization method will allow patients to be simultaneously planned for dosimetric quality and delivery efficiency without switching between delivery techniques. Example phantom and clinical cases suggest that the conversion of only three VMAT segments to modulated beams may result in a good combination of quality and efficiency.

Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy.

PubMed

Meille, Christophe; Barbolosi, Dominique; Ciccolini, Joseph; Freyer, Gilles; Iliadis, Athanassios

2016-08-01

Controlling effects of drugs administered in combination is particularly challenging with a densified regimen because of life-threatening hematological toxicities. We have developed a mathematical model to optimize drug dosing regimens and to redesign the dose intensification-dose escalation process, using densified cycles of combined anticancer drugs. A generic mathematical model was developed to describe the main components of the real process, including pharmacokinetics, safety and efficacy pharmacodynamics, and non-hematological toxicity risk. This model allowed for computing the distribution of the total drug amount of each drug in combination, for each escalation dose level, in order to minimize the average tumor mass for each cycle. This was achieved while complying with absolute neutrophil count clinical constraints and without exceeding a fixed risk of non-hematological dose-limiting toxicity. The innovative part of this work was the development of densifying and intensifying designs in a unified procedure. This model enabled us to determine the appropriate regimen in a pilot phase I/II study in metastatic breast patients for a 2-week-cycle treatment of docetaxel plus epirubicin doublet, and to propose a new dose-ranging process. In addition to the present application, this method can be further used to achieve optimization of any combination therapy, thus improving the efficacy versus toxicity balance of such a regimen.

[Comparative evaluation of the effectiveness of various treatment modalities for accommodation disorders and acquired progressive myopia].

PubMed

Tarutta, E P; Tarasova, N A

2015-01-01

To evaluate the effectiveness of non-surgical treatment of accommodation disorders and progressive myopia in children. A total of 190 patients (380 eyes) with myopia aged from 6 to 18 years (10.79±0.18 years on average) were enrolled and divided into 9 groups depending on the treatment prescribed. Comparative evaluation of different hardware-based treatment modalities for progressive myopia allowed to work out their optimal combination: "Visotronic", "MACDEL 09", and magnetophoresis of Taufon 4%. Such courses, provided twice a year, were associated with optimization of accommodative response and 1.9-2.8 times reduction of the rate of myopia progression. On the contrary, pleoptic therapy showed a negative effect on accommodative tonus and the rate of progression of acquired myopia. Comparative evaluation of different hardware-based treatment modalities for progressive myopia and accommodation disorders allowed to work out their optimal combination: "Visotronic", "MACDEL 09" and magnetophoresis of Taufon 4%. This treatment, provided twice a year, allows to increase accommodative reserves and volume, improve objective accommodative response, and reduce accommodative hypertonus as well as the rate of myopia progression (1.9-2.8 times over a 1.5-year period). Under pleoptic therapy (specialized software, near field speckles, color pulse therapy, Ambliokor device), both accommodative tonus and the rate of myopia progression increased (1.3-1.5 and 1.6 times correspondingly).

Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma.

PubMed

Solorzano, C C; Baker, C H; Tsan, R; Traxler, P; Cohen, P; Buchdunger, E; Killion, J J; Fidler, I J

2001-08-01

We determined the optimal administration schedule of a novel epidermal growth factor receptor (EGFR) protein tyrosine kinase inhibitor (PKI), PKI 166 (4-(R)-phenethylamino-6-(hydroxyl)phenyl-7H-pyrrolo[2.3-d]-pyrimidine), alone or in combination with gemcitabine (administered i.p.) for therapy of L3.6pl human pancreatic carcinoma growing in the pancreas of nude mice. Seven days after orthotopic implantation of L3.6pl cells, the mice received daily oral doses of PKI 166. PKI 166 therapy significantly inhibited phosphorylation of the EGFR without affecting EGFR expression. EGFR phosphorylation was restored 72 h after cessation of therapy. Seven days after orthotopic injection of L3.6pl cells, groups of mice received daily or thrice weekly oral doses of PKI 166 alone or in combination with gemcitabine. Treatment with PKI 166 (daily), PKI 166 (3 times/week), or gemcitabine alone produced a 72%, 69%, or 70% reduction in the volume of pancreatic tumors in mice, respectively. Daily oral PKI 166 or thrice weekly oral PKI 166 in combination with injected gemcitabine produced 97% and 95% decreases in volume of pancreatic cancers and significant inhibition of lymph node and liver metastasis. Daily oral PKI 166 produced a 20% decrease in body weight, whereas treatment 3 times/week did not. Decreased microvessel density, decreased proliferating cell nuclear antigen staining, and increased tumor cell and endothelial cell apoptosis correlated with therapeutic success. Collectively, our results demonstrate that three weekly oral administrations of an EGFR tyrosine kinase inhibitor in combination with gemcitabine are sufficient to significantly inhibit primary and metastatic human pancreatic carcinoma.

Optimization of Breast Tomosynthesis Imaging Systems for Computer-Aided Detection

DTIC Science & Technology

2011-05-01

R. Saunders, E. Samei, C. Badea, H. Yuan, K. Ghaghada, Y. Qi, L. Hedlund, and S. Mukundan, “Optimization of dual energy contrast enhanced breast...14 4 1 Introduction This is the final report for this body of research. Screen-film mammography and...digital mammography have been used for over 30 years in the early detection of cancer. The combination of screening and adjuvant therapies have led to

Speedup of lexicographic optimization by superiorization and its applications to cancer radiotherapy treatment

NASA Astrophysics Data System (ADS)

Bonacker, Esther; Gibali, Aviv; Küfer, Karl-Heinz; Süss, Philipp

2017-04-01

Multicriteria optimization problems occur in many real life applications, for example in cancer radiotherapy treatment and in particular in intensity modulated radiation therapy (IMRT). In this work we focus on optimization problems with multiple objectives that are ranked according to their importance. We solve these problems numerically by combining lexicographic optimization with our recently proposed level set scheme, which yields a sequence of auxiliary convex feasibility problems; solved here via projection methods. The projection enables us to combine the newly introduced superiorization methodology with multicriteria optimization methods to speed up computation while guaranteeing convergence of the optimization. We demonstrate our scheme with a simple 2D academic example (used in the literature) and also present results from calculations on four real head neck cases in IMRT (Radiation Oncology of the Ludwig-Maximilians University, Munich, Germany) for two different choices of superiorization parameter sets suited to yield fast convergence for each case individually or robust behavior for all four cases.

The role of systemic therapy in the management of sinonasal cancer: A critical review.

PubMed

Bossi, Paolo; Saba, Nabil F; Vermorken, Jan B; Strojan, Primoz; Pala, Laura; de Bree, Remco; Rodrigo, Juan Pablo; Lopez, Fernando; Hanna, Ehab Y; Haigentz, Missak; Takes, Robert P; Slootweg, Piet J; Silver, Carl E; Rinaldo, Alessandra; Ferlito, Alfio

2015-12-01

Due to the rarity and the variety of histological types of sinonasal cancers, there is a paucity of data regarding strategy for their optimal treatment. Generally, outcomes of advanced and higher grade tumors remain unsatisfactory, despite the employment of sophisticated surgical approaches, technical advances in radiation techniques and the use of heavy ion particles. In this context, we critically evaluated the role of systemic therapy as part of a multidisciplinary approach to locally advanced disease. Induction chemotherapy has shown encouraging activity and could have a role in the multimodal treatment of patients with advanced sinonasal tumors. For epithelial tumors, the most frequently employed chemotherapy is cisplatin, in combination with either 5-fluorouracil, taxane, ifosfamide, or vincristine. Only limited experiences with concurrent chemoradiation exist with sinonasal cancer. The role of systemic treatment for each histological type (intestinal-type adenocarcinoma, sinonasal undifferentiated carcinoma, sinonasal neuroendocrine carcinoma, olfactory neuroblastoma, sinonasal primary mucosal melanoma, sarcoma) is discussed. The treatment of SNC requires a multimodal approach. Employment of systemic therapy for locally advanced disease could result in better outcomes, and optimize the therapeutic armamentarium. Further studies are needed to precisely define the role of systemic therapy and identify the optimal sequencing for its administration in relation to local therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Taking Sides: An Integrative Review of the Impact of Laterality and Polarity on Efficacy of Therapeutic Transcranial Direct Current Stimulation for Anomia in Chronic Poststroke Aphasia

PubMed Central

Sandars, Margaret; Cloutman, Lauren; Woollams, Anna M.

2016-01-01

Anomia is a frequent and persistent symptom of poststroke aphasia, resulting from damage to areas of the brain involved in language production. Cortical neuroplasticity plays a significant role in language recovery following stroke and can be facilitated by behavioral speech and language therapy. Recent research suggests that complementing therapy with neurostimulation techniques may enhance functional gains, even amongst those with chronic aphasia. The current review focuses on the use of transcranial Direct Current Stimulation (tDCS) as an adjunct to naming therapy for individuals with chronic poststroke aphasia. Our survey of the literature indicates that combining therapy with anodal (excitatory) stimulation to the left hemisphere and/or cathodal (inhibitory) stimulation to the right hemisphere can increase both naming accuracy and speed when compared to the effects of therapy alone. However, the benefits of tDCS as a complement to therapy have not been yet systematically investigated with respect to site and polarity of stimulation. Recommendations for future research to help determine optimal protocols for combined therapy and tDCS are outlined. PMID:26819777

[Classical antihypertensive drugs: diuretics].

PubMed

Nagy, Viktor László

2017-03-01

The diuretics are essential medicaments of antihypertensive therapy. They reduce blood pressure and cardiovascular events optimally. With increasing doses of thiazides and thiazide analogs do not come further powerful effect of reducing blood pressure or cardiovascular mortality and morbidity, but clearly elevate the side effects. Because of it, the minimum effective dose level and the fixed-dose combination therapy should be preferred. The use these drugs leads to especially positive outcome in elder patients, isolated systolic hypertension, heart failure, after stroke and in black population. Loop diuretics as antihypertensive therapy can be used only by renal impairment. The use of aldosterone antagonists can have a good effect not only on heart failure but also on prevention of atrial fibrillation. Furthermore, using it in a combination therapy with thiazides, it reduces the risk of hypokalemia. Therefore, the diuretic treatment in hypertension is flourishing again. Orv. Hetil., 2017, 158(11), 403-408.

Options for the management of antiviral resistance during hepatitis B therapy: reflections on battles over a decade

PubMed Central

2013-01-01

Although much advancement has been achieved in the treatment of chronic hepatitis B, antiviral resistance is still a challenging issue. Previous generation antiviral agents have already developed resistance in a number of patients, and it is still being used especially in resource limited countries. Once antiviral resistance occurs, it predisposes to subsequent resistance, resulting in multidrug resistance. Therefore, prevention of initial antiviral resistance is the most important strategy, and appropriate choice and modification of therapy would be the cornerstone in avoiding treatment failures. Until now, management of antiviral resistance has been evolving from sequential therapy to combination therapy. In the era of tenofovir, the paradigm shifts again, and we have to decide when to switch and when to combine on the basis of newly emerging clinical data. We expect future eradication of chronic hepatitis B virus infection by proper prevention and optimal management of antiviral resistance. PMID:24133659

Antibody-cytokine fusion proteins for treatment of cancer: engineering cytokines for improved efficacy and safety.

PubMed

Young, Patricia A; Morrison, Sherie L; Timmerman, John M

2014-10-01

The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing interleukin (IL)-2, IL-12, IL-21, tumor necrosis factor (TNF)α, and interferons (IFNs) α, β, and γ have been constructed and have shown anti-tumor activity in preclinical and early-phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody-cytokine fusion protein, focusing on previously developed constructs and their clinical trial results. Copyright © 2014 Elsevier Inc. All rights reserved.

Optimizing Surveillance Performance of Alpha-Fetoprotein by Selection of Proper Target Population in Chronic Hepatitis B

PubMed Central

Chung, Jung Wha; Kim, Beom Hee; Lee, Chung Seop; Kim, Gi Hyun; Sohn, Hyung Rae; Min, Bo Young; Song, Joon Chang; Park, Hyun Kyung; Jang, Eun Sun; Yoon, Hyuk; Kim, Jaihwan; Shin, Cheol Min; Park, Young Soo; Hwang, Jin-Hyeok; Jeong, Sook-Hyang; Kim, Nayoung; Lee, Dong Ho; Lee, Jaebong; Ahn, Soyeon

2016-01-01

Although alpha-fetoprotein (AFP) is the most widely used biomarker in hepatocellular carcinoma (HCC) surveillance, disease activity may also increase AFP levels in chronic hepatitis B (CHB). Since nucleos(t)ide analog (NA) therapy may reduce not only HBV viral loads and transaminase levels but also the falsely elevated AFP levels in CHB, we tried to determine whether exposure to NA therapy influences AFP performance and whether selective application can optimize the performance of AFP testing in CHB during HCC surveillance. A retrospective cohort of 6,453 CHB patients who received HCC surveillance was constructed from the electronic clinical data warehouse. Covariates of AFP elevation were determined from 53,137 AFP measurements, and covariate-specific receiver operating characteristics regression analysis revealed that albumin levels and exposure to NA therapy were independent determinants of AFP performance. C statistics were largest in patients with albumin levels ≥ 3.7 g/dL who were followed without NA therapy during study period, whereas AFP performance was poorest when tested in patients with NA therapy during study and albumin levels were < 3.7 g/dL (difference in C statics = 0.35, p < 0.0001). Contrary to expectation, CHB patients with current or recent exposure to NA therapy showed poorer performance of AFP during HCC surveillance. Combination of concomitant albumin levels and status of NA therapy can identify subgroup of CHB patients who will show optimized AFP performance. PMID:27997559

Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism?

PubMed

Biondi, Bernadette; Wartofsky, Leonard

2012-07-01

Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combined T(3) and T(4) treatment to improve the quality of life, cognition, and peripheral parameters of thyroid hormone action in hypothyroidism. The aim of this review is to assess the physiological basis and the results of current studies on this topic. We searched Medline for reports published with the following search terms: hypothyroidism, levothyroxine, triiodothyronine, thyroid, guidelines, treatment, deiodinases, clinical symptoms, quality of life, cognition, mood, depression, body weight, heart rate, cholesterol, bone markers, SHBG, and patient preference for combined therapy. The search was restricted to reports published in English since 1970, but some reports published before 1970 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included the rationale for combination treatment, the type of patients to be selected, the optimal T(4)/T(3) ratio, and the potential benefits of this therapy on symptoms of hypothyroidism, quality of life, mood, cognition, and peripheral parameters of thyroid hormone action. The outcome of our analysis suggests that it may be time to consider a personalized regimen of thyroid hormone replacement therapy in hypothyroid patients. Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.

Evaluation of the optimal combinations of modulation factor and pitch for Helical TomoTherapy plans made with TomoEdge using Pareto optimal fronts.

PubMed

De Kerf, Geert; Van Gestel, Dirk; Mommaerts, Lobke; Van den Weyngaert, Danielle; Verellen, Dirk

2015-09-17

Modulation factor (MF) and pitch have an impact on Helical TomoTherapy (HT) plan quality and HT users mostly use vendor-recommended settings. This study analyses the effect of these two parameters on both plan quality and treatment time for plans made with TomoEdge planning software by using the concept of Pareto optimal fronts. More than 450 plans with different combinations of pitch [0.10-0.50] and MF [1.2-3.0] were produced. These HT plans, with a field width (FW) of 5 cm, were created for five head and neck patients and homogeneity index, conformity index, dose-near-maximum (D2), and dose-near-minimum (D98) were analysed for the planning target volumes, as well as the mean dose and D2 for most critical organs at risk. For every dose metric the median value will be plotted against treatment time. A Pareto-like method is used in the analysis which will show how pitch and MF influence both treatment time and plan quality. For small pitches (≤0.20), MF does not influence treatment time. The contrary is true for larger pitches (≥0.25) as lowering MF will both decrease treatment time and plan quality until maximum gantry speed is reached. At this moment, treatment time is saturated and only plan quality will further decrease. The Pareto front analysis showed optimal combinations of pitch [0.23-0.45] and MF > 2.0 for a FW of 5 cm. Outside this range, plans will become less optimal. As the vendor-recommended settings fall within this range, the use of these settings is validated.

Management and Rehabilitation of Joint Disease in Sport Horses.

PubMed

Contino, Erin K

2018-05-21

Joint disease is one of the most common issues effecting sport horses. Because there is no cure for joint disease, treatment goals surround slowing progression of the disease, minimizing pain, increasing function, and optimizing performance. Accomplishing these goals often requires a multimodal approach that combines systemic medications or supplements; intra-articular therapies, such as corticosteroids or biologics; management considerations; and physical therapy exercises. Copyright © 2018 Elsevier Inc. All rights reserved.

Tuberculosis Control in South African Gold Mines: Mathematical Modeling of a Trial of Community-Wide Isoniazid Preventive Therapy

PubMed Central

Vynnycky, Emilia; Sumner, Tom; Fielding, Katherine L.; Lewis, James J.; Cox, Andrew P.; Hayes, Richard J.; Corbett, Elizabeth L.; Churchyard, Gavin J.; Grant, Alison D.; White, Richard G.

2015-01-01

A recent major cluster randomized trial of screening, active disease treatment, and mass isoniazid preventive therapy for 9 months during 2006–2011 among South African gold miners showed reduced individual-level tuberculosis incidence but no detectable population-level impact. We fitted a dynamic mathematical model to trial data and explored 1) factors contributing to the lack of population-level impact, 2) the best-achievable impact if all implementation characteristics were increased to the highest level achieved during the trial (“optimized intervention”), and 3) how tuberculosis might be better controlled with additional interventions (improving diagnostics, reducing treatment delay, providing isoniazid preventive therapy continuously to human immunodeficiency virus–positive people, or scaling up antiretroviral treatment coverage) individually and in combination. We found the following: 1) The model suggests that a small proportion of latent infections among human immunodeficiency virus–positive people were cured, which could have been a key factor explaining the lack of detectable population-level impact. 2) The optimized implementation increased impact by only 10%. 3) Implementing additional interventions individually and in combination led to up to 30% and 75% reductions, respectively, in tuberculosis incidence after 10 years. Tuberculosis control requires a combination prevention approach, including health systems strengthening to minimize treatment delay, improving diagnostics, increased antiretroviral treatment coverage, and effective preventive treatment regimens. PMID:25792607

New Basal Insulins: a Clinical Perspective of Their Use in the Treatment of Type 2 Diabetes and Novel Treatment Options Beyond Basal Insulin.

PubMed

Frias, Patrick F; Frias, Juan Pablo

2017-08-18

The purpose of this review was to review advances in basal insulin formulations and new treatment options for patients with type 2 diabetes not achieving glycemic targets despite optimized basal insulin therapy. Advances in basal insulin formulations have resulted in products with increasingly favorable pharmacokinetic and pharmacodynamic properties, including flatter, peakless action profiles, less inter- and intra-patient variability, and longer duration of activity. These properties have translated to significantly reduced risk of hypoglycemia (particularly during the night) compared with previous generation basal insulins. When optimized basal insulin therapy is not sufficient to obtain or maintain glycemic goals, various options exist to improve glycemic control, including intensification of insulin therapy with the addition of prandial insulin or changing to pre-mixed insulin and, more recently, the addition of a GLP-1 receptor agonist, either as a separate injection or as a component of one of the new fixed-ratio combinations of a basal insulin and GLP-1 RA. New safer and often more convenient basal insulins and fixed ratio combinations containing basal insulin (and GLP-1 receptor agonist) are available today for patients with type 2 diabetes not achieving glycemic goals. Head-to-head studies comparing the latest generation basal insulins are underway, and future studies assessing the fixed-ratio combinations will be important to better understand their differentiating features.

Optimization of combined electron and photon beams for breast cancer

NASA Astrophysics Data System (ADS)

Xiong, W.; Li, J.; Chen, L.; Price, R. A.; Freedman, G.; Ding, M.; Qin, L.; Yang, J.; Ma, C.-M.

2004-05-01

Recently, intensity-modulated radiation therapy and modulated electron radiotherapy have gathered a growing interest for the treatment of breast and head and neck tumours. In this work, we carried out a study to combine electron and photon beams to achieve differential dose distributions for multiple target volumes simultaneously. A Monte Carlo based treatment planning system was investigated, which consists of a set of software tools to perform accurate dose calculation, treatment optimization, leaf sequencing and plan analysis. We compared breast treatment plans generated using this home-grown optimization and dose calculation software for different treatment techniques. Five different planning techniques have been developed for this study based on a standard photon beam whole breast treatment and an electron beam tumour bed cone down. Technique 1 includes two 6 MV tangential wedged photon beams followed by an anterior boost electron field. Technique 2 includes two 6 MV tangential intensity-modulated photon beams and the same boost electron field. Technique 3 optimizes two intensity-modulated photon beams based on a boost electron field. Technique 4 optimizes two intensity-modulated photon beams and the weight of the boost electron field. Technique 5 combines two intensity-modulated photon beams with an intensity-modulated electron field. Our results show that technique 2 can reduce hot spots both in the breast and the tumour bed compared to technique 1 (dose inhomogeneity is reduced from 34% to 28% for the target). Techniques 3, 4 and 5 can deliver a more homogeneous dose distribution to the target (with dose inhomogeneities for the target of 22%, 20% and 9%, respectively). In many cases techniques 3, 4 and 5 can reduce the dose to the lung and heart. It is concluded that combined photon and electron beam therapy may be advantageous for treating breast cancer compared to conventional treatment techniques using tangential wedged photon beams followed by a boost electron field.

Optimal CINAHL search strategies for identifying therapy studies and review articles.

PubMed

Wong, Sharon S L; Wilczynski, Nancy L; Haynes, R Brian

2006-01-01

To design optimal search strategies for locating sound therapy studies and review articles in CiNAHL in the year 2000. An analytic survey was conducted, comparing hand searches of 75 journals with retrievals from CINAHL for 5,020 candidate search terms and 17,900 combinations for therapy and 5,977 combinations for review articles. All articles were rated with purpose and quality indicators. Candidate search strategies were used in CINAHL, and the retrievals were compared with results of the hand searches. The proposed search strategies were treated as "diagnostic tests" for sound studies and the manual review of the literature was treated as the "gold standard." Operating characteristics of the search strategies were calculated. Of the 1,383 articles about treatment, 506 (36.6%) met basic criteria for scientific merit and 127 (17.9%) of the 711 articles classified as a review met the criteria for systematic reviews. For locating sound treatment studies, a three-term strategy maximized sensitivity at 99.4% but with compromised specificity at 58.3%, and a two-term strategy maximized specificity at 98.5% but with compromised sensitivity at 52.0%. For detecting systematic reviews, a three-term strategy maximized sensitivity at 91.3% while keeping specificity high at 95.4%, and a single-term strategy maximized specificity at 99.6% but with compromised sensitivity at 42.5%. Three-term search strategies optimizing sensitivity and specificity achieved these values over 91% for detecting sound treatment studies and over 76% for detecting systematic reviews. Search strategies combining indexing terms and text words can achieve high sensitivity and specificity for retrieving sound treatment studies and review articles in CINAHL.

Wireless gyroscope platform enabled by a portable media device for quantifying wobble board therapy.

PubMed

LeMoyne, Robert; Mastroianni, Timothy

2017-07-01

The wobble board enables a therapy strategy for rehabilitation of the ankle foot complex. Quantification of therapy, such as through the use of a wobble board, can facilitate a therapist's acuity for advancing and optimizing the overall therapy strategy. The portable media device, such as an iPod, can be equipped with a software application to function as a wireless gyroscope platform. Integration of the wobble board with the portable media device functioning as a wireless gyroscope enables the potential for patient to therapist interaction through connectivity to the Internet. A patient can conduct wobble board therapy for the ankle foot complex from the convenient vantage point of a homebound setting with therapy data transmitted wirelessly as email attachments. The gyroscope signal of the wobble board therapy can be consolidated into a feature set for machine learning classification. Using a multilayer perceptron neural network considerable classification accuracy has been achieved for differentiating between a hemiplegic affected ankle and unaffected ankle while using a wobble board. The combination of machine learning, wireless systems, such as a portable media device functioning as a wireless gyroscope, and a conventional therapy device, such as a wobble board, are envisioned to advance the capability to optimally impact the rehabilitation experience.

Febuxostat as a novel option to optimize thiopurines' metabolism in patients with inadequate metabolite levels.

PubMed

Doré, Maxime; Frenette, Anne Julie; Mansour, Anne-Marie; Troyanov, Yves; Bégin, Josiane

2014-05-01

To report the use of febuxostat in order to potentiate thiopurines' metabolism in a patient on azathioprine (AZA) therapy with low metabolite 6-thioguanine nucleotides (6-TGN) levels and elevated metabolite 6-methylmercaptopurine (6-MMP) levels. A 44-year-old woman with a history of anti-signal recognition particle necrotizing myopathy was treated with AZA-allopurinol combination therapy. When she developed an atypical drug-induced hypersensitivity syndrome, allopurinol was replaced by the new xanthine oxidase (XO) inhibitor febuxostat, at a daily dose of 40 mg. Febuxostat-AZA combination was successful with 6-TGN reaching therapeutic levels while 6-MMP levels remained low. After 5 months, she developed similar manifestations that she had presented on AZA-allopurinol combination. Febuxostat and AZA were then stopped. AZA and 6-MP are both inactive pro-drugs that undergo a complex metabolic transformation leading to active 6-TGN and potentially hepatotoxic 6-MMP. Some patients with unfavorable thiopurine metabolism might benefit from addition of XO inhibitor allopurinol in order to potentiate 6-TGN and reduce 6-MMP levels. It is likely that febuxostat, via its XO inhibition, would exhibit the same effect on thiopurines' metabolism. It has been shown that low dose of febuxostat was able to prevent hypermethylation and to potentiate 6-TGN levels in an AZA-treated patient. Thus, febuxostat could be useful in optimizing thiopurines' metabolism, but more data are needed before this practice can be recommended. The mechanisms by which febuxostat optimizes thiopurines' metabolism remain to be confirmed. Also, the optimal dose of febuxostat for this use remains to be determined.

Outcome of E1224-Benznidazole Combination Treatment for Infection with a Multidrug-Resistant Trypanosoma cruzi Strain in Mice.

PubMed

Diniz, Lívia de Figueiredo; Mazzeti, Ana Lia; Caldas, Ivo Santana; Ribeiro, Isabela; Bahia, Maria Terezinha

2018-06-01

Combination therapy has been proposed as an alternative therapeutic approach for the treatment of Chagas disease. In this study, we evaluated the effect of treatment with benznidazole combined with E1224 (ravuconazole prodrug) in an experimental murine model of acute infection. The first set of experiments assessed the range of E1224 doses required to induce parasitological cure using Trypanosoma cruzi strains with different susceptibilities to benznidazole (Y and Colombian). All E1224 doses were effective in suppressing the parasitemia and preventing death; however, parasitological cure was observed only in mice infected with Y strain. Considering these results, we evaluated the effect of combined treatment against Colombian, a multidrug-resistant T. cruzi strain. After exclusion of antagonistic effects using in vitro assays, infected mice were treated with E1224 and benznidazole in monotherapy or in combination at day 4 or 10 postinoculation. All treatments were well tolerated and effective in suppressing parasitemia; however, parasitological and PCR assays indicated no cure among mice treated with monotherapies. Intriguingly, the outcome of combination therapy was dependent on treatment onset. Early treatment using optimal doses of E1224-benznidazole induced a 100% cure rate, but this association could not eliminate a well-established infection. The beneficial effect of combination therapy was evidenced by further reductions of the patent parasitemia period in the group receiving combined therapy compared with monotherapies. Our results demonstrated a positive interaction between E1224 and benznidazole against murine T. cruzi infection using a multidrug-resistant strain and highlighted the importance of a stringent experimental model in the evaluation of new therapies. Copyright © 2018 Diniz et al.

Outcome of E1224-Benznidazole Combination Treatment for Infection with a Multidrug-Resistant Trypanosoma cruzi Strain in Mice

PubMed Central

Mazzeti, Ana Lia; Caldas, Ivo Santana; Ribeiro, Isabela; Bahia, Maria Terezinha

2018-01-01

ABSTRACT Combination therapy has been proposed as an alternative therapeutic approach for the treatment of Chagas disease. In this study, we evaluated the effect of treatment with benznidazole combined with E1224 (ravuconazole prodrug) in an experimental murine model of acute infection. The first set of experiments assessed the range of E1224 doses required to induce parasitological cure using Trypanosoma cruzi strains with different susceptibilities to benznidazole (Y and Colombian). All E1224 doses were effective in suppressing the parasitemia and preventing death; however, parasitological cure was observed only in mice infected with Y strain. Considering these results, we evaluated the effect of combined treatment against Colombian, a multidrug-resistant T. cruzi strain. After exclusion of antagonistic effects using in vitro assays, infected mice were treated with E1224 and benznidazole in monotherapy or in combination at day 4 or 10 postinoculation. All treatments were well tolerated and effective in suppressing parasitemia; however, parasitological and PCR assays indicated no cure among mice treated with monotherapies. Intriguingly, the outcome of combination therapy was dependent on treatment onset. Early treatment using optimal doses of E1224-benznidazole induced a 100% cure rate, but this association could not eliminate a well-established infection. The beneficial effect of combination therapy was evidenced by further reductions of the patent parasitemia period in the group receiving combined therapy compared with monotherapies. Our results demonstrated a positive interaction between E1224 and benznidazole against murine T. cruzi infection using a multidrug-resistant strain and highlighted the importance of a stringent experimental model in the evaluation of new therapies. PMID:29555633

Breaking down patient and physician barriers to optimize glycemic control in type 2 diabetes.

PubMed

Ross, Stuart A

2013-09-01

Approximately half of patients with type 2 diabetes (T2D) do not achieve globally recognized blood glucose targets, despite the availability of a wide range of effective glucose-lowering therapies. Failure to maintain good glycemic control increases the risk of diabetes-related complications and long-term health care costs. Patients must be brought under glycemic control to improve treatment outcomes, but existing barriers to optimizing glycemic control must first be overcome, including patient nonadherence to treatment, the failure of physicians to intensify therapy in a timely manner, and inadequacies in the health care system itself. The reasons for such barriers include treatment side effects, complex treatment regimens, needle anxiety, poor patient education, and the absence of an adequate patient care plan; however, newer therapies and devices, combined with comprehensive care plans involving adequate patient education, can help to minimize barriers and improve treatment outcomes. Copyright © 2013 Elsevier Inc. All rights reserved.

Defining the possibilities: is short duration treatment of chronic hepatitis C genotype 1 with sofosbuvir-containing regimens likely to be as effective as current regimens?

PubMed

Nafisi, Shirin; Roy, Sabyasachi; Gish, Robert; Manch, Richard; Kohli, Anita

2016-01-01

This review summarizes published data on sofosbuvir-based regimens for patients infected with HCV GT1 with a focus on evaluating the optimal and possible durations of treatment. PubMed and conference abstract books published between 2011-2015 were searched. HCV treatment has decreased from 24 week regimens to studies done as short as 4 weeks. History of prior treatment or cirrhosis have consistently shown lower SVR12 rates with shorter duration therapies. Low cure rates have been seen in patients within 4 week trials, however, select patients with low fibrosis scores, low HCV VL and HCV GT-1b have moderate cure rates. Most patients will require 12-24 weeks of therapy. Further studies are needed to elucidate the predictors of treatment response to short duration therapies and optimal combination of DAAs.

Supportive care for children with cancer. Guidelines of the Childrens Cancer Study Group. The use of nutritional therapy.

PubMed

Lukens, J N

1984-01-01

Nutritional support for children with cancer is predicated on the belief that optimal nutrition promotes tolerance of anti-neoplastic therapy and preserves immunologic responsiveness. The use of nutritional support is based on the assumption that there is effective therapy for the primary disease and that there will be a predictable period of nutritional stress. The most common nutritional problem is posed by the failure of sick children willingly to eat enough to maintain nutritional homeostasis. Supplementation of oral intake with a nutritional formula given by a small-bore nasogastric tube is simple, effective, and economical. If the sum of oral and tolerated nasogastric tube feedings is less than that required for optimal nutrition, unmet needs may be satisfied by nutrients given into a peripheral vein. Total parenteral nutrition, given by central vein, is reserved for situations in which the combination of enteral and peripheral venous alimentation is inadequate.

The future of epigenetic therapy in solid tumours--lessons from the past.

PubMed

Azad, Nilofer; Zahnow, Cynthia A; Rudin, Charles M; Baylin, Stephen B

2013-05-01

The promise of targeting epigenetic abnormalities for cancer therapy has not been realized for solid tumours, although increasing evidence is demonstrating its worth in haematological malignancies. In fact, true clinical efficacy in haematopoietic-related neoplasms has only become evident at low doses of epigenetic-targeting drugs (namely, inhibitors of histone deacetylase and DNA methyltransferases). Describing data from preclinical studies and early clinical trial results, we hypothesize that in using low-dose epigenetic-modulating agents, tumour cells can be reprogrammed, which overrides any immediate cytotoxic and off-target effect observed at high dose. We suggest that such optimization of drug dosing and scheduling of currently available agents could give these agents a prominent place in cancer management--when used alone or in combination with other therapies. If so, optimal use of these known agents might also pave the way for the introduction of other agents that target the epigenome.

Cell cycle-tailored targeting of metastatic melanoma: Challenges and opportunities.

PubMed

Haass, Nikolas K; Gabrielli, Brian

2017-07-01

The advent of targeted therapies of metastatic melanoma, such as MAPK pathway inhibitors and immune checkpoint antagonists, has turned dermato-oncology from the "bad guy" to the "poster child" in oncology. Current targeted therapies are effective, although here is a clear need to develop combination therapies to delay the onset of resistance. Many antimelanoma drugs impact on the cell cycle but are also dependent on certain cell cycle phases resulting in cell cycle phase-specific drug insensitivity. Here, we raise the question: Have combination trials been abandoned prematurely as ineffective possibly only because drug scheduling was not optimized? Firstly, if both drugs of a combination hit targets in the same melanoma cell, cell cycle-mediated drug insensitivity should be taken into account when planning combination therapies, timing of dosing schedules and choice of drug therapies in solid tumors. Secondly, if the combination is designed to target different tumor cell subpopulations of a heterogeneous tumor, one drug effective in a particular subpopulation should not negatively impact on the other drug targeting another subpopulation. In addition to the role of cell cycle stage and progression on standard chemotherapeutics and targeted drugs, we discuss the utilization of cell cycle checkpoint control defects to enhance chemotherapeutic responses or as targets themselves. We propose that cell cycle-tailored targeting of metastatic melanoma could further improve therapy outcomes and that our real-time cell cycle imaging 3D melanoma spheroid model could be utilized as a tool to measure and design drug scheduling approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Management of pulmonary arterial hypertension with a focus on combination therapies.

PubMed

Benza, Raymond L; Park, Myung H; Keogh, Anne; Girgis, Reda E

2007-05-01

Pulmonary arterial hypertension (PAH) is a rare but frequently fatal condition marked by vasoconstriction and vascular remodeling within small pulmonary arteries. The pathobiology of PAH involves imbalances in a multitude of endogenous mediators, which promote aberrant cellular growth, vasoconstriction and hemostasis within the pulmonary vascular tree. The mechanisms promoting these pathologic effects are complex. This complexity is highlighted by the many overlapping secondary messenger systems through which these mediators work. In light of this natural redundancy, it is not surprising that many of the drugs used to treat PAH, which have shown short-term efficacy, fall "short of the mark" in reversing or halting the progression of this disease in the long run. This very redundancy in pathways makes the case for the use of combination of drugs with differing mechanisms of action to treat PAH. Similar to what is now accepted as the standard of care for the treatment of cancer and left ventricular dysfunction, combination therapy has the greatest promise for inducing the most complete vascular remodeling of the pulmonary vasculature by "shutting down" as many of these pathologic pathways as possible. Combination therapies involving existing therapies or new agents with improved pharmacokinetic and/or pharmacodynamic properties represent an emerging clinical paradigm for patients with sub-optimally managed disease. As emerging data in this field of therapy comes to fruition, further reductions in the morbidity and mortality associated with PAH will manifest. The goal of this report is to review the philosophy of combination therapy and present the available data in this area of study.

Optimizing Quality of Life in Patients with Hormone Receptor-Positive Metastatic Breast Cancer: Treatment Options and Considerations.

PubMed

Chalasani, Pavani

2017-01-01

The treatment landscape for hormone receptor-positive metastatic breast cancer continues to evolve as the molecular mechanisms of this heterogeneous disease are better understood and targeted treatment strategies are developed. Patients are now living for extended periods of time with this disease as they progress through sequential lines of treatment. With a rapidly expanding therapeutic armamentarium, the prevalence of metastatic breast cancer patients with prolonged survival is expected to increase, as is the duration of survival. Practice guidelines recommend endocrine therapy alone as first-line therapy for the majority of patients with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The approval of new agents and expanded combination options has extended their use beyond first line, but endocrine therapy is not used as widely in clinical practice as recommended. As all treatments are palliative, even as survival is prolonged, optimizing and maintaining patient quality of life is crucial. This article surveys data relevant to the use of endocrine therapy in the setting of hormone receptor-positive metastatic breast cancer, including key clinical evidence regarding approved therapies and the impact of these therapies on patient quality of life. © 2017 S. Karger AG, Basel.

Antibiotic prescription patterns in the empiric therapy of severe sepsis: combination of antimicrobials with different mechanisms of action reduces mortality.

PubMed

Díaz-Martín, Ana; Martínez-González, María Luisa; Ferrer, Ricard; Ortiz-Leyba, Carlos; Piacentini, Enrique; Lopez-Pueyo, Maria Jesus; Martín-Loeches, Ignacio; Levy, Mitchell M; Artigas, Antoni; Garnacho-Montero, José

2012-11-18

Although early institution of adequate antimicrobial therapy is lifesaving in sepsis patients, optimal antimicrobial strategy has not been established. Moreover, the benefit of combination therapy over monotherapy remains to be determined. Our aims are to describe patterns of empiric antimicrobial therapy in severe sepsis, assessing the impact of combination therapy, including antimicrobials with different mechanisms of action, on mortality. This is a Spanish national multicenter study, analyzing all patients admitted to ICUs who received antibiotics within the first 6 hours of diagnosis of severe sepsis or septic shock. Antibiotic-prescription patterns in community-acquired infections and nosocomial infections were analyzed separately and compared. We compared the impact on mortality of empiric antibiotic treatment, including antibiotics with different mechanisms of action, termed different-class combination therapy (DCCT), with that of monotherapy and any other combination therapy possibilities (non-DCCT). We included 1,372 patients, 1,022 (74.5%) of whom had community-acquired sepsis and 350 (25.5%) of whom had nosocomial sepsis. The most frequently prescribed antibiotic agents were β-lactams (902, 65.7%) and carbapenems (345, 25.1%). DCCT was administered to 388 patients (28.3%), whereas non-DCCT was administered to 984 (71.7%). The mortality rate was significantly lower in patients administered DCCTs than in those who were administered non-DCCTs (34% versus 40%; P = 0.042). The variables independently associated with mortality were age, male sex, APACHE II score, and community origin of the infection. DCCT was a protective factor against in-hospital mortality (odds ratio (OR), 0.699; 95% confidence interval (CI), 0.522 to 0.936; P = 0.016), as was urologic focus of infection (OR, 0.241; 95% CI, 0.102 to 0.569; P = 0.001). β-Lactams, including carbapenems, are the most frequently prescribed antibiotics in empiric therapy in patients with severe sepsis and septic shock. Administering a combination of antimicrobials with different mechanisms of action is associated with decreased mortality.

Management of delayed cerebral ischemia after subarachnoid hemorrhage.

PubMed

Francoeur, Charles L; Mayer, Stephan A

2016-10-14

For patients who survive the initial bleeding event of a ruptured brain aneurysm, delayed cerebral ischemia (DCI) is one of the most important causes of mortality and poor neurological outcome. New insights in the last decade have led to an important paradigm shift in the understanding of DCI pathogenesis. Large-vessel cerebral vasospasm has been challenged as the sole causal mechanism; new hypotheses now focus on the early brain injury, microcirculatory dysfunction, impaired autoregulation, and spreading depolarization. Prevention of DCI primarily relies on nimodipine administration and optimization of blood volume and cardiac performance. Neurological monitoring is essential for early DCI detection and intervention. Serial clinical examination combined with intermittent transcranial Doppler ultrasonography and CT angiography (with or without perfusion) is the most commonly used monitoring paradigm, and usually suffices in good grade patients. By contrast, poor grade patients (WFNS grades 4 and 5) require more advanced monitoring because stupor and coma reduce sensitivity to the effects of ischemia. Greater reliance on CT perfusion imaging, continuous electroencephalography, and invasive brain multimodality monitoring are potential strategies to improve situational awareness as it relates to detecting DCI. Pharmacologically-induced hypertension combined with volume is the established first-line therapy for DCI; a good clinical response with reversal of the presenting deficit occurs in 70 % of patients. Medically refractory DCI, defined as failure to respond adequately to these measures, should trigger step-wise escalation of rescue therapy. Level 1 rescue therapy consists of cardiac output optimization, hemoglobin optimization, and endovascular intervention, including angioplasty and intra-arterial vasodilator infusion. In highly refractory cases, level 2 rescue therapies are also considered, none of which have been validated. This review provides an overview of current state-of-the-art care for DCI management.

Targeted therapy using nanotechnology: focus on cancer

PubMed Central

Sanna, Vanna; Pala, Nicolino; Sechi, Mario

2014-01-01

Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication. PMID:24531078

Multimodal Surgical and Medical Treatment for Extensive Rhinocerebral Mucormycosis in an Elderly Diabetic Patient: A Case Report and Literature Review

PubMed Central

Pirrello, Roberto; Guadagnino, Giuliana; Richiusa, Pierina; Lo Casto, Antonio; Sarno, Caterina; Moschella, Francesco; Cabibi, Daniela

2014-01-01

Diabetes is a well-known risk factor for invasive mucormycosis with rhinocerebral involvement. Acute necrosis of the maxilla is seldom seen and extensive facial bone involvement is rare in patients with rhino-orbital-cerebral mucormycosis. An aggressive surgical approach combined with antifungal therapy is usually necessary. In this report, we describe the successful, personalized medical and surgical management of extensive periorbital mucormycosis in an elderly diabetic, HIV-negative woman. Mono- or combination therapy with liposomal amphotericin B (L-AmB) and posaconazole (PSO) and withheld debridement is discussed. The role of aesthetic plastic surgery to preserve the patient's physical appearance is also reported. Any diabetic patient with sinonasal disease, regardless of their degree of metabolic control, is a candidate for prompt evaluation to rule out mucormycosis. Therapeutic and surgical strategies and adjunctive treatments are essential for successful disease management. These interventions may include combination therapy. Finally, a judicious multimodal treatment approach can improve appearance and optimize outcome in elderly patients. PMID:24982678

Optimal temperature control of tissue embedded with gold nanoparticles for enhanced thermal therapy based on two-energy equation model.

PubMed

Wang, Shen-Ling; Qi, Hong; Ren, Ya-Tao; Chen, Qin; Ruan, Li-Ming

2018-05-01

Thermal therapy is a very promising method for cancer treatment, which can be combined with chemotherapy, radiotherapy and other programs for enhanced cancer treatment. In order to get a better effect of thermal therapy in clinical applications, optimal internal temperature distribution of the tissue embedded with gold nanoparticles (GNPs) for enhanced thermal therapy was investigated in present research. The Monte Carlo method was applied to calculate the heat generation of the tissue embedded with GNPs irradiated by continuous laser. To have a better insight into the physical problem of heat transfer in tissues, the two-energy equation was employed to calculate the temperature distribution of the tissue in the process of GNPs enhanced therapy. The Arrhenius equation was applied to evaluate the degree of permanent thermal damage. A parametric study was performed to investigate the influence factors on the tissue internal temperature distribution, such as incident light intensity, the GNPs volume fraction, the periodic heating and cooling time, and the incident light position. It was found that period heating and cooling strategy can effectively avoid overheating of skin surface and heat damage of healthy tissue. Lower GNPs volume fraction will be better for the heat source distribution. Furthermore, the ring heating strategy is superior to the central heating strategy in the treatment effect. All the analysis provides theoretical guidance for optimal temperature control of tissue embedded with GNP for enhanced thermal therapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Non-viral gene therapy for bone tissue engineering.

PubMed

Wegman, Fiona; Oner, F Cumhur; Dhert, Wouter J A; Alblas, Jacqueline

2013-01-01

The possibilities of using gene therapy for bone regeneration have been extensively investigated. Improvements in the design of new transfection agents, combining vectors and delivery/release systems to diminish cytotoxicity and increase transfection efficiencies have led to several successful in vitro, ex vivo and in vivo strategies. These include growth factor or short interfering ribonucleic acid (siRNA) delivery, or even enzyme replacement therapies, and have led to increased osteogenic differentiation and bone formation in vivo. These results provide optimism to consider use in humans with some of these gene-delivery strategies in the near future.

Antithrombotic Therapy for Atrial Fibrillation

PubMed Central

You, John J.; Singer, Daniel E.; Howard, Patricia A.; Lane, Deirdre A.; Eckman, Mark H.; Fang, Margaret C.; Hylek, Elaine M.; Schulman, Sam; Go, Alan S.; Hughes, Michael; Spencer, Frederick A.; Manning, Warren J.; Halperin, Jonathan L.

2012-01-01

Background: The risk of stroke varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios. Methods: We used the methods described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement. Results: For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (eg, CHADS2 [congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather than antithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirin rather than oral anticoagulation or combination therapy with aspirin and clopidogrel; (2) at intermediate risk of stroke (eg, CHADS2 score of 1), we recommend oral anticoagulation rather than no therapy, and we suggest oral anticoagulation rather than aspirin or combination therapy with aspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS2 score of ≥ 2), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy. Conclusions: Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (CHADS2 score of ≥ 2). At lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized approach. PMID:22315271

Hodgkin lymphoma: 2018 update on diagnosis, risk-stratification, and management.

PubMed

Ansell, Stephen M

2018-05-01

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 8500 new patients annually and representing approximately 10.2% of all lymphomas in the United States. HL is composed of two distinct disease entities: classical HL and nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy. Initial therapy for HL patients is based on the histology of the disease, the anatomical stage and the presence of poor prognostic features. Patients with early stage disease are typically treated with combined modality strategies utilizing abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Newer agents including brentuximab vedotin are now being incorporated into frontline therapy and these new combinations are becoming a standard of care. High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, PD-1 blockade, nonmyeloablative allogeneic transplant or participation in a clinical trial should be considered. © 2018 Wiley Periodicals, Inc.

Advances in drug delivery system for platinum agents based combination therapy.

PubMed

Kang, Xiang; Xiao, Hai-Hua; Song, Hai-Qin; Jing, Xia-Bin; Yan, Le-San; Qi, Ruo-Gu

2015-12-01

Platinum-based anticancer agents are widely used as first-line drugs in cancer chemotherapy for various solid tumors. However, great side effects and occurrence of resistance remain as the major drawbacks for almost all the platinum drugs developed. To conquer these problems, new strategies should be adopted for platinum drug based chemotherapy. Modern nanotechnology has been widely employed in the delivery of various therapeutics and diagnostic. It provides the possibility of targeted delivery of a certain anticancer drug to the tumor site, which could minimize toxicity and optimize the drug efficacy. Here, in this review, we focused on the recent progress in polymer based drug delivery systems for platinum-based combination therapy.

Optimal Anticoagulant Therapy in ST Elevation Myocardial Infarction Interventions.

PubMed

Oliveros, Estefania; Mehta, Sameer; Flores, Ana Isabel; Pena, Camilo; Cohen, Salomon; Kostela, Jennifer C; Rowen, Rebecca; Treto, Kevin

2012-10-01

Bivalirudin is a direct thrombin inhibitor. It is a new recommendation for the treatment of patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention. Bivalirudin combined with aspirin and P2Y 12 inhibitors has proved to be an effective and safe choice for the management of thrombus in coronary artery disease. The use of bivalirudin compared with the combination of heparin plus glycoprotein IIb/IIIa inhibitors as anticoagulant therapy is associated with reduced severe bleeding and inpatient mortality, as well as diminished costs. There is only a slight increase of late stent thrombosis, which may be controlled with the use of thienopyridines. Copyright © 2012 Elsevier Inc. All rights reserved.

Optimal Use of Combined Modality Therapy in the Treatment of Esophageal Cancer.

PubMed

Shaikh, Talha; Meyer, Joshua E; Horwitz, Eric M

2017-07-01

Esophageal cancer is associated with a poor prognosis with 5-year survival rates of approximately 15% to 20%. Although patients with early stage disease may adequately be treated with a single modality, combined therapy typically consisting of neoadjuvant chemoradiation followed by esophagectomy is being adopted increasingly in patients with locally advanced disease. In patients who are not surgical candidates, definitive chemoradiation is the preferred treatment approach. All patients with newly diagnosed esophageal cancer should be evaluated in the multidisciplinary setting by a surgeon, radiation oncologist, and medical oncologist owing to the importance of each specialty in the management of these patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Distinct roles of dopamine and subthalamic nucleus in learning and probabilistic decision making.

PubMed

Coulthard, Elizabeth J; Bogacz, Rafal; Javed, Shazia; Mooney, Lucy K; Murphy, Gillian; Keeley, Sophie; Whone, Alan L

2012-12-01

Even simple behaviour requires us to make decisions based on combining multiple pieces of learned and new information. Making such decisions requires both learning the optimal response to each given stimulus as well as combining probabilistic information from multiple stimuli before selecting a response. Computational theories of decision making predict that learning individual stimulus-response associations and rapid combination of information from multiple stimuli are dependent on different components of basal ganglia circuitry. In particular, learning and retention of memory, required for optimal response choice, are significantly reliant on dopamine, whereas integrating information probabilistically is critically dependent upon functioning of the glutamatergic subthalamic nucleus (computing the 'normalization term' in Bayes' theorem). Here, we test these theories by investigating 22 patients with Parkinson's disease either treated with deep brain stimulation to the subthalamic nucleus and dopaminergic therapy or managed with dopaminergic therapy alone. We use computerized tasks that probe three cognitive functions-information acquisition (learning), memory over a delay and information integration when multiple pieces of sequentially presented information have to be combined. Patients performed the tasks ON or OFF deep brain stimulation and/or ON or OFF dopaminergic therapy. Consistent with the computational theories, we show that stopping dopaminergic therapy impairs memory for probabilistic information over a delay, whereas deep brain stimulation to the region of the subthalamic nucleus disrupts decision making when multiple pieces of acquired information must be combined. Furthermore, we found that when participants needed to update their decision on the basis of the last piece of information presented in the decision-making task, patients with deep brain stimulation of the subthalamic nucleus region did not slow down appropriately to revise their plan, a pattern of behaviour that mirrors the impulsivity described clinically in some patients with subthalamic nucleus deep brain stimulation. Thus, we demonstrate distinct mechanisms for two important facets of human decision making: first, a role for dopamine in memory consolidation, and second, the critical importance of the subthalamic nucleus in successful decision making when multiple pieces of information must be combined.

Optimization and evaluation of lipid emulsions for intravenous co-delivery of artemether and lumefantrine in severe malaria treatment.

PubMed

Yang, Yinxian; Gao, Hailing; Zhou, Shuang; Kuang, Xiao; Wang, Zhenjie; Liu, Hongzhuo; Sun, Jin

2018-05-10

Parenteral therapy for severe and complicated malaria is necessary, but currently available parenteral antimalarials have their own drawbacks. As for recommended artemisinin-based combination therapy, antimalarial artemether and lumefantrine are limited in parenteral delivery due to their poor water solubility. Herein, the aim of this study was to develop the lipid-based emulsions for intravenous co-delivery of artemether and lumefantrine. The lipid emulsion was prepared by high-speed shear and high-pressure homogenization, and the formulations were optimized mainly by monitoring particle size distribution under autoclaved conditions. The final optimal formulation was with uniform particle size distribution (~ 220 nm), high encapsulation efficiency (~ 99%), good physiochemical stability, and acceptable hemolysis potential. The pharmacokinetic study in rats showed that C max of artemether and lumefantrine for the optimized lipid emulsions were significantly increased than the injectable solution, which was critical for rapid antimalarial activity. Furthermore, the AUC 0-t of artemether and lumefantrine in the lipid emulsion group were 5.01- and 1.39-fold of those from the solution, respectively, suggesting enhanced bioavailability. With these findings, the developed lipid emulsion is a promising alternative parenteral therapy for the malaria treatment, especially for severe or complicated malaria.

Cognitive-behavior therapy singly and combined with medication for persistent insomnia: Impact on psychological and daytime functioning.

PubMed

Morin, Charles M; Beaulieu-Bonneau, Simon; Bélanger, Lynda; Ivers, Hans; Sánchez Ortuño, Montserrat; Vallières, Annie; Savard, Josée; Guay, Bernard; Mérette, Chantal

2016-12-01

While impairment of daytime functioning due to poor sleep is often the main determinant for seeking treatment, few studies have examined the clinical impact of insomnia therapies on daytime outcomes. The main objective of this study was to evaluate the impact of cognitive-behavior therapy (CBT), alone and combined with medication, on various indices of daytime and psychological functioning. Participants were 160 individuals with chronic insomnia who received CBT alone or CBT plus medication (zolpidem) for an initial six-week therapy, followed by an extended six-month therapy. Participants treated with CBT initially received maintenance CBT or no additional treatment and those treated with combined therapy initially continued with CBT plus intermittent medication (prn) or CBT without medication (taper). Measures of anxiety and depressive symptoms, fatigue, quality of life, and perceived impact of sleep difficulties on various indices of daytime functioning were completed at baseline, after each treatment stage, and at six-month follow-up. Following acute treatment, significant improvements of fatigue, quality of life (mental component), anxiety, and depression were obtained in the CBT alone condition but not in the combined CBT plus medication condition. Following extended treatment, further improvements were noted for the subgroup receiving extended CBT relative to that with no additional treatment, and for the subgroup receiving CBT and intermittent medication relative to that with CBT but no medication. Improvements were well maintained at the 6-month follow-up. These findings indicate that insomnia-specific therapy is effective at improving daytime and psychological functioning in the short term, and that maintenance therapy produces an added value to optimize long-term outcomes. www.clinicaltrials.gov (#NCT 00042146). Copyright © 2016 Elsevier Ltd. All rights reserved.

[Treatment strategy of type 2 diabetes used in Czech Republic after metformin therapy failure].

PubMed

Svačina, Štěpán; Ovesná, Petra; Kuhn, Matyáš; Nováčková, Martina

Type 2 diabetes is an enormous medical problem caused by increasing prevalence of the disease and increasing prevalence of severe chronic complications of diabetes. New ADA/EASD guidelines and also Czech diabetes society guidelines enable effective individual approach to the patient. Goal of the therapy is optimal compensation of diabetes and prevention of acute and chronic complications of diabetes and decrease of mortality. Diabetes therapy is started by education in diet a regime combined with metformin. According to the progressive character of the disease it is usually necessary to intensify the therapy by adding antidiabetics from other groups. This study was proposed to analyse the use of therapy algorithm in Czech Republic in patients with insufficient metformin therapy. Secondary objectives were to describe level of compensation of diabetes in time and level of components of the metabolic syndrome in different treatment combinations.Methodic and results: In the sample of 1 516 patients, frequency of use of antidiabetic medication after metformin it was gliflozins 33% and gliptins 28% in the first phase of the study and the number increased later during the study. Median of HbA1c in the beginning of the study was 65 mmol/mol, greatest decrease was found in patents using combination of incretine analogs with metformin - 89 % of them had the HbA1c level < 60 mmol/mol. The study showed also that antidiabetic drugs used after metformin in Czech Republic are very effective in reducing weight, and improving blood pressure and lipid profile. Therapy using combination of metformin with gliflozins, gliptins or incretin analogs is most effective when metformin is not effective enough.Key words: diabetes type 2 - gliflozins - gliptins - incretine analogs - metformin therapy failure.

Multifunctional hollow gold nanoparticles designed for triple combination therapy and CT imaging.

PubMed

Park, Jaesook; Park, Jin; Ju, Eun Jin; Park, Seok Soon; Choi, Jinhyang; Lee, Jae Hee; Lee, Kyoung Jin; Shin, Seol Hwa; Ko, Eun Jung; Park, Intae; Kim, Chulhee; Hwang, Jung Jin; Lee, Jung Shin; Song, Si Yeol; Jeong, Seong-Yun; Choi, Eun Kyung

2015-06-10

Hollow gold nanoparticles (HGNP) are a novel class of hybrid metal nanoparticles whose unique optical and morphological properties have spawned new applications including more effective cancer therapy. The shell thickness of HGNPs can tune the surface plasmon resonance to the near infrared light, resulting in photothermal ablation of tumors with optimal light penetration in tissue. The hollow cavity within a HGNP is able to accommodate a high payload of chemotherapeutic agents. They have also been used for enhancing radiosensitization in tumors during radiotherapy due to the high X-ray absorption capability of gold particles. However, no report has yet been published that utilize HGNPs for the triple combination therapy and CT imaging. In this study, we synthesized HGNPs which exhibit better response to radiation for therapy and imaging and demonstrated the effects of combined chemotherapy, thermal and radiotherapy. This combination strategy presented delayed tumor growth by 4.3-fold and reduced tumor's weight by 6.8-fold compared to control tumors. In addition, we demonstrated the feasibility of HGNP as a CT imaging agent. It is expected that translating these capabilities to human cancer patients could dramatically increase the antitumor effect and potentially overcome resistance to chemotherapeutic agents and radiation. Copyright © 2015 Elsevier B.V. All rights reserved.

Radiolabeled Adenoviral Sub-unit Proteins for Molecular Imaging and Therapeutic Applications in Oncology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srivastava, S.; Meinken, G.; Springer, K. Awasthi, V.

2004-10-06

The objective of this project was to develop and optimize new ligand systems, based on adenoviral vectors (intact adenovirus, adeno-viral fiber protein, and the knob protein), for delivering suitable radionuclides into tumor cells for molecular imaging and combined gene/radionuclide therapy of cancer.

Irrigation in endodontic treatment.

PubMed

Basrani, Bettina

2011-01-01

The primary endodontic treatment goal is to optimize root canal disinfection and to prevent reinfection. Successful root canal therapy relies on the combination of proper instrumentation, irrigation, and obturation of the root canal system. In this review of the literature, various irrigants and the interactions between irrigants are discussed and new delivery systems are introduced.

Current management of atopic dermatitis and interruption of the atopic march.

PubMed

Boguniewicz, Mark; Eichenfield, Lawrence F; Hultsch, Thomas

2003-12-01

Treatment of atopic dermatitis requires a comprehensive approach that includes evaluation of potential triggers and education of the patient and family regarding proper avoidance measures. Hydration of the skin and maintenance of an intact skin barrier remain integral to proper management. Although topical corticosteroids have been a mainstay of anti-inflammatory therapy, the newer topical calcineurin inhibitors offer advantages for treatment of this chronic, relapsing disease. Studies aimed at defining optimal combination therapy and early intervention might change the treatment paradigm for atopic dermatitis.

Memory reconsolidation and psychotherapeutic process.

PubMed

Liberzon, Israel; Javanbakht, Arash

2015-01-01

Lane et al. propose a heuristic model in which distinct, and seemingly irreconcilable, therapies can coexist. Authors postulate that memory reconsolidation is a key common neurobiological process mediating the therapeutic effects. This conceptualization raises a set of important questions regarding neuroscience and translational aspects of fear memory reconsolidation. We discuss the implications of the target article's memory reconsolidation model in the development of more effective interventions, and in the identification of less effective, or potentially harmful approaches, as well as concepts of contextualization, optimal arousal, and combined therapy.

[Design and study of parallel computing environment of Monte Carlo simulation for particle therapy planning using a public cloud-computing infrastructure].

PubMed

Yokohama, Noriya

2013-07-01

This report was aimed at structuring the design of architectures and studying performance measurement of a parallel computing environment using a Monte Carlo simulation for particle therapy using a high performance computing (HPC) instance within a public cloud-computing infrastructure. Performance measurements showed an approximately 28 times faster speed than seen with single-thread architecture, combined with improved stability. A study of methods of optimizing the system operations also indicated lower cost.

TH-AB-202-09: Direct-Aperture Optimization for Combined MV+kV Dose Planning in Fluoroscopic Real-Time Tumor-Tracking Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, X; Belcher, AH; Grelewicz, Z

Purpose: Real-time kV fluoroscopic tumor tracking has the benefit of direct tumor position monitoring. However, there is clinical concern over the excess kV imaging dose cost to the patient when imaging in continuous fluoroscopic mode. This work addresses this specific issue by proposing a combined MV+kV direct-aperture optimization (DAO) approach to integrate the kV imaging beam into a treatment planning such that the kV radiation is considered as a contributor to the overall dose delivery. Methods: The combined MV+kV DAO approach includes three algorithms. First, a projected Quasi-Newton algorithm (L-BFGS) is used to find optimized fluence with MV+kV dose formore » the best possible dose distribution. Then, Engel’s algorithm is applied to optimize the total number of monitor units and heuristically optimize the number of apertures. Finally, an aperture shape optimization (ASO) algorithm is applied to locally optimize the leaf positions of MLC. Results: Compared to conventional DAO MV plans with continuous kV fluoroscopic tracking, combined MV+kV DAO plan leads to a reduction in the total number of MV monitor units due to inclusion of kV dose as part of the PTV, and was also found to reduce the mean and maximum doses on the organs at risk (OAR). Compared to conventional DAO MV plan without kV tracking, the OAR dose in the combined MV+kV DAO plan was only slightly higher. DVH curves show that combined MV+kV DAO plan provided about the same PTV coverage as that in the conventional DAO plans without kV imaging. Conclusion: We report a combined MV+kV DAO approach that allows real time kV imager tumor tracking with only a trivial increasing on the OAR doses while providing the same coverage to PTV. The approach is suitable for clinic implementation.« less

The effect of combined therapies on recovery after acquired brain injury: Systematic review of preclinical studies combining enriched environment, exercise, or task-specific training with other therapies.

PubMed

Malá, Hana; Rasmussen, Camilla Pihl

2017-01-01

Acquired brain injuries (ABI) have devastating effects for the affected individual as well as society. Many studies have investigated the effect of different monotherapies. However, functional recovery is typically only partial. One possible strategy to promote a greater degree of recovery is to apply monotherapies in combination with one or more treatments. The objective of this systematic review is to investigate if approaches combining enriched environment (EE), exercise, or task-specific training with other monotherapies, further enhance the degree of recovery after ABI. Scopus, PsychINFO, and PubMed databases were searched in March 2016 with the following search strings: exercise (or) enriched environment (or) environmental enrichment (or) rehabilitation (and) traumatic brain injury (or) ischemia (or) stroke (and) rat (or) rodent. Studies were included if they (1) were in English, (2) used adult animals subjected to brain injury, (3) included EE, and/or exercise, and/or task-specific training as post-injury treatment strategies, (4) included at least one group receiving another monotherapy. Out of 2.168 hits, 29 studies fulfilled the inclusion criteria. Despite several trends for enhanced recovery after combined therapies, this systematic review of 29 studies does not indicate that combined therapies confer consistent combined effects on motor, cognitive, or cerebral recovery according to present criteria for combined effect. Combined treatments continue to provide hope for enhanced recovery after ABI, however, the research area is in its infancy. This systematic review does not provide conclusive evidence. This is likely due to sparse knowledge regarding optimal treatment parameters. Combined treatments, however, hold the best promise regarding treatment of the complex changes induced by ABI.

SU-F-T-193: Evaluation of a GPU-Based Fast Monte Carlo Code for Proton Therapy Biological Optimization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taleei, R; Qin, N; Jiang, S

2016-06-15

Purpose: Biological treatment plan optimization is of great interest for proton therapy. It requires extensive Monte Carlo (MC) simulations to compute physical dose and biological quantities. Recently, a gPMC package was developed for rapid MC dose calculations on a GPU platform. This work investigated its suitability for proton therapy biological optimization in terms of accuracy and efficiency. Methods: We performed simulations of a proton pencil beam with energies of 75, 150 and 225 MeV in a homogeneous water phantom using gPMC and FLUKA. Physical dose and energy spectra for each ion type on the central beam axis were scored. Relativemore » Biological Effectiveness (RBE) was calculated using repair-misrepair-fixation model. Microdosimetry calculations were performed using Monte Carlo Damage Simulation (MCDS). Results: Ranges computed by the two codes agreed within 1 mm. Physical dose difference was less than 2.5 % at the Bragg peak. RBE-weighted dose agreed within 5 % at the Bragg peak. Differences in microdosimetric quantities such as dose average lineal energy transfer and specific energy were < 10%. The simulation time per source particle with FLUKA was 0.0018 sec, while gPMC was ∼ 600 times faster. Conclusion: Physical dose computed by FLUKA and gPMC were in a good agreement. The RBE differences along the central axis were small, and RBE-weighted dose difference was found to be acceptable. The combined accuracy and efficiency makes gPMC suitable for proton therapy biological optimization.« less

Optimal management for alcoholic liver disease: Conventional medications, natural therapy or combination?

PubMed

Kim, Moon-Sun; Ong, Madeleine; Qu, Xianqin

2016-01-07

Alcohol consumption is the principal factor in the pathogenesis of chronic liver diseases. Alcoholic liver disease (ALD) is defined by histological lesions on the liver that can range from simple hepatic steatosis to more advanced stages such as alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma and liver failure. As one of the oldest forms of liver injury known to humans, ALD is still a leading cause of liver-related morbidity and mortality and the burden is exerting on medical systems with hospitalization and management costs rising constantly worldwide. Although the biological mechanisms, including increasing of acetaldehyde, oxidative stress with induction of cytochrome p450 2E1, inflammatory cytokine release, abnormal lipid metabolism and induction of hepatocyte apoptosis, by which chronic alcohol consumption triggers serious complex progression of ALD is well established, there is no universally accepted therapy to prevent or reverse. In this article, we have briefly reviewed the pathogenesis of ALD and the molecular targets for development of novel therapies. This review is focused on current therapeutic strategies for ALD, including lifestyle modification with nutrition supplements, available pharmacological drugs and new agents that are under development, liver transplantation, application of complementary medicines, and their combination. The relevant molecular mechanisms of each conventional medication and natural agent have been reviewed according to current available knowledge in the literature. We also summarized efficacy vs safety on conventional and herbal medicines which are specifically used for the prevention and treatment of ALD. Through a system review, this article highlighted that the combination of pharmaceutical drugs with naturally occurring agents may offer an optimal management for ALD and its complications. It is worthwhile to conduct large-scale, multiple centre clinical trials to further prove the safety and benefits for the integrative therapy on ALD.

Hodgkin Lymphoma: Diagnosis and Treatment.

PubMed

Ansell, Stephen M

2015-11-01

Hodgkin lymphoma is a rare B-cell malignant neoplasm affecting approximately 9000 new patients annually. This disease represents approximately 11% of all lymphomas seen in the United States and comprises 2 discrete disease entities--classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. Within the subcategorization of classical Hodgkin lymphoma are defined subgroups: nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich Hodgkin lymphoma. Staging of this disease is essential for the choice of optimal therapy. Prognostic models to identify patients at high or low risk for recurrence have been developed, and these models, along with positron emission tomography, are used to provide optimal therapy. The initial treatment for patients with Hodgkin lymphoma is based on the histologic characteristics of the disease, the stage at presentation, and the presence or absence of prognostic factors associated with poor outcome. Patients with early-stage Hodgkin lymphoma commonly receive combined-modality therapies that include abbreviated courses of chemotherapy followed by involved-field radiation treatment. In contrast, patients with advanced-stage Hodgkin lymphoma commonly receive a more prolonged course of combination chemotherapy, with radiation therapy used only in selected cases. For patients with relapse or refractory disease, salvage chemotherapy followed by high-dose treatment and an autologous stem cell transplant is the standard of care. For patients who are ineligible for this therapy or those in whom high-dose therapy and autologous stem cell transplant have failed, treatment with brentuximab vedotin is a standard approach. Additional options include palliative chemotherapy, immune checkpoint inhibitors, nonmyeloablative allogeneic stem cell transplant, or participation in a clinical trial testing novel agents. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Triple antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention: a viewpoint.

PubMed

Gwyn, Jennifer C V; Thomas, Mark R; Kirchhof, Paulus

2017-07-01

Patients undergoing percutaneous coronary intervention (PCI) are treated with dual antiplatelet therapy to reduce the risk of subsequent myocardial infarction (MI) and stent thrombosis. Approximately 5-10% of patients undergoing PCI also have atrial fibrillation (AF). Patients with AF have an additional requirement for anticoagulation, as dual antiplatelet therapy alone is insufficient to adequately reduce the risk of stroke in patients with AF. However, it is now well established that combining anticoagulants with dual antiplatelet therapy also causes a significant increase in the risk of bleeding. Hence, there is great interest in discovering the optimal blend of antiplatelet therapy and oral anticoagulation in this situation, aiming to reduce the risk of stent thrombosis, recurrent MI, and stroke, while also minimizing the risk of bleeding. Recent studies have experimented with combining oral anticoagulation with a single antiplatelet agent, rather than combining oral anticoagulation with dual antiplatelet therapy. These studies show that this reduces the risk of bleeding but are underpowered to determine whether this still provides as much cardiovascular benefit. This review summarizes the currently available evidence on this topic and highlights the key questions that remain to be answered including ongoing clinical trials in the field. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

The Impact of Combination Therapy with a-Blockers and 5ARIs on the Progression of BPH.

PubMed

Sountoulides, Petros; Gravas, Stavros

2015-01-01

Benign prostatic hyperplasia (BPH) can be a progressive disease for some men with significant impact on their quality of life due to worsening of symptoms, risk of acute urinary retention (AUR) and surgery. Certain clinical parameters such as age, prostate volume and PSA are able to predict those patients with BPH-associated LUTS that are at risk of disease progression. These patients will likely benefit most from medical therapy that provides symptom relief while at the same time may prevent disease progression. Studies have shown that a-blockers, although able to rapidly alleviate symptoms, have no effect on prostate volume, risk for AUR and BPH-related surgery. On the other hand 5ARIs have proven their efficacy in reducing prostate size, the risk of AUR and prostate surgery. Therefore combination therapy with an a-blocker and a 5ARI can be the mainstay of treatment for those patients at risk of BPH progression. Patients' perspective and their needs and expectations from treatment are other crucial parameters to consider in order selecting the optimal management of BPH. Therefore physicians should take into consideration the drug properties and also the patients' preferences before deciding on the optimal pharmacological treatment for BPH-associated LUTS.

Sound waves and antineoplastic drugs: The possibility of an enhanced combined anticancer therapy.

PubMed

Feril, Loreto B; Kondo, Takashi; Umemura, Shin-Ichiro; Tachibana, Katsuro; Manalo, Angelo H; Riesz, Peter

2002-12-01

Kremkau wrote a historical review of the use of ultrasound in cancer therapy in 1979((1)) In 1990, Kondo and Kano published a Japanese review of the implications of the thermal and nonthermal effects of ultrasound in the treatment of cancer(2)). Again in 2000, Kondo et al reviewed the therapeutic applications of ultrasound and shock wave, emphasizing their thermal and cavitational effects(3)). Here we focus on the effects of ultrasound or shock waves in combination with anticancer agents, emphasizing their mechanisms of action and interaction. Most of the studies cited here reported promising results. Although the extent of the augmented combined effects in vivo is limited, synergism is the rule in vitro. In addition to the thermal effect of ultrasound, cavitational effects undoubtedly played a major role in both ultrasound and, more prominently, in shock wave therapy. Although the mechanism of the nonthermal noncavitational effects on biological processes is obscure, several factors, including temperature and the occurrence of cavitation and inertial cavitation, probably coexist and blend with these other effects. Magnification of anticancer activity results mainly from increased localization of drugs or other agents in vivo and increased intracellular permeabilisation both in vivo and in vitro. On the other hand, sublethal damage caused by ultrasound or shock waves may render cells more susceptible, to the effects of the agents, and both may act together, further amplifying these effects. We thus conclude that proper combination of an appropriate agent and ultrasound or shock wave should help improve cancer therapy by minimizing the side effects of drugs by lowering the effective dose and reducing the systemic concentration while increasing the efficiency of the therapy as a whole. Future studies should reveal specific conditions in this combined therapy that will lead to optimal outcome.

Incorporating uncertainty and motion in Intensity Modulated Radiation Therapy treatment planning

NASA Astrophysics Data System (ADS)

Martin, Benjamin Charles

In radiation therapy, one seeks to destroy a tumor while minimizing the damage to surrounding healthy tissue. Intensity Modulated Radiation Therapy (IMRT) uses overlapping beams of x-rays that add up to a high dose within the target and a lower dose in the surrounding healthy tissue. IMRT relies on optimization techniques to create high quality treatments. Unfortunately, the possible conformality is limited by the need to ensure coverage even if there is organ movement or deformation. Currently, margins are added around the tumor to ensure coverage based on an assumed motion range. This approach does not ensure high quality treatments. In the standard IMRT optimization problem, an objective function measures the deviation of the dose from the clinical goals. The optimization then finds the beamlet intensities that minimize the objective function. When modeling uncertainty, the dose delivered from a given set of beamlet intensities is a random variable. Thus the objective function is also a random variable. In our stochastic formulation we minimize the expected value of this objective function. We developed a problem formulation that is both flexible and fast enough for use on real clinical cases. While working on accelerating the stochastic optimization, we developed a technique of voxel sampling. Voxel sampling is a randomized algorithms approach to a steepest descent problem based on estimating the gradient by only calculating the dose to a fraction of the voxels within the patient. When combined with an automatic sampling rate adaptation technique, voxel sampling produced an order of magnitude speed up in IMRT optimization. We also develop extensions of our results to Intensity Modulated Proton Therapy (IMPT). Due to the physics of proton beams the stochastic formulation yields visibly different and better plans than normal optimization. The results of our research have been incorporated into a software package OPT4D, which is an IMRT and IMPT optimization tool that we developed.

Meta-analysis of first-line therapies with maintenance regimens for advanced non-small-cell lung cancer (NSCLC) in molecularly and clinically selected populations.

PubMed

Tan, Pui San; Bilger, Marcel; de Lima Lopes, Gilberto; Acharyya, Sanchalika; Haaland, Benjamin

2017-08-01

Evidence has suggested survival benefits of maintenance for advanced NSCLC patients not progressing after first-line chemotherapy. Additionally, particular first-line targeted therapies have shown survival improvements in selected populations. Optimal first-line and maintenance therapies remain unclear. Here, currently available evidence was synthesized to elucidate optimal first-line and maintenance therapy within patient groups. Literature was searched for randomized trials evaluating first-line and maintenance regimens in advanced NSCLC patients. Bayesian network meta-analysis was performed within molecularly and clinically selected groups. The primary outcome was combined clinically meaningful OS and PFS benefits. A total of 87 records on 56 trials evaluating first-line treatments with maintenance were included. Results showed combined clinically meaningful OS and PFS benefits with particular first-line with maintenance treatments, (1) first-line intercalated chemotherapy+erlotinib, maintenance erlotinib in patients with EGFR mutations, (2) first-line afatinib, maintenance afatinib in patients with EGFR deletion 19, (3) first-line chemotherapy + bevacizumab, maintenance bevacizumab in EGFR wild-type patients, (4) chemotherapy+conatumumab, maintenance conatumumab in patients with squamous histology, (5) chemotherapy+cetuximab, maintenance cetuximab or chemotherapy + necitumumab, maintenance necitumumab in EGFR FISH-positive patients with squamous histology, and (6) first-line chemotherapy+bevacizumab, maintenance bevacizumab or first-line sequential chemotherapy+gefitinib, maintenance gefitinib in patients clinically enriched for EGFR mutations with nonsquamous histology. No treatment showed combined clinically meaningful OS and PFS benefits in patients with EGFR L858R or nonsquamous histology. Particular first-line with maintenance treatments show meaningful OS and PFS benefits in patients selected by EGFR mutation or histology. Further research is needed to achieve effective therapy for patients with EGFR mutation L858R or nonsquamous histology. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Hybrid Therapy in the Management of Atrial Fibrillation

PubMed Central

Stárek, Zdeněk; Lehar, František; Jež, Jiří; Wolf, Jiří; Novák, Miroslav

2015-01-01

Atrial fibrillation is the most common sustained arrhythmia. Because of the sub-optimal outcomes and associated risks of medical therapy as well as the recent advances in non-pharmacologic strategies, a multitude of combined (hybrid) algorithms have been introduced that improve efficacy of standalone therapies while maintaining a high safety profile. Antiarrhythmic administration enhances success rate of electrical cardioversion. Catheter ablation of antiarrhythmic drug-induced typical atrial flutter may prevent recurrent atrial fibrillation. Through simple ablation in the right atrium, suppression of atrial fibrillation may be achieved in patients with previously ineffective antiarrhythmic therapy. Efficacy of complex catheter ablation in the left atrium is improved with antiarrhythmic drugs. Catheter ablation followed by permanent pacemaker implantation is an effective and safe treatment option for selected patients. Additional strategies include pacing therapies such as atrial pacing with permanent pacemakers, preventive pacing algorithms, and/or implantable dual-chamber defibrillators are available. Modern hybrid strategies combining both epicardial and endocardial approaches in order to create a complex set of radiofrequency lesions in the left atrium have demonstrated a high rate of success and warrant further research. Hybrid therapy for atrial fibrillation reviews history of development of non-pharmacological treatment strategies and outlines avenues of ongoing research in this field. PMID:25028165

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder

PubMed Central

Quilty, Lena C.; Ravitz, Paula; Rosenbluth, Michael; Pavlova, Barbara; Grigoriadis, Sophie; Velyvis, Vytas; Kennedy, Sidney H.; Lam, Raymond W.; MacQueen, Glenda M.; Milev, Roumen V.; Ravindran, Arun V.; Uher, Rudolf

2016-01-01

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) has revised its 2009 guidelines for the management of major depressive disorder (MDD) in adults by updating the evidence and recommendations. The target audiences for these 2016 guidelines are psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. “Psychological Treatments” is the second of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 25 questions under 5 broad categories: 1) patient characteristics relevant to using psychological interventions; 2) therapist and health system characteristics associated with optimizing outcomes; 3) descriptions of major psychotherapies and their efficacy; 4) additional psychological interventions, such as peer interventions and computer- and technology-delivered interventions; and 5) combining and/or sequencing psychological and pharmacological interventions. Conclusions: First-line psychological treatment recommendations for acute MDD include cognitive-behavioural therapy (CBT), interpersonal therapy (IPT), and behavioural activation (BA). Second-line recommendations include computer-based and telephone-delivered psychotherapy. Where feasible, combining psychological treatment (CBT or IPT) with antidepressant treatment is recommended because combined treatment is superior to either treatment alone. First-line psychological treatments for maintenance include CBT and mindfulness-based cognitive therapy (MBCT). Patient preference, in combination with evidence-based treatments and clinician/system capacity, will yield the optimal treatment strategies for improving individual outcomes in MDD. PMID:27486150

Metabolic autofluorescence imaging of head and neck cancer organoids quantifies cellular heterogeneity and treatment response (Conference Presentation)

NASA Astrophysics Data System (ADS)

Shah, Amy T.; Heaster, Tiffany M.; Skala, Melissa C.

2017-02-01

Treatment options for head and neck cancer are limited, and can cause an impaired ability to eat, talk, and breathe. Therefore, optimized and personalized therapies could reduce unnecessary toxicities from ineffective treatments. Organoids are generated from primary tumor tissue and provide a physiologically-relevant in vitro model to measure drug response. Additionally, multiphoton fluorescence lifetime imaging (FLIM) of the metabolic cofactors NAD(P)H and FAD can resolve dynamic cellular response to anti-cancer treatment. This study applies FLIM of NAD(P)H and FAD to head and neck cancer organoids. Head and neck cancer tissue was digested and grown in culture as three-dimensional organoids. Gold standard measures of therapeutic response in vivo indicate stable disease after treatment with cetuximab (antibody therapy) or cisplatin (chemotherapy), and treatment response after combination treatment. In parallel, organoids were treated with cetuximab, cisplatin, or combination therapy for 24 hours. Treated organoids exhibit decreased NAD(P)H lifetime (p<0.05) and increased FAD lifetime (p<0.05) compared with control organoids. Additionally, analysis of cellular heterogeneity identifies distinct subpopulations of cells in response to treatment. A quantitative heterogeneity index predicts in vivo treatment response and demonstrates increased cellular heterogeneity in organoids treated with cetuximab or cisplatin compared with combination treatment. Mapping of cell subpopulations enables characterization of spatial relationships between cell subpopulations. Ultimately, an organoid model combined with metabolic fluorescence imaging could provide a high-throughput platform for drug discovery. Organoids grown from patient tissue could enable individualized treatment planning. These achievements could optimize quality of life and treatment outcomes for head and neck cancer patients.

Preoperative therapy in locally advanced esophageal cancer.

PubMed

Garg, Pankaj Kumar; Sharma, Jyoti; Jakhetiya, Ashish; Goel, Aakanksha; Gaur, Manish Kumar

2016-10-21

Esophageal cancer is an aggressive malignancy associated with dismal treatment outcomes. Presence of two distinct histopathological types distinguishes it from other gastrointestinal tract malignancies. Surgery is the cornerstone of treatment in locally advanced esophageal cancer (T2 or greater or node positive); however, a high rate of disease recurrence (systemic and loco-regional) and poor survival justifies a continued search for optimal therapy. Various combinations of multimodality treatment (preoperative/perioperative, or postoperative; radiotherapy, chemotherapy, or chemoradiotherapy) are being explored to lower disease recurrence and improve survival. Preoperative therapy followed by surgery is presently considered the standard of care in resectable locally advanced esophageal cancer as postoperative treatment may not be feasible for all the patients due to the morbidity of esophagectomy and prolonged recovery time limiting the tolerance of patient. There are wide variations in the preoperative therapy practiced across the centres depending upon the institutional practices, availability of facilities and personal experiences. There is paucity of literature to standardize the preoperative therapy. Broadly, chemoradiotherapy is the preferred neo-adjuvant modality in western countries whereas chemotherapy alone is considered optimal in the far East. The present review highlights the significant studies to assist in opting for the best evidence based preoperative therapy (radiotherapy, chemotherapy or chemoradiotherapy) for locally advanced esophageal cancer.

The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy.

PubMed

Nguyen, Geoffrey C; Seow, Cynthia H; Maxwell, Cynthia; Huang, Vivian; Leung, Yvette; Jones, Jennifer; Leontiadis, Grigorios I; Tse, Frances; Mahadevan, Uma; van der Woude, C Janneke

2016-03-01

The management of inflammatory bowel disease (IBD) poses a particular challenge during pregnancy because the health of both the mother and the fetus must be considered. A systematic literature search identified studies on the management of IBD during pregnancy. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti-tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohn's disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy. Optimal management of IBD before and during pregnancy is essential to achieving favorable maternal and neonatal outcomes. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload.

PubMed

Daar, S; Pathare, A V

2006-05-01

Iron overload is the main cause of morbidity and mortality especially from heart failure in patients with beta thalassemia major (TM). Successful iron chelation is therefore essential for the optimal management of TM. Although desferrioxamine (DFX) has been the major iron-chelating treatment of transfusional iron overload, compliance is a major hindrance in achieving optimal therapeutic results. The availability of oral iron chelation with deferiprone (L(1)) since 1987 is useful but showed poor efficacy when used alone as compared to DFX. We therefore decided to compare DFX alone with a prospective combined therapy with DFX and L(1) in beta thalassemia major patients with iron overload. We studied 91 patients with beta thalassemia major (mean age+/-SD, 15.02+/-5.8; range 2-30 years) attending the day care unit for regular transfusional support. They received packed red cells every 3-4 weeks to maintain pretransfusion hemoglobin concentration above 9 g/dl. They had been receiving DFX at a daily dose of 40 mg kg(-1) day(-1) by subcutaneous infusion for 8-10 h on 4-5 nights each week for the past several years. However, due to various reasons, they had developed considerable transfusional iron overload. These patients were allocated to prospectively receive additional therapy with oral iron chelator L(1) at 75 mg kg(-1) day(-1) body weight in three divided doses with food after informed consent and continued to receive treatment with DFX as per the above dosage. Of the 91 patients, six developed severe gastrointestinal (GI) upset, two agranulocytosis, two arthropathy, one persistently raised liver enzymes, two died owing to sepsis, and two received allogeneic bone marrow transplantation. Amongst the remaining 76 patients, 21 were found noncompliant (not taking DFX regularly, but taking L(1) regularly). Thus, in the 55 evaluable patients {6-48 months on combination therapy; mean [(+/-SD)22+/-12 months]}, the mean serum ferritin (+/-SD) fell dramatically from 3,088 (+/-1,299) ng/ml (DFX alone) to 2,051 (+/-935) ng/ml (DFX and L(1); p<0.001). It is interesting to note that there was also a significant improvement in the myocardial function as assessed by the ejection fraction (p<0.004) and fractional shortening (p<0.05) in those patients (n=42) who could be studied after being on combination therapy for a minimum of 1 year. The study emphasizes that beta thalassemia major patients with transfusional iron overload can be successfully treated with a combination of DFX and L(1). Our results also demonstrate a significant statistical improvement after as little as 6 months of combination therapy. Furthermore, these improvements lead to a progressive fall in the mean serum ferritin. Lastly, the study also demonstrates significant improvement in the echocardiographic parameters of myocardial performance in these patients receiving combination therapy.

Recent developments in the search for a cure for HIV-1 infection: targeting the latent reservoir for HIV-1.

PubMed

Siliciano, Janet D; Siliciano, Robert F

2014-07-01

HIV-1 infection can now be readily controlled with combination antiretroviral therapy. However, the virus persists indefinitely in a stable latent reservoir in resting CD4(+) T cells. This reservoir generally prevents cure of the infection with combination antiretroviral therapy alone. However, several recent cases of potential HIV-1 cure have generated renewed optimism. Here we review these cases and consider new developments in our understanding of the latent reservoir. In addition, we consider clinical aspects of curative strategies to provide a more realistic picture of what a generally applicable cure for HIV-1 infection is likely to entail. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

A comparative study of symptoms and quality of life among patients with breast cancer receiving target, chemotherapy, or combined therapy.

PubMed

Huang, Sheng-Miauh; Tai, Chen-Jei; Lin, Kuan-Chia; Tai, Cheng-Jeng; Tseng, Ling-Ming; Chien, Li-Yin

2013-01-01

Studies have rarely compared health outcomes for patients with breast cancer at different treatment stages. The purpose of the study was to compare symptoms and quality of life among patients with breast carcinoma receiving target, chemotherapy, or combined therapy. A longitudinal study was carried out with 57 patients receiving chemotherapy, 30 receiving target therapy, and 34 receiving combined therapy. Data were collected before the start of treatment, at 4 weeks, and at 12 weeks following the start of treatment. Symptom severity and interference were assessed by the M. D. Anderson Symptom Inventory. The physical and mental components of quality of life (physical component score [PCS] and mental component score [MCS]) were assessed using SF-36. There were no significant differences in symptom severity and interference for patients in the 3 therapy groups. The PCSs did not differ significantly according to the therapy group but did decrease significantly after each treatment. Patients receiving target therapy had significantly higher MCSs than did patients receiving chemotherapy, but the MCSs did not differ significantly before and after the treatment. Patients with higher symptom severity and interference had worse PCS and MCS. Patients at all treatment groups had worse physical components quality of life after treatment as compared with before treatment. Patients receiving target therapy had better mental components of quality of life. The mental components of quality of life remained stable during treatment. Nurses should assess the patients' symptoms during treatment and provide timely intervention to optimize their quality of life.

Hybrid assistive systems for rehabilitation: lessons learned from functional electrical therapy in hemiplegics.

PubMed

Popović, Dejan B; Popović, Mirjana B

2006-01-01

This paper suggests that the optimal method for promoting of the recovery of upper extremity function in hemiplegic individuals is the use of hybrid assistive systems (HAS). The suggested HAS is a combination of stimulation of paralyzed distal segments (hand) in synchrony with robot controlled movements of proximal segments (upper arm and forearm). The use of HAS is envisioned as part of voluntary activation of preserved sensory-motor systems during task related exercise. This HAS design follows our results from functional electrical therapy, constraint induced movement therapy, intensive exercise therapy, and use of robots for rehabilitation. The suggestion is also based on strong evidences that cortical plasticity is best promoted by task related exercise and patterned electrical stimulation.

Current and future therapies for gout.

PubMed

Pascart, Tristan; Richette, Pascal

2017-08-01

Gout is a common disease responsible for recurrent flares triggered by the deposition of monosodium urate crystals secondary to longstanding hyperuricaemia. The management of gout implies both the treatment of flares and the treatment of hyperuricaemia itself. Recent improvement in the understanding of the disease led to the development of new drugs. Areas covered: This review covers data related to 'old' treatments of flares and hyperuricaemia, evidence on the recently approved drugs and emerging therapies in development. Expert opinion: Recent data provide a good grasp of the optimal use of colchicine, corticosteroids and NSAIDs for the treatment of flares. Interleukin-1 blocking therapies have an increasing role in the management of difficult-to-treat gout. Sub-optimal use of allopurinol is common and its potency to reduce serum uric acid (SUA) levels is underestimated. Febuxostat effectively reduces SUA levels. New uricosurics, notably lesinurad and arhalofenate, in combination with xanthine oxidase inhibitors, offer promising perspectives to help a greater number of patients achieve sufficient SUA reduction.

Management of Itch in Atopic Dermatitis

PubMed Central

Hong, Judith; Buddenkotte, Joerg; Berger, Timothy G.; Steinhoff, Martin

2013-01-01

Atopic dermatitis is a common, pruritic, inflammatory skin disorder. Chronic, localized, or even generalized pruritus is the diagnostic hallmark of atopic dermatitis, and its management remains a challenge for physicians. The threshold for itch and alloknesis is markedly reduced in these patients, and infections can promote exacerbation and thereby increase the itch. Modern management consists of anti-inflammatory, occasionally antiseptic, as well as antipruritic therapies to address the epidermal barrier as well as immunomodulation or infection. Mild forms of atopic dermatitis may be controlled with topical therapies, but moderate-to-severe forms often require a combination of systemic treatments consisting of antipruritic and immunosuppressive drugs, phototherapy, and topical compounds. In addition, patient education and a therapeutic regimen to help the patient cope with the itch and eczema are important adjuvant strategies for optimized long-term management. This review highlights various topical, systemic, and complementary and alternative therapies, as well as provide a therapeutic ladder for optimized long-term control of itch in atopic dermatitis. PMID:21767767

Cost-Effectiveness of Nivolumab-Ipilimumab Combination Therapy Compared to Monotherapy for First-Line Treatment of Metastatic Melanoma in the United States

PubMed Central

Oh, Anna; Tran, Dang M; McDowell, Leann C; Keyvani, Dor; Barcelon, Jay Andrew; Merino, Oscar; Wilson, Leslie

2018-01-01

BACKGROUND The approval of new immunotherapies has dramatically changed the treatment landscape of metastatic melanoma. These survival gains come with trade-offs in side effects and costs, as well as important considerations to third-party payer systems, physicians, and patients. OBJECTIVE Develop a Markov model to determine the cost-effectiveness of nivolumab, ipilimumab, and nivolumab-ipilimumab combination as first-line therapy in metastatic melanoma while accounting for differential effectiveness in PD-L1 positive and negative patients. METHODS A three-state Markov model (‘PD-L1 positive stable disease’, ‘PD-L1 negative stable disease’, and ‘Progression and/or Death’) was developed using a US societal perspective with a lifetime time horizon of 14.5 years. Transition probabilities were calculated from progression-free survival data reported in the CheckMate-067 trial. Costs were expressed in 2015 US dollars and were determined using national sources. Adverse event (AE) management was determined using immune-related AE (irAE) data from CheckMate-067, irAE management guides for nivolumab and ipilimumab, and treatment guidelines. Utilities were obtained from published literature, using melanoma-specific studies when available, and were weighted based on incidence and duration of irAEs. Base case, one-way sensitivity, and probabilistic sensitivity analyses were conducted. RESULTS Nivolumab-ipilimumab combination therapy is not the cost effective choice ($454,092 per progression-free quality-adjusted-life-year [PFQALY]) compared to nivolumab monotherapy in our base case analysis at a willingness-to-pay threshold of $100,000/PFQALY. Both combination therapy and nivolumab monotherapy were cost-effective choices compared to ipilimumab monotherapy. PD-L1 positive status, utility of nivolumab and combination therapy, and medication costs contributed the most uncertainty to the model. In a population of 100% PD-L1 negative patients, nivolumab was still the optimal treatment but combination therapy had an improved ICER of $295,903/PFQALY. Combination therapy became dominated by nivolumab when 68% of the sample was PD-L1 positive. In addition, the cost of ipilimumab would have to decrease to <$21,555 per dose for combination therapy to have an ICER <$100,000/PFQALY, and to <$19,151 (a 42% reduction) to be more cost-effective than nivolumab monotherapy. CONCLUSIONS Nivolumab-ipilimumab combination therapy is not cost-effective compared to nivolumab monotherapy, which is the most cost-effective option. Professionals in managed care settings should consider the pharmacoeconomic implications of these new immunotherapies as they make value-based formulary decisions and future cost-effectiveness studies are completed. PMID:28530525

Managing cryptococcosis in the immunocompromised host.

PubMed

Jarvis, Joseph N; Dromer, Francoise; Harrison, Thomas S; Lortholary, Olivier

2008-12-01

Expanding access to antiretroviral treatment has dramatically improved the long-term prognosis of patients with HIV-associated cryptococcal disease who survive the acute infection. However, the incidence and acute mortality of HIV-associated cryptococcal meningitis remain high. In this context, this review summarizes urgently needed recent work aimed at improving the acute management of cryptococcal infection in immunocompromised hosts. Studies have started to optimize antifungal regimens and address the complications of raised cerebrospinal fluid pressure and cryptococcal immune reconstitution syndrome. Amphotericin B at 1 mg/kg per day has been shown to be more rapidly fungicidal than the standard dose of 0.7 mg/kg per day, and new data support the importance of combination therapy with flucytosine. Amphotericin B and fluconazole at 800 mg is an alternative combination that appears superior to amphotericin B alone. At a dosage of 400 mg per day, fluconazole alone is much less rapidly fungicidal than amphotericin B and is associated with the development of secondary resistance. Recent findings support the use of rapidly fungicidal initial antifungal therapy with amphotericin B-based combination treatment. Where amphotericin B treatment is not yet feasible, studies are needed to optimize oral regimens. Based on accumulating data on rate of clearance of infection, the most promising new regimens in terms of fungicidal activity and safety could be selected for clinical endpoint trials.

Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors.

PubMed

Ramachandran, Sreekanth A; Jadhavar, Pradeep S; Miglani, Sandeep K; Singh, Manvendra P; Kalane, Deepak P; Agarwal, Anil K; Sathe, Balaji D; Mukherjee, Kakoli; Gupta, Ashu; Haldar, Srijan; Raja, Mohd; Singh, Siddhartha; Pham, Son M; Chakravarty, Sarvajit; Quinn, Kevin; Belmar, Sebastian; Alfaro, Ivan E; Higgs, Christopher; Bernales, Sebastian; Herrera, Francisco J; Rai, Roopa

2017-05-15

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) Alone versus MALDI-TOF MS Combined with Real-Time Antimicrobial Stewardship Interventions on Time to Optimal Antimicrobial Therapy in Patients with Positive Blood Cultures.

PubMed

Beganovic, Maya; Costello, Michael; Wieczorkiewicz, Sarah M

2017-05-01

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) decreases the time to organism identification and improves clinical and financial outcomes. The purpose of this study was to evaluate the impact of MALDI-TOF MS alone versus MALDI-TOF MS combined with real-time, pharmacist-driven, antimicrobial stewardship (AMS) intervention on patient outcomes. This single-center, pre-post, quasiexperimental study evaluated hospitalized patients with positive blood cultures identified via MALDI-TOF MS combined with prospective AMS intervention compared to a control cohort with MALDI-TOF MS identification without AMS intervention. AMS intervention included: real-time MALDI-TOF MS pharmacist notification and prospective AMS provider feedback. The primary outcome was the time to optimal therapy (TTOT). A total of 252 blood cultures, 126 in each group, were included in the final analysis. MALDI-TOF MS plus AMS intervention significantly reduced the overall TTOT (75.17 versus 43.06 h; P < 0.001), the Gram-positive contaminant TTOT (48.21 versus 11.75 h; P < 0.001), the Gram-negative infection (GNI) TTOT (71.83 versus 35.98 h; P < 0.001), and the overall hospital length of stay (LOS; 15.03 versus 9.02 days; P = 0.021). The TTOT for Gram-positive infection (GPI) was improved (64.04 versus 41.61 h; P = 0.082). For GPI, the hospital LOS (14.64 versus 10.31 days; P = 0.002) and length of antimicrobial therapy 24.30 versus 18.97 days; P = 0.018) were reduced. For GNI, the time to microbiologic clearance (51.13 versus 34.51 h; P < 0.001), the hospital LOS (15.40 versus 7.90 days; P = 0.027), and the intensive care unit LOS (5.55 versus 1.19 days; P = 0.035) were reduced. To achieve optimal outcomes, rapid identification with MALDI-TOF MS combined with real-time AMS intervention is more impactful than MALDI-TOF MS alone. Copyright © 2017 American Society for Microbiology.

Limited Impact of Setup and Range Uncertainties, Breathing Motion, and Interplay Effects in Robustly Optimized Intensity Modulated Proton Therapy for Stage III Non-small Cell Lung Cancer.

PubMed

Inoue, Tatsuya; Widder, Joachim; van Dijk, Lisanne V; Takegawa, Hideki; Koizumi, Masahiko; Takashina, Masaaki; Usui, Keisuke; Kurokawa, Chie; Sugimoto, Satoru; Saito, Anneyuko I; Sasai, Keisuke; Van't Veld, Aart A; Langendijk, Johannes A; Korevaar, Erik W

2016-11-01

To investigate the impact of setup and range uncertainties, breathing motion, and interplay effects using scanning pencil beams in robustly optimized intensity modulated proton therapy (IMPT) for stage III non-small cell lung cancer (NSCLC). Three-field IMPT plans were created using a minimax robust optimization technique for 10 NSCLC patients. The plans accounted for 5- or 7-mm setup errors with ±3% range uncertainties. The robustness of the IMPT nominal plans was evaluated considering (1) isotropic 5-mm setup errors with ±3% range uncertainties; (2) breathing motion; (3) interplay effects; and (4) a combination of items 1 and 2. The plans were calculated using 4-dimensional and average intensity projection computed tomography images. The target coverage (TC, volume receiving 95% of prescribed dose) and homogeneity index (D2 - D98, where D2 and D98 are the least doses received by 2% and 98% of the volume) for the internal clinical target volume, and dose indexes for lung, esophagus, heart and spinal cord were compared with that of clinical volumetric modulated arc therapy plans. The TC and homogeneity index for all plans were within clinical limits when considering the breathing motion and interplay effects independently. The setup and range uncertainties had a larger effect when considering their combined effect. The TC decreased to <98% (clinical threshold) in 3 of 10 patients for robust 5-mm evaluations. However, the TC remained >98% for robust 7-mm evaluations for all patients. The organ at risk dose parameters did not significantly vary between the respective robust 5-mm and robust 7-mm evaluations for the 4 error types. Compared with the volumetric modulated arc therapy plans, the IMPT plans showed better target homogeneity and mean lung and heart dose parameters reduced by about 40% and 60%, respectively. In robustly optimized IMPT for stage III NSCLC, the setup and range uncertainties, breathing motion, and interplay effects have limited impact on target coverage, dose homogeneity, and organ-at-risk dose parameters. Copyright © 2016 Elsevier Inc. All rights reserved.

Neuroendocrine tumors: insights into innovative therapeutic options and rational development of targeted therapies.

PubMed

Barbieri, Federica; Albertelli, Manuela; Grillo, Federica; Mohamed, Amira; Saveanu, Alexandru; Barlier, Anne; Ferone, Diego; Florio, Tullio

2014-04-01

Neuroendocrine tumors (NETs) are heterogeneous neoplasms with respect to molecular characteristics and clinical outcome. Although slow-growing, NETs are often late diagnosed, already showing invasion of adjacent tissues and metastases. Precise knowledge of NET biological and molecular features has opened the door to the identification of novel pharmacological targets. Therapeutic options include somatostatin analogs, alone or in combination with interferon-α, multi-targeted tyrosine kinase inhibitors (e.g. sunitinib) or mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus). Antiangiogenic approaches and anti insulin-like growth factor receptor (IGFR) compounds have been also proposed as combination therapies with the aforementioned compounds. This review will focus on recent studies that have improved therapeutic strategies in NETs, discussing management challenges such as drug resistance development as well as focusing on the need for predictive biomarkers to design distinct drug combinations and optimize pharmacological control. Copyright © 2013 Elsevier Ltd. All rights reserved.

Targeting EGFR with photodynamic therapy in combination with Erbitux enhances in vivo bladder tumor response

PubMed Central

Bhuvaneswari, Ramaswamy; Gan, Yik Yuen; Soo, Khee Chee; Olivo, Malini

2009-01-01

Background Photodynamic therapy (PDT) is a promising cancer treatment modality that involves the interaction of the photosensitizer, molecular oxygen and light of specific wavelength to destroy tumor cells. Treatment induced hypoxia is one of the main side effects of PDT and efforts are underway to optimize PDT protocols for improved efficacy. The aim of this study was to investigate the anti-tumor effects of PDT plus Erbitux, an angiogenesis inhibitor that targets epidermal growth factor receptor (EGFR), on human bladder cancer model. Tumor-bearing nude mice were assigned to four groups that included control, PDT, Erbitux and PDT plus Erbitux and tumor volume was charted over 90-day period. Results Our results demonstrate that combination of Erbitux with PDT strongly inhibits tumor growth in the bladder tumor xenograft model when compared to the other groups. Downregulation of EGFR was detected using immunohistochemistry, immunofluorescence and western blotting. Increased apoptosis was associated with tumor inhibition in the combination therapy group. In addition, we identified the dephosphorylation of ErbB4 at tyrosine 1284 site to play a major role in tumor inhibition. Also, at the RNA level downregulation of EGFR target genes cyclin D1 and c-myc was observed in tumors treated with PDT plus Erbitux. Conclusion The combination therapy of PDT and Erbitux effectively inhibits tumor growth and is a promising therapeutic approach in the treatment of bladder tumors. PMID:19878607

Osteoarticular infection caused by MDR Pseudomonas aeruginosa: the benefits of combination therapy with colistin plus β-lactams.

PubMed

Ribera, Alba; Benavent, Eva; Lora-Tamayo, Jaime; Tubau, Fe; Pedrero, Salvador; Cabo, Xavier; Ariza, Javier; Murillo, Oscar

2015-12-01

In the era of emergence of MDR Pseudomonas aeruginosa, osteoarticular infections (OIs) add more difficulties to its treatment. The role of β-lactams (BLs) is questioned and older drugs need to be reconsidered. The objective of this study was to describe our experience in the management of OIs caused by MDR P. aeruginosa and evaluate different therapeutic options. This was a retrospective analysis of a prospectively collected cohort (2004-13) of patients with OI caused by MDR P. aeruginosa. We created two groups: (i) Group A (more difficult to treat), prosthetic joint infections (PJIs) and osteoarthritis (OA) managed with device retention; and (ii) Group B (less difficult to treat), OA managed without device retention. Antibiotic treatment was administered according to clinician criteria: monotherapy/combined therapy; and BL used by intermittent bolus (IB)/continuous infusion. Of 34 patients, 15 (44.1%) had PJI and 19 (55.9%) had OA (8 related to an orthopaedic device). Twenty-three cases (68%) were caused by XDR P. aeruginosa. The initial management included removal of an orthopaedic device in 14 cases, together with antibiotic [alone, 19 (55.9%; 4 colistin, 14 BL-IB and 1 BL continuous infusion); and in combination, 15 (44.1%; 5 BL-IB and 10 BL continuous infusion)]. The overall cure rate was 50% (39% and 63% in Groups A and B, respectively), ranging from 31.6% with monotherapy to 73.3% with combined therapy (P = 0.016), with special interest within Group A (cure rate with combined therapy 71.4%, P = 0.049). After rescue therapy, which included removal of remaining devices, the cure rate reached 85.3%. We suggest that the BL/colistin combination is an optimized therapy for OI caused by MDR P. aeruginosa, together with an appropriate surgical treatment. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Modern Radiation Therapy for Hodgkin Lymphoma: Field and Dose Guidelines From the International Lymphoma Radiation Oncology Group (ILROG)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Specht, Lena, E-mail: lena.specht@regionh.dk; Yahalom, Joachim; Illidge, Tim

2014-07-15

Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solelymore » on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines.« less

Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG).

PubMed

Specht, Lena; Yahalom, Joachim; Illidge, Tim; Berthelsen, Anne Kiil; Constine, Louis S; Eich, Hans Theodor; Girinsky, Theodore; Hoppe, Richard T; Mauch, Peter; Mikhaeel, N George; Ng, Andrea

2014-07-15

Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solely on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines. Copyright © 2014 Elsevier Inc. All rights reserved.

Advances in Meniscal Tissue Engineering

PubMed Central

Longo, Umile Giuseppe; Loppini, Mattia; Forriol, Francisco; Romeo, Giovanni; Maffulli, Nicola; Denaro, Vincenzo

2012-01-01

Meniscal tears are the most common knee injuries and have a poor ability of healing. In the last few decades, several techniques have been increasingly used to optimize meniscal healing. Current research efforts of tissue engineering try to combine cell-based therapy, growth factors, gene therapy, and reabsorbable scaffolds to promote healing of meniscal defects. Preliminary studies did not allow to draw definitive conclusions on the use of these techniques for routine management of meniscal lesions. We performed a review of the available literature on current techniques of tissue engineering for the management of meniscal tears. PMID:25098366

Antiplatelet Drugs

PubMed Central

Hirsh, Jack; Spencer, Frederick A.; Baglin, Trevor P.; Weitz, Jeffrey I.

2012-01-01

The article describes the mechanisms of action, pharmacokinetics, and pharmacodynamics of aspirin, dipyridamole, cilostazol, the thienopyridines, and the glycoprotein IIb/IIIa antagonists. The relationships among dose, efficacy, and safety are discussed along with a mechanistic overview of results of randomized clinical trials. The article does not provide specific management recommendations but highlights important practical aspects of antiplatelet therapy, including optimal dosing, the variable balance between benefits and risks when antiplatelet therapies are used alone or in combination with other antiplatelet drugs in different clinical settings, and the implications of persistently high platelet reactivity despite such treatment. PMID:22315278

Topical treatment of psoriasis.

PubMed

Laws, Philip M; Young, Helen S

2010-08-01

The majority of patients with psoriasis can be safely and effectively treated with topical therapy alone, either under the supervision of a family physician or dermatologist. For those requiring systemic agents, topical therapies can provide additional benefit. Optimal use of topical therapy requires an awareness of the range and efficacy of all products. The review covers the efficacy and role of topical therapies including emollients, corticosteroids, vitamin D analogs, calcineurin inhibitors, dithranol, coal tar, retinoids, keratolyics and combination therapy. The report was prepared following a PubMed and Embase literature search up to April 2010. The paper provides a broad review of the relevant topical therapeutic options available in routine clinical practice for the management of psoriasis and a recommendation for selection of treatment. Topical therapies used appropriately provide a safe and effective option for the management of psoriasis. An awareness of the available products and their efficacy is key to treatment selection and patient satisfaction.

Basis for selecting optimum antibiotic regimens for secondary peritonitis.

PubMed

Maseda, Emilio; Gimenez, Maria-Jose; Gilsanz, Fernando; Aguilar, Lorenzo

2016-01-01

Adequate management of severely ill patients with secondary peritonitis requires supportive therapy of organ dysfunction, source control of infection and antimicrobial therapy. Since secondary peritonitis is polymicrobial, appropriate empiric therapy requires combination therapy in order to achieve the needed coverage for both common and more unusual organisms. This article reviews etiological agents, resistance mechanisms and their prevalence, how and when to cover them and guidelines for treatment in the literature. Local surveillances are the basis for the selection of compounds in antibiotic regimens, which should be further adapted to the increasing number of patients with risk factors for resistance (clinical setting, comorbidities, previous antibiotic treatments, previous colonization, severity…). Inadequate antimicrobial regimens are strongly associated with unfavorable outcomes. Awareness of resistance epidemiology and of clinical consequences of inadequate therapy against resistant bacteria is crucial for clinicians treating secondary peritonitis, with delicate balance between optimization of empirical therapy (improving outcomes) and antimicrobial overuse (increasing resistance emergence).

Can magneto-plasmonic nanohybrids efficiently combine photothermia with magnetic hyperthermia?

PubMed

Espinosa, Ana; Bugnet, Mathieu; Radtke, Guillaume; Neveu, Sophie; Botton, Gianluigi A; Wilhelm, Claire; Abou-Hassan, Ali

2015-12-07

Multifunctional hybrid-design nanomaterials appear to be a promising route to meet the current therapeutics needs required for efficient cancer treatment. Herein, two efficient heat nano-generators were combined into a multifunctional single nanohybrid (a multi-core iron oxide nanoparticle optimized for magnetic hyperthermia, and a gold branched shell with tunable plasmonic properties in the NIR region, for photothermal therapy) which impressively enhanced heat generation, in suspension or in vivo in tumours, opening up exciting new therapeutic perspectives.

Enhancing exposure therapy for anxiety disorders with glucocorticoids: from basic mechanisms of emotional learning to clinical applications.

PubMed

Bentz, Dorothée; Michael, Tanja; de Quervain, Dominique J-F; Wilhelm, Frank H

2010-03-01

Current neurophysiological and psychological accounts view exposure therapy as the clinical analog of extinction learning that results in persistent modifications of the fear memory involved in the pathogenesis, symptomatology, and maintenance of anxiety disorders. Evidence from studies in animals and humans indicate that glucocorticoids have the potential to facilitate the processes that underlie extinction learning during exposure therapy. Particularly, glucocorticoids can restrict retrieval of previous aversive learning episodes and enhance consolidation of memory traces relating to non-fearful responding in feared situations. Thus, glucocorticoid treatment especially in combination with exposure therapy might be a promising approach to optimize treatment of anxiety disorders. This review examines the processes involved in aversive conditioning, fear learning and fear extinction, and how glucocorticoids might enhance restructuring of fear memories during therapy. Copyright 2009 Elsevier Ltd. All rights reserved.

Improved outcome with early rifampicin combination treatment in methicillin-sensitive Staphylococcus aureus bacteraemia with a deep infection focus - a retrospective cohort study.

PubMed

Forsblom, Erik; Ruotsalainen, Eeva; Järvinen, Asko

2015-01-01

Rifampicin has been used as adjunctive therapy in Staphylococcus aureus bacteraemia (SAB) with a deep infection focus. However, data for prognostic impact of rifampicin therapy is unestablished including the optimal initiation time point. We studied the impact of rifampicin therapy and the optimal initiation time for rifampicin treatment on prognosis in methicillin-sensitive S. aureus bacteraemia with a deep infection. Retrospective, multicentre study in Finland including 357 SAB patients with a deep infection focus. Patients with alcoholism, liver disease or patients who died within 3 days were excluded. Patients were categorised according to duration of rifampicin therapy and according to whether rifampicin was initiated early (within 7 days) or late (7 days after) after the positive blood cultures. Primary end point was 90 days mortality. Twenty-seven percent of patients received no rifampicin therapy, 14% received rifampicin for 1-13 days whereas 59% received rifampicin ≥14 days. The 90 day mortality was; 26% for patients treated without rifampicin, 16% for rifampicin therapy of any length and 10% for early onset rifampicin therapy ≥14 days. Lack of rifampicin therapy increased (OR 1.89, p=0.026), rifampicin of any duration decreased (OR 0.53, p=0.026) and rifampicin therapy ≥14 days with early onset lowered the risk for a fatal outcome (OR 0.33, p<0.01) during 90 days follow-up. Rifampicin adjunctive therapy for at least 14 days and initiated within 7 days of positive blood culture associated with improved outcome among SAB patients with a deep infection.

Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy

PubMed Central

Meng, Fanfei; Han, Ning; Yeo, Yoon

2017-01-01

Introduction Chemotherapeutic drugs are used in combination to target multiple mechanisms involved in cancer cell survival and proliferation. Carriers are developed to deliver drug combinations to common target tissues in optimal ratios and desirable sequences. Nanoparticles (NP) have been a popular choice for this purpose due to their ability to increase the circulation half-life and tumor accumulation of a drug. Areas covered We review organic NP carriers based on polymers, proteins, peptides, and lipids for simultaneous delivery of multiple anticancer drugs, drug/sensitizer combinations, drug/photodynamic- or photothermal therapy combinations, and drug/gene therapeutics with examples in the past three years. Sequential delivery of drug combinations, based on either sequential administration or built-in release control, is introduced with an emphasis on the mechanistic understanding of such control. Expert opinion Recent studies demonstrate how a drug carrier can contribute to co-localizing drug combinations in optimal ratios and dosing sequences to maximize the synergistic effects. We identify several areas for improvement in future research, including the choice of drug combinations, circulation stability of carriers, spatiotemporal control of drug release, and the evaluation and clinical translation of combination delivery. PMID:27476442

Drug delivery optimization through Bayesian networks.

PubMed Central

Bellazzi, R.

1992-01-01

This paper describes how Bayesian Networks can be used in combination with compartmental models to plan Recombinant Human Erythropoietin (r-HuEPO) delivery in the treatment of anemia of chronic uremic patients. Past measurements of hematocrit or hemoglobin concentration in a patient during the therapy can be exploited to adjust the parameters of a compartmental model of the erythropoiesis. This adaptive process allows more accurate patient-specific predictions, and hence a more rational dosage planning. We describe a drug delivery optimization protocol, based on our approach. Some results obtained on real data are presented. PMID:1482938

Antihypertensive and anti-inflammatory actions of combined azilsartan and chlorthalidone in Dahl salt-sensitive rats on a high-fat, high-salt diet.

PubMed

Jin, Chunhua; O'Boyle, Sean; Kleven, Daniel T; Pollock, Jennifer S; Pollock, David M; White, John J

2014-08-01

Metabolic syndrome (MetS) and chronic kidney disease are global health issues. Metabolic syndrome induces hypertension and commonly results in renal damage. The optimal therapy for hypertension in MetS is unknown. Thiazide diuretics are first-line therapy; however, these drugs may have untoward effects. In the present study we investigated the effects of azilsartan (AZL), chlorthalidone (CLTD) and their combination on blood pressure and renal injury in a rodent model with features of MetS. Dahl salt-sensitive rats were fed high-fat (36% fat), high-salt (4% NaCl) diet. Groups were then treated with vehicle, AZL (3 mg/kg per day), CLTD (5 mg/kg per day) or AZL + CLTD. Mean arterial pressure was recorded continuously by telemetry. After 26 days, rats were killed humanely and their kidneys were harvested for histology. Both AZL and CLTD attenuated the rise in blood pressure compared with vehicle and the combination further reduced blood pressure compared with CLTD alone. All treatments reduced proteinuria and albuminuria. Nephrinuria was prevented only in groups treated with AZL. Nephrinuria was 57% lower and proteinuria was 47% lower with combination therapy compared with AZL alone. All treatments reduced the number of inflammatory cells in the kidney. In conclusion, in our model, AZL and CLTD lower blood pressure and exhibit renal protective effects. Treatment with AZL offers additional protection, as evidenced by lower nephrinuria and plasma monocyte chemoattractant protein-1 levels. Combination therapy afforded the greatest protective effects and may be the best choice for hypertensive therapy in MetS. © 2014 Wiley Publishing Asia Pty Ltd.

Durable treatment response of relapsing CNS plasmacytoma using intrathecal chemotherapy, radiotherapy, and Daratumumab.

PubMed

Elhassadi, Ezzat; Murphy, Maurice; Hacking, Dayle; Farrell, Michael

2018-04-01

CNS myelomatous involvement is a rare complication of multiple myeloma with dismal outcome. This disease's optimal treatment is unclear. Combined approach of systemic therapy, radiotherapy, and intrathecal injections chemotherapy should be considered and autologous stem cell transplant consolidation is offered to eligible patients. The role of Daratumumab in this disease deserves further evaluation.

Stuttering Treatment for a School-Age Child with Down Syndrome: A Descriptive Case Report

ERIC Educational Resources Information Center

Harasym, Jessica; Langevin, Marilyn

2012-01-01

Background: Little is known about optimal treatment approaches and stuttering treatment outcomes for children with Down syndrome. Aims and method: The purpose of this study was to investigate outcomes for a child with Down syndrome who received a combination of fluency shaping therapy and parent delivered contingencies for normally fluent speech,…

Conventional and molecular diagnostic strategies for prosthetic joint infections.

PubMed

Esteban, Jaime; Sorlí, Luisa; Alentorn-Geli, Eduard; Puig, Lluís; Horcajada, Juan P

2014-01-01

An accurate diagnosis of prosthetic joint infection (PJI) is the mainstay for an optimized clinical management. This review analyzes different diagnostic strategies of PJI, with special emphasis on molecular diagnostic tools and their current and future applications. Until now, the culture of periprosthetic tissues has been considered the gold standard for the diagnosis of PJI. However, sonication of the implant increases the sensitivity of those cultures and is being increasingly adopted by many centers. Molecular diagnostic methods compared with intraoperative tissue culture, especially if combined with sonication, have a higher sensitivity, a faster turnaround time and are not influenced by previous antimicrobial therapy. However, they still lack a system for detection of antimicrobial susceptibility, which is crucial for an optimized and less toxic therapy of PJI. More studies are needed to assess the clinical value of these methods and their cost-effectiveness.

Feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the Activity and Cognitive Therapy in ICU (ACT-ICU) trial.

PubMed

Brummel, N E; Girard, T D; Ely, E W; Pandharipande, P P; Morandi, A; Hughes, C G; Graves, A J; Shintani, A; Murphy, E; Work, B; Pun, B T; Boehm, L; Gill, T M; Dittus, R S; Jackson, J C

2014-03-01

Cognitive impairment after critical illness is common and debilitating. We developed a cognitive therapy program for critically ill patients and assessed the feasibility and safety of administering combined cognitive and physical therapy early during a critical illness. We randomized 87 medical and surgical ICU patients with respiratory failure and/or shock in a 1:1:2 manner to three groups: usual care, early once-daily physical therapy, or early once-daily physical therapy plus a novel, progressive, twice-daily cognitive therapy protocol. Cognitive therapy included orientation, memory, attention, and problem-solving exercises, and other activities. We assessed feasibility outcomes of the early cognitive plus physical therapy intervention. At 3 months, we also assessed cognitive, functional, and health-related quality of life outcomes. Data are presented as median (interquartile range) or frequency (%). Early cognitive therapy was a delivered to 41/43 (95%) of cognitive plus physical therapy patients on 100% (92-100%) of study days beginning 1.0 (1.0-1.0) day following enrollment. Physical therapy was received by 17/22 (77%) of usual care patients, by 21/22 (95%) of physical therapy only patients, and 42/43 (98%) of cognitive plus physical therapy patients on 17% (10-26%), 67% (46-87%), and 75% (59-88%) of study days, respectively. Cognitive, functional, and health-related quality of life outcomes did not differ between groups at 3-month follow-up. This pilot study demonstrates that early rehabilitation can be extended beyond physical therapy to include cognitive therapy. Future work to determine optimal patient selection, intensity of treatment, and benefits of cognitive therapy in the critically ill is needed.

Feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the Activity and Cognitive Therapy in ICU (ACT-ICU) trial

PubMed Central

Brummel, N.E.; Girard, T.D.; Ely, E.W.; Pandharipande, P.P.; Morandi, A.; Hughes, C.G.; Graves, A.J.; Shintani, A.K.; Murphy, E.; Work, B.; Pun, B.T.; Boehm, L.; Gill, T.M.; Dittus, R.S.; Jackson, J.C.

2013-01-01

PURPOSE Cognitive impairment after critical illness is common and debilitating. We developed a cognitive therapy program for critically ill patients and assessed the feasibility and safety of administering combined cognitive and physical therapy early during a critical illness. METHODS We randomized 87 medical and surgical ICU patients with respiratory failure and/or shock in a 1:1:2 manner to three groups: usual care, early once-daily physical therapy, or early once-daily physical therapy plus a novel, progressive, twice-daily cognitive therapy protocol. Cognitive therapy included orientation, memory, attention, and problem solving exercises, and other activities. We assessed feasibility outcomes of the early cognitive plus physical therapy intervention. At 3-months, we also assessed cognitive, functional and health-related quality of life outcomes. Data are presented as median [interquartile range] or frequency (%). RESULTS Early cognitive therapy was a delivered to 41/43 (95%) of cognitive plus physical therapy patients on 100% [92–100%] of study days beginning 1.0 [1.0–1.0] day following enrollment. Physical therapy was received by 17/22 (77%) of usual care patients, by 21/22 (95%) of physical therapy only patients and 42/43 (98%) of cognitive plus physical therapy patients on 17% [10–26%], 67% [46–87%] and 75% [59–88%] of study days, respectively. Cognitive, functional and health-related quality of life outcomes did not differ between groups at 3-month follow-up. CONCLUSIONS This pilot study demonstrates that early rehabilitation can be extended beyond physical therapy to include cognitive therapy. Future work to determine optimal patient selection, intensity of treatment and benefits of cognitive therapy in the critically ill is needed. PMID:24257969

The fluctuation of blood glucose, insulin and glucagon concentrations before and after insulin therapy in type 1 diabetes

NASA Astrophysics Data System (ADS)

Arif, Idam; Nasir, Zulfa

2015-09-01

A dynamical-systems model of plasma glucose, insulin and glucagon concentrations has been developed to investigate the effects of insulin therapy on blood glucose, insulin and glucagon regulations in type 1 diabetic patients. Simulation results show that the normal regulation of blood glucose concentration depends on insulin and glucagon concentrations. On type 1 diabetic case, the role of insulin on regulating blood glucose is not optimal because of the destruction of β cells in pancreas. These β cells destructions cause hyperglycemic episode affecting the whole body metabolism. To get over this, type 1 diabetic patients need insulin therapy to control the blood glucose level. This research has been done by using rapid acting insulin (lispro), long-acting insulin (glargine) and the combination between them to know the effects of insulin therapy on blood glucose, insulin and glucagon concentrations. Simulation results show that these different types of insulin have different effects on blood glucose concentration. Insulin therapy using lispro shows better blood glucose control after consumption of meals. Glargin gives better blood glucose control between meals and during sleep. Combination between lispro and glargine shows better glycemic control for whole day blood glucose level.

Predictors of viral suppression and rebound among HIV-positive men who have sex with men in a large multi-site Canadian cohort.

PubMed

Tanner, Zachary; Lachowsky, Nathan; Ding, Erin; Samji, Hasina; Hull, Mark; Cescon, Angela; Patterson, Sophie; Chia, Jason; Leslie, Alia; Raboud, Janet; Loutfy, Mona; Cooper, Curtis; Klein, Marina; Machouf, Nima; Tsoukas, Christos; Montaner, Julio; Hogg, Robert S

2016-10-21

Gay, bisexual and other men who have sex with men (MSM) are disproportionately affected by HIV in Canada. Combination antiretroviral therapy has been shown to dramatically decrease progression to AIDS, premature death and HIV transmission. However, there are no comprehensive data regarding combination antiretroviral therapy outcomes among this population. We sought to identify socio-demographic and clinical correlates of viral suppression and rebound. Our analysis included MSM participants in the Canadian Observational Cohort, a multi-site cohort of HIV-positive adults from Canada's three most populous provinces, aged ≥18 years who first initiated combination antiretroviral therapy between 2000 and 2011. We used accelerated failure time models to identify factors predicting time to suppression (2 measures <50 copies/mL ≥30 days apart) and subsequent rebound (2 measures >200 copies/mL ≥30 days apart). Of 2,858 participants, 2,448 (86 %) achieved viral suppression in a median time of 5 months (Q1-Q3: 3-7 months). Viral suppression was significantly associated with later calendar year of antiretroviral therapy initiation, no history of injection drug use, lower baseline viral load, being on an initial regimen consisting of non-nucleoside reverse-transcriptase inhibitors, and older age. Among those who suppressed, 295 (12 %) experienced viral rebound. This was associated with earlier calendar year of antiretroviral therapy initiation, injection drug use history, younger age, higher baseline CD4 cell count, and living in British Columbia. Further strategies are required to optimize combination antiretroviral therapy outcomes in men who have sex with men in Canada, specifically targeting younger MSM and those with a history of injection drug use.

[Electrical stimulation therapy and its effects on the general activity of motor impaired cerebral palsied children; a comparative study of the Bobath physiotherapy and its combination with the Hufschmidt electrical stimulation therapy (author's transl)].

PubMed

Leyendecker, C

1975-08-01

The purpose of this study was to answer the following questions: (1) Is it more effective to treat spastic cerebral palsy with the Hufschmidt electrical stimulation therapy combined with the Bobath neuro-development treatment or only with the Bobath therapy? (2) Can a general increase in activity be obtained by the electrotherapeutic muscle stimulation? A test group (combined Hufschmidt/Bobath therapy) and a control group (Bobath), both consisting of 10 subjects, were observed for four months. The duration of observation was divided into two four months treatment periods with a rest interval of two months in between. At the start of therapeutic measures, motor activity and psychic condition were tested with corresponding motormetric and psychodiagnostic techniques; three check-up examinations were carried out at the end of the first, and at the beginning and end of the second period of treatment. The motor-metric control examination showed that at the end of the first period the test group had achieved by far the better results, but at the end of the second therapeutic period, both groups were equally successful. The combined electrophysiotherapy hence reached in a relatively shorter time - as it were by leaps and bounds - the optimal obtainable state of functional improvements which, with the Bobath therapy alone, can be effected more slowly but with more continuity. The psychodiagnostic controls clearly indicate that the electrical stimulation produced an unspecified increase in activity, especially after the first phase of treatment, whereas in the second phase this could only be proven in a graded form. The report closes with an examination of the results and their consequences for the implementation of the treatment for cerebral palsied children.

Lipid-lowering nutraceuticals in clinical practice: position paper from an International Lipid Expert Panel.

PubMed

Cicero, Arrigo F G; Colletti, Alessandro; Bajraktari, Gani; Descamps, Olivier; Djuric, Dragan M; Ezhov, Marat; Fras, Zlatko; Katsiki, Niki; Langlois, Michel; Latkovskis, Gustavs; Panagiotakos, Demosthenes B; Paragh, Gyorgy; Mikhailidis, Dimitri P; Mitchenko, Olena; Paulweber, Bernhard; Pella, Daniel; Pitsavos, Christos; Reiner, Željko; Ray, Kausik K; Rizzo, Manfredi; Sahebkar, Amirhossein; Serban, Maria-Corina; Sperling, Laurence S; Toth, Peter P; Vinereanu, Dragos; Vrablík, Michal; Wong, Nathan D; Banach, Maciej

2017-09-01

In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipid-lowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting. © The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Multidisciplinary therapy for the treatment of malocclusion in a patient with chronic periodontitis with a five-year follow-up: A case report.

PubMed

Zhang, Dongmei; Lin, Li; Tang, Xiaoling; Li, Chen; Liu, Jingbo; Wang, Hongyang; Pan, Yaping

2017-10-01

Multidisciplinary therapy is essential in dental practice to achieve optimized outcomes. The present case report describes the application of periodontal surgery with a five-year follow-up in a patient with malocclusion and chronic periodontitis. In the presence of periodontal inflammation, orthodontic therapy may result in further periodontal breakdown due to plaque accumulation. In order to prevent this progression, scaling and root planning with a periodontal endoscope was applied, and continuous clinical monitoring and risk assessment was performed every 3 months using a Florida Probe. This combined treatment supports the long-term maintenance of periodontal conditions, functional occlusion and harmony of the facial profile.

Acute exacerbation of idiopathic pulmonary fibrosis triggered by Aspergillus empyema.

PubMed

Suzuki, Atsushi; Kimura, Tomoki; Kataoka, Kensuke; Matsuda, Toshiaki; Yokoyama, Toshiki; Mori, Yuta; Kondoh, Yasuhiro

2018-01-01

Acute exacerbation (AE) is a severe and life-threatening complication of idiopathic pulmonary fibrosis (IPF). In 2016, the definition and diagnostic criteria for AE-IPF were updated by an international working group. The new definition includes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events) characterized by evidence of new widespread alveolar abnormality in patients with IPF. There are no currently proven beneficial management strategies for idiopathic and triggered AE-IPF. This is the first report describing AE-IPF triggered by Aspergillus empyema, which was improved by a combination of corticosteroid, systemic antifungal therapy, local antifungal therapy, and additional pharmacological therapies. Future research may reveal optimal strategies for both idiopathic and triggered AE-IPF.

Somatic Treatments for Mood Disorders

PubMed Central

Rosa, Moacyr A; Lisanby, Sarah H

2012-01-01

Somatic treatments for mood disorders represent a class of interventions available either as a stand-alone option, or in combination with psychopharmacology and/or psychotherapy. Here, we review the currently available techniques, including those already in clinical use and those still under research. Techniques are grouped into the following categories: (1) seizure therapies, including electroconvulsive therapy and magnetic seizure therapy, (2) noninvasive techniques, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and cranial electric stimulation, (3) surgical approaches, including vagus nerve stimulation, epidural electrical stimulation, and deep brain stimulation, and (4) technologies on the horizon. Additionally, we discuss novel approaches to the optimization of each treatment, and new techniques that are under active investigation. PMID:21976043

Nonstatin therapies for management of dyslipidemia: a review.

PubMed

Sando, Karen R; Knight, Michelle

2015-10-01

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Recently published cholesterol treatment guidelines emphasize the use of statins as the preferred treatment strategy for both primary and secondary prevention of CVD. However, the optimal treatment strategy for patients who cannot tolerate statin therapy or those who need additional lipid-lowering therapy is unclear in light of recent evidence that demonstrates a lack of improved cardiovascular outcomes with combination therapy. The purpose of this review is to summarize and interpret evidence that evaluates nonstatin drug classes in reducing cardiovascular outcomes, to provide recommendations for use of nonstatin therapies in clinical practice, and to review emerging nonstatin therapies for management of dyslipidemia. Relevant articles were identified through searches of PubMed, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews by using the terms niacin, omega-3 fatty acids (FAs), clofibrate, fibrate, fenofibrate, fenofibric acid, gemfibrozil, cholestyramine, colestipol, colesevelam, ezetimibe, proprotein convertase subtilisin/kexin 9 (PCSK9), cholesteryl ester transfer protein (CETP), and cardiovascular outcomes. Only English language, human clinical trials, meta-analyses, and systematic reviews were included. Additional references were identified from citations of published articles. Niacin may reduce cardiovascular events as monotherapy; however, recent trials in combination with statins have failed to show a benefit. Trials with omega-3 FAs have failed to demonstrate significant reductions in cardiovascular outcomes. Fibrates may improve cardiovascular outcomes as monotherapy; however, trials in combination with statins have failed to show a benefit, except in those with elevated triglycerides (>200 mg/dL) or low HDL-C (<40 mg/dL). There is a lack of data that evaluates bile acid sequestrant in combination with statin therapy on reducing cardiovascular events. Ezetimibe-statin combination therapy can reduce cardiovascular outcomes in those with chronic kidney disease and following vascular surgery or acute coronary syndrome. Long-term effects of emerging nonstatin therapies (CETP and PCSK9 inhibitors) are currently being evaluated in ongoing Phase III trials. Nonstatin therapies have a limited role in reducing cardiovascular events in those maintained on guideline-directed statin therapy. In certain clinical situations, such as patients who are unable to tolerate statin therapy or recommended intensities of statin therapy, those with persistent severe elevations in triglycerides, or patients with high cardiovascular risk, some nonstatin therapies may be useful in reducing cardiovascular events. Future research is needed to evaluate the role of nonstatin therapies in those who are unable to tolerate guideline-directed statin doses. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Mixing Online and Face-to-Face Therapy: How to Benefit From Blended Care in Mental Health Care.

PubMed

Wentzel, Jobke; van der Vaart, Rosalie; Bohlmeijer, Ernst T; van Gemert-Pijnen, Julia E W C

2016-02-09

Blended care, a combination of online and face-to-face therapy, is increasingly being applied in mental health care to obtain optimal benefit from the advantages these two treatment modalities have. Promising results have been reported, but a variety in descriptions and ways of operationalizing blended care exists. Currently, what type of "blend" works for whom, and why, is unclear. Furthermore, a rationale for setting up blended care is often lacking. In this viewpoint paper, we describe postulates for blended care and provide an instrument (Fit for Blended Care) that aims to assist therapists and patients whether and how to set up blended care treatment. A review of the literature, two focus groups (n=5 and n=5), interviews with therapists (n=14), and interviews with clients (n=2) were conducted to develop postulates of eHealth and blended care and an instrument to assist therapists and clients in setting up optimal blended care. Important postulates for blended care are the notion that both treatment modalities should complement each other and that set up of blended treatment should be based on shared decision making between patient and therapist. The "Fit for Blended Care" instrument is presented which addresses the following relevant themes: possible barriers to receiving blended treatment such as the risk of crisis, issues in communication (at a distance), as well as possible facilitators such as social support. More research into the reasons why and for whom blended care works is needed. To benefit from blended care, face-to-face and online care should be combined in such way that the potentials of both treatment modalities are used optimally, depending on patient abilities, needs, and preferences. To facilitate the process of setting up a personalized blended treatment, the Fit for Blended Care instrument can be used. By applying this approach in research and practice, more insight into the working mechanisms and optimal (personal) "blends" of online and face-to-face therapy becomes within reach.

Improved outcomes with intensity modulated radiation therapy combined with temozolomide for newly diagnosed glioblastoma multiforme.

PubMed

Aherne, Noel J; Benjamin, Linus C; Horsley, Patrick J; Silva, Thomaz; Wilcox, Shea; Amalaseelan, Julan; Dwyer, Patrick; Tahir, Abdul M R; Hill, Jacques; Last, Andrew; Hansen, Carmen; McLachlan, Craig S; Lee, Yvonne L; McKay, Michael J; Shakespeare, Thomas P

2014-01-01

Purpose. Glioblastoma multiforme (GBM) is optimally treated by maximal debulking followed by combined chemoradiation. Intensity modulated radiation therapy (IMRT) is gaining widespread acceptance in other tumour sites, although evidence to support its use over three-dimensional conformal radiation therapy (3DCRT) in the treatment of gliomas is currently lacking. We examined the survival outcomes for patients with GBM treated with IMRT and Temozolomide. Methods and Materials. In all, 31 patients with GBM were treated with IMRT and 23 of these received chemoradiation with Temozolomide. We correlated survival outcomes with patient functional status, extent of surgery, radiation dose, and use of chemotherapy. Results. Median survival for all patients was 11.3 months, with a median survival of 7.2 months for patients receiving 40.05 Gray (Gy) and a median survival of 17.4 months for patients receiving 60 Gy. Conclusions. We report one of the few series of IMRT in patients with GBM. In our group, median survival for those receiving 60 Gy with Temozolomide compared favourably to the combined therapy arm of the largest randomised trial of chemoradiation versus radiation to date (17.4 months versus 14.6 months). We propose that IMRT should be considered as an alternative to 3DCRT for patients with GBM.

Improved Outcomes with Intensity Modulated Radiation Therapy Combined with Temozolomide for Newly Diagnosed Glioblastoma Multiforme

PubMed Central

Aherne, Noel J.; Benjamin, Linus C.; Horsley, Patrick J.; Silva, Thomaz; Wilcox, Shea; Amalaseelan, Julan; Dwyer, Patrick; Tahir, Abdul M. R.; Hill, Jacques; Last, Andrew; Hansen, Carmen; McLachlan, Craig S.; Lee, Yvonne L.; McKay, Michael J.; Shakespeare, Thomas P.

2014-01-01

Purpose. Glioblastoma multiforme (GBM) is optimally treated by maximal debulking followed by combined chemoradiation. Intensity modulated radiation therapy (IMRT) is gaining widespread acceptance in other tumour sites, although evidence to support its use over three-dimensional conformal radiation therapy (3DCRT) in the treatment of gliomas is currently lacking. We examined the survival outcomes for patients with GBM treated with IMRT and Temozolomide. Methods and Materials. In all, 31 patients with GBM were treated with IMRT and 23 of these received chemoradiation with Temozolomide. We correlated survival outcomes with patient functional status, extent of surgery, radiation dose, and use of chemotherapy. Results. Median survival for all patients was 11.3 months, with a median survival of 7.2 months for patients receiving 40.05 Gray (Gy) and a median survival of 17.4 months for patients receiving 60 Gy. Conclusions. We report one of the few series of IMRT in patients with GBM. In our group, median survival for those receiving 60 Gy with Temozolomide compared favourably to the combined therapy arm of the largest randomised trial of chemoradiation versus radiation to date (17.4 months versus 14.6 months). We propose that IMRT should be considered as an alternative to 3DCRT for patients with GBM. PMID:24563782

Medication use pattern and predictors of optimal therapy at discharge in 8176 patients with acute coronary syndrome from 6 Middle Eastern countries: data from the gulf registry of acute coronary events.

PubMed

Al-Zakwani, Ibrahim; Zubaid, Mohammad; Panduranga, Prashanth; Rashed, Wafa; Sulaiman, Kadhim; Almahmeed, Wael; Al-Motarreb, Ahmed; Al Suwaidi, Jassim; Amin, Haitham

2011-08-01

We evaluated the use of quadruple evidence-based medication (EBM) combination consisting of antiplatelet therapy, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, β-blocker, and lipid-lowering agent concurrently at discharge among patients (n = 8154) with acute coronary syndrome (ACS) in 6 Middle Eastern countries. In all, 49% of the patients received the quadruple EBM combination concurrently at discharge. An adjusted model demonstrated that old age, diabetes mellitus, hyperlipidemia, hypertension, ST-segment elevation myocardial infarction, cardiac catheterization, as well as cardiologists as care providers and hospitals with cardiac catheterization facilities were all positively correlated with the use of the quadruple EBM combination. However, patients with cardiogenic shock, renal impairment, higher risk score, congestive heart failure, recurrent ischemia, and those admitted to academic hospitals were negatively correlated with the use of the quadruple EBM combination. Guideline adherence to the concurrent use of quadruple EBM combination in patients with ACS at discharge was suboptimal with wide disparity among the 6 countries.

[Optimization of enuresis therapy in children using transcranial magnetotherapy].

PubMed

Otpushchennikova, T V; Kazanskaia, I V; Volkov, S V; Raĭgorodskaia, Iu M

2010-01-01

A total of 58 children (age from 6 to 14 years) suffering from nocturnal enuresis (NE) were divided into two groups. The study group received basic therapy (driptan dose was reduced to 2.5 mg twice a day) in combination with transcranial bitemporal magnetotherapy (TcMT). The control group received placebo TcMT and basic therapy. It is shown that addition of TcMT to reduced basic therapy lowered the score of imperative voiding symptoms 1.3-fold, number of enuresis patients 1.7-fold, volume of the bladder 6.8 months after the treatment 1.9-fold, corrected vegetative status and activity of the subcortical nervous center in 24% children according to cardiointervalography versus the controls. Thus, TcMT improves clinical effect in NE patients in 2-fold reduction of pharmacological burden.

Combining Gene and Stem Cell Therapy for Peripheral Nerve Tissue Engineering.

PubMed

Busuttil, Francesca; Rahim, Ahad A; Phillips, James B

2017-02-15

Despite a substantially increased understanding of neuropathophysiology, insufficient functional recovery after peripheral nerve injury remains a significant clinical challenge. Nerve regeneration following injury is dependent on Schwann cells, the supporting cells in the peripheral nervous system. Following nerve injury, Schwann cells adopt a proregenerative phenotype, which supports and guides regenerating nerves. However, this phenotype may not persist long enough to ensure functional recovery. Tissue-engineered nerve repair devices containing therapeutic cells that maintain the appropriate phenotype may help enhance nerve regeneration. The combination of gene and cell therapy is an emerging experimental strategy that seeks to provide the optimal environment for axonal regeneration and reestablishment of functional circuits. This review aims to summarize current preclinical evidence with potential for future translation from bench to bedside.

Correction of murine Rag2 severe combined immunodeficiency by lentiviral gene therapy using a codon-optimized RAG2 therapeutic transgene.

PubMed

van Til, Niek P; de Boer, Helen; Mashamba, Nomusa; Wabik, Agnieszka; Huston, Marshall; Visser, Trudi P; Fontana, Elena; Poliani, Pietro Luigi; Cassani, Barbara; Zhang, Fang; Thrasher, Adrian J; Villa, Anna; Wagemaker, Gerard

2012-10-01

Recombination activating gene 2 (RAG2) deficiency results in severe combined immunodeficiency (SCID) with complete lack of T and B lymphocytes. Initial gammaretroviral gene therapy trials for other types of SCID proved effective, but also revealed the necessity of safe vector design. We report the development of lentiviral vectors with the spleen focus forming virus (SF) promoter driving codon-optimized human RAG2 (RAG2co), which improved phenotype amelioration compared to native RAG2 in Rag2(-/-) mice. With the RAG2co therapeutic transgene, T-cell receptor (TCR) and immunoglobulin repertoire, T-cell mitogen responses, plasma immunoglobulin levels and T-cell dependent and independent specific antibody responses were restored. However, the thymus double positive T-cell population remained subnormal, possibly due to the SF virus derived element being sensitive to methylation/silencing in the thymus, which was prevented by replacing the SF promoter by the previously reported silencing resistant element (ubiquitous chromatin opening element (UCOE)), and also improved B-cell reconstitution to eventually near normal levels. Weak cellular promoters were effective in T-cell reconstitution, but deficient in B-cell reconstitution. We conclude that immune functions are corrected in Rag2(-/-) mice by genetic modification of stem cells using the UCOE driven codon-optimized RAG2, providing a valid optional vector for clinical implementation.

What are the arguments for and against rational therapy for epilepsy?

PubMed

Barker-Haliski, Melissa; Sills, Graeme J; White, H Steve

2014-01-01

Although more than a dozen new anti-seizure drugs (ASDs) have entered the market since 1993, a substantial proportion of patients (~30 %) remain refractory to current treatments. Thus, a concerted effort to identify and develop new therapies that will help these patients continues. Until this effort succeeds, it is reasonable to re-assess the use of currently available therapies and to consider how these therapies might be utilized in a more efficacious manner. This applies to the selection of monotherapies in newly-diagnosed epilepsy, but perhaps, more importantly, to the choice of combination treatments in otherwise drug-refractory epilepsy. Rational polytherapy is a concept that is predicated on the combination of drugs with complementary mechanisms of action (MoAs) that work synergistically to maximize efficacy and minimize the potential for adverse events. Furthermore, rational polytherapy requires a detailed understanding of the MoA subclasses amongst available ASDs and an appreciation of the empirical evidence that supports the use of specific combinations. The majority of ASDs can be loosely categorized into those that target neurotransmission and network hyperexcitability, modulate intrinsic neuronal properties through ion channels, or possess broad-spectrum efficacy as a result of multiple mechanisms. Within each of these categories, there are discrete pharmacological profiles that differentiate individual ASDs. This chapter will consider how knowledge of MoA can help guide therapy in a rational manner, both in the selection of monotherapies for specific seizure types and syndromes, but also in the choice of drug combinations for patients whose epilepsy is not optimally controlled with a single ASD.

Spatially Uniform Tumor Treatment and Drug Penetration by Regulating Ultrasound with Microbubbles.

PubMed

Ho, Yi-Ju; Wang, Tzu-Chia; Fan, Ching-Hsiang; Yeh, Chih-Kuang

2018-05-30

Tumor microenvironment has different morphologies of vessels in the core and rim regions, which influences the efficacy of tumor therapy. Our study proposed to improve the spatial uniformity of the antivascular effect and drug penetration within the tumor core and rim in combination therapies by regulating ultrasound-stimulated microbubble destruction (USMD). Focused ultrasound at 2 MHz and lipid-shell microbubbles (1.12 ± 0.08 μm, mean ± standard deviation) were used to perform USMD. The efficiency of the antivascular effect was evaluated by intravital imaging to determine the optimal USMD parameters. Tumor perfusion and histological alterations in the tumor core and rim were used to analyze the spatial uniformity of the antivascular effect and liposomal-doxorubicin (5 mg/kg) penetration in the combination therapy. Tumor vessels of specific sizes were disrupted by regulating USMD: vessels with sizes of 11 ± 3, 14 ± 5, 19 ± 7, and 23 ± 10 μm were disrupted by stimulation at acoustic pressures of 3, 5, 7, and 9 MPa, respectively (each p < 0.05). The effective treatment time of USMD (at 2 × 10 7 microbubbles/mouse, 7 MPa, and three cycles) was 60-120 min, which resulted in the disruption of 21-44% of vessels smaller than 50 μm. The reductions in perfusion and vascular density after combination therapy did not differ significantly between the tumor core and rim. This study found that regulating USMD can result in homogeneous antivascular effects and drug penetration within tumors and thereby improve the efficacy of combination therapies.

Optimizing catecholaminergic polymorphic ventricular tachycardia therapy in calsequestrin-mutant mice

PubMed Central

Katz, Guy; Khoury, Assad; Kurtzwald, Efrat; Hochhauser, Edith; Porat, Eyal; Shainberg, Asher; Seidman, Jonathan G.; Seidman, Christine E.; Lorber, Abraham; Eldar, Michael; Arad, Michael

2014-01-01

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal arrhythmia provoked by physical or emotional stress and mediated by spontaneous Ca2+ release and delayed after-depolarizations. Beta-adrenergic blockers are the therapy of choice but fail to control arrhythmia in up to 50% of patients. OBJECTIVE To optimize antiarrhythmic therapy in recessively inherited CPVT caused by calsequestrin (CASQ2) mutations. METHODS Murine heart rhythm telemetry was obtained at rest, during treadmill exercise, and after injection of epinephrine. The protocol was repeated after injection of different antiarrhythmic drugs. Results were then validated in human patients. RESULTS Adult CASQ2 mutant mice had complex ventricular arrhythmia at rest and developed bidirectional and polymorphic ventricular tachycardia on exertion. Class I antiarrhythmic agents (procainamide, lidocaine, flecainide) were ineffective in controlling arrhythmia. Propranolol and sotalol attenuated arrhythmia at rest but failed to prevent VT during sympathetic stimulation. The calcium channel blocker verapamil showed a dose-dependent protection against CPVT. Verapamil was more effective than the dihydropyridine L-type Ca2+ channel blocker nifedipine, and its activity was markedly enhanced when combined with propranolol. Human patients homozygous for CASQ2D307H mutation, remaining symptomatic despite chronic β-blocker therapy, underwent exercise testing according to the Bruce protocol with continuous electrocardiogram recording. Verapamil was combined with propranolol at maximum tolerated doses. Adding verapamil attenuated ventricular arrhythmia and prolonged exercise duration in five of 11 patients. CONCLUSION Verapamil is highly effective against catecholamine-induced arrhythmia in mice with CASQ2 mutations and may potentiate the antiarrhythmic activity of β-blockers in humans with CPVT2. PMID:20620233

Insulin Therapy in People With Type 2 Diabetes: Opportunities and Challenges?

PubMed Central

Home, Philip; Riddle, Matthew; Cefalu, William T.; Bailey, Clifford J.; Bretzel, Reinhard G.; del Prato, Stefano; Leroith, Derek; Schernthaner, Guntram; van Gaal, Luc; Raz, Itamar

2014-01-01

Given the continued interest in defining the optimal management of individuals with type 2 diabetes, the Editor of Diabetes Care convened a working party of diabetes specialists to examine this topic in the context of insulin therapy. This was prompted by recent new evidence on the use of insulin in such people. The group was aware of evidence that the benefits of insulin therapy are still usually offered late, and thus the aim of the discussion was how to define the optimal timing and basis for decisions regarding insulin and to apply these concepts in practice. It was noted that recent evidence had built upon that of the previous decades, together confirming the benefits and safety of insulin therapy, albeit with concerns about the potential for hypoglycemia and gain in body weight. Insulin offers a unique ability to control hyperglycemia, being used from the time of diagnosis in some circumstances, when metabolic control is disturbed by medical illness, procedures, or therapy, as well as in the longer term in ambulatory care. For those previously starting insulin, various other forms of therapy can be added later, which offer complementary effects appropriate to individual needs. Here we review current evidence and circumstances in which insulin can be used, consider individualized choices of alternatives and combination regimens, and offer some guidance on personalized targets and tactics for glycemic control in type 2 diabetes. PMID:24855154

Fast Biological Modeling for Voxel-based Heavy Ion Treatment Planning Using the Mechanistic Repair-Misrepair-Fixation Model and Nuclear Fragment Spectra

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamp, Florian; Department of Radiation Oncology, Technische Universität München, Klinikum Rechts der Isar, München; Physik-Department, Technische Universität München, Garching

2015-11-01

Purpose: The physical and biological differences between heavy ions and photons have not been fully exploited and could improve treatment outcomes. In carbon ion therapy, treatment planning must account for physical properties, such as the absorbed dose and nuclear fragmentation, and for differences in the relative biological effectiveness (RBE) of ions compared with photons. We combined the mechanistic repair-misrepair-fixation (RMF) model with Monte Carlo-generated fragmentation spectra for biological optimization of carbon ion treatment plans. Methods and Materials: Relative changes in double-strand break yields and radiosensitivity parameters with particle type and energy were determined using the independently benchmarked Monte Carlo damagemore » simulation and the RMF model to estimate the RBE values for primary carbon ions and secondary fragments. Depth-dependent energy spectra were generated with the Monte Carlo code FLUKA for clinically relevant initial carbon ion energies. The predicted trends in RBE were compared with the published experimental data. Biological optimization for carbon ions was implemented in a 3-dimensional research treatment planning tool. Results: We compared the RBE and RBE-weighted dose (RWD) distributions of different carbon ion treatment scenarios with and without nuclear fragments. The inclusion of fragments in the simulations led to smaller RBE predictions. A validation of RMF against measured cell survival data reported in published studies showed reasonable agreement. We calculated and optimized the RWD distributions on patient data and compared the RMF predictions with those from other biological models. The RBE values in an astrocytoma tumor ranged from 2.2 to 4.9 (mean 2.8) for a RWD of 3 Gy(RBE) assuming (α/β){sub X} = 2 Gy. Conclusions: These studies provide new information to quantify and assess uncertainties in the clinically relevant RBE values for carbon ion therapy based on biophysical mechanisms. We present results from the first biological optimization of carbon ion radiation therapy beams on patient data using a combined RMF and Monte Carlo damage simulation modeling approach. The presented method is advantageous for fast biological optimization.« less

Fast Biological Modeling for Voxel-based Heavy Ion Treatment Planning Using the Mechanistic Repair-Misrepair-Fixation Model and Nuclear Fragment Spectra.

PubMed

Kamp, Florian; Cabal, Gonzalo; Mairani, Andrea; Parodi, Katia; Wilkens, Jan J; Carlson, David J

2015-11-01

The physical and biological differences between heavy ions and photons have not been fully exploited and could improve treatment outcomes. In carbon ion therapy, treatment planning must account for physical properties, such as the absorbed dose and nuclear fragmentation, and for differences in the relative biological effectiveness (RBE) of ions compared with photons. We combined the mechanistic repair-misrepair-fixation (RMF) model with Monte Carlo-generated fragmentation spectra for biological optimization of carbon ion treatment plans. Relative changes in double-strand break yields and radiosensitivity parameters with particle type and energy were determined using the independently benchmarked Monte Carlo damage simulation and the RMF model to estimate the RBE values for primary carbon ions and secondary fragments. Depth-dependent energy spectra were generated with the Monte Carlo code FLUKA for clinically relevant initial carbon ion energies. The predicted trends in RBE were compared with the published experimental data. Biological optimization for carbon ions was implemented in a 3-dimensional research treatment planning tool. We compared the RBE and RBE-weighted dose (RWD) distributions of different carbon ion treatment scenarios with and without nuclear fragments. The inclusion of fragments in the simulations led to smaller RBE predictions. A validation of RMF against measured cell survival data reported in published studies showed reasonable agreement. We calculated and optimized the RWD distributions on patient data and compared the RMF predictions with those from other biological models. The RBE values in an astrocytoma tumor ranged from 2.2 to 4.9 (mean 2.8) for a RWD of 3 Gy(RBE) assuming (α/β)X = 2 Gy. These studies provide new information to quantify and assess uncertainties in the clinically relevant RBE values for carbon ion therapy based on biophysical mechanisms. We present results from the first biological optimization of carbon ion radiation therapy beams on patient data using a combined RMF and Monte Carlo damage simulation modeling approach. The presented method is advantageous for fast biological optimization. Copyright © 2015 Elsevier Inc. All rights reserved.

Considerations, challenges and future of anti-TNF therapy in treating inflammatory bowel disease.

PubMed

Pouillon, Lieven; Bossuyt, Peter; Peyrin-Biroulet, Laurent

2016-10-01

Crohn's disease (CD) and ulcerative colitis (UC) are chronic disabling conditions. Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNF) has revolutionized the care of patients with inflammatory bowel disease (IBD). Considerations before starting anti-TNF therapy are highlighted: the best time to start with anti-TNF therapy, either alone or in combination with an immunomodulator, the choice of an anti-TNF agent and the contra-indications to anti-TNF therapy. Primary nonresponse and secondary loss of response are discussed. De-escalating therapy, the role of therapeutic drug monitoring and the use of biosimilars, are handled. Finally, the future directions of anti-TNF therapy are emphasized. Anti-TNF therapy remains the cornerstone in the treatment of IBD. When initiating long-term therapy, safety and cost issues are of great importance. The therapeutic armamentarium in the treatment of IBD is rapidly growing. Therefore, the challenge is to optimize the use and refine the exact position of anti-TNF therapy in the near future, with personalized medicine as the ultimate goal.

Operative management of chronic pancreatitis: A review.

PubMed

Tillou, John D; Tatum, Jacob A; Jolissaint, Joshua S; Strand, Daniel S; Wang, Andrew Y; Zaydfudim, Victor; Adams, Reid B; Brayman, Kenneth L

2017-08-01

Pain secondary to chronic pancreatitis is a difficult clinical problem to manage. Many patients are treated medically or undergo endoscopic therapy and surgical intervention is often reserved for those who have failed to gain adequate pain relief from a more conservative approach. There have been a number of advances in the operative management of chronic pancreatitis over the last few decades and current therapies include drainage procedures (pancreaticojejunostomy, etc.), resection (pancreticoduodenectomy, etc.) and combined drainage/resection procedures (Frey procedure, etc.). Additionally, many centers currently perform total pancreatectomy with islet autotransplantation, in addition to minimally invasive options that are intended to tailor therapy to individual patients. Operative management of chronic pancreatitis often improves quality of life, and is associated with low rates of morbidity and mortality. The decision as to which procedure is optimal for each patient should be based on a combination of pathologic changes, prior interventions, and individual surgeon and center experience. Copyright © 2017 Elsevier Inc. All rights reserved.

Property-Guided Synthesis of Aza-Tricyclic Indolines: Development of Gold Catalysis En Route.

PubMed

Barbour, Patrick M; Wang, Wei; Chang, Le; Pickard, Kasey L; Rais, Rana; Slusher, Barbara S; Wang, Xiang

2016-04-28

Antibiotic resistance is a worldwide public health threat that needs to be addressed by improved antibiotic stewardship and continuing development of new chemical entities to treat resistant bacterial infections. Compounds that work alongside known antibiotics as combination therapies offer an efficient and sustainable approach to counteract antibiotic resistance in bacteria. Guided by property-based analysis, a series of aza-tricyclic indolines (ATIs) were synthesized to optimize their physiochemical properties as novel combination therapies with β-lactams to treat methicillin-resistant S. aureus (MRSA) infections. A novel and highly efficient gold-catalyzed tandem cyclization was developed to facilitate the synthesis of these ATIs. One guanidine-containing ATI was discovered to possess both improved anti-MRSA activity and lower mammalian toxicity both in vitro and in vivo. In addition, it also showed significantly enhanced aqueous solubility and metabolic stability. These results indicated that the ATIs are a novel class of anti-MRSA agents suitable for further evaluations as adjuvant therapy in animal model studies.

The continuing role of chemotherapy for advanced non-small cell lung cancer in the targeted therapy era.

PubMed

Lwin, Zarnie; Riess, Jonathan W; Gandara, David

2013-10-01

There have been remarkable advances in the targeted treatment of advanced non-small cell lung cancer (NSCLC) over the past several years. Survival outcomes are steadily improving as management paradigms shift in the diagnosis and treatment of advanced NSCLC. Customizing treatment based on histology and molecular typing has become a standard of care in this era of targeted therapy. While new chemotherapeutic agents have proven effective, the pivotal role of platinum-based chemotherapy doublets has been confirmed. Maintenance chemotherapy has become an option, but who to employ it in remains unclear in the real-world setting. Efforts to overcome resistance to targeted agents are ongoing utilizing combination regimens of chemotherapy plus targeted agents, but optimizing combination strategies needs further exploration. This review highlights recent developments in novel chemotherapeutics and in chemotherapy strategies over the past two years. Despite advances in molecular medicine, there remains an essential role for chemotherapy in advanced NSCLC, even in the recent targeted therapy era.

Oral Candida in Patients with Fixed Orthodontic Appliance: In Vitro Combination Therapy.

PubMed

Alhamadi, Wisam; Al-Saigh, Rafal J; Al-Dabagh, Nebras N; Al-Humadi, Hussam W

2017-01-01

Fixed orthodontic appliance (FOA) increases the cariogenic microorganisms of mouth including candida. The aim was to evaluate the pharmacodynamic effects of some antibacterial drugs in combination with most applicable antifungal agents on candida isolated from patients with FOA. Three antifungal agents (amphotericin B (AMB), ketoconazole (KET), and itraconazole (ITZ)) and three antibacterial drugs (ciprofloxacin (CIP), doxycycline (DOX), and metronidazole (MET)) with serial concentrations have been used and microdilution broth method has been done for single and combination therapy, then fungal growth was assessed spectrophotometrically, and the combinations were evaluated by bliss independent analysis. According to bliss independent interaction, the synergistic interactions depended on Δ E values that showed the best for CIP was with AMB (Δ E = 55.14) followed with KET (Δ E = 41.23) and lastly ITR (Δ E = 39.67) at CIP = 150 mg/L. DOX was optimal with KET (Δ E = 42.11) followed with AMB (Δ E = 40.77) and the lowest with ITR (Δ E = 9.12) at DOX = 75 mg/L. MET is the best with AMB (Δ E = 40.95) and then with ITR (Δ E = 35.45) and finally KET (Δ E = 15.15) at MET 200 mg/L. Moreover, usage of higher concentrations of antibacterial agents revealed inhibitory effects. This study uncovers the optimum antibiotic combination therapy against cariogenic candida with FOA by usage of low therapeutic concentrations.

CD28z CARs and Armored CARs

PubMed Central

Pegram, Hollie J.; Park, Jae H.; Brentjens, Renier J.

2015-01-01

CD19-targeted chimeric antigen receptor (CAR) T cells are currently being tested in the clinic with very promising outcomes. However, limitations to CAR T cell therapy exist. These include lack of efficacy against some tumors, specific targeting of tumor cells without affecting normal tissue and retaining activity within the suppressive tumor microenvironment. Whilst promising clinical trials are in progress, preclinical development is focused on optimizing CAR design, to generate “armored CAR T cells” which are protected from the inhibitory tumor microenvironment. Studies investigating the expression of cytokine transgenes, combination therapy with small molecule inhibitors or monoclonal antibodies are aimed at improving the anti-tumor efficacy of CAR T cell therapy. Other strategies aimed at improving CAR T cell therapy include utilizing dual CARs and chemokine receptors to more specifically target tumor cells. This review will describe the current clinical data and some novel “armored CAR T cell” approaches for improving anti-tumor efficacy therapy. PMID:24667958

CD28z CARs and armored CARs.

PubMed

Pegram, Hollie J; Park, Jae H; Brentjens, Renier J

2014-01-01

CD19-targeted chimeric antigen receptor (CAR) T cells are currently being tested in the clinic with very promising outcomes. However, limitations to CAR T cell therapy exist. These include lack of efficacy against some tumors, specific targeting of tumor cells without affecting normal tissue and retaining activity within the suppressive tumor microenvironment. Whereas promising clinical trials are in progress, preclinical development is focused on optimizing CAR design, to generate "armored CAR T cells," which are protected from the inhibitory tumor microenvironment. Studies investigating the expression of cytokine transgenes, combination therapy with small molecule inhibitors, or monoclonal antibodies, are aimed at improving the antitumor efficacy of CAR T cell therapy. Other strategies aimed at improving CAR T cell therapy include using dual CARs and chemokine receptors to more specifically target tumor cells. This review will describe the current clinical data and some novel armored CAR T cell approaches for improving antitumor efficacy therapy.

The Role of Surgery, Radiosurgery and Whole Brain Radiation Therapy in the Management of Patients with Metastatic Brain Tumors

PubMed Central

Ellis, Thomas L.; Neal, Matthew T.; Chan, Michael D.

2012-01-01

Brain tumors constitute the most common intracranial tumor. Management of brain metastases has become increasingly complex as patients with brain metastases are living longer and more treatment options develop. The goal of this paper is to review the role of stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and surgery, in isolation and in combination, in the contemporary treatment of brain metastases. Surgery and SRS both offer management options that may help to optimize therapy in selected patients. WBRT is another option but can lead to late toxicity and suboptimal local control in longer term survivors. Improved prognostic indices will be critical for selecting the best therapies. Further prospective trials are necessary to continue to elucidate factors that will help triage patients to the proper brain-directed therapy for their cancer. PMID:22312545

Optimizing fluid management in patients with acute decompensated heart failure (ADHF): the emerging role of combined measurement of body hydration status and brain natriuretic peptide (BNP) levels.

PubMed

Valle, Roberto; Aspromonte, Nadia; Milani, Loredano; Peacock, Frank W; Maisel, Alan S; Santini, Massimo; Ronco, Claudio

2011-11-01

The study tests the hypothesis that in patients admitted with acutely decompensated heart failure (ADHF), achievement of adequate body hydration status with intensive medical therapy, modulated by combined bioelectrical vectorial impedance analysis (BIVA) and B-type natriuretic peptide (BNP) measurement, may contribute to optimize the timing of patient's discharge and to improve clinical outcomes. Three hundred patients admitted for ADHF underwent serial BIVA and BNP measurement. Therapy was titrated to reach a BNP value of <250 pg/ml, whenever possible. Patients were categorized as early responders (rapid BNP fall below 250 pg/ml); late responders (slow BNP fall below 250 pg/ml, after aggressive therapy); and non-responders (BNP persistently >250 pg/ml). Worsening of renal function (WRF) was evaluated during hospitalization. Death and rehospitalization were monitored with a 6-month follow-up. BNP value on discharge of ≤250 pg/ml led to a 25% event rate within 6 months (Group A: 17.4%; Group B: 21%, Chi2; n.s.), whereas a value >250 pg/ml (Group C) was associated with a far higher percentage (37%). At discharge, body hydration was 73.8 ± 3.2% in the total population and 73.2 ± 2.1, 73.5 ± 2.8, 74.1 ± 3.6% in the three groups, respectively. WRF was observed in 22.3% of the total. WRF occurred in 22% in Group A, 32% in Group B, and 20% in Group C (P = n.s.). Our study confirms the hypothesis that combined BNP/BIVA sequential measurements help to achieve adequate fluid balance status in patients with ADHF and can be used to drive a "tailored therapy," allowing clinicians to identify high-risk patients and possibly to reduce the incidence of complications secondary to fluid management strategies.

Getting to goal in newly diagnosed type 2 diabetes using combination drug "subtraction therapy".

PubMed

Jennings, Anthony S; Lovett, Alexandra J; George, Tina M; Jennings, Jonathan S

2015-09-01

The treatment of newly diagnosed type 2 diabetes mellitus is diverse, with no clear consensus regarding the initial drug regimen or dosing to achieve optimal glycemic control. We treated 44 consecutive patients with newly diagnosed type 2 diabetes with maximally tolerated doses of pioglitazone 45 mg/day, metformin 1000-2000 mg/day, and repaglinide 1-4 mg before meals. The doses and drugs were subsequently decreased ("subtraction therapy") to achieve optimal glycemic control and minimize side effects. Three primary outcomes were measured: the short term HbA1c response, the long term HbA1c response, and the incidence of hypoglycemia. All 44 patients responded with a rapid, progressive decline in their HbA1c levels from 11.43±2.3% to 6.17±0.72% (101±25.1 mmol/mol to 44±7.9 mmol/mol) by three months, and remained stable thereafter. An HbA1c ≤7.0% (≤53 mmol/mol) was reached within 1-4 months in 42 of 44 patients, and in every patient by 12 months. Each patient's lowest HbA1c level, 5.65±0.6% (38±6.6 mmol/mol), was reached over 6.3±2.9 months. Patients with initial HbA1c levels >10% (>86 mmol/mol) (n=33) responded similarly as those with HbA1c levels <10% (<86 mmol/mol) (n=11). Combination drug therapy maintained HbA1c levels between 5.0 and 7.0% (31 and 53 mmol/mol) for up to 14.83 years. Only one clinically significant hypoglycemic event occurred during 261.08 person-years of follow-up. In our experience, combination drug "subtraction therapy" was safe and effective for treating all newly diagnosed type 2 diabetic patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Initial Steps to inform selection of continuation cognitive therapy or fluoxetine for higher risk responders to cognitive therapy for recurrent major depressive disorder.

PubMed

Vittengl, Jeffrey R; Anna Clark, Lee; Thase, Michael E; Jarrett, Robin B

2017-07-01

Responders to acute-phase cognitive therapy (A-CT) for major depressive disorder (MDD) often relapse or recur, but continuation-phase cognitive therapy (C-CT) or fluoxetine reduces risks for some patients. We tested composite moderators of C-CT versus fluoxetine's preventive effects to inform continuation treatment selection. Responders to A-CT for MDD judged to be at higher risk for relapse due to unstable or partial remission (N=172) were randomized to 8 months of C-CT or fluoxetine with clinical management and assessed, free from protocol treatment, for 24 additional months. Pre-continuation-treatment characteristics that in survival analyses moderated treatments' effects on relapse over 8 months of continuation-phase treatment (residual symptoms and negative temperament) and on relapse/recurrence over the full observation period's 32 months (residual symptoms and age) were combined to estimate the potential advantage of C-CT versus fluoxetine for individual patients. Assigning patients to optimal continuation treatment (i.e., to C-CT or fluoxetine, depending on patients' pre-continuation-treatment characteristics) resulted in absolute reduction of relapse or recurrence risk by 16-21% compared to the other non-optimal treatment. Although these novel results require replication before clinical application, selecting optimal continuation treatment (i.e., personalizing treatment) for higher risk A-CT responders may decrease risks of MDD relapse and recurrence substantively. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Efficacy of rasagiline for the treatment of Parkinson's disease: an updated meta-analysis.

PubMed

Chang, Ying; Wang, Li-Bo; Li, Dan; Lei, Ke; Liu, Song-Yan

2017-08-01

Rasagiline is a second-generation potent selective inhibitor of monoamine oxidase-B. The aim of the study was to analyze the effectiveness of rasagiline in treatment of Parkinson's disease (PD), both as monotherapy and combination therapy. Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 9 March 2016 using the keywords: Rasagiline, Azilect, Parkinson's disease. Randomized controlled trials of patients with PD who were randomized to treatment with rasagiline or placebo were included. Outcomes were unified Parkinson's disease rating scale (UPDRS) and the three subscales. Ten studies fulfilled the inclusion criteria and 2709 patients were evaluated. The overall analysis revealed a significant improvement in change of total UPDRS scores in 1 mg/day and 2 mg/day rasagiline groups compared to placebo. Significant improvement in Part I (Mentation) of UPDRS scores was observed in 1 mg/day, but not in 2 mg/day rasagiline treatment group. Part II (ADL) and Part III (Motor) subscales significantly improved with both doses of rasagiline. Both monotherapy and combination therapy significantly improved total UPDRS scores. Our results confirm the efficacy of rasagiline in PD. Further studies are required to establish the optimal dose of rasagiline, as well as to determine its effectiveness in different combination therapy protocols. KEY MESSAGES Rasagiline treatment was associated with significant improvement of UPDRS scores and the scores of the subscales. Both monotherapy and combination therapy significantly improved total UPDRS scores. Effect of rasagiline on total UPDRS scores was not dose-dependent.

Physical Therapy Adjuvants to Promote Optimization of Walking Recovery after Stroke

PubMed Central

Bowden, Mark G.; Embry, Aaron E.; Gregory, Chris M.

2011-01-01

Stroke commonly results in substantial and persistent deficits in locomotor function. The majority of scientific inquiries have focused on singular intervention approaches, with recent attention given to task specific therapies. We propose that measurement should indicate the most critical limiting factor(s) to be addressed and that a combination of adjuvant treatments individualized to target accompanying impairment(s) will result in the greatest improvements in locomotor function. We explore training to improve walking performance by addressing a combination of: (1) walking specific motor control; (2) dynamic balance; (3) cardiorespiratory fitness and (4) muscle strength and put forward a theoretical framework to maximize the functional benefits of these strategies as physical adjuvants. The extent to which any of these impairments contribute to locomotor dysfunction is dependent on the individual and will undoubtedly change throughout the rehabilitation intervention. Thus, the ability to identify and measure the relative contributions of these elements will allow for identification of a primary intervention as well as prescription of additional adjuvant approaches. Importantly, we highlight the need for future studies as appropriate dosing of each of these elements is contingent on improving the capacity to measure each element and to titrate the contribution of each to optimal walking performance. PMID:22013549

An update on adjunctive treatment options for bipolar disorder.

PubMed

Dean, Olivia M; Gliddon, Emma; Van Rheenen, Tamsyn E; Giorlando, Francesco; Davidson, Sandra K; Kaur, Manreena; Ngo, Trung T; Williams, Lana J

2018-03-01

Bipolar disorder is a complex illness often requiring combinations of therapies to successfully treat symptoms. In recent years, there have been significant advancements in a number of therapies for bipolar disorder. It is therefore timely to provide an overview of current adjunctive therapeutic options to help treating clinicians to inform their patients and work towards optimal outcomes. Publications were identified from PubMed searches on bipolar disorder and pharmacotherapy, nutraceuticals, hormone therapy, psychoeducation, interpersonal and social rhythm therapy, cognitive remediation, mindfulness, e-Health and brain stimulation techniques. Relevant articles in these areas were selected for further review. This paper provides a narrative review of adjunctive treatment options and is not a systematic review of the literature. A number of pharmacotherapeutic, psychological and neuromodulation treatment options are available. These have varying efficacy but all have shown benefit to people with bipolar disorder. Due to the complex nature of treating the disorder, combination treatments are often required. Adjunctive treatments to traditional pharmacological and psychological therapies are proving useful in closing the gap between initial symptom remission and full functional recovery. Given that response to monotherapy is often inadequate, combination regimens for bipolar disorder are typical. Correspondingly, psychiatric research is working towards a better understanding of the disorder's underlying biology. Therefore, treatment options are changing and adjunctive therapies are being increasingly recognized as providing significant tools to improve patient outcomes. Towards this end, this paper provides an overview of novel treatments that may improve clinical outcomes for people with bipolar disorder. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Is there an additional benefit of serial NT-proBNP measurements in patients with stable chronic heart failure receiving individually optimized therapy?

PubMed

Franke, Jennifer; Frankenstein, Lutz; Schellberg, Dieter; Bajrovic, Amer; Wolter, Jan Sebastian; Ehlermann, Philipp; Doesch, Andreas O; Nelles, Manfred; Katus, Hugo A; Zugck, Christian

2011-12-01

The role of serial NT-proBNP measurements in patients suffering from chronic systolic heart failure (CHF) who already receive individually optimized pharmacotherapy is still unresolved. NT-proBNP was assessed at baseline and at 6 months follow-up in 504 stable CHF patients treated with individually optimized pharmacotherapy. After assessment of clinical stability at 6 months, patients were followed up for at least 1 year. The combined primary endpoint was defined as death, hospitalization due to cardiac reasons or heart transplantation in 1-year follow-up. We stratified our patients according to two principles: first, a percent change of value (CV) between the first and second measurement of NT-proBNP and secondly, the transformed logarithm of NT-proBNP measured at 6 months. During the follow-up period of 1 year, 50 patients (9.9%) reached the combined primary endpoint. Stratification according to percentage CV was less accurate in predicting endpoint-free survival compared to a classification in categories of lnNT-proBNP measured at 6 months (ROC AUC = 0.615; 95% CI 0.525-0.70 vs. ROC AUC = 0.790; 95% CI 0.721-0.856, respectively). When entered into proportional hazard regression analysis, lnNT-proBNP measured at 6 months remained an independent predictor of the combined primary endpoint with an associated HR of 2.53 (95% CI 1.385-4.280). To date, this is the largest analysis of serial NT-proBNP measurements in patients with CHF receiving individually optimized medical therapy. These data suggest that a single NT-proBNP measurement after 6 months in stable clinical conditions may have higher predictive value than stratification of change in serial measurements.

Inactivation of nuclear factor κB by MIP-based drug combinations augments cell death of breast cancer cells.

PubMed

Subramaniam, Menaga; Liew, Su Ki; In, Lionel LA; Awang, Khalijah; Ahmed, Niyaz; Nagoor, Noor Hasima

2018-01-01

Drug combination therapy to treat cancer is a strategic approach to increase successful treatment rate. Optimizing combination regimens is vital to increase therapeutic efficacy with minimal side effects. In the present study, we evaluated the in vitro cytotoxicity of double and triple combinations consisting of 1'S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP) and cisplatin (CDDP) against 14 various human cancer cell lines to address the need for more effective therapy. Our data show synergistic effects in MCF-7 cells treated with MIP:ACA, MIP:CDDP and MIP:ACA:CDDP combinations. The type of interaction between MIP, ACA and CDDP was evaluated based on combination index being <0.8 for synergistic effect. Identifying the mechanism of cell death based on previous studies involved intrinsic apoptosis and nuclear factor kappa B (NF-κB) and tested in Western blot analysis. Inactivation of NF-κB was confirmed by p65 and IκBα, while intrinsic apoptosis pathway activation was confirmed by caspase-9 and Apaf-1 expression. All combinations confirmed intrinsic apoptosis activation and NF-κB inactivation. Double and triple combination regimens that target induction of the same death mechanism with reduced dosage of each drug could potentially be clinically beneficial in reducing dose-related toxicities.

Beneficial effects of the combination of amlodipine and losartan for lowering blood pressure in spontaneously hypertensive rats.

PubMed

Choi, Seul Min; Seo, Mi Jeong; Kang, Kyung Koo; Kim, Jeong Hoon; Ahn, Byoung Ok; Yoo, Moohi

2009-03-01

A combination of antihypertensive agents can better control blood pressure and reduce the number and severity of side effects than a monotherapy. Since both CCBs (calcium channel blockers) and ARBs (angiotensin II receptor type-1 blockers) are current and effective antihypertensive drugs, this study assessed the synergistic antihypertensive effects as well as the optimal combination ratio of these two drugs. Amlodipine (3 mg/kg) or losartan (30 mg/kg) alone or a combination of each drug at a ratio 1:10 and 1:20 was administered orally to spontaneously hypertensive rats (SHR). A four-week treatment of either 3 mg/kg amlodipine or 30 mg/kg losartan alone decreased the systolic blood pressure (SBP). However, their combination significantly lowered the SBP from the 3(rd) week, and there was a positive correlation between this reduction in blood pressure and the improvement in arterial endothelium-dependent relaxation. In addition, the combination therapy (1:20) decreased both the cardiac mass and left ventricular weight to a greater extent than with either amlodipine or losartan alone. The collagen content in the cardiac tissue was also significantly lower after the 4-week combination therapy (1:10). These results suggest that the combined use of amlodipine and losartan might be more effective in treating hypertension than a monotherapy.

Iterative dataset optimization in automated planning: Implementation for breast and rectal cancer radiotherapy.

PubMed

Fan, Jiawei; Wang, Jiazhou; Zhang, Zhen; Hu, Weigang

2017-06-01

To develop a new automated treatment planning solution for breast and rectal cancer radiotherapy. The automated treatment planning solution developed in this study includes selection of the iterative optimized training dataset, dose volume histogram (DVH) prediction for the organs at risk (OARs), and automatic generation of clinically acceptable treatment plans. The iterative optimized training dataset is selected by an iterative optimization from 40 treatment plans for left-breast and rectal cancer patients who received radiation therapy. A two-dimensional kernel density estimation algorithm (noted as two parameters KDE) which incorporated two predictive features was implemented to produce the predicted DVHs. Finally, 10 additional new left-breast treatment plans are re-planned using the Pinnacle 3 Auto-Planning (AP) module (version 9.10, Philips Medical Systems) with the objective functions derived from the predicted DVH curves. Automatically generated re-optimized treatment plans are compared with the original manually optimized plans. By combining the iterative optimized training dataset methodology and two parameters KDE prediction algorithm, our proposed automated planning strategy improves the accuracy of the DVH prediction. The automatically generated treatment plans using the dose derived from the predicted DVHs can achieve better dose sparing for some OARs without compromising other metrics of plan quality. The proposed new automated treatment planning solution can be used to efficiently evaluate and improve the quality and consistency of the treatment plans for intensity-modulated breast and rectal cancer radiation therapy. © 2017 American Association of Physicists in Medicine.

SOP conservative (medical and mechanical) treatment of erectile dysfunction.

PubMed

Porst, Hartmut; Burnett, Arthur; Brock, Gerald; Ghanem, Hussein; Giuliano, Francois; Glina, Sidney; Hellstrom, Wayne; Martin-Morales, Antonio; Salonia, Andrea; Sharlip, Ira

2013-01-01

Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships. The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures. The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included. Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation. © 2013 International Society for Sexual Medicine.

Combined p16 and p53 expression in cervical cancer of unknown primary and other prognostic parameters : A single-center analysis.

PubMed

Yildirim, Müjdat; Müller von der Grün, Jens; Winkelmann, Ria; Fokas, Emmanouil; Rödel, Franz; Ackermann, Hanns; Rödel, Claus; Balermpas, Panagiotis

2017-04-01

Cervical cancer of unknown primary (CUP) represents an uncommon and heterogeneous subentity of head and neck cancer. However, both optimal diagnostics and therapy remain unclear. An improved understanding of the underlying pathology is essential to enable future tailored therapies and optimized outcomes. We retrospectively analyzed 53 patients with head and neck CUP and 48 available cervical lymph node specimens. All patients have received radiotherapy between 2007 and 2015. Preradiotherapy involved lymph node specimens were analyzed for p16 and p53 immunoreactivity. The prognostic relevance of the combined p16 and p53 status and other clinical parameters were examined by univariate and multivariate analyses. Median patient age was 61.5 years and median irradiation dose to the involved nodal levels was 66 Gy. Of the 48 evaluated specimens, 13 (27%) were p16-positive and 31 (64.6%) p53-positive. After a median follow up of 32.9 months, patients with p16-negative and simultaneously p53-positive tumors showed a significantly inferior tumor-specific survival (TSS) compared to those with either p16+/p53-, p16+/p53+, or p16-/p53- (univariate: p = 0.055, multivariate: p = 0.038). Other factors with an adverse impact on TSS in the univariate analysis were smoking history (p = 0.032) and nodal stage (p = 0.038). The combined p16- and p53-expression status in cervical metastases of CUP may represent a simple method for risk stratification. Further validation of these biomarkers in large prospective trials is essential to design rational trials for CUP treatment optimization.

Towards reducing thrombogenicity of LVAD therapy: optimizing surgical and patient management strategies

NASA Astrophysics Data System (ADS)

Chivukula, Venkat Keshav; Lafzi, Ali; Mokadam, Nahush; Beckman, Jennifer; Mahr, Claudius; Aliseda, Alberto

2017-11-01

Unfavourable hemodynamics in heart failure patients implanted with left ventricular assist devices (LVAD), due to non-optimal surgical configurations and patient management, strongly influence thrombogenicity. This is consistent with the increase in devastating thromboembolic complications (specifically thrombosis and stroke) in patients, even as the risk of thrombosis inside the device decreases with modern designs. Inflow cannula and outflow graft surgical configurations have been optimized via patient-specific modeling that computes the thrombogenic potential with a combination of Eulerian (endothelial) wall shear stress and Lagrangian (platelet shear history) tracking. Using this view of hemodynamics, the benefits of intermittent aortic valve opening (promoting washout and reducing stagnant flow in the aortic valve region) have been assessed in managing the patient's residual native cardiac output. The use of this methodology to understand the contribution of the hemodynamics in the flow surrounding the LVAD itself to thrombogenesis show promise in developing holistic patient-specific management strategies to minimize stroke risk and enhance efficacy of LVAD therapy. Funded in part by an AHA postdoctoral fellowship 16POST30520004.

Fighting cancers from within: augmenting tumor immunity with cytokine therapy.

PubMed

Pellegrini, Marc; Mak, Tak W; Ohashi, Pamela S

2010-08-01

The human immune system has successfully evolved to fight many pathogens. Through vaccination, we can harness and improve immune responses to eradicate infections. Despite this success, we are only now beginning to understand the natural tumor immune surveillance mechanisms and why, in some instances, our immune system fails to abrogate the development and growth of tumors. Encouraging results with the latest immunotherapies have renewed enthusiasm in the field. A central component of these therapies is the contribution of cytokines. Here we review our expanding knowledge of cytokine-induced effects as well as preclinical and clinical data that indicate adjuvant cytokine therapies may hold much promise in improving anti-tumor immunity. Further studies on optimal synergistic combinations, timing, duration and additional adjuvant therapies are required to realize the full potential of cytokines as immunotherapeutic agents. 2010 Elsevier Ltd. All rights reserved.

Simultaneous beam sampling and aperture shape optimization for SPORT.

PubMed

Zarepisheh, Masoud; Li, Ruijiang; Ye, Yinyu; Xing, Lei

2015-02-01

Station parameter optimized radiation therapy (SPORT) was recently proposed to fully utilize the technical capability of emerging digital linear accelerators, in which the station parameters of a delivery system, such as aperture shape and weight, couch position/angle, gantry/collimator angle, can be optimized simultaneously. SPORT promises to deliver remarkable radiation dose distributions in an efficient manner, yet there exists no optimization algorithm for its implementation. The purpose of this work is to develop an algorithm to simultaneously optimize the beam sampling and aperture shapes. The authors build a mathematical model with the fundamental station point parameters as the decision variables. To solve the resulting large-scale optimization problem, the authors devise an effective algorithm by integrating three advanced optimization techniques: column generation, subgradient method, and pattern search. Column generation adds the most beneficial stations sequentially until the plan quality improvement saturates and provides a good starting point for the subsequent optimization. It also adds the new stations during the algorithm if beneficial. For each update resulted from column generation, the subgradient method improves the selected stations locally by reshaping the apertures and updating the beam angles toward a descent subgradient direction. The algorithm continues to improve the selected stations locally and globally by a pattern search algorithm to explore the part of search space not reachable by the subgradient method. By combining these three techniques together, all plausible combinations of station parameters are searched efficiently to yield the optimal solution. A SPORT optimization framework with seamlessly integration of three complementary algorithms, column generation, subgradient method, and pattern search, was established. The proposed technique was applied to two previously treated clinical cases: a head and neck and a prostate case. It significantly improved the target conformality and at the same time critical structure sparing compared with conventional intensity modulated radiation therapy (IMRT). In the head and neck case, for example, the average PTV coverage D99% for two PTVs, cord and brainstem max doses, and right parotid gland mean dose were improved, respectively, by about 7%, 37%, 12%, and 16%. The proposed method automatically determines the number of the stations required to generate a satisfactory plan and optimizes simultaneously the involved station parameters, leading to improved quality of the resultant treatment plans as compared with the conventional IMRT plans.

Simultaneous beam sampling and aperture shape optimization for SPORT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zarepisheh, Masoud; Li, Ruijiang; Xing, Lei, E-mail: Lei@stanford.edu

Purpose: Station parameter optimized radiation therapy (SPORT) was recently proposed to fully utilize the technical capability of emerging digital linear accelerators, in which the station parameters of a delivery system, such as aperture shape and weight, couch position/angle, gantry/collimator angle, can be optimized simultaneously. SPORT promises to deliver remarkable radiation dose distributions in an efficient manner, yet there exists no optimization algorithm for its implementation. The purpose of this work is to develop an algorithm to simultaneously optimize the beam sampling and aperture shapes. Methods: The authors build a mathematical model with the fundamental station point parameters as the decisionmore » variables. To solve the resulting large-scale optimization problem, the authors devise an effective algorithm by integrating three advanced optimization techniques: column generation, subgradient method, and pattern search. Column generation adds the most beneficial stations sequentially until the plan quality improvement saturates and provides a good starting point for the subsequent optimization. It also adds the new stations during the algorithm if beneficial. For each update resulted from column generation, the subgradient method improves the selected stations locally by reshaping the apertures and updating the beam angles toward a descent subgradient direction. The algorithm continues to improve the selected stations locally and globally by a pattern search algorithm to explore the part of search space not reachable by the subgradient method. By combining these three techniques together, all plausible combinations of station parameters are searched efficiently to yield the optimal solution. Results: A SPORT optimization framework with seamlessly integration of three complementary algorithms, column generation, subgradient method, and pattern search, was established. The proposed technique was applied to two previously treated clinical cases: a head and neck and a prostate case. It significantly improved the target conformality and at the same time critical structure sparing compared with conventional intensity modulated radiation therapy (IMRT). In the head and neck case, for example, the average PTV coverage D99% for two PTVs, cord and brainstem max doses, and right parotid gland mean dose were improved, respectively, by about 7%, 37%, 12%, and 16%. Conclusions: The proposed method automatically determines the number of the stations required to generate a satisfactory plan and optimizes simultaneously the involved station parameters, leading to improved quality of the resultant treatment plans as compared with the conventional IMRT plans.« less

Optimal management of metastatic renal cell carcinoma: current status.

PubMed

Escudier, Bernard; Albiges, Laurence; Sonpavde, Guru

2013-04-01

The armamentarium for the systemic therapy of advanced renal cell carcinoma (RCC) has undergone dramatic changes over the past 6 years. While high-dose interleukin (IL)-2 remains an option for highly selected good and intermediate risk patients with clear-cell histology because of durable complete responses in a small fraction of patients, cytokine-based therapy including interferon (IFN) has been supplanted by vascular-endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors. Treatment decision is initially based on prognostication of the disease. As metastatic RCC (mRCC) is commonly an indolent disease, a period of observation should always been considered. For good and intermediate risk disease, pazopanib, sunitinib or the combination of bevacizumab plus IFN are considered. Notably, recent data suggest non-inferiority for the efficacy of pazopanib compared to sunitinib coupled with a better toxicity profile. A novel VEGF receptor inhibitor, tivozanib, is expected to be approved based on improvement in PFS when compared to sorafenib in the first-line setting. The use of temsirolimus for poor risk disease is supported by a phase III trial dedicated to this group of patients. The role of cytoreductive nephrectomy in the context of VEGF and mTOR inhibitors is being studied in randomized trials. Selected patients with solitary or oligometastatic disease may be eligible for metastatectomy. Following first-line VEGF inhibitors, second-line therapy with everolimus and axitinib have demonstrated benefits in progression-free survival (PFS). One phase III trial comparing sorafenib and temsirolimus in the post-sunitinib setting showed no difference in PFS, the primary endpoint, but did show a superior overall survival for sorafenib. Sorafenib, pazopanib and axitinib have all demonstrated clinical benefit following cytokines. Therapy following first-line mTOR inhibitors remains undefined, although VEGF inhibitors have demonstrated activity in this setting. Optimal sequencing of agents and individualized therapy based on biomarkers is undergoing investigation. Today, the choice of therapy is based on patient and physician decision, which is a function of comorbidities, toxicity profiles and costs. Clinical trials evaluating novel agents and combinations should be preferred when available since agents in the current therapeutic arsenal have not yielded cures despite extending median survival to greater than 2 years. One noteworthy new class of agents that has yielded durable responses is programmed death (PD)-1 inhibitors, which target a T-lymphocyte checkpoint and are heralding a resurgence of immunotherapy. Finally, optimal therapy for non-clear cell RCC remains to be delineated, although sunitinib, everolimus and other VEGFR-TKI or mTOR inhibitors have all demonstrated modest benefit.

Bioengineering Strategies for Designing Targeted Cancer Therapies

PubMed Central

Wen, Xuejun

2014-01-01

The goals of bioengineering strategies for targeted cancer therapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumor, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by nonmalignant cells. Effective cancer-targeting therapies will require both passive- and active targeting strategies and a thorough understanding of physiologic barriers to targeted drug delivery. Designing a targeted therapy includes the selection and optimization of a nanoparticle delivery vehicle for passive accumulation in tumors, a targeting moiety for active receptor-mediated uptake, and stimuli-responsive polymers for control of drug release. The future direction of cancer targeting is a combinatorial approach, in which targeting therapies are designed to use multiple targeting strategies. The combinatorial approach will enable combination therapy for delivery of multiple drugs and dual ligand targeting to improve targeting specificity. Targeted cancer treatments in development and the new combinatorial approaches show promise for improving targeted anticancer drug delivery and improving treatment outcomes. PMID:23768509

Aspirin and proton pump inhibitor combination therapy for prevention of cardiovascular disease and Barrett's esophagus.

PubMed

Peura, David A; Wilcox, C Mel

2014-01-01

Aspirin, used at low doses (75-325 mg daily), prevents aggregation of platelets and is prescribed for patients as pharmacologic prevention of cardiovascular disease. Despite the well-documented beneficial effects of aspirin, prolonged use is associated with damage to the gastrointestinal (GI) mucosa in the upper and lower GI tract. Patient risk of hemorrhage and peptic ulcer formation is increased with older age, previous ulcer history, Helicobacter pylori infection, and concomitant use of nonsteroidal anti-inflammatory drugs, corticosteroids, or antithrombotic agents. As termination of aspirin therapy can precipitate a cardiovascular event, patients at risk need co-therapy with gastroprotective agents, such as proton pump inhibitors (PPIs), to reduce the GI side effects of aspirin treatment. Fixed-dose combinations of low-dose aspirin and gastroprotective agents have been designed to increase medication compliance, improve clinical outcomes, and reduce the overall cost of therapy. Prolonged use of PPIs may, however, lead to serious adverse effects or, in some cases, reduce the cardioprotective effects of aspirin. Hence, physicians need to carefully consider the benefits and risks associated with the condition of each patient to optimize clinical outcomes of combination therapy. A growing body of clinical evidence indicates that aspirin may decrease the risk of colorectal and other GI cancers, as well as reduce progression from Barrett's esophagus (BE) to esophageal adenocarcinoma. Furthermore, PPIs have recently been shown to reduce neoplastic transformation in patients with BE. Thus, the use of a fixed-dose aspirin/PPI combination could potentially provide chemopreventive benefit to patients with BE, and, at the same time, treat the underlying gastroesophageal reflux responsible for the condition.

A combination hepatoma-targeted therapy based on nanotechnology: pHRE-Egr1-HSV-TK/131I-antiAFPMcAb-GCV/MFH

NASA Astrophysics Data System (ADS)

Lin, Mei; Huang, Junxing; Jiang, Xingmao; Zhang, Jia; Yu, Hong; Ye, Jun; Zhang, Dongsheng

2016-09-01

Combination targeted therapy is a promising cancer therapeutic strategy. Here, using PEI-Mn0.5Zn0.5Fe2O4 nanoparticles (PEI-MZF-NPs) as magnetic media for MFH (magnetic fluid hyperthermia) and gene transfer vector for gene-therapy, a combined therapy, pHRE-Egr1-HSV-TK/131I-antiAFPMcAb-GCV/MFH, for hepatoma is developed. AntiAFPMcAb (Monoclonal antibody AFP) is exploited for targeting. The plasmids pHRE-Egr1-HSV-TK are achieved by incorporation of pEgr1-HSV-TK and pHRE-Egr1-EGFP. Restriction enzyme digestion and PCR confirm the recombinant plasmids pHRE-Egr1-HSV-TK are successfully constructed. After exposure to the magnetic field, PEI-MZF-NPs/pHRE-Egr1-EGFP fluid is warmed rapidly and then the temperature is maintained at 43 °C or so, which is quite appropriate for cancer treatment. The gene expression reaches the peak when treated with 200 μCi 131I for 24 hours, indicating that the dose of 200 μCi might be the optimal dose for irradiation and 24 h irradiation later is the best time to initiate MFH. The in vitro and in vivo experiments demonstrate that pHRE-Egr1-HSV-TK/131I-antiAFPMcAb-GCV/MFH can greatly suppress hepatic tumor cell proliferation and induce cell apoptosis and necrosis and effectively inhibit the tumor growth, much better than any monotherapy does alone. Furthermore, the combination therapy has few or no adverse effects. It might be applicable as a strategy to treat hepatic cancer.

Impact of vitreomacular adhesion on ranibizumab mono- and combination therapy for neovascular age-related macular degeneration.

PubMed

Waldstein, Sebastian M; Ritter, Markus; Simader, Christian; Mayr-Sponer, Ulrike; Kundi, Michael; Schmidt-Erfurth, Ursula

2014-08-01

To investigate the influence of vitreomacular adhesion on the efficacy of pro re nata (PRN) ranibizumab monotherapy and verteporfin photodynamic therapy (PDT) combination therapy for neovascular age-related macular degeneration. Post hoc analysis of prospective randomized 12-month multicenter clinical trial data. Total of 255 treatment-naïve patients with subfoveal choroidal neovascularization. Assessment of the vitreomacular interface on monthly optical coherence tomography with division of patients into the following categories according to continuous 1-year grading: posterior vitreous detachment (n=154), dynamic release of vitreomacular adhesion (n=32), stable vitreomacular adhesion (n=51). Mean best-corrected visual acuity (BCVA) letter and central retinal thickness changes at month 12 in the vitreomacular interface groups. Mean BCVA changes at month 12 were +3.5 (posterior vitreous detachment), +4.3 (release of vitreomacular adhesion), and +6.3 (vitreomacular adhesion) in patients receiving monotherapy (P=.767), and +0.1 (posterior vitreous detachment), +6.6 (release of vitreomacular adhesion), and +9.2 (vitreomacular adhesion) in patients receiving combination therapy (P=.009). Mean central retinal thickness changes were -113 μm (posterior vitreous detachment), -89 μm (release of vitreomacular adhesion), and -122 μm (vitreomacular adhesion) in monotherapy (P=.725) and -121 μm (posterior vitreous detachment), -113 μm (release of vitreomacular adhesion), and -113 μm (vitreomacular adhesion) in combination therapy (P=.924). Mean ranibizumab retreatments during 12 months were 4.9 (posterior vitreous detachment), 6.6 (release of vitreomacular adhesion), and 5.3 (vitreomacular adhesion) in monotherapy (P=.018) and 4.7 (posterior vitreous detachment), 5.2 (release of vitreomacular adhesion), and 5.8 (vitreomacular adhesion) in combination therapy (P=.942). This study adds evidence that the vitreomacular interface status impacts functional outcomes and retreatment requirements. Patients with posterior vitreous detachment achieve acceptable results with fewer injections in PRN monotherapy, but lose potential vision gain with PDT. Patients with other vitreomacular interface configurations may potentially achieve optimized vision outcomes by combination of antiangiogenic treatment and vaso-occlusive PDT. Copyright © 2014 Elsevier Inc. All rights reserved.

Personalized treatment planning with a model of radiation therapy outcomes for use in multiobjective optimization of IMRT plans for prostate cancer.

PubMed

Smith, Wade P; Kim, Minsun; Holdsworth, Clay; Liao, Jay; Phillips, Mark H

2016-03-11

To build a new treatment planning approach that extends beyond radiation transport and IMRT optimization by modeling the radiation therapy process and prognostic indicators for more outcome-focused decision making. An in-house treatment planning system was modified to include multiobjective inverse planning, a probabilistic outcome model, and a multi-attribute decision aid. A genetic algorithm generated a set of plans embodying trade-offs between the separate objectives. An influence diagram network modeled the radiation therapy process of prostate cancer using expert opinion, results of clinical trials, and published research. A Markov model calculated a quality adjusted life expectancy (QALE), which was the endpoint for ranking plans. The Multiobjective Evolutionary Algorithm (MOEA) was designed to produce an approximation of the Pareto Front representing optimal tradeoffs for IMRT plans. Prognostic information from the dosimetrics of the plans, and from patient-specific clinical variables were combined by the influence diagram. QALEs were calculated for each plan for each set of patient characteristics. Sensitivity analyses were conducted to explore changes in outcomes for variations in patient characteristics and dosimetric variables. The model calculated life expectancies that were in agreement with an independent clinical study. The radiation therapy model proposed has integrated a number of different physical, biological and clinical models into a more comprehensive model. It illustrates a number of the critical aspects of treatment planning that can be improved and represents a more detailed description of the therapy process. A Markov model was implemented to provide a stronger connection between dosimetric variables and clinical outcomes and could provide a practical, quantitative method for making difficult clinical decisions.

Optimal In-Hospital and Discharge Medical Therapy in Acute Coronary Syndromes in Kerala: Results from the Kerala ACS Registry

PubMed Central

Huffman, Mark D; Prabhakaran, Dorairaj; Abraham, AK; Krishnan, Mangalath Narayanan; Nambiar, C. Asokan; Mohanan, Padinhare Purayil

2013-01-01

Background In-hospital and post-discharge treatment rates for acute coronary syndrome (ACS) remain low in India. However, little is known about the prevalence and predictors of the package of optimal ACS medical care in India. Our objective was to define the prevalence, predictors, and impact of optimal in-hospital and discharge medical therapy in the Kerala ACS Registry of 25,718 admissions. Methods and Results We defined optimal in-hospital ACS medical therapy as receiving the following five medications: aspirin, clopidogrel, heparin, beta-blocker, and statin. We defined optimal discharge ACS medical therapy as receiving all of the above therapies except heparin. Comparisons by optimal vs. non-optimal ACS care were made via Student’s t test for continuous variables and chi-square test for categorical variables. We created random effects logistic regression models to evaluate the association between GRACE risk score variables and optimal in-hospital or discharge medical therapy. Optimal in-hospital and discharge medical care was delivered in 40% and 46% of admissions, respectively. Wide variability in both in-hospital and discharge medical care was present with few hospitals reaching consistently high (>90%) levels. Patients receiving optimal in-hospital medical therapy had an adjusted OR (95%CI)=0.93 (0.71, 1.22) for in-hospital death and an adjusted OR (95%CI)=0.79 (0.63, 0.99) for MACE. Patients who received optimal in-hospital medical care were far more likely to receive optimal discharge care (adjusted OR [95%CI]=10.48 [9.37, 11.72]). Conclusions Strategies to improve in-hospital and discharge medical therapy are needed to improve local process-of-care measures and improve ACS outcomes in Kerala. PMID:23800985

Limited Impact of Setup and Range Uncertainties, Breathing Motion, and Interplay Effects in Robustly Optimized Intensity Modulated Proton Therapy for Stage III Non-small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inoue, Tatsuya; Widder, Joachim; Dijk, Lisanne V. van

2016-11-01

Purpose: To investigate the impact of setup and range uncertainties, breathing motion, and interplay effects using scanning pencil beams in robustly optimized intensity modulated proton therapy (IMPT) for stage III non-small cell lung cancer (NSCLC). Methods and Materials: Three-field IMPT plans were created using a minimax robust optimization technique for 10 NSCLC patients. The plans accounted for 5- or 7-mm setup errors with ±3% range uncertainties. The robustness of the IMPT nominal plans was evaluated considering (1) isotropic 5-mm setup errors with ±3% range uncertainties; (2) breathing motion; (3) interplay effects; and (4) a combination of items 1 and 2.more » The plans were calculated using 4-dimensional and average intensity projection computed tomography images. The target coverage (TC, volume receiving 95% of prescribed dose) and homogeneity index (D{sub 2} − D{sub 98}, where D{sub 2} and D{sub 98} are the least doses received by 2% and 98% of the volume) for the internal clinical target volume, and dose indexes for lung, esophagus, heart and spinal cord were compared with that of clinical volumetric modulated arc therapy plans. Results: The TC and homogeneity index for all plans were within clinical limits when considering the breathing motion and interplay effects independently. The setup and range uncertainties had a larger effect when considering their combined effect. The TC decreased to <98% (clinical threshold) in 3 of 10 patients for robust 5-mm evaluations. However, the TC remained >98% for robust 7-mm evaluations for all patients. The organ at risk dose parameters did not significantly vary between the respective robust 5-mm and robust 7-mm evaluations for the 4 error types. Compared with the volumetric modulated arc therapy plans, the IMPT plans showed better target homogeneity and mean lung and heart dose parameters reduced by about 40% and 60%, respectively. Conclusions: In robustly optimized IMPT for stage III NSCLC, the setup and range uncertainties, breathing motion, and interplay effects have limited impact on target coverage, dose homogeneity, and organ-at-risk dose parameters.« less

Flow and Grit by Design: Exploring Gamification in Facilitating Adherence to Swallowing Therapy.

PubMed

Constantinescu, Gabriela; Rieger, Jana; Mummery, Kerry; Hodgetts, William

2017-11-08

Delivery of swallowing therapy is faced with challenges regarding access to in-clinic services and adherence to prescribed home programs. Mobile health (mHealth) technologies are being developed at a rapid pace to address these difficulties. Whereas some benefits to using these modern tools for therapy are obvious (e.g., electronic reminders), other advantages are not as well understood. One example is the potential for mHealth devices and apps to enhance adherence to treatment regimens. This article introduces a number of psychological concepts that relate to adherence and that can be leveraged by mHealth. Elements that contribute to flow (optimal experience) during an activity and those that reinforce grit (perseverance to achieve a long-term goal) can be used to engage patients in their own rehabilitation. The experience of flow can be targeted by presenting the rehabilitation exercise as an optimally challenging game, one that offers a match between challenge and ability. Grit can be supported by reinforcing routine and by varying the therapy experience using different games. A combination of hardware and software design approaches have the potential to transform uninteresting and repetitive activities, such as those that make up swallowing therapy regimens, into engaging ones. The field of gamification, however, is still developing, and gamified mHealth apps will need to withstand scientific testing of their claims and demonstrate effectiveness in all phases of outcome research.

Assessing the Optimal Position for Vedolizumab in the Treatment of Ulcerative Colitis: A Simulation Model.

PubMed

Scott, Frank I; Shah, Yash; Lasch, Karen; Luo, Michelle; Lewis, James D

2018-01-18

Vedolizumab, an α4β7 integrin monoclonal antibody inhibiting gut lymphocyte trafficking, is an effective treatment for ulcerative colitis (UC). We evaluated the optimal position of vedolizumab in the UC treatment paradigm. Using Markov modeling, we assessed multiple algorithms for the treatment of UC. The base case was a 35-year-old male with steroid-dependent moderately to severely active UC without previous immunomodulator or biologic use. The model included 4 different algorithms over 1 year, with vedolizumab use prior to: initiating azathioprine (Algorithm 1), combination therapy with infliximab and azathioprine (Algorithm 2), combination therapy with an alternative anti-tumor necrosis factor (anti-TNF) and azathioprine (Algorithm 3), and colectomy (Algorithm 4). Transition probabilities and quality-adjusted life-year (QALY) estimates were derived from the published literature. Primary analyses included simulating 100 trials of 100,000 individuals, assessing clinical outcomes, and QALYs. Sensitivity analyses employed longer time horizons and ranges for all variables. Algorithm 1 (vedolizumab use prior to all other therapies) was the preferred strategy, resulting in 8981 additional individuals in remission, 18 fewer cases of lymphoma, and 1087 fewer serious infections per 100,000 patients compared with last-line use (A4). Algorithm 1 also resulted in 0.0197 to 0.0205 more QALYs compared with other algorithms. This benefit increased with longer time horizons. Algorithm 1 was preferred in all sensitivity analyses. The model suggests that treatment algorithms positioning vedolizumab prior to other therapies should be considered for individuals with moderately to severely active steroid-dependent UC. Further prospective research is needed to confirm these simulated results. © 2018 Crohn’s & Colitis Foundation of America. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

[Monitoring and Modern Hemodynamic Concepts in Cardiac Anesthesia].

PubMed

Heringlake, Matthias; Schmidt, Christian; Brandt, Sebastian

2018-05-01

Patients undergoing cardiac surgery are growing older, present with more comorbidities, and are frequently scheduled for more complex and prolonged surgical procedures. Routine application of neurological as well as extended hemodynamic monitoring combined with goal-directed perioperative hemodynamic optimization, targeting optimization of systemic and cerebral oxygen balance, show promise to reduce postoperative complications and to improve mortality in this high risk population. Expert recommendations suggest to avoid synthetic colloids for fluid optimization. Additionally, pathophysiological reasoning and results from recent trials suggest to start inotropic and vasoactive therapy primarily with non-adrenergic drugs like levosimendan and vasopressin and to add classical catecholamines like dobutamine and noradrenalin only if necessary to accomplish hemodynamic goals. Georg Thieme Verlag KG Stuttgart · New York.

Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors.

PubMed

Lindsay, Danika; Garvey, Colleen M; Mumenthaler, Shannon M; Foo, Jasmine

2016-08-01

Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs) are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i) combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii) sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii) strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the clinic.

Annual clinical updates in hematological malignancies: a continuing medical education series. Hodgkin lymphoma: 2011 update on diagnosis, risk-stratification, and management.

PubMed

Ansell, Stephen M

2011-10-01

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 8,500 new patients annually and representing approximately 11% of all lymphomas in the United States. HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence are used to optimize therapy for patients with limited or advanced stage disease. Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. High-dose chemotherapy (HDCT) followed by an autologous stem-cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, palliative chemotherapy, nonmyeloablative allogeneic transplant, or participation in a clinical trial should be considered. 2011 Wiley-Liss, Inc.

Hodgkin lymphoma: 2012 update on diagnosis, risk-stratification, and management.

PubMed

Ansell, Stephen M

2012-12-01

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 9,000 new patients annually and representing approximately 11% of all lymphomas in the United States. HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence are used to optimize therapy for patients with limited or advanced stage disease. Initial therapy for HL patients is based on the histology of the disease, the anatomical stage and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies utilizing abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, palliative chemotherapy, non-myeloablative allogeneic transplant or participation in a clinical trial should be considered. Copyright © 2012 Wiley Periodicals, Inc.

Long-term intravital imaging of the multicolor-coded tumor microenvironment during combination immunotherapy

PubMed Central

Qi, Shuhong; Li, Hui; Lu, Lisen; Qi, Zhongyang; Liu, Lei; Chen, Lu; Shen, Guanxin; Fu, Ling; Luo, Qingming; Zhang, Zhihong

2016-01-01

The combined-immunotherapy of adoptive cell therapy (ACT) and cyclophosphamide (CTX) is one of the most efficient treatments for melanoma patients. However, no synergistic effects of CTX and ACT on the spatio-temporal dynamics of immunocytes in vivo have been described. Here, we visualized key cell events in immunotherapy-elicited immunoreactions in a multicolor-coded tumor microenvironment, and then established an optimal strategy of metronomic combined-immunotherapy to enhance anti-tumor efficacy. Intravital imaging data indicated that regulatory T cells formed an 'immunosuppressive ring' around a solid tumor. The CTX-ACT combined-treatment elicited synergistic immunoreactions in tumor areas, which included relieving the immune suppression, triggering the transient activation of endogenous tumor-infiltrating immunocytes, increasing the accumulation of adoptive cytotoxic T lymphocytes, and accelerating the infiltration of dendritic cells. These insights into the spatio-temporal dynamics of immunocytes are beneficial for optimizing immunotherapy and provide new approaches for elucidating the mechanisms underlying the involvement of immunocytes in cancer immunotherapy. DOI: http://dx.doi.org/10.7554/eLife.14756.001 PMID:27855783

Machine Learning Approach to Optimizing Combined Stimulation and Medication Therapies for Parkinson's Disease.

PubMed

Shamir, Reuben R; Dolber, Trygve; Noecker, Angela M; Walter, Benjamin L; McIntyre, Cameron C

2015-01-01

Deep brain stimulation (DBS) of the subthalamic region is an established therapy for advanced Parkinson's disease (PD). However, patients often require time-intensive post-operative management to balance their coupled stimulation and medication treatments. Given the large and complex parameter space associated with this task, we propose that clinical decision support systems (CDSS) based on machine learning algorithms could assist in treatment optimization. Develop a proof-of-concept implementation of a CDSS that incorporates patient-specific details on both stimulation and medication. Clinical data from 10 patients, and 89 post-DBS surgery visits, were used to create a prototype CDSS. The system was designed to provide three key functions: (1) information retrieval; (2) visualization of treatment, and; (3) recommendation on expected effective stimulation and drug dosages, based on three machine learning methods that included support vector machines, Naïve Bayes, and random forest. Measures of medication dosages, time factors, and symptom-specific pre-operative response to levodopa were significantly correlated with post-operative outcomes (P < 0.05) and their effect on outcomes was of similar magnitude to that of DBS. Using those results, the combined machine learning algorithms were able to accurately predict 86% (12/14) of the motor improvement scores at one year after surgery. Using patient-specific details, an appropriately parameterized CDSS could help select theoretically optimal DBS parameter settings and medication dosages that have potential to improve the clinical management of PD patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Online stochastic optimization of radiotherapy patient scheduling.

PubMed

Legrain, Antoine; Fortin, Marie-Andrée; Lahrichi, Nadia; Rousseau, Louis-Martin

2015-06-01

The effective management of a cancer treatment facility for radiation therapy depends mainly on optimizing the use of the linear accelerators. In this project, we schedule patients on these machines taking into account their priority for treatment, the maximum waiting time before the first treatment, and the treatment duration. We collaborate with the Centre Intégré de Cancérologie de Laval to determine the best scheduling policy. Furthermore, we integrate the uncertainty related to the arrival of patients at the center. We develop a hybrid method combining stochastic optimization and online optimization to better meet the needs of central planning. We use information on the future arrivals of patients to provide an accurate picture of the expected utilization of resources. Results based on real data show that our method outperforms the policies typically used in treatment centers.

Antiretroviral therapy in children: recent advances.

PubMed

Lodha, Rakesh; Manglani, Mamta

2012-12-01

Availability and successful use of various antiretroviral drugs has transformed HIV/AIDS from an incurable to a treatable chronic condition. The antiretroviral therapy can successfully suppress viral replication and preserve the immune system for many years. The implementation of antiretroviral therapy program in resource limited settings using the 'public health approach' of the World Health Organization has had a dramatic impact on the lives of millions of HIV infected individuals. Antiretroviral therapy (ART) in children has many challenges: use of appropriate formulations, regular need for modification of doses as the child grows, adherence issues, etc. To reduce the high morbidity and mortality in HIV infected children, it is currently recommended that all HIV infected children less than 24 mo should receive ART; in older children the indications are based on clinical and/or immunological criteria. Highly active antiretroviral therapy regimens include at least 3 antiretroviral drugs. The first line therapy recommended for children is a combination of two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor. Infants who have had exposure to nevirapine should receive a combination of two nucleoside reverse transcriptase inhibitors and a protease inhibitor; the protease inhibitor of choice is ritonavir boosted lopinavir. The success of therapy is dependent on >95 % adherence. The second line regimen, used when the first line therapy fails, is based on a protease inhibitor. The ongoing research focuses on simplification of regimen, discovery of more potent drugs, availability of more pediatric formulations, treatment of drug resistant strains etc. The optimal indications for initiation of therapy in children, are also being studied.

[Theoretical and practical considerations in rational polytherapy for epilepsy].

PubMed

Rajna, Péter

2011-11-30

Author analyses the consideration of rational polytherapy for epilepsy. Among the theoretical aspects he points the different effect of seizure inhibitory drugs on the epilepsy models but didn't find data enough for the basis of any successful combination. Combinations of compounds having different way of action are more promising. Rational polytherapy can serve also the epileptic patients' tailored therapy in the daily routine. There have already been some proved synergisms concerning drug interactions. Based on detailed analysis of side effects a possibility occurs for neutralization of side effects when anticonvulsants with side effects of opposite nature are combined. Considering both the side effect profiles and the different (somatic and psychic) habits of the patients we can create a special list of favourable combinations. Co-morbid states and their treatments play a significant role in the application of rational polytherapy. Combination of anticonvulsants of lower potential but without drug-interactions can be the choice in these cases. The non-epileptic indications of the anticonvulsants can also be utilized in polymorbid patients. Based on the theoretical and practical considerations the author defines the ten-step-cognitive-preparation-process in planning the optimal (poly)therapy. On speculative basis he suggests eight beneficial versions of seizure inhibitory rational polytherapy.

Hodgkin lymphoma: 2016 update on diagnosis, risk-stratification, and management.

PubMed

Ansell, Stephen M

2016-06-01

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 9,050 new patients annually and representing approximately 11.2% of all lymphomas in the United States. HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography (PET) scan, are used to optimize therapy. Initial therapy for HL patients is based on the histology of the disease, the anatomical stage and the presence of poor prognostic features. Patients with early stage disease are typically treated with combined modality strategies utilizing abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Management of relapsed/refractory disease: High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, PD-1 blockade, nonmyeloablative allogeneic transplant or participation in a clinical trial should be considered. © 2016 Wiley Periodicals, Inc.

Hodgkin lymphoma: 2014 update on diagnosis, risk-stratification, and management.

PubMed

Ansell, Stephen M

2014-07-01

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 9,200 new patients annually and representing approximately 11.5% of all lymphomas in the United States. HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte-predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy. Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Management of relapsed/refractory disease: High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, palliative chemotherapy, nonmyeloablative allogeneic transplant, or participation in a clinical trial should be considered. © 2014 Wiley Periodicals, Inc.

In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib.

PubMed

Chakraborty, Ashok K; Zerillo, Cynthia; DiGiovanna, Michael P

2015-08-01

The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile.

Impact of pharmacy technician-centered medication reconciliation on optimization of antiretroviral therapy and opportunistic infection prophylaxis in hospitalized patients with HIV/AIDS.

PubMed

Siemianowski, Laura A; Sen, Sanchita; George, Jomy M

2013-08-01

This study aimed to examine the role of a pharmacy technician-centered medication reconciliation (PTMR) program in optimization of medication therapy in hospitalized patients with HIV/AIDS. A chart review was conducted for all inpatients that had a medication reconciliation performed by the PTMR program. Adult patients with HIV and antiretroviral therapy (ART) and/or the opportunistic infection (OI) prophylaxis listed on the medication reconciliation form were included. The primary objective is to describe the (1) number and types of medication errors and (2) the percentage of patients who received appropriate ART. The secondary objective is a comparison of the number of medication errors between standard mediation reconciliation and a pharmacy-led program. In the PTMR period, 55 admissions were evaluated. In all, 50% of the patients received appropriate ART. In 27of the 55 admissions, there were 49 combined ART and OI-related errors. The most common ART-related errors were drug-drug interactions. The incidence of ART-related medication errors that included drug-drug interactions and renal dosing adjustments were similar between the pre-PTMR and PTMR groups (P = .0868). Of the 49 errors in the PTMR group, 18 were intervened by a medication reconciliation pharmacist. A PTMR program has a positive impact on optimizing ART and OI prophylaxis in patients with HIV/AIDS.

Opportunities and Challenges for Niosomes as Drug Delivery Systems.

PubMed

Thakkar, Miloni; Brijesh, S

2016-01-01

With the increase in drug resistance observed in most infectious diseases as well as some forms of cancer, and with the chances of development of new drug molecules to address this issue looking bleak, one of the most plausible ways to disease treatment is combination therapy. Combination therapy would ensure delay in drug resistance, if utilized rationally. However, the biggest difficulty in employing combination therapy are adverse effects due to potential drug-drug interactions and patient compliance due to multiple routes of administration or multiple dosing that may be required. To overcome these issues, researchers have utilized nanoparticle-based systems that can hold multiple drugs in a single carrier. There are several nanocarrier systems available for such purposes. However, the focus of this review will be non-ionic surfactant-based systems (niosomes) for delivery of multiple therapeutic agents. Niosomes are artificially prepared drug delivery carriers. They are structurally similar to liposomes albeit more stable than them. Literature pertaining to combination drug delivery and various drug delivery systems was reviewed. It was conceptualized that many of the methods used to prepare various types of carriers for combination delivery of drugs may be used for niosomal systems as well. We envisage that niosomes may effectively be utilized to package older drugs in newer ways. The review will thus focus on techniques that may be used for the formulation of niosomes, ways to encapsulate multiple-drug moieties, and challenges associated in preparing and optimizing such systems.

Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy

NASA Astrophysics Data System (ADS)

Kim, Kyoung Sub; Kim, Jiyoung; Lee, Joo Young; Matsuda, Shofu; Hideshima, Sho; Mori, Yasurou; Osaka, Tetsuya; Na, Kun

2016-06-01

Despite magnetic nanoparticles having shown great potential in cancer treatment, tremendous challenges related to diagnostic sensitivity and treatment efficacy for clinical application remain. Herein, we designed optimized multifunctional magnetite nanoparticles (AHP@MNPs), composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid (AHP), to achieve enhanced tumor diagnosis and therapy. Fe3O4 nanoparticles (MNPs) were synthesized by a facile hydrolysis method. MNPs have higher biocompatibility, controllable particle sizes, and desirable magnetic properties. The fabricated AHP@MNPs have enhanced water solubility (average size: 108.13 +/- 1.08 nm), heat generation properties, and singlet oxygen generation properties upon magnetic and laser irradiation. The AHP@MNPs can target tumors via CD44 receptor-mediated endocytosis, which have enhanced tumor therapeutic effects through photodynamic/hyperthermia-combined treatment without any drugs. We successfully detected tumors implanted in mice via magnetic resonance imaging and optical imaging. Furthermore, we demonstrated the photodynamic/hyperthermia-combined therapeutic efficacy of AHP@MNPs with synergistically enhanced efficacy against cancer.Despite magnetic nanoparticles having shown great potential in cancer treatment, tremendous challenges related to diagnostic sensitivity and treatment efficacy for clinical application remain. Herein, we designed optimized multifunctional magnetite nanoparticles (AHP@MNPs), composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid (AHP), to achieve enhanced tumor diagnosis and therapy. Fe3O4 nanoparticles (MNPs) were synthesized by a facile hydrolysis method. MNPs have higher biocompatibility, controllable particle sizes, and desirable magnetic properties. The fabricated AHP@MNPs have enhanced water solubility (average size: 108.13 +/- 1.08 nm), heat generation properties, and singlet oxygen generation properties upon magnetic and laser irradiation. The AHP@MNPs can target tumors via CD44 receptor-mediated endocytosis, which have enhanced tumor therapeutic effects through photodynamic/hyperthermia-combined treatment without any drugs. We successfully detected tumors implanted in mice via magnetic resonance imaging and optical imaging. Furthermore, we demonstrated the photodynamic/hyperthermia-combined therapeutic efficacy of AHP@MNPs with synergistically enhanced efficacy against cancer. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr02273a

DRUG-NEM: Optimizing drug combinations using single-cell perturbation response to account for intratumoral heterogeneity

PubMed Central

Anchang, Benedict; Davis, Kara L.; Fienberg, Harris G.; Bendall, Sean C.; Karacosta, Loukia G.; Tibshirani, Robert; Nolan, Garry P.; Plevritis, Sylvia K.

2018-01-01

An individual malignant tumor is composed of a heterogeneous collection of single cells with distinct molecular and phenotypic features, a phenomenon termed intratumoral heterogeneity. Intratumoral heterogeneity poses challenges for cancer treatment, motivating the need for combination therapies. Single-cell technologies are now available to guide effective drug combinations by accounting for intratumoral heterogeneity through the analysis of the signaling perturbations of an individual tumor sample screened by a drug panel. In particular, Mass Cytometry Time-of-Flight (CyTOF) is a high-throughput single-cell technology that enables the simultaneous measurements of multiple (>40) intracellular and surface markers at the level of single cells for hundreds of thousands of cells in a sample. We developed a computational framework, entitled Drug Nested Effects Models (DRUG-NEM), to analyze CyTOF single-drug perturbation data for the purpose of individualizing drug combinations. DRUG-NEM optimizes drug combinations by choosing the minimum number of drugs that produce the maximal desired intracellular effects based on nested effects modeling. We demonstrate the performance of DRUG-NEM using single-cell drug perturbation data from tumor cell lines and primary leukemia samples. PMID:29654148

Combination of Anti-angiogenesis with Chemotherapy for More Effective Cancer Treatment*

PubMed Central

Ma, Jie; Waxman, David J.

2008-01-01

Angiogenesis is a hallmark of tumor development and metastasis and is now a validated target for cancer treatment. Overall, however, the survival benefits of anti-angiogenic drugs have, thus far, been rather modest, stimulating interest in developing more effective ways to combine anti-angiogenic drugs with established chemotherapies. This review discusses recent progress and emerging challenges in this field; interactions between anti-angiogenic drugs and conventional chemotherapeutic agents are examined, and strategies for the optimization of combination therapies are discussed. Anti-angiogenic drugs such as the anti-VEGF antibody bevacizumab can induce a functional normalization of the tumor vasculature that is transient and can potentiate the activity of co-administered chemoradiotherapies. However, chronic angiogenesis inhibition typically reduces tumor uptake of co-administered chemotherapeutics, indicating a need to explore new approaches, including intermittent treatment schedules and provascular strategies to increase chemotherapeutic drug exposure. In cases where anti-angiogenesis-induced tumor cell starvation augments the intrinsic cytotoxic effects of a conventional chemotherapeutic drug, combination therapy may increase anti-tumor activity despite a decrease in cytotoxic drug exposure. As new angiogenesis inhibitors enter the clinic, reliable surrogate markers are needed to monitor the progress of anti-angiogenic therapies and to identify responsive patients. New targets for anti-angiogenesis continue to be discovered, increasing the opportunities to interdict tumor angiogenesis and circumvent resistance mechanisms that may emerge with chronic use of these drugs. PMID:19074844

Clinical relevance of total HCV core antigen testing for hepatitis C monitoring and for predicting patients' response to therapy.

PubMed

Maynard, M; Pradat, P; Berthillon, P; Picchio, G; Voirin, N; Martinot, M; Marcellin, P; Trepo, C

2003-07-01

To study the correlation between total Hepatitis C virus (HCV) Core antigen (Ag) and HCV-RNA, and to assess the proficiency of HCV Core Ag testing in monitoring and predicting virologic response during and after pegylated interferon (PEG-IFN) and ribavirin combination therapy. A total of 307 samples from treated and untreated patients were used to assess the correlation between the total HCV Core Ag test and quantitative HCV-RNA assays (Superquant, and Quantiplex branched DNA 2.0 assay). Twenty-four patients received combination therapy for 48 weeks. Blood samples were collected at day 0, and week 2, 4, 12, 24, 48 and 72 for virologic evaluation. A linear relation exists between total HCV Core Ag and HCV-RNA levels. At 3 months the positive predictive value (PPV) of response to therapy was 100% with either HCV Core Ag or HCV-RNA. For HCV Core Ag the negative predictive value (NPV) was 100% whereas for HCV-RNA the NPV was 80% (P > 0.05). At month 1, the PPV was 95% and 100% when determined by HCV Core Ag and HCV-RNA, respectively. The NPV value was 100% for HCV Core Ag and 33% for HCV-RNA (P = 0.005). HCV Core Ag quantification could be useful in clinical practice to predict a sustained virological response early during therapy (4 weeks), reaching an optimal performance at month 3. The determination of total HCV Core Ag levels in serum, constitutes an accurate and reliable alternative to HCV-RNA for monitoring and predicting treatment outcome in patients receiving PEG-IFN/Ribavirin combination therapy.

Recent Advances in Cancer Therapy Based on Dual Mode Gold Nanoparticles

PubMed Central

Spyratou, Ellas; Makropoulou, Mersini; Sihver, Lembit

2017-01-01

Many tumor-targeted strategies have been used worldwide to limit the side effects and improve the effectiveness of therapies, such as chemotherapy, radiotherapy (RT), etc. Biophotonic therapy modalities comprise very promising alternative techniques for cancer treatment with minimal invasiveness and side-effects. These modalities use light e.g., laser irradiation in an extracorporeal or intravenous mode to activate photosensitizer agents with selectivity in the target tissue. Photothermal therapy (PTT) is a minimally invasive technique for cancer treatment which uses laser-activated photoabsorbers to convert photon energy into heat sufficient to induce cells destruction via apoptosis, necroptosis and/or necrosis. During the last decade, PTT has attracted an increased interest since the therapy can be combined with customized functionalized nanoparticles (NPs). Recent advances in nanotechnology have given rise to generation of various types of NPs, like gold NPs (AuNPs), designed to act both as radiosensitizers and photothermal sensitizing agents due to their unique optical and electrical properties i.e., functioning in dual mode. Functionalized AuNPS can be employed in combination with non-ionizing and ionizing radiation to significantly improve the efficacy of cancer treatment while at the same time sparing normal tissues. Here, we first provide an overview of the use of NPs for cancer therapy. Then we review many recent advances on the use of gold NPs in PTT, RT and PTT/RT based on different types of AuNPs, irradiation conditions and protocols. We refer to the interaction mechanisms of AuNPs with cancer cells via the effects of non-ionizing and ionizing radiations and we provide recent existing experimental data as a baseline for the design of optimized protocols in PTT, RT and PTT/RT combined treatment. PMID:29257070

Night Blood Pressure Responses to Atenolol and Hydrochlorothiazide in Black and White Patients With Essential Hypertension

PubMed Central

2014-01-01

BACKGROUND Night blood pressure (BP) predicts patient outcomes. Variables associated with night BP response to antihypertensive agents have not been fully evaluated in essential hypertension. METHODS We sought to measure night BP responses to hydrochlorothiazide (HCTZ), atenolol (ATEN), and combined therapy using ambulatory blood pressure (ABP) monitoring in 204 black and 281 white essential hypertensive patients. Initial therapy was randomized; HCTZ and ATEN once daily doses were doubled after 3 weeks and continued for 6 more weeks with the alternate medication added for combined therapy arms. ABP was measured at baseline and after completion of each drug. Night, day, and night/day BP ratio responses (treatment − baseline) were compared in race/sex subgroups. RESULTS Baseline night systolic BP and diastolic BP, and night/day ratios were greater in blacks than whites (P < 0.01, all comparisons). Night BP responses to ATEN were absent and night/day ratios increased significantly in blacks (P < 0.05). At the end of combined therapy, women, blacks, and those starting with HCTZ as opposed to ATEN had significantly greater night BP responses (P < 0.01). Variables that significantly associated with ATEN response differed from those that associated with HCTZ response and those that associated with night BP response differed from those that associated with day BP response. CONCLUSIONS In summary, after completion of HCTZ and ATEN therapy, women, blacks, and those who started with HCTZ had greater night BP responses. Reduced night BP response and increased night/day BP ratios occured with ATEN in blacks. Given the prognostic significance of night BP, strategies for optimizing night BP antihypertensive therapy should be considered. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov identifier NCT00246519 PMID:23886594

Adoptive immunotherapy against ovarian cancer.

PubMed

Mittica, Gloria; Capellero, Sonia; Genta, Sofia; Cagnazzo, Celeste; Aglietta, Massimo; Sangiolo, Dario; Valabrega, Giorgio

2016-05-17

The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC.Recently, several preclinical and clinical studies investigated feasibility and activity of adoptive immunotherapy in EOC. Our aim is to highlight prospective of adoptive immunotherapy in EOC, focusing on HLA-restricted Tumor Infiltrating Lymphocytes (TILs), and MHC-independent immune effectors such as natural killer (NK), and cytokine-induced killer (CIK). Adoptive cell therapy (ACT) has shown activity in several pre-clinical models. Available preclinical and clinical data suggest that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. Further studies are needed to better define the optimal clinical setting.

Anithrombotic prevention in vascular disease: bases for a new strategy in antithrombotic therapy

PubMed Central

Altman, Raul

2007-01-01

A tendency toward bleeding often undercuts the beneficial preventive effect of higher doses of a single antithrombotic drug or combined antithrombotic therapy. Although high doses of antithrombotic drugs may be necessary for optimal prevention, such therapy can also elicit more frequent bleeding. Although major bleeding could be a reversible event is likely to lead clinicians to discontinue antithrombotic therapy which in turn could increase the risk of myocardial infarction, stroke, and cardiovascular death. Thus, to prevent thrombotic events without frequent bleeding complications, the preferred approach might be to use anti-inflammatory drugs in addition to the first-line antithrombotic drugs to reduce inflammation and thrombin formation in atheroma. Although some preliminary data have been already published, to confirm the potential benefit of anti-inflammatory drugs in acute coronary syndromes large prospective double-bind randomized trials are necessary. PMID:17727726

Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects.

PubMed

Shi, Huan; Sun, Meili; Liu, Lin; Wang, Zhehai

2014-09-21

Chimeric antigen receptors (CARs) are recombinant receptors that combine the specificity of an antigen-specific antibody with the T-cell's activating functions. Initial clinical trials of genetically engineered CAR T cells have significantly raised the profile of T cell therapy, and great efforts have been made to improve this approach. In this review, we provide a structural overview of the development of CAR technology and highlight areas that require further refinement. We also discuss critical issues related to CAR therapy, including the optimization of CAR T cells, the route of administration, CAR toxicity and the blocking of inhibitory molecules.

Comparative efficacy, acceptability, and safety of medicinal, cognitive-behavioral therapy, and placebo treatments for acute major depressive disorder in children and adolescents: a multiple-treatments meta-analysis.

PubMed

Ma, Dongfeng; Zhang, Zhijun; Zhang, Xiangrong; Li, Lingjiang

2014-06-01

New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) were introduced in the late 1980s; however, few comprehensive studies compared the benefits and risks of various contemporary treatments for major depressive disorder (MDD) in pediatric patients. Multiple-treatments meta-analysis (MTM) was conducted to assess efficacy, acceptability, and safety of contemporary interventions in children and adolescents with MDD. Cochrane Library, AMED, CINAHL, EMBASE, LiLACS, MEDLINE, PSYCINFO, PSYNDEX, and Journal of Medicine and Pharmacy databases were searched for randomized controlled trials (RCTs) comparing medicinal interventions (citalopram, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, venlafaxine), cognitive behavioral therapy (CBT), combined fluoxetine with CBT, and placebo treatment for acute MDD from January 1988 to March 2013. Treatment success, dropout rate, and suicidal ideation/attempt outcomes were measured. Bayesian methods were used to conduct a MTM including age and funding subgroups. A total of 21 RCTs (4969 participants) were identified. Combined fluoxetine/CBT exhibited the highest efficacy, with fluoxetine alone superior to CBT, paroxetine, sertraline, citalopram, escitalopram, and placebo treatment. Sertraline, paroxetine, escitalopram, and venlafaxine showed superior acceptability to fluoxetine and combined fluoxetine/CBT. Combined fluoxetine/CBT combination was less safe, though CBT was safer than fluoxetine alone. Combined fluoxetine/CBT, fluoxetine, and mirtazapine exhibited the highest efficacy; sertraline, escitalopram, venlafaxine, and paroxetine were the best tolerated; and mirtazapine and venlafaxine were the safest. Sertraline and mirtazapine exhibited optimally balanced efficacy, acceptability, and safety for first-line acute treatment of child and adolescent MDD.

Free terminal time optimal control problem of an HIV model based on a conjugate gradient method.

PubMed

Jang, Taesoo; Kwon, Hee-Dae; Lee, Jeehyun

2011-10-01

The minimum duration of treatment periods and the optimal multidrug therapy for human immunodeficiency virus (HIV) type 1 infection are considered. We formulate an optimal tracking problem, attempting to drive the states of the model to a "healthy" steady state in which the viral load is low and the immune response is strong. We study an optimal time frame as well as HIV therapeutic strategies by analyzing the free terminal time optimal tracking control problem. The minimum duration of treatment periods and the optimal multidrug therapy are found by solving the corresponding optimality systems with the additional transversality condition for the terminal time. We demonstrate by numerical simulations that the optimal dynamic multidrug therapy can lead to the long-term control of HIV by the strong immune response after discontinuation of therapy.

The new era of cardiac surgery: hybrid therapy for cardiovascular disease.

PubMed

Solenkova, Natalia V; Umakanthan, Ramanan; Leacche, Marzia; Zhao, David X; Byrne, John G

2010-11-01

Surgical therapy for cardiovascular disease carries excellent long-term outcomes but it is relatively invasive. With the development of new devices and techniques, modern cardiovascular surgery is trending toward less invasive approaches, especially for patients at high risk for traditional open heart surgery. A hybrid strategy combines traditional surgical treatments performed in the operating room with treatments traditionally available only in the catheterization laboratory with the goal of offering patients the best available therapy for any set of cardiovascular diseases. Examples of hybrid procedures include hybrid coronary artery bypass grafting, hybrid valve surgery and percutaneous coronary intervention, hybrid endocardial and epicardial atrial fibrillation procedures, and hybrid coronary artery bypass grafting/carotid artery stenting. This multidisciplinary approach requires strong collaboration between cardiac surgeons, vascular surgeons, and interventional cardiologists to obtain optimal patient outcomes.

A Dual Anticancer Efficacy Molecule: A Selective Dark Cytotoxicity Photosensitizer.

PubMed

Chen, Jyun-Wei; Chang, Cheng-Chung

2016-11-09

Unlike traditional binary nanostructures that construct chemotherapy drugs and photodynamic therapy photosensitizers, we introduce a molecule with a chemo-photodynamic dual therapy function. A water-soluble aggregation-induced emission enhancement (AIEE) fluorogen, NV-12P, was designed and synthesized based on asymmetric 1,6-disubstituted naphthalene and can generate particular reactive oxygen species to undergo type I photodynamic therapy under irradiation. Furthermore, this compound can specifically localize in mitochondria and, after biological evaluation, can cause mitochondrial dysfunction and potent cytotoxicity to cancer cells but not normal cells. We conclude that this compound is a potential dual-toxic efficacy molecule because it exhibits selective dark cytotoxicity and efficient photodamage in cancer cells. Additionally, we also supported the optimal combinational treatment course for the best chemo-phototherapy efficacy.

State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012.

PubMed

Sartor, Oliver

2012-01-01

Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future, we will develop molecular "stratification systems" to better guide therapeutic choices in CRPC.

Regenerative Rehabilitation: Combining Stem Cell Therapies and Activity-Dependent Stimulation.

PubMed

Moritz, Chet T; Ambrosio, Fabrisia

2017-07-01

The number of clinical trials in regenerative medicine is burgeoning, and stem cell/tissue engineering technologies hold the possibility of becoming the standard of care for a multitude of diseases and injuries. Advances in regenerative biology reveal novel molecular and cellular targets, with potential to optimize tissue healing and functional recovery, thereby refining rehabilitation clinical practice. The purpose of this review is to (1) highlight the potential for synergy between the fields of regenerative medicine and rehabilitation, a convergence of disciplines known as regenerative rehabilitation; (2) provide translational examples of regenerative rehabilitation within the context of neuromuscular injuries and diseases; and (3) offer recommendations for ways to leverage activity dependence via combined therapy and technology, with the goal of enhancing long-term recovery. The potential clinical benefits of regenerative rehabilitation will likely become a critical aspect in the standard of care for many neurological and musculoskeletal disorders.

An update on the management of peripheral T-cell lymphoma and emerging treatment options

PubMed Central

Phillips, Adrienne A; Owens, Colette; Lee, Sangmin; Bhagat, Govind

2011-01-01

Peripheral T-cell lymphomas (PTCLs) comprise a rare and heterogeneous subset of non-Hodgkin’s lymphomas (NHLs) that arise from post-thymic T-cells or natural killer (NK)-cells at nodal or extranodal sites. Worldwide, PTCLs represent approximately 12% of all NHLs and the 2008 World Health Organization (WHO) classification includes over 20 biologically and clinically distinct T/NK-cell neoplasms that differ significantly in presentation, pathology, and response to therapy. Because of the rarity and heterogeneity of these diseases, large clinical trials have not been conducted and optimal therapy is not well defined. Most subtypes are treated with similar combination chemotherapy regimens as used for aggressive B-cell NHL, but with poorer outcomes. New treatment combinations and novel agents are currently being explored for PTCLs and this review highlights a number of options that appear promising. PMID:22287871

Photodynamic therapy as a local therapeutic adjunct for the treatment of vertebral metastases

NASA Astrophysics Data System (ADS)

Yee, Albert; Burch, Shane; Akens, Margarete; Won, Emily; Lo, Victor; Wise-Milestone, Lisa; Bisland, Stuart; Theriault, Aimee; Niu, Carolyn; Wilson, Brian C.; Whyne, Cari

2013-03-01

Metastatic cancer causes the majority of tumors in bone, most frequently detected in the spinal column. Skeletal complications cause pain and neurologic impairment. Photodynamic therapy (PDT) has been used to treat a variety of cancers. Minimally invasive surgical (MIS) strategies may allow targeted light application essential for PDT within bone structures. The purpose of this manuscript is to provide an update on pre-clinical status as well as early clinical experience of a Phase I clinical trial on vertebral PDT. A pre-clinical (rnu/rnu rat) vertebral metastasis model of osteolytic (MT-1 breast cancer) was optimized and used to evaluate the effect of vertebral PDT. PDT alone and in combination with other standard local (radiation therapy, RT) and systemic (bisphosphonates, BP) therapies was evaluated through bioluminescence imaging, micro-CT based stereology, histology, and biomechanical testing. Single PDT treatment (photosensitizer BPD-MA, 690nm light) ablated tumor tissue in targeted vertebrae. PDT led to significant increases in bone structural properties, with greatest benefits observed from combined BP+PDT therapy: 76% and 19% increases in bone volume fraction in treated tumor-bearing and healthy untreated controls, respectively. Similar synergistic improvements (but of lesser magnitude) were found in combined PDT+RT treatments. The safety and feasibility of MIS+PDT were evaluated in scale-up animal studies, refining surgical technique for clinical translation. Following appropriate institutional review board as well as Health Canada approval, 5 patients (light only control group) have undergone protocoled treatment to date. These patients have guided further refinement of human therapeutic application from a laser delivery and vertebral bone access perspective.

Emerging immunotherapy for the treatment of esophageal cancer.

PubMed

Jackie Oh, SeungJu; Han, Songhee; Lee, Wooin; Lockhart, A Craig

2016-06-01

Esophageal cancer is the third most common cancer of the gastrointestinal tract. Despite new therapies, the prognosis for patients with these cancers remains poor with 5-year survival rates lower than 15%. Recently, immunotherapy has increasingly gained attention as a novel treatment strategy for advanced esophageal cancer. Recent success of immunotherapy in treating other solid tumors has shed light on the utility of these approaches for esophageal cancers. Here, the authors focus on antibody-based, adoptive-cell-therapy-based, and vaccine-based immunotherapies, and briefly address their rationale, clinical data, and implications. Immunotherapy is now established to be a key treatment modality that can improve the outcomes of many cancer patients and appears to be ushering in a new era in cancer treatment. Checkpoint inhibitor drugs have shown preliminary favorable results in esophageal cancer treatment. Adoptive cell therapy and vaccine studies have also shown some promise in various clinical studies. Future endeavors will need to focus on identifying patients who are likely to benefit from immunotherapy, monitoring and managing immune responses and designing optimal combination strategies where immunotherapy agents are combined with other traditional treatment modalities.

Efficacy and safety of a ceramide containing moisturizer followed by fixed-dose clindamycin phosphate 1.2%/benzoyl peroxide 2.5% gel in the morning in combination with a ceramide containing moisturizer followed by tretinoin 0.05% gel in the evening for the treatment of facial acne vulgaris.

PubMed

Zeichner, Joshua A; Patel, Rita V; Haddican, Madelaine; Wong, Vicky

2012-06-01

Combination therapy addressing multiple pathogenic factors should be used to achieve optimal outcomes in treating acne. The following study demonstrated both safety and efficacy of fixed-dose clindamycin phosphate 1.2%/benzoyl peroxide 2.5% in the morning with micronized tretinoin 0.05% gel in the evening. Both products were applied to the skin following the use of a ceramide containing moisturizing lotion.

WE-AB-207B-07: Dose Cloud: Generating “Big Data” for Radiation Therapy Treatment Plan Optimization Research

DOE Office of Scientific and Technical Information (OSTI.GOV)

Folkerts, MM; University of California San Diego, La Jolla, California; Long, T

Purpose: To provide a tool to generate large sets of realistic virtual patient geometries and beamlet doses for treatment optimization research. This tool enables countless studies exploring the fundamental interplay between patient geometry, objective functions, weight selections, and achievable dose distributions for various algorithms and modalities. Methods: Generating realistic virtual patient geometries requires a small set of real patient data. We developed a normalized patient shape model (PSM) which captures organ and target contours in a correspondence-preserving manner. Using PSM-processed data, we perform principal component analysis (PCA) to extract major modes of variation from the population. These PCA modes canmore » be shared without exposing patient information. The modes are re-combined with different weights to produce sets of realistic virtual patient contours. Because virtual patients lack imaging information, we developed a shape-based dose calculation (SBD) relying on the assumption that the region inside the body contour is water. SBD utilizes a 2D fluence-convolved scatter kernel, derived from Monte Carlo simulations, and can compute both full dose for a given set of fluence maps, or produce a dose matrix (dose per fluence pixel) for many modalities. Combining the shape model with SBD provides the data needed for treatment plan optimization research. Results: We used PSM to capture organ and target contours for 96 prostate cases, extracted the first 20 PCA modes, and generated 2048 virtual patient shapes by randomly sampling mode scores. Nearly half of the shapes were thrown out for failing anatomical checks, the remaining 1124 were used in computing dose matrices via SBD and a standard 7-beam protocol. As a proof of concept, and to generate data for later study, we performed fluence map optimization emphasizing PTV coverage. Conclusions: We successfully developed and tested a tool for creating customizable sets of virtual patients suitable for large-scale radiation therapy optimization research.« less

What is the best frontline therapy for patients with CLL and 17p deletion?

PubMed

Badoux, Xavier C; Keating, Michael J; Wierda, William G

2011-03-01

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease with significant variation in disease progression, response to therapy, and survival outcome. Deletions of 17p or mutations of TP53 have been identified as one of the poorest prognostic factors, being predictive of short time for disease progression, lack of response to therapy, short response duration, and short overall survival. The treatment of patients with CLL has improved significantly with the development of chemoimmunotherapy, but this benefit was not pronounced in patients with 17p deletion. We compare various treatment strategies used in these patients, including FCR-like chemoimmunotherapy, alemtuzumab, other antibody combinations, or novel targeted therapies with promising results. Allogeneic stem cell transplantation offers the possibility for long-term disease control in these patients and should be considered early in younger, transplant-eligible patients. The current state of therapy is far from optimal and resources should be applied to studying therapeutic options for patients who have CLL with loss of p53 function.

Opioid pharmaceuticals and addiction: the issues, and research directions seeking solutions.

PubMed

Walwyn, Wendy M; Miotto, Karen A; Evans, Christopher J

2010-05-01

There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies.

Opioid pharmaceuticals and addiction: The issues, and research directions seeking solutions

PubMed Central

Walwyn, Wendy M.; Miotto, Karen A.; Evans, Christopher J.

2011-01-01

There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies. PMID:20188495

Asthma control in patients on fixed dose combination evaluated with mannitol challenge test.

PubMed

Romberg, Kerstin A M; Berggren, Anna-Carin; Bjermer, Leif

2014-02-01

Asthma is often difficult to control and it is likely that not all patients are optimally treated. This study aimed to explore asthma control in adults receiving fixed dose combination (FDC) therapy. Control of asthma was assessed using the mannitol challenge test as a monitoring tool to see if this would give additional information compared to the asthma control test (ACT). The study was an open-label, prospective study on 98 adults prescribed with FDC therapies for at least three months. 74 patients considered that their asthma was well controlled. However, 60 patients had a positive mannitol challenge test (PD15 < 635 mg), and when those with a positive response to the short-acting β2-agonist (≥15%) after the mannitol challenge test were included, this increased to 64 patients (65%). Exploratory analysis determined that the spirometry parameters; FEV1/FVC and FEV1% of predicted, were statistically significant predictors of a positive mannitol challenge test. Co-morbid conditions such as concomitant upper airway involvement or eczema did not predict mannitol reactivity. Although most patients rated their asthma as well controlled, many provided a positive mannitol challenge test, suggesting the presence of underlying inflammation, despite treatment with fixed dose combination therapy. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Carbohydrate-Restriction with High-Intensity Interval Training: An Optimal Combination for Treating Metabolic Diseases?

PubMed

Francois, Monique E; Gillen, Jenna B; Little, Jonathan P

2017-01-01

Lifestyle interventions incorporating both diet and exercise strategies remain cornerstone therapies for treating metabolic disease. Carbohydrate-restriction and high-intensity interval training (HIIT) have independently been shown to improve cardiovascular and metabolic health. Carbohydrate-restriction reduces postprandial hyperglycemia, thereby limiting potential deleterious metabolic and cardiovascular consequences of excessive glucose excursions. Additionally, carbohydrate-restriction has been shown to improve body composition and blood lipids. The benefits of exercise for improving insulin sensitivity are well known. In this regard, HIIT has been shown to rapidly improve glucose control, endothelial function, and cardiorespiratory fitness. Here, we report the available evidence for each strategy and speculate that the combination of carbohydrate-restriction and HIIT will synergistically maximize the benefits of both approaches. We hypothesize that this lifestyle strategy represents an optimal intervention to treat metabolic disease; however, further research is warranted in order to harness the potential benefits of carbohydrate-restriction and HIIT for improving cardiometabolic health.

Addressing current challenges in cancer immunotherapy with mathematical and computational modelling.

PubMed

Konstorum, Anna; Vella, Anthony T; Adler, Adam J; Laubenbacher, Reinhard C

2017-06-01

The goal of cancer immunotherapy is to boost a patient's immune response to a tumour. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumour microenvironment, immune-modulating effects of conventional treatments and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modelling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumour classification, optimal treatment scheduling and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modellers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumour-immune biology. We conclude the review with recommendations for modellers both with respect to methodology and biological direction that might help keep modellers at the forefront of cancer immunotherapy development. © 2017 The Author(s).

Optimizing Culture Medium Composition to Improve Oligodendrocyte Progenitor Cell Yields In Vitro from Subventricular Zone-Derived Neural Progenitor Cell Neurospheres

PubMed Central

Franco, Paula G.; Pasquini, Juana M.; Silvestroff, Lucas

2015-01-01

Neural Stem and Progenitor Cells (NSC/NPC) are gathering tangible recognition for their uses in cell therapy and cell replacement therapies for human disease, as well as a model system to continue research on overall neural developmental processes in vitro. The Subventricular Zone is one of the largest NSC/NPC niches in the developing mammalian Central Nervous System, and persists through to adulthood. Oligodendrocyte progenitor cell (OPC) enriched cultures are usefull tools for in vitro studies as well as for cell replacement therapies for treating demyelination diseases. We used Subventricular Zone-derived NSC/NPC primary cultures from newborn mice and compared the effects of different growth factor combinations on cell proliferation and OPC yield. The Platelet Derived Growth Factor-AA and BB homodimers had a positive and significant impact on OPC generation. Furthermore, heparin addition to the culture media contributed to further increase overall culture yields. The OPC generated by this protocol were able to mature into Myelin Basic Protein-expressing cells and to interact with neurons in an in vitro co-culture system. As a whole, we describe an optimized in vitro method for increasing OPC. PMID:25837625

Pharmacogenetics and breast cancer management: current status and perspectives.

PubMed

Ciccolini, Joseph; Fanciullino, Raphaelle; Serdjebi, Cindy; Milano, Gérard

2015-05-01

Breast cancer has benefited from a number of innovative therapeutics over the last decade. Cytotoxics, hormone therapy, targeted therapies and biologics can now be given to ensure optimal management of patients. As life expectancy of breast cancer patients has been significantly stretched and that several lines of treatment are now made available, determining the best drug or drug combinations to be primarily given and the best dosing and scheduling for each patient is critical for ensuring an optimal toxicity/efficacy balance. Defining patient's characteristics at the tumor level (pharmacogenomics) and the constitutional level (pharmacogenetics) is a rising trend in oncology. This review covers the latest strategies based upon the search of relevant biomarkers for efficacy, resistance and toxicity to be undertaken at the bedside to shift towards precision medicine in breast cancer patients. In the expanding era of bioguided medicine, identifying relevant and clinically validated biomarkers from the plethora of published material remains an uneasy task. Sorting the variety of genetic and molecular markers that have been investigated over the last decade on their level of evidence and addressing the issue of drug exposure should help to improve the management of breast cancer therapy.

Sci-Fri PM: Radiation Therapy, Planning, Imaging, and Special Techniques - 01: On the use of proton radiography to reduce beam range uncertainties and improve patient positioning accuracy in proton therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Collins-Fekete, Charles-Antoine; Beaulieu, Luc; Se

2016-08-15

To present two related developments of proton radiography (pRad) to minimize range uncertainty in proton therapy. The first combines a pRad with an X-ray CT to produce a patient-specific relative stopping power (RSP) map. The second aims to improve the pRad spatial resolution for accurate registration prior to the first. The enhanced-pRad can also be used in a novel proton-CT reconstruction algorithm. Monte Carlo pRad were computed from three phantoms; the Gammex, the Catphan and an anthropomorphic head. An optimized cubic-spline estimator derives the most likely path. The length crossed by the protons voxel-by-voxel was calculated by combining their estimatedmore » paths with the CT. The difference between the theoretical (length×RSP) and measured energy loss was minimized through a least squares optimization (LSO) algorithm yielding the RSP map. To increase pRad spatial resolution for registration with the CT, the phantom was discretized into voxels columns. The average column RSP was optimized to maximize the proton energy loss likelihood (MLE). Simulations showed precise RSP (<0.75%) for Gammex materials except low-density lung (<1.2%). For the head, accurate RSP were obtained (µ=−0.10%1.5σ=1.12%) and the range precision was improved (ΔR80 of −0.20±0.35%). Spatial resolution was increased in pRad (2.75 to 6.71 lp/cm) and pCT from MLE-enhanced pRad (2.83 to 5.86 lp/cm). The LSO decreases the range uncertainty (R80σ<1.0%) while the MLE-enhanced pRad spatial resolution (+244%) and is a great candidate for pCT reconstruction.« less

Recent insights in the therapeutic management of patients with gastric cancer.

PubMed

de Mestier, Louis; Lardière-Deguelte, Sophie; Volet, Julien; Kianmanesh, Reza; Bouché, Olivier

2016-09-01

Gastric cancer remains frequent and one of the most lethal malignancies worldwide. In this article, we aimed to comprehensively review recent insights in the therapeutic management of gastric cancer, with focus on the surgical and perioperative management of resectable forms, and the latest advances regarding advanced diseases. Surgical improvements comprise the use of laparoscopic surgery including staging laparoscopy, a better definition of nodal dissection, and the development of hyperthermic intraperitoneal chemotherapy. The best individualized perioperative management should be assessed before curative-intent surgery for all patients and can consists in perioperative chemotherapy, adjuvant chemo-radiation therapy or adjuvant chemotherapy alone. The optimal timing and sequence of chemotherapy and radiation therapy with respect to surgery should be further explored. Patients with advanced gastric cancer have a poor prognosis. Nevertheless, they can benefit from doublet or triplet chemotherapy combination, including trastuzumab in HER2-positive patients. Upon progression, second-line therapy can be considered in patients with good performance status. Although anti-HER2 (trastuzumab) and anti-VEGFR (ramucirumab) may yield survival benefit, anti-EGFR and anti-HGFR therapies have failed to improve outcomes. Nevertheless, combination regimens containing cytotoxic drugs and targeted therapies should be further evaluated; keeping in mind that gastric cancer biology is different between Asia and the Western countries. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Severe group A streptococcal infection and streptococcal toxic shock syndrome.

PubMed

Baxter, F; McChesney, J

2000-11-01

To review the literature on group A streptococcal toxic shock syndrome, (STSS). Medline and EMBASE searches were conducted using the key words group A streptococcal toxic shock syndrome, alone and in combination with anesthesia; and septic shock, combined with anesthesia. Medline was also searched using key words intravenous immunoglobulin, (IVIG) and group A streptococcus, (GAS); and group A streptococcus and antibiotic therapy. Other references were included in this review if they addressed the history, microbiology, pathophysiology, incidence, mortality, presentation and management of invasive GAS infections. Relevant references from the papers reviewed were also considered. Articles on the foregoing topics were included regardless of study design. Non-English language studies were excluded. Literature on the efficacy of IVIG and optimal antibiotic therapy was specifically searched. Reports of invasive GAS infections have recently increased. Invasive GAS infection is associated with a toxic shock syndrome, (STSS), in 8-14% of cases. The STSS characteristically results in shock and multi-organ failure soon after the onset of symptoms, and is associated with a mortality of 33-81%. Many of these patients will require extensive soft tissue debridement or amputation in the operating room, on an emergency basis. The extent of tissue debridement required is often underestimated before skin incision. Management of STSS requires volume resuscitation, vasopressor/inotrope infusion, antibiotic therapy and supportive care in an intensive care unit, usually including mechanical ventilation. Intravenous immunoglobulin infusion has been recommended. Further studies are needed to define the role of IVIG in STSS management and to determine optimal anesthetic management of patients with septic shock.

Pulmonary co-infection with nocardia species and nontuberculous mycobacteria mimicking miliary tuberculosis in a patient with Crohn's disease under combined immunosuppressive therapy.

PubMed

Weber, Marko; Rüddel, Jessica; Bruns, Tony; Pletz, Mathias W; Stallmach, Andreas

2018-06-01

Nocardiosis is a rare infection caused by ubiquitous soil-born, acid-resistant, Gram-positive bacteria that can be life-threatening in immunocompromised patients. Originally usually diagnosed in HIV-positive patients, only few cases have been reported in patients on immunosuppressive therapy for inflammatory bowel disease or rheumatologic disorders. We present a case of a 32-year-old man who was treated with infliximab, prednisolone, and azathioprine for severe terminal ileitis. Although the clinical status improved under triple immunosuppressive therapy, weight loss, weakness, and fatigue persisted. Laboratory studies revealed iron deficiency anemia, hypalbuminemia and raised inflammatory markers. Chest computed tomography scan showed multiple pulmonary nodules and a large cavity in the left upper lobe (segment 3a). Empiric tuberculostatic therapy was introduced for suspected miliary tuberculosis but stopped for lack of clinical improvement and negative tuberculosis tests (interferon-gamma release assay, microscopy, polymerase chain reaction). Finally, the diagnosis of pulmonary nocardiosis with concomitant pulmonary Mycobacterium avium infection was confirmed microbiologically, and the patient was treated with high-dose co-trimoxazole, clarithromycin, ethambutol, and rifampicin for 12 months.This case report underlines the increased risk of severe and rare infections like nocardiosis with combination immunosuppressive therapy and the necessity for thorough diagnostic screening for opportunistic infection. Although long-term antibiotic treatment for nocardiosis is mandatory, the optimal timing to restart immunosuppressive therapy remains ambiguous. © Georg Thieme Verlag KG Stuttgart · New York.

Advancing cancer drug discovery towards more agile development of targeted combination therapies.

PubMed

Carragher, Neil O; Unciti-Broceta, Asier; Cameron, David A

2012-01-01

Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.

Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial.

PubMed

Khan, Fakhar Z; Virdee, Mumohan S; Palmer, Christopher R; Pugh, Peter J; O'Halloran, Denis; Elsik, Maros; Read, Philip A; Begley, David; Fynn, Simon P; Dutka, David P

2012-04-24

This study sought to assess the impact of targeted left ventricular (LV) lead placement on outcomes of cardiac resynchronization therapy (CRT). Placement of the LV lead to the latest sites of contraction and away from the scar confers the best response to CRT. We conducted a randomized, controlled trial to compare a targeted approach to LV lead placement with usual care. A total of 220 patients scheduled for CRT underwent baseline echocardiographic speckle-tracking 2-dimensional radial strain imaging and were then randomized 1:1 into 2 groups. In group 1 (TARGET [Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy]), the LV lead was positioned at the latest site of peak contraction with an amplitude of >10% to signify freedom from scar. In group 2 (control) patients underwent standard unguided CRT. Patients were classified by the relationship of the LV lead to the optimal site as concordant (at optimal site), adjacent (within 1 segment), or remote (≥2 segments away). The primary endpoint was a ≥15% reduction in LV end-systolic volume at 6 months. Secondary endpoints were clinical response (≥1 improvement in New York Heart Association functional class), all-cause mortality, and combined all-cause mortality and heart failure-related hospitalization. The groups were balanced at randomization. In the TARGET group, there was a greater proportion of responders at 6 months (70% vs. 55%, p = 0.031), giving an absolute difference in the primary endpoint of 15% (95% confidence interval: 2% to 28%). Compared with controls, TARGET patients had a higher clinical response (83% vs. 65%, p = 0.003) and lower rates of the combined endpoint (log-rank test, p = 0.031). Compared with standard CRT treatment, the use of speckle-tracking echocardiography to the target LV lead placement yields significantly improved response and clinical status and lower rates of combined death and heart failure-related hospitalization. (Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy [TARGET] study); ISRCTN19717943). Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Current treatment paradigms in rheumatoid arthritis.

PubMed

Fries, J F

2000-06-01

Rheumatoid arthritis (RA) has traditionally been treated using the pyramid approach, in which non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment and disease-modifying anti-rheumatic drugs (DMARDs) are introduced relatively late in the disease. This approach is no longer valid. Previously regarded as a benign disease, RA is now recognized as causing substantial morbidity and mortality, as do the NSAIDs used in treatment. DMARDs are more effective in controlling the pain and disability of RA than NSAIDs, and are often no more toxic. The current treatment paradigm emphasizes early, consistent use of DMARDs. A 'sawtooth' strategy of DMARD use has been proposed, in which a rising but low level of disability triggers a change in therapy. Determining the most clinically useful DMARD combinations and the optimal sequence of DMARD use requires effectiveness studies, Bayesian approaches and analyses of long-term outcomes. Such approaches will allow optimization of multiple drug therapies in RA, and should substantially improve the long-term outcome for many patients.

What is the Optimal Strategy for Adaptive Servo-Ventilation Therapy?

PubMed

Imamura, Teruhiko; Kinugawa, Koichiro

2018-05-23

Clinical advantages in the adaptive servo-ventilation (ASV) therapy have been reported in selected heart failure patients with/without sleep-disorder breathing, whereas multicenter randomized control trials could not demonstrate such advantages. Considering this discrepancy, optimal patient selection and device setting may be a key for the successful ASV therapy. Hemodynamic and echocardiographic parameters indicating pulmonary congestion such as elevated pulmonary capillary wedge pressure were reported as predictors of good response to ASV therapy. Recently, parameters indicating right ventricular dysfunction also have been reported as good predictors. Optimal device setting with appropriate pressure setting during appropriate time may also be a key. Large-scale prospective trial with optimal patient selection and optimal device setting is warranted.

SU-E-T-295: Simultaneous Beam Sampling and Aperture Shape Optimization for Station Parameter Optimized Radiation Therapy (SPORT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zarepisheh, M; Li, R; Xing, L

Purpose: Station Parameter Optimized Radiation Therapy (SPORT) was recently proposed to fully utilize the technical capability of emerging digital LINACs, in which the station parameters of a delivery system, (such as aperture shape and weight, couch position/angle, gantry/collimator angle) are optimized altogether. SPORT promises to deliver unprecedented radiation dose distributions efficiently, yet there does not exist any optimization algorithm to implement it. The purpose of this work is to propose an optimization algorithm to simultaneously optimize the beam sampling and aperture shapes. Methods: We build a mathematical model whose variables are beam angles (including non-coplanar and/or even nonisocentric beams) andmore » aperture shapes. To solve the resulting large scale optimization problem, we devise an exact, convergent and fast optimization algorithm by integrating three advanced optimization techniques named column generation, gradient method, and pattern search. Column generation is used to find a good set of aperture shapes as an initial solution by adding apertures sequentially. Then we apply the gradient method to iteratively improve the current solution by reshaping the aperture shapes and updating the beam angles toward the gradient. Algorithm continues by pattern search method to explore the part of the search space that cannot be reached by the gradient method. Results: The proposed technique is applied to a series of patient cases and significantly improves the plan quality. In a head-and-neck case, for example, the left parotid gland mean-dose, brainstem max-dose, spinal cord max-dose, and mandible mean-dose are reduced by 10%, 7%, 24% and 12% respectively, compared to the conventional VMAT plan while maintaining the same PTV coverage. Conclusion: Combined use of column generation, gradient search and pattern search algorithms provide an effective way to optimize simultaneously the large collection of station parameters and significantly improves quality of resultant treatment plans as compared with conventional VMAT or IMRT treatments.« less

Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution.

PubMed

Chakrabarti, Shaon; Michor, Franziska

2017-07-15

The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908-21. ©2017 AACR . ©2017 American Association for Cancer Research.

A challenge for theranostics: is the optimal particle for therapy also optimal for diagnostics?

NASA Astrophysics Data System (ADS)

Dreifuss, Tamar; Betzer, Oshra; Shilo, Malka; Popovtzer, Aron; Motiei, Menachem; Popovtzer, Rachela

2015-09-01

Theranostics is defined as the combination of therapeutic and diagnostic capabilities in the same agent. Nanotechnology is emerging as an efficient platform for theranostics, since nanoparticle-based contrast agents are powerful tools for enhancing in vivo imaging, while therapeutic nanoparticles may overcome several limitations of conventional drug delivery systems. Theranostic nanoparticles have drawn particular interest in cancer treatment, as they offer significant advantages over both common imaging contrast agents and chemotherapeutic drugs. However, the development of platforms for theranostic applications raises critical questions; is the optimal particle for therapy also the optimal particle for diagnostics? Are the specific characteristics needed to optimize diagnostic imaging parallel to those required for treatment applications? This issue is examined in the present study, by investigating the effect of the gold nanoparticle (GNP) size on tumor uptake and tumor imaging. A series of anti-epidermal growth factor receptor conjugated GNPs of different sizes (diameter range: 20-120 nm) was synthesized, and then their uptake by human squamous cell carcinoma head and neck cancer cells, in vitro and in vivo, as well as their tumor visualization capabilities were evaluated using CT. The results showed that the size of the nanoparticle plays an instrumental role in determining its potential activity in vivo. Interestingly, we found that although the highest tumor uptake was obtained with 20 nm C225-GNPs, the highest contrast enhancement in the tumor was obtained with 50 nm C225-GNPs, thus leading to the conclusion that the optimal particle size for drug delivery is not necessarily optimal for imaging. These findings stress the importance of the investigation and design of optimal nanoparticles for theranostic applications.Theranostics is defined as the combination of therapeutic and diagnostic capabilities in the same agent. Nanotechnology is emerging as an efficient platform for theranostics, since nanoparticle-based contrast agents are powerful tools for enhancing in vivo imaging, while therapeutic nanoparticles may overcome several limitations of conventional drug delivery systems. Theranostic nanoparticles have drawn particular interest in cancer treatment, as they offer significant advantages over both common imaging contrast agents and chemotherapeutic drugs. However, the development of platforms for theranostic applications raises critical questions; is the optimal particle for therapy also the optimal particle for diagnostics? Are the specific characteristics needed to optimize diagnostic imaging parallel to those required for treatment applications? This issue is examined in the present study, by investigating the effect of the gold nanoparticle (GNP) size on tumor uptake and tumor imaging. A series of anti-epidermal growth factor receptor conjugated GNPs of different sizes (diameter range: 20-120 nm) was synthesized, and then their uptake by human squamous cell carcinoma head and neck cancer cells, in vitro and in vivo, as well as their tumor visualization capabilities were evaluated using CT. The results showed that the size of the nanoparticle plays an instrumental role in determining its potential activity in vivo. Interestingly, we found that although the highest tumor uptake was obtained with 20 nm C225-GNPs, the highest contrast enhancement in the tumor was obtained with 50 nm C225-GNPs, thus leading to the conclusion that the optimal particle size for drug delivery is not necessarily optimal for imaging. These findings stress the importance of the investigation and design of optimal nanoparticles for theranostic applications. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr03119b

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

PubMed Central

Elgogary, Amira; Xu, Qingguo; Poore, Brad; Alt, Jesse; Zimmermann, Sarah C.; Zhao, Liang; Fu, Jie; Chen, Baiwei; Xia, Shiyu; Liu, Yanfei; Neisser, Marc; Nguyen, Christopher; Lee, Ramon; Park, Joshua K.; Reyes, Juvenal; Hartung, Thomas; Rojas, Camilo; Rais, Rana; Tsukamoto, Takashi; Semenza, Gregg L.; Hanes, Justin; Slusher, Barbara S.; Le, Anne

2016-01-01

Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer. PMID:27559084

Optimal therapies of a virus replication model with pharmacological delays based on reverse transcriptase inhibitors and protease inhibitors

NASA Astrophysics Data System (ADS)

Pei, Yongzhen; Li, Changguo; Liang, Xiyin

2017-11-01

A short delay in the pharmacological effect on account of the time required for drug absorption, distribution, and penetration into target cells after application of any anti-viral drug, is defined by the pharmacological delay (Herz et al 1996 Proc. Natl Acad. Sci. USA 93 7247-51). In this paper, a virus replication model with Beddington-DeAngelis incidence rate and the pharmacological and intracellular delays is presented to describe the treatment to cure the virus infection. The optimal controls represent the efficiency of reverse transcriptase inhibitors and protease inhibitors in suppressing viral production and prohibiting new infections. Due to the fact that both the control and state variables contain delays, we derive a necessary conditions for our optimal problem. Based on these results, numerical simulations are implemented not only to show the optimal therapeutic schedules for different infection and release rates, but also to compare the effective of three treatment programs. Furthermore, comparison of therapeutic effects under different maximum tolerable dosages is shown. Our research indicates that (1) the proper and specific treatment program should be determined according to the infection rates of different virus particles; (2) the optimal combined drug treatment is the most efficient; (3) the appropriate proportion of medicament must be formulated during the therapy due to the non-monotonic relationship between maximum tolerable dosages and therapeutic effects; (4) the therapeutic effect is advantageous when the pharmacological delay is considered.

Combination nucleoside/nucleotide reverse transcriptase inhibitors for treatment of HIV infection.

PubMed

Akanbi, Maxwell O; Scarsi, Kimberly K; Scarci, Kimberly; Taiwo, Babafemi; Murphy, Robert L

2012-01-01

The combination of two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) and a third agent from another antiretroviral class is currently recommended for initial antiretroviral therapy. In general, N(t)RTIs remain relevant in subsequent regimens. There are currently six nucleoside reverse transcriptase inhibitors and one nucleotide reverse transcriptase inhibitor drug entities available, and several formulations that include two or more N(t)RTIs in a fixed-dose combination. These entities have heterogeneous pharmacological and clinical properties. Accordingly, toxicity, pill burden, dosing frequency, potential drug-drug interaction, preexisting antiretroviral drug resistance and comorbid conditions should be considered when constructing a regimen. This approach is critical in order to optimize virologic efficacy and clinical outcomes. This article reviews N(t)RTI combinations used in the treatment of HIV-infected adults. The pharmacological properties of each N(t)RTI, and the clinical trials that have influenced treatment guidelines are discussed. It is likely that N(t)RTIs will continue to dominate the global landscape of HIV treatment and prevention, despite emerging interest in N(t)RTI-free combination therapy. Clinical domains where only few alternatives to N(t)RTIs exist include treatment of HIV/HBV coinfection and HIV-2. There is a need for novel N(t)RTIs with enhanced safety and resistance profiles compared with current N(t)RTIs.

[Hepatitis C treatment in special patient groups].

PubMed

Berenguer, Marina; Jorquera, Francisco; Ángel Serra, Miguel; Sola, Ricard; Castellano, Gregorio

2014-07-01

The treatment plan for chronic hepatitis C in special populations varies according to comorbidity and the current evidence on treatment. In patients with hepatitis C virus and HIV coinfection, the results of dual therapy (pegylated interferon plus ribavirin) are poor. In patients with genotype 1 infection, triple therapy (dual therapy plus boceprevir or telaprevir) has doubled the response rate, but protease inhibitors can interact with some antiretroviral drugs and provoke more adverse effects. These disadvantages are avoided by the new, second-generation, direct-acting antiviral agents. In patients who are candidates for liver transplantation or are already liver transplant recipients, the optimal therapeutic option at present is to combine the new antiviral agents, with or without ribavirin and without interferon. The treatment of patients under hemodialysis due to chronic renal disease continues to be dual therapy (often with reduced doses of pegylated interferon and ribavirin), since there is still insufficient information on triple therapy and the new antiviral agents. In mixed cryoglobulinemia, despite the scarcity of experience, triple therapy seems to be superior to dual therapy and may be used as rescue therapy in non-responders to dual therapy. However, a decision must always be made on whether antiviral treatment should be used concomitantly or after immunosuppressive therapy. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Therapeutic Vascular Targeting and Irradiation: Correlation of MRI Tissue Changes at Cellular and Molecular Levels to Optimizing Outcome

DTIC Science & Technology

2008-06-01

cascade of tumor cell death in experimental tumors (4-6). However, survived tissues in a thin viable rim of tumor usually re-grow in spite of...changes monitored by MRI, optimum scheme of the combined radiation and CA4P will be designed and experimental treatment will be performed on the...CD31 Overlap Figure 4 CD 10 Task 2. Experimental tumor therapy

Therapy induces widespread reorganization of motor cortex after complete spinal transection that supports motor recovery.

PubMed

Ganzer, Patrick D; Manohar, Anitha; Shumsky, Jed S; Moxon, Karen A

2016-05-01

Reorganization of the somatosensory system and its relationship to functional recovery after spinal cord injury (SCI) has been well studied. However, little is known about the impact of SCI on organization of the motor system. Recent studies suggest that step-training paradigms in combination with spinal stimulation, either electrically or through pharmacology, are more effective than step training alone at inducing recovery and that reorganization of descending corticospinal circuits is necessary. However, simpler, passive exercise combined with pharmacotherapy has also shown functional improvement after SCI and reorganization of, at least, the sensory cortex. In this study we assessed the effect of passive exercise and serotonergic (5-HT) pharmacological therapies on behavioral recovery and organization of the motor cortex. We compared the effects of passive hindlimb bike exercise to bike exercise combined with daily injections of 5-HT agonists in a rat model of complete mid-thoracic transection. 5-HT pharmacotherapy combined with bike exercise allowed the animals to achieve unassisted weight support in the open field. This combination of therapies also produced extensive expansion of the axial trunk motor cortex into the deafferented hindlimb motor cortex and, surprisingly, reorganization within the caudal and even the rostral forelimb motor cortex areas. The extent of the axial trunk expansion was correlated to improvement in behavioral recovery of hindlimbs during open field locomotion, including weight support. From a translational perspective, these data suggest a rationale for developing and optimizing cost-effective, non-invasive, pharmacological and passive exercise regimes to promote plasticity that supports restoration of movement after spinal cord injury. Copyright © 2016. Published by Elsevier Inc.

Commentary on "Optimal schedule of bacillus Calmette-Guérin for non-muscle-invasive bladder cancer: A meta-analysis of comparative studies." Zhu S, Tang Y, Li K, Shang Z, Jiang N, Nian X, Sun L, Niu Y, Department of Urology Tianjin Institute of Urology, 2nd Hospital of Tianjin Medical University, People's Republic of China.: BMC Cancer 2013; 13:332. doi:10.1186/1471-2407-13-332.

PubMed

See, William A

2014-11-01

To explore the necessity of maintenance, efficacy of low-dose and superiority of various combination therapies of Bacillus Calmette-Guérin (BCG) in treatment of superficial bladder cancer (BCa). Comprehensive searches of electronic databases (PubMed, Embase, and the Cochrane Library), were performed, then a systematic review and cumulative meta-analysis of 21 randomized, controlled trials (RCTs) and 9 retrospective comparative studies were carried out according to, predefined inclusion criteria. Significantly better recurrence-free survivals (RFS) were observed respectively in patients who received BCG maintenance, standard-dose and BCG plus epirubicin therapy comparing to those received induction, low-dose and BCG alone. BCG maintenance therapy was also associated with significantly better progression-free survival (PFS), but there were more incidences of adverse events. Pooled results showed no remarkable advantage of BCG combined with Mitomycin C or with interferon α-2b in improving oncologic outcomes. Sensitivity-analyses stratified by study-design and tumor stage led to very similar overall results and often to a decrease of the between-study heterogeneity. Our data confirmed that non-RCT only affected strength rather than direction of the overall results. All patients with superficial BCa should be encouraged to accept BCG maintenance therapy with standard-dose if well tolerated. Patients can benefit from BCG combined with epirubicin but not from BCG combined with Mitomycin C or interferon α-2b. Copyright © 2014 Elsevier Inc. All rights reserved.

Activity of glycated chitosan and other adjuvants to PDT vaccines

NASA Astrophysics Data System (ADS)

Korbelik, Mladen; Banáth, Judit; Čiplys, Evaldas; Szulc, Zdzislaw; Bielawska, Alicja; Chen, Wei R.

2015-03-01

Glycated chitosan (GC), a water soluble galactose-conjugated natural polysaccharide, has proven to be an effective immunoadjuvant for treatment of tumors based on laser thermal therapy. It was also shown to act as adjuvant for tumor therapy with high-intensity ultrasound and in situ photodynamic therapy (PDT). In the present study, GC was examined as potential adjuvant to PDT-generated cancer vaccine. Two other agents, pure calreticulin protein and acid ceramidase inhibitor LCL521, were also tested as prospective adjuvants for use in conjunction with PDT vaccines. Single treatment with GC, included with PDT vaccine cells suspension, improved the therapeutic efficacy when compared to vaccine alone. This attractive prospect of GC application remains to be carefully optimized and mechanistically elucidated. Both calreticulin and LCL521 proved also effective adjuvants when combined with PDT vaccine tumor treatment.

Haemodynamic coherence - The relevance of fluid therapy.

PubMed

Arnemann, Philip; Seidel, Laura; Ertmer, Christian

2016-12-01

The ultimate goal of fluid therapy is to improve the oxygenation of cells by improving the cardiac output, thus improving microcirculation by optimizing macrocirculation. This haemodynamic coherence is often altered in patients with haemorrhagic shock and sepsis. The loss of haemodynamic coherence is associated with adverse outcomes. It may be influenced by the mechanisms of the underlying disease and properties of different fluids used for resuscitation in these critically ill patients. Monitoring microcirculation and haemodynamic coherence may be an additional tool to predict the response to fluid administration. In addition, microcirculatory analysis may support the clinician in his decision to not administer fluids when microcirculatory blood flow is preserved. In future, the indication, guidance and termination of fluid therapy may be assessed by bedside microvascular analysis in combination with standard haemodynamic monitoring. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synthesis and evaluation of alendronate-modified gelatin biopolymer as a novel osteotropic nanocarrier for gene therapy.

PubMed

Mekhail, George M; Kamel, Amany O; Awad, Gehanne As; Mortada, Nahed D; Rodrigo, Rowena L; Spagnuolo, Paul A; Wettig, Shawn D

2016-09-01

To synthesize an osteotropic alendronate functionalized gelatin (ALN-gelatin) biopolymer for nanoparticle preparation and targeted delivery of DNA to osteoblasts for gene therapy applications. Alendronate coupling to gelatin was confirmed using Fourier transform IR, (31)PNMR, x-ray diffraction (XRD) and differential scanning calorimetry. ALN-gelatin biopolymers prepared at various alendronate/gelatin ratios were utilized to prepare nanoparticles and were optimized in combination with DNA and gemini surfactant for transfecting both HEK-293 and MG-63 cell lines. Gelatin functionalization was confirmed using the above methods. Uniform nanoparticles were obtained from a nanoprecipitation technique. ALN-gelatin/gemini/DNA complexes exhibited higher transfection efficiency in MG-63 osteosarcoma cell line compared with the positive control. ALN-gelatin is a promising biopolymer for bone targeting of either small molecules or gene therapy applications.

Trajectory Modulated Arc Therapy: A Fully Dynamic Delivery With Synchronized Couch and Gantry Motion Significantly Improves Dosimetric Indices Correlated With Poor Cosmesis in Accelerated Partial Breast Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liang, Jieming; Atwood, Todd; Eyben, Rie von

2015-08-01

Purpose: To develop planning and delivery capabilities for linear accelerator–based nonisocentric trajectory modulated arc therapy (TMAT) and to evaluate the benefit of TMAT for accelerated partial breast irradiation (APBI) with the patient in prone position. Methods and Materials: An optimization algorithm for volumetrically modulated arc therapy (VMAT) was generalized to allow for user-defined nonisocentric TMAT trajectories combining couch rotations and translations. After optimization, XML scripts were automatically generated to program and subsequently deliver the TMAT plans. For 10 breast patients in the prone position, TMAT and 6-field noncoplanar intensity modulated radiation therapy (IMRT) plans were generated under equivalent objectives andmore » constraints. These plans were compared with regard to whole breast tissue volume receiving more than 100%, 80%, 50%, and 20% of the prescription dose. Results: For TMAT APBI, nonisocentric collision-free horizontal arcs with large angular span (251.5 ± 7.9°) were optimized and delivered with delivery time of ∼4.5 minutes. Percentage changes of whole breast tissue volume receiving more than 100%, 80%, 50%, and 20% of the prescription dose for TMAT relative to IMRT were −10.81% ± 6.91%, −27.81% ± 7.39%, −14.82% ± 9.67%, and 39.40% ± 10.53% (P≤.01). Conclusions: This is a first demonstration of end-to-end planning and delivery implementation of a fully dynamic APBI TMAT. Compared with IMRT, TMAT resulted in marked reduction of the breast tissue volume irradiated at high doses.« less

A neurochemical closed-loop controller for deep brain stimulation: toward individualized smart neuromodulation therapies.

PubMed

Grahn, Peter J; Mallory, Grant W; Khurram, Obaid U; Berry, B Michael; Hachmann, Jan T; Bieber, Allan J; Bennet, Kevin E; Min, Hoon-Ki; Chang, Su-Youne; Lee, Kendall H; Lujan, J L

2014-01-01

Current strategies for optimizing deep brain stimulation (DBS) therapy involve multiple postoperative visits. During each visit, stimulation parameters are adjusted until desired therapeutic effects are achieved and adverse effects are minimized. However, the efficacy of these therapeutic parameters may decline with time due at least in part to disease progression, interactions between the host environment and the electrode, and lead migration. As such, development of closed-loop control systems that can respond to changing neurochemical environments, tailoring DBS therapy to individual patients, is paramount for improving the therapeutic efficacy of DBS. Evidence obtained using electrophysiology and imaging techniques in both animals and humans suggests that DBS works by modulating neural network activity. Recently, animal studies have shown that stimulation-evoked changes in neurotransmitter release that mirror normal physiology are associated with the therapeutic benefits of DBS. Therefore, to fully understand the neurophysiology of DBS and optimize its efficacy, it may be necessary to look beyond conventional electrophysiological analyses and characterize the neurochemical effects of therapeutic and non-therapeutic stimulation. By combining electrochemical monitoring and mathematical modeling techniques, we can potentially replace the trial-and-error process used in clinical programming with deterministic approaches that help attain optimal and stable neurochemical profiles. In this manuscript, we summarize the current understanding of electrophysiological and electrochemical processing for control of neuromodulation therapies. Additionally, we describe a proof-of-principle closed-loop controller that characterizes DBS-evoked dopamine changes to adjust stimulation parameters in a rodent model of DBS. The work described herein represents the initial steps toward achieving a "smart" neuroprosthetic system for treatment of neurologic and psychiatric disorders.

A Preliminary In Vitro Study on the Efficacy of High-Power Photodynamic Therapy (HLLT): Comparison between Pulsed Diode Lasers and Superpulsed Diode Lasers and Impact of Hydrogen Peroxide with Controlled Stabilization

PubMed Central

Baldoni, Marco; Ghisalberti, Carlo Angelo; Paiusco, Alessio

2016-01-01

Aim. In periodontology lasers have been suggested for the photodynamic therapy (PDT): such therapy can be defined as the inactivation of cells, microorganisms, or molecules induced by light and not by heat. The aim of this study was to evaluate results of PDT using a 980 nm diode laser (Wiser Doctor Smile, Lambda SPA, Italy) combined with hydrogen peroxide, comparing a pulsed diode laser (LI) activity to a high-frequency superpulsed diode laser (LII). Materials and Methods. Primary fibroblasts and keratinocytes cell lines, isolated from human dermis, were irradiated every 48 h for 10 days using LI and LII combined with SiOxyL+ ™ Solution (hydrogen peroxide (HP) stabilized with a glycerol phosphate complex). Two days after the last irradiation, the treated cultures were analyzed by flow cytofluorometry (FACS) and western blotting to quantify keratin 5 and keratin 8 with monoclonal antibodies reactive to cytokeratin 5 and cytokeratin 8. Antimicrobial activity was also evaluated. Results. Both experimental models show the superiority of LII against LI. In parallel, stabilized HP provided better results in the regeneration test in respect to common HP, while the biocidal activity remains comparable. Conclusion. The use of high-frequency lasers combined with stabilized hydrogen peroxide can provide optimal results for a substantial decrease of bacterial count combined with a maximal biostimulation induction of soft tissues and osteogenesis. PMID:27631000

A Preliminary In Vitro Study on the Efficacy of High-Power Photodynamic Therapy (HLLT): Comparison between Pulsed Diode Lasers and Superpulsed Diode Lasers and Impact of Hydrogen Peroxide with Controlled Stabilization.

PubMed

Caccianiga, Gianluigi; Baldoni, Marco; Ghisalberti, Carlo Angelo; Paiusco, Alessio

2016-01-01

Aim. In periodontology lasers have been suggested for the photodynamic therapy (PDT): such therapy can be defined as the inactivation of cells, microorganisms, or molecules induced by light and not by heat. The aim of this study was to evaluate results of PDT using a 980 nm diode laser (Wiser Doctor Smile, Lambda SPA, Italy) combined with hydrogen peroxide, comparing a pulsed diode laser (LI) activity to a high-frequency superpulsed diode laser (LII). Materials and Methods. Primary fibroblasts and keratinocytes cell lines, isolated from human dermis, were irradiated every 48 h for 10 days using LI and LII combined with SiOxyL(+) ™ Solution (hydrogen peroxide (HP) stabilized with a glycerol phosphate complex). Two days after the last irradiation, the treated cultures were analyzed by flow cytofluorometry (FACS) and western blotting to quantify keratin 5 and keratin 8 with monoclonal antibodies reactive to cytokeratin 5 and cytokeratin 8. Antimicrobial activity was also evaluated. Results. Both experimental models show the superiority of LII against LI. In parallel, stabilized HP provided better results in the regeneration test in respect to common HP, while the biocidal activity remains comparable. Conclusion. The use of high-frequency lasers combined with stabilized hydrogen peroxide can provide optimal results for a substantial decrease of bacterial count combined with a maximal biostimulation induction of soft tissues and osteogenesis.

Hemodialysis and nutritional status in children: malnutrition and cachexia.

PubMed

Fischbach, Michel; Dheu, Céline; Seuge, Laure; Orfanos, Nadia

2009-01-01

Malnutrition is a common state in chronic hemodialyzed children. More than malnutrition, which infers that dietary supplementation would be curative, cachexia, which implies loss of protein stores, are combined factors of impaired linear growth and reduced muscle mass in uremic patients. Adequate diet to prevent malnutrition is of major importance. But to avoid cachexia in children on chronic hemodialysis, the management of acidosis, inflammation, abnormal metabolic rate, and endocrine disturbances should not, be forgotten. Daily hemodialysis regimen using convective flow therapy and ultrapure dialysate, i.e., on line hemodiafiltration together with growth hormone therapy, appears as a hopeful strategy for the chronic dialyzed child to achieve catch-up growth, a parameter of optimal nutrition.

Root canal irrigants

PubMed Central

Kandaswamy, Deivanayagam; Venkateshbabu, Nagendrababu

2010-01-01

Successful root canal therapy relies on the combination of proper instrumentation, irrigation, and obturation of the root canal. Of these three essential steps of root canal therapy, irrigation of the root canal is the most important determinant in the healing of the periapical tissues. The primary endodontic treatment goal must thus be to optimize root canal disinfection and to prevent reinfection. In this review of the literature, various irrigants and the interactions between irrigants are discussed. We performed a Medline search for English-language papers published untill July 2010. The keywords used were ‘root canal irrigants’ and ‘endodontic irrigants.’ The reference lists of each article were manually checked for additional articles of relevance. PMID:21217955

Emerging Vaccine Therapy Approaches for Prostate Cancer

PubMed Central

Sonpavde, Guru; Slawin, Kevin M; Spencer, David M; Levitt, Jonathan M

2010-01-01

Prostate cancer vaccines attempt to induce clinically relevant, cancer-specific systemic immune responses in patients with prostate cancer and represent a new class of targeted, nontoxic therapies. With a growing array of vaccine technologies in preclinical or clinical development, autologous antigen-presenting cell vaccines loaded with the antigen, prostate acid phosphatase, and poxvirus vaccines targeting prostate-specific antigen have recently demonstrated a significant survival benefit in randomized trials of patients with metastatic castration-resistant prostate cancer, whereas others have failed to demonstrate any benefit. The combination of vaccines with chemotherapy, radiotherapy, and other biologic agents is also being evaluated. Efforts to optimize vaccine approaches and select ideal patient populations need to continue to build on these early successes. PMID:20428291

Challenges faced when identifying patients for combination immunotherapy.

PubMed

Ernstoff, Marc S; Gandhi, Shipra; Pandey, Manu; Puzanov, Igor; Grivas, Petros; Montero, Alberto; Velcheti, Vamsidhar; Turk, Mary Jo; Diaz-Montero, Claudia Marcela; Lewis, Lionel D; Morrison, Carl

2017-08-01

In 1996, Jim Allison demonstrated that blocking the immune regulatory molecule CTLA-4 with anit-CTLA4 antibody led to enhance tumor responses in mice. It would take an additional 15 years for human studies to confirm the potency and clinical efficacy of anti-CTLA4, ultimately leading to US FDA approval of the first checkpoint inhibitor, ipilimumab. Now with a plethora of immune-modulating agents demonstrating single agent safety and benefit across many tumor types, investigation on the optimal combination of immune-based therapies has begun in earnest. While there are many challenges, a central one is how to select which combination for which patient is the best. Here we review the current approaches that a practitioner can use to achieve this therapeutic goal.

Stem cells and combination therapy for the treatment of traumatic brain injury.

PubMed

Dekmak, AmiraSan; Mantash, Sarah; Shaito, Abdullah; Toutonji, Amer; Ramadan, Naify; Ghazale, Hussein; Kassem, Nouhad; Darwish, Hala; Zibara, Kazem

2018-03-15

TBI is a nondegenerative, noncongenital insult to the brain from an external mechanical force; for instance a violent blow in a car accident. It is a complex injury with a broad spectrum of symptoms and has become a major cause of death and disability in addition to being a burden on public health and societies worldwide. As such, finding a therapy for TBI has become a major health concern for many countries, which has led to the emergence of many monotherapies that have shown promising effects in animal models of TBI, but have not yet proven any significant efficacy in clinical trials. In this paper, we will review existing and novel TBI treatment options. We will first shed light on the complex pathophysiology and molecular mechanisms of this disorder, understanding of which is a necessity for launching any treatment option. We will then review most of the currently available treatments for TBI including the recent approaches in the field of stem cell therapy as an optimal solution to treat TBI. Therapy using endogenous stem cells will be reviewed, followed by therapies utilizing exogenous stem cells from embryonic, induced pluripotent, mesenchymal, and neural origin. Combination therapy is also discussed as an emergent novel approach to treat TBI. Two approaches are highlighted, an approach concerning growth factors and another using ROCK inhibitors. These approaches are highlighted with regard to their benefits in minimizing the outcomes of TBI. Finally, we focus on the consequent improvements in motor and cognitive functions after stem cell therapy. Overall, this review will cover existing treatment options and recent advancements in TBI therapy, with a focus on the potential application of these strategies as a solution to improve the functional outcomes of TBI. Copyright © 2017 Elsevier B.V. All rights reserved.

Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study.

PubMed

Martin, N K; Robey, I F; Gaffney, E A; Gillies, R J; Gatenby, R A; Maini, P K

2012-03-27

Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts. We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies. The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1-7.2. Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1-7.2 is most promising.

When to Initiate Combined Antiretroviral Therapy to Reduce Mortality and AIDS-Defining Illness in HIV-Infected Persons in Developed Countries

PubMed Central

2012-01-01

Background Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 109 cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. Objective To identify the optimal CD4 cell count at which cART should be initiated. Design Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 109 cells/L. Setting HIV clinics in Europe and the Veterans Health Administration system in the United States. Patients 20 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 109 cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 109 cells/L and were included in the analysis. Measurements Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. Results Compared with initiating cART at the CD4 cell count threshold of 0.500 × 109 cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. Limitations CD4 cell count at cART initiation was not randomized. Residual confounding may exist. Conclusion Initiation of cART at a threshold CD4 count of 0.500 × 109 cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 ×109 cells/L. Primary Funding Source National Institutes of Health. PMID:21502648

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

PubMed

Cain, Lauren E; Logan, Roger; Robins, James M; Sterne, Jonathan A C; Sabin, Caroline; Bansi, Loveleen; Justice, Amy; Goulet, Joseph; van Sighem, Ard; de Wolf, Frank; Bucher, Heiner C; von Wyl, Viktor; Esteve, Anna; Casabona, Jordi; del Amo, Julia; Moreno, Santiago; Seng, Remonie; Meyer, Laurence; Perez-Hoyos, Santiago; Muga, Roberto; Lodi, Sara; Lanoy, Emilie; Costagliola, Dominique; Hernan, Miguel A

2011-04-19

Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. To identify the optimal CD4 cell count at which cART should be initiated. Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. HIV clinics in Europe and the Veterans Health Administration system in the United States. 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. CD4 cell count at cART initiation was not randomized. Residual confounding may exist. Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

Synergistic effects of Combined Therapy: nonfocused ultrasound plus Aussie current for noninvasive body contouring

PubMed Central

Canela, Vivianne Carvalho; Crivelaro, Cinthia Nicoletti; Ferla, Luciane Zacchi; Pelozo, Gisele Marques; Azevedo, Juliana; Liebano, Richard Eloin; Nogueira, Caroline; Guidi, Renata Michelini; Grecco, Clóvis; Sant’Ana, Estela

2018-01-01

Background and objectives Nowadays, there are several noninvasive technologies being used for improving of body contouring. The objectives of this pilot study were to verify the effectiveness of the Heccus® device, emphasizing the synergism between nonfocused ultrasound plus Aussie current in the improvement of body contour, and to determine if the association of this therapy with whole-body vibration exercises can have additional positive effects in the results of the treatments. Subjects and methods Twenty healthy women aged 20–40 years participated in the study. Ten patients received Combined Therapy treatment (G1) and the other 10 participants received Combined Therapy with additional vibratory platform treatment (G2). Anthropometric and standardized photography analysis, ultrasonography, cutometry and self-adminestered questionnaires of tolerance and satisfaction levels with the treatment were used. Results Compared with baseline values, reduction of fat thickness was observed by ultrasonography in the posterior thigh area in the G1 group (P<0.05) and in the buttocks (P<0.05) and the posterior thigh areas (P<0.05) in the G2. All the treated areas in both groups showed reduction in cellulite degree in the buttocks, G1 (P<0.05) and G2 (P<0.05), and in posterior thigh areas, G1 (P<0.05) and G2 (P<0.05). Optimal improvement of skin firmness (G1, P<0.0001; G2, P=0.0034) in the treated areas was observed in both groups. Conclusion We conclude that the synergistic effects of the Combined Therapy (nonfocused ultrasound plus Aussie current) might be a good option with noninvasive body contouring treatment for improving the aspect of the cellulite, skin firmness and localized fat. If used in association with the whole-body vibratory platform, the results can be better, especially in the treatment of localized fat. Further studies with larger sample size should be performed to confirm these results. PMID:29731654

Synergistic effects of Combined Therapy: nonfocused ultrasound plus Aussie current for noninvasive body contouring.

PubMed

Canela, Vivianne Carvalho; Crivelaro, Cinthia Nicoletti; Ferla, Luciane Zacchi; Pelozo, Gisele Marques; Azevedo, Juliana; Liebano, Richard Eloin; Nogueira, Caroline; Guidi, Renata Michelini; Grecco, Clóvis; Sant'Ana, Estela

2018-01-01

Nowadays, there are several noninvasive technologies being used for improving of body contouring. The objectives of this pilot study were to verify the effectiveness of the Heccus ® device, emphasizing the synergism between nonfocused ultrasound plus Aussie current in the improvement of body contour, and to determine if the association of this therapy with whole-body vibration exercises can have additional positive effects in the results of the treatments. Twenty healthy women aged 20-40 years participated in the study. Ten patients received Combined Therapy treatment (G1) and the other 10 participants received Combined Therapy with additional vibratory platform treatment (G2). Anthropometric and standardized photography analysis, ultrasonography, cutometry and self-adminestered questionnaires of tolerance and satisfaction levels with the treatment were used. Compared with baseline values, reduction of fat thickness was observed by ultrasonography in the posterior thigh area in the G1 group ( P <0.05) and in the buttocks ( P <0.05) and the posterior thigh areas ( P <0.05) in the G2. All the treated areas in both groups showed reduction in cellulite degree in the buttocks, G1 ( P <0.05) and G2 ( P <0.05), and in posterior thigh areas, G1 ( P <0.05) and G2 ( P <0.05). Optimal improvement of skin firmness (G1, P <0.0001; G2, P =0.0034) in the treated areas was observed in both groups. We conclude that the synergistic effects of the Combined Therapy (nonfocused ultrasound plus Aussie current) might be a good option with noninvasive body contouring treatment for improving the aspect of the cellulite, skin firmness and localized fat. If used in association with the whole-body vibratory platform, the results can be better, especially in the treatment of localized fat. Further studies with larger sample size should be performed to confirm these results.

Applications of Pharmacometrics in the Clinical Development and Pharmacotherapy of Anti-Infectives

PubMed Central

Trivedi, Ashit; Lee, Richard E; Meibohm, Bernd

2013-01-01

With the increased emergence of anti-infective resistance in recent years, much focus has recently been drawn to the development of new anti-infectives and the optimization of treatment regimens and combination therapies for established antimicrobials. In this context, the field of pharmacometrics using quantitative numerical modeling and simulation techniques has in recent years emerged as an invaluable tool in the pharmaceutical industry, academia and regulatory agencies to facilitate the integration of preclinical and clinical development data and to provide a scientifically based framework for rationale dosage regimen design and treatment optimization. This review highlights the usefulness of pharmacometric analyses in anti-infective drug development and applied pharmacotherapy with select examples. PMID:23473593

[Optimization of parodontitis treatment of patients with tuberculosis].

PubMed

Aleksandrova, E A; Lepilin, A V; Kazimirova, N E; Shul'diakov, A A

2010-01-01

For the purpose to determine the clinic-pathogenetic efficacy of Cycloferon liniment in the combined therapy of parodontitis of patients with focal tuberculosis medical examination and treatment of 40 patients is carried out. It is established, that use of liniment Cycloferon in the combined treatment of patients with focal tuberculosis allows to accelerate process of normalization of lipid peroxidation parameters and antioxidant potential of blood, to decrease infection load (Herpes symplex virus I, Candida albicans, Staphylococcus aureus) in parodontal recess and evidence of local inflammation with reduction of activity of the tumours necrosis factor and interleukin 1beta, that provides acceleration of recuperation processes, lowering the frequency of parodontitis relapses.

Translational PK/PD of Anti-Infective Therapeutics

PubMed Central

Rathi, Chetan; Lee, Richard E.; Meibohm, Bernd

2016-01-01

Translational PK/PD modeling has emerged as a critical technique for quantitative analysis of the relationship between dose, exposure and response of antibiotics. By combining model components for pharmacokinetics, bacterial growth kinetics and concentration-dependent drug effects, these models are able to quantitatively capture and simulate the complex interplay between antibiotic, bacterium and host organism. Fine-tuning of these basic model structures allows to further account for complicating factors such as resistance development, combination therapy, or host responses. With this tool set at hand, mechanism-based PK/PD modeling and simulation allows to develop optimal dosing regimens for novel and established antibiotics for maximum efficacy and minimal resistance development. PMID:27978987

Noninvasive, automatic optimization strategy in cardiac resynchronization therapy.

PubMed

Reumann, Matthias; Osswald, Brigitte; Doessel, Olaf

2007-07-01

Optimization of cardiac resynchronization therapy (CRT) is still unsolved. It has been shown that optimal electrode position,atrioventricular (AV) and interventricular (VV) delays improve the success of CRT and reduce the number of non-responders. However, no automatic, noninvasive optimization strategy exists to date. Cardiac resynchronization therapy was simulated on the Visible Man and a patient data-set including fiber orientation and ventricular heterogeneity. A cellular automaton was used for fast computation of ventricular excitation. An AV block and a left bundle branch block were simulated with 100%, 80% and 60% interventricular conduction velocity. A right apical and 12 left ventricular lead positions were set. Sequential optimization and optimization with the downhill simplex algorithm (DSA) were carried out. The minimal error between isochrones of the physiologic excitation and the therapy was computed automatically and leads to an optimal lead position and timing. Up to 1512 simulations were carried out per pathology per patient. One simulation took 4 minutes on an Apple Macintosh 2 GHz PowerPC G5. For each electrode pair an optimal pacemaker delay was found. The DSA reduced the number of simulations by an order of magnitude and the AV-delay and VV - delay were determined with a much higher resolution. The findings are well comparable with clinical studies. The presented computer model of CRT automatically evaluates an optimal lead position and AV-delay and VV-delay, which can be used to noninvasively plan an optimal therapy for an individual patient. The application of the DSA reduces the simulation time so that the strategy is suitable for pre-operative planning in clinical routine. Future work will focus on clinical evaluation of the computer models and integration of patient data for individualized therapy planning and optimization.

Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy.

PubMed

Polackwich, A S; Shoskes, D A

2016-06-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as NIH Category III Prostatitis is a highly prevalent syndrome with significant impact on quality of life. As a heterogeneous syndrome, there exists no 'one size fits all' therapy with level 1 evidence to guide therapy. This often leads to a nihilistic approach to patients and clinical outcomes are poor. In this review, we examine the evidence for CP/CPPS therapies and discuss our technique of clinical phenotyping combined with multimodal therapy. Review of Medline articles with terms 'non-bacterial prostatitis', 'abacterial prostatitis' and 'chronic pelvic pain syndrome'. Many individual therapies have been evaluated in the treatment of CP/CPPS; antibiotics, anti-inflammatory medications (including bioflavonoids), neuromodulators, alpha blockers, pelvic floor physical therapy and cognitive behavior therapy. Each of these has been found to have varying success in alleviating symptoms. UPOINT is a system of clinical phenotyping for CP/CPPS patients that has 6 defined domains, which guide multimodal therapy. It has been validated to correlate with symptom burden and therapy guided by UPOINT leads to significant symptom improvement in 75-84% of patients based on three independent studies. CP/CPPS is a heterogeneous condition and, much like with prostate cancer, optimal therapy can only be achieved by classifying patients into clinically meaningful phenotypic groups (much like TNM) and letting the phenotype drive therapy.

Gene therapy approaches for spinal cord injury

NASA Astrophysics Data System (ADS)

Bright, Corinne

As the biomedical engineering field expands, combination technologies are demonstrating enormous potential for treating human disease. In particular, intersections between the rapidly developing fields of gene therapy and tissue engineering hold promise to achieve tissue regeneration. Nonviral gene therapy uses plasmid DNA to deliver therapeutic proteins in vivo for extended periods of time. Tissue engineering employs biomedical materials, such as polymers, to support the regrowth of injured tissue. In this thesis, a combination strategy to deliver genes and drugs in a polymeric scaffold was applied to a spinal cord injury model. In order to develop a platform technology to treat spinal cord injury, several nonviral gene delivery systems and polymeric scaffolds were evaluated in vitro and in vivo. Nonviral vector trafficking was evaluated in primary neuronal culture to develop an understanding of the barriers to gene transfer in neurons and their supporting glia. Although the most efficient gene carrier in vitro differed from the optimal gene carrier in vivo, confocal and electron microscopy of these nonviral vectors provided insights into the interaction of these vectors with the nucleus. A novel pathway for delivering nanoparticles into the nuclei of neurons and Schwann cells via vesicle trafficking was observed in this study. Reporter gene expression levels were evaluated after direct and remote delivery to the spinal cord, and the optimal nonviral vector, dose, and delivery strategy were applied to deliver the gene encoding the basic fibroblast growth factor (bFGF) to the spinal cord. An injectable and biocompatible gel, composed of the amphiphillic polymer poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG) was evaluated as a drug and gene delivery system in vitro, and combined with the optimized nonviral gene delivery system to treat spinal cord injury. Plasmid DNA encoding the bFGF gene and the therapeutic NEP1--40 peptide were incorporated in the PEG-PCL-PEG gel and injected into a lesion transecting the main dorsomedial and minor ventral medial corticospinal tract (CST). The degree of collateralization of the transected CST was quantified as an indicator of the regenerative potential of these treatments. At one month post-injury, we observed the robust rostral collateralization of the CST tract in response to the bFGF plasmid-loaded gel. In conclusion, we hope that this platform technology can be applied to the sustained local delivery of other proteins for the treatment of spinal cord injury.

Combined motor cortex and spinal cord neuromodulation promotes corticospinal system functional and structural plasticity and motor function after injury.

PubMed

Song, Weiguo; Amer, Alzahraa; Ryan, Daniel; Martin, John H

2016-03-01

An important strategy for promoting voluntary movements after motor system injury is to harness activity-dependent corticospinal tract (CST) plasticity. We combine forelimb motor cortex (M1) activation with co-activation of its cervical spinal targets in rats to promote CST sprouting and skilled limb movement after pyramidal tract lesion (PTX). We used a two-step experimental design in which we first established the optimal combined stimulation protocol in intact rats and then used the optimal protocol in injured animals to promote CST repair and motor recovery. M1 was activated epidurally using an electrical analog of intermittent theta burst stimulation (iTBS). The cervical spinal cord was co-activated by trans-spinal direct current stimulation (tsDCS) that was targeted to the cervical enlargement, simulated from finite element method. In intact rats, forelimb motor evoked potentials (MEPs) were strongly facilitated during iTBS and for 10 min after cessation of stimulation. Cathodal, not anodal, tsDCS alone facilitated MEPs and also produced a facilitatory aftereffect that peaked at 10 min. Combined iTBS and cathodal tsDCS (c-tsDCS) produced further MEP enhancement during stimulation, but without further aftereffect enhancement. Correlations between forelimb M1 local field potentials and forelimb electromyogram (EMG) during locomotion increased after electrical iTBS alone and further increased with combined stimulation (iTBS+c-tsDCS). This optimized combined stimulation was then used to promote function after PTX because it enhanced functional connections between M1 and spinal circuits and greater M1 engagement in muscle contraction than either stimulation alone. Daily application of combined M1 iTBS on the intact side and c-tsDCS after PTX (10 days, 27 min/day) significantly restored skilled movements during horizontal ladder walking. Stimulation produced a 5.4-fold increase in spared ipsilateral CST terminations. Combined neuromodulation achieves optimal motor recovery and substantial CST outgrowth with only 27 min of daily stimulation compared with 6h, as in our prior study, making it a potential therapy for humans with spinal cord injury. Copyright © 2015 Elsevier Inc. All rights reserved.

Combined motor cortex and spinal cord neuromodulation promotes corticospinal system functional and structural plasticity and motor function after injury

PubMed Central

Song, Weiguo; Amer, Alzahraa; Ryan, Daniel; Martin, John H.

2016-01-01

An important strategy for promoting voluntary movements after motor system injury is to harness activity-dependent corticospinal tract (CST) plasticity. We combine forelimb motor cortex (M1) activation with co-activation of its cervical spinal targets in rats to promote CST sprouting and skilled limb movement after pyramidal tract lesion (PTX). We used a two-step experimental design in which we first established the optimal combined stimulation protocol in intact rats and then used the optimal protocol in injured animals to promote CST repair and motor recovery. M1 was activated epidurally using an electrical analog of intermittent theta burst stimulation (iTBS). The cervical spinal cord was co-activated by trans-spinal direct current stimulation (tsDCS) that was targeted to the cervical enlargement, simulated from finite element method. In intact rats, forelimb motor evoked potentials (MEPs) were strongly facilitated during iTBS and for 10 minutes after cessation of stimulation. Cathodal, not anodal, tsDCS alone facilitated MEPs and also produced a facilitatory aftereffect that peaked at 10 minutes. Combined iTBS and cathodal tsDCS (c-tsDCS) produced further MEP enhancement during stimulation, but without further aftereffect enhancement. Correlations between forelimb M1 local field potentials and forelimb electromyogram (EMG) during locomotion increased after electrical iTBS alone and further increased with combined stimulation (iTBS + c-tsDCS). This optimized combined stimulation was then used to promote function after PTX because it enhanced functional connections between M1 and spinal circuits and greater M1 engagement in muscle contraction than either stimulation alone. Daily application of combined M1 iTBS on the intact side and c-tsDCS after PTX (10 days, 27 minutes/day) significantly restored skilled movements during horizontal ladder walking. Stimulation produced a 5.4-fold increase in spared ipsilateral CST terminations. Combined neuromodulation achieves optimal motor recovery and substantial CST outgrowth with only 27 minutes of daily stimulation compared with 6 hours, as in our prior study, making it a potential therapy for humans with spinal cord injury. PMID:26708732

The interplay between the immune system and chemotherapy: emerging methods for optimizing therapy.

PubMed

Ghiringhelli, François; Apetoh, Lionel

2014-01-01

Preclinical studies have revealed an unexpected ability of the immune system to contribute to the success of chemotherapy and radiotherapy. Anticancer therapies can trigger immune system activation by promoting the release of danger signals from dying tumor cells and/or the elimination of immunosuppressive cells. We have, however, recently discovered that some chemotherapies, such as 5-fluorouracil and gemcitabine, exert conflicting effects on anticancer immune responses. Although 5-fluorouracil and Gem selectively eliminated myeloid-derived suppressive cells in tumor-bearing rodents, these chemotherapies promoted the release of IL-1β and the development of pro-angiogenic IL-17-producing CD4 T cells. The ambivalent effects of chemotherapy on immune responses should thus be carefully considered to design effective combination therapies based on chemotherapy and immune modulators. Herein, we discuss how the initial findings underscoring the key role of the immune system in mediating the antitumor efficacy of anticancer agents could begin to translate into effective therapies in humans.

New Paradigms for Advanced Prostate Cancer

PubMed Central

Petrylak, Daniel P

2007-01-01

In men with metastatic hormone-refractory prostate cancer, androgen blockade produces dramatic and rapid declines in prostate-specific antigen (PSA), bone pain, and urinary tract obstruction. Nevertheless, there have been limited options with at best palliative results for patients who progress despite a castrate testosterone level. This paradigm changed in 2004 with the publication of 2 randomized clinical trials that demonstrated a 20% to 24% survival benefit for docetaxel-based therapy when compared to mitoxantrone and prednisone, data that supported US Food and Drug Administration approval of docetaxel-based therapy for the treatment of metastatic hormone-refractory prostate cancer. This article reviews the preliminary data and the timing and sequencing implications of ongoing clinical trials. Studies are evaluating the combination of docetaxel with agents that target bone, tumor vasculature, and the vitamin D receptor as well as second-line agents, such as satraplatin. The role of immune therapy is also evolving, and further studies will define the optimal timing of chemotherapy with immune therapy. PMID:17554403

Staphylococcus aureus Prostatic abscess: a clinical case report and a review of the literature.

PubMed

Carroll, David E; Marr, Ian; Huang, G Khai Lin; Holt, Deborah C; Tong, Steven Y C; Boutlis, Craig S

2017-07-21

Prostatic abscess is a rare complication of acute bacterial prostatitis and is most commonly caused by Enterobacteriaceae. We report on a case of prostatic abscess caused by Staphylococcus aureus and conduct a review of the literature. We present a case of S. aureus prostatic abscess that was successfully treated with a combination of antibiotic and surgical therapy. The isolate was non–multidrug-resistant, methicillin-resistant Staphylococcus aureus and was genotyped as clonal complex 5, an emerging regional clone that is trimethoprim resistant and Panton-Valentine leukocidin positive. This current case report is the first to describe the use of clindamycin step-down therapy. A literature review identified a further 39 cases of S. aureus prostatic abscesses, of which 26 were methicillin resistant. S. aureus is an uncommon cause of prostatic abscess. Optimal management includes both antibiotic therapy and surgical drainage. Our use of clindamycin as step-down therapy was guided by its excellent prostatic penetration.

Adjuvant therapy in early-stage non-small cell lung cancer.

PubMed

Serke, Monika

2010-01-01

Evidence clearly supports adjuvant chemotherapy following resection in patients with stage II or III non-small cell lung cancer (NSCLC). Based on 3 landmark studies, adjuvant chemotherapy has become standard in completely resected NSCLC stage II and IIIA. Survival benefit from adjuvant chemotherapy is estimated to be between 3% and 15%, depending on stage. Treatment should include 4 cycles of platinum-based combination chemotherapy. There is uncertainty about chemotherapy prescription in those patients with resected stage IB NSCLC, as the risk of recurrence is lower in early NSCLC and the magnitude of benefit of adjuvant therapy is proportional to the risk of relapse according to stage. Postoperative radiotherapy (PORT) should not be used for stage I or II NSCLC, and remains controversial in resected stage IIIA (N2) disease. All positive adjuvant trials have utilized a cisplatin-based regimen, usually in combination with vinorelbine, and this should be considered the standard approach. Prognostic factors to select patients who will benefit from adjuvant therapy in general or from platinum-based chemotherapy are under discussion, but not yet established. In future we hope to optimize treatment convenience for the patients by using other combinations with the hope of better efficacy results. Work is currently under way to identify prognostic factors which in future may help to identify patients who are most likely to benefit from chemotherapy. Copyright 2010 S. Karger AG, Basel.

Management of erectile dysfunction post-radical prostatectomy

PubMed Central

Saleh, Alan; Abboudi, Hamid; Ghazal-Aswad, MB; Mayer, Erik K; Vale, Justin A

2015-01-01

Radical prostatectomy is a commonly performed procedure for the treatment of localized prostate cancer. One of the long-term complications is erectile dysfunction. There is little consensus on the optimal management; however, it is agreed that treatment must be prompt to prevent fibrosis and increase oxygenation of penile tissue. It is vital that patient expectations are discussed, a realistic time frame of treatment provided, and treatment started as close to the prostatectomy as possible. Current treatment regimens rely on phosphodiesterase 5 inhibitors as a first-line therapy, with vacuum erection devices and intraurethral suppositories of alprostadil as possible treatment combination options. With nonresponders to these therapies, intracavernosal injections are resorted to. As a final measure, patients undergo the highly invasive penile prosthesis implantation. There is no uniform, objective treatment program for erectile dysfunction post-radical prostatectomy. Management plans are based on poorly conducted and often underpowered studies in combination with physician and patient preferences. They involve the aforementioned drugs and treatment methods in different sequences and doses. Prospective treatments include dietary supplements and gene therapy, which have shown promise with there proposed mechanisms of improving erectile function but are yet to be applied successfully in human patients. PMID:25750901

Advanced bioanalytics for precision medicine.

PubMed

Roda, Aldo; Michelini, Elisa; Caliceti, Cristiana; Guardigli, Massimo; Mirasoli, Mara; Simoni, Patrizia

2018-01-01

Precision medicine is a new paradigm that combines diagnostic, imaging, and analytical tools to produce accurate diagnoses and therapeutic interventions tailored to the individual patient. This approach stands in contrast to the traditional "one size fits all" concept, according to which researchers develop disease treatments and preventions for an "average" patient without considering individual differences. The "one size fits all" concept has led to many ineffective or inappropriate treatments, especially for pathologies such as Alzheimer's disease and cancer. Now, precision medicine is receiving massive funding in many countries, thanks to its social and economic potential in terms of improved disease prevention, diagnosis, and therapy. Bioanalytical chemistry is critical to precision medicine. This is because identifying an appropriate tailored therapy requires researchers to collect and analyze information on each patient's specific molecular biomarkers (e.g., proteins, nucleic acids, and metabolites). In other words, precision diagnostics is not possible without precise bioanalytical chemistry. This Trend article highlights some of the most recent advances, including massive analysis of multilayer omics, and new imaging technique applications suitable for implementing precision medicine. Graphical abstract Precision medicine combines bioanalytical chemistry, molecular diagnostics, and imaging tools for performing accurate diagnoses and selecting optimal therapies for each patient.

Implementation of a volumetric modulated arc therapy treatment planning solution for kidney and adrenal stereotactic body radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sonier, Marcus, E-mail: Marcus.Sonier@bccancer.bc.ca; Chu, William; Department of Radiation Oncology, University of Toronto, Toronto, ON

To develop a volumetric modulated arc therapy (VMAT) treatment planning solution in the treatment of primary renal cell carcinoma and oligometastatic adrenal lesions with stereotactic body radiation therapy. Single-arc VMAT plans (n = 5) were compared with clinically delivered step-and-shoot intensity-modulated radiotherapy (IMRT) with planning target volume coverage normalized between techniques. Target volume conformity, organ-at-risk (OAR) dose, treatment time, and monitor units were compared. A VMAT planning solution, created from a combination of arc settings and optimization constraints, auto-generated treatment plans in a single optimization. The treatment planning solution was evaluated on 15 consecutive patients receiving kidney and adrenal stereotacticmore » body radiation therapy. Treatment time was reduced from 13.0 ± 2.6 to 4.0 ± 0.9 minutes for IMRT and VMAT, respectively. The VMAT planning solution generated treatment plans with increased target homogeneity, improved 95% conformity index, and a reduced maximum point dose to nearby OARs but with increased intermediate dose to distant OARs. The conformity of the 95% isodose improved from 1.32 ± 0.39 to 1.12 ± 0.05 for IMRT and VMAT treatment plans, respectively. Evaluation of the planning solution showed clinically acceptable dose distributions for 13 of 15 cases with tight conformity of the prescription isodose to the planning target volume of 1.07 ± 0.04, delivering minimal dose to OARs. The introduction of a stereotactic body radiation therapy VMAT treatment planning solution improves the efficiency of planning and delivery time, producing treatment plans of comparable or superior quality to IMRT in the case of primary renal cell carcinoma and oligometastatic adrenal lesions.« less

Cost-effectiveness of cardioversion and antiarrhythmic therapy in nonvalvular atrial fibrillation.

PubMed

Catherwood, E; Fitzpatrick, W D; Greenberg, M L; Holzberger, P T; Malenka, D J; Gerling, B R; Birkmeyer, J D

1999-04-20

Physicians managing patients with nonvalvular atrial fibrillation must consider the risks, benefits, and costs of treatments designed to restore and maintain sinus rhythm compared with those of rate control with antithrombotic prophylaxis. To compare the cost-effectiveness of cardioversion, with or without antiarrhythmic agents, with that of rate control plus warfarin or aspirin. A Markov decision-analytic model was designed to simulate long-term health and economic outcomes. Published literature and hospital accounting information. Hypothetical cohort of 70-year-old patients with different baseline risks for stroke. 3 months. Societal. Therapeutic strategies using different combinations of cardioversion alone, cardioversion plus amiodarone or quinidine therapy, and rate control with antithrombotic treatment. Expected costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness. Strategies involving cardioversion alone were more effective and less costly than those not involving this option. For patients at high risk for ischemic stroke (5.3% per year), cardioversion alone followed by repeated cardioversion plus amiodarone therapy on relapse was most cost-effective ($9300 per QALY) compared with cardioversion alone followed by warfarin therapy on relapse. This strategy was also preferred for the moderate-risk cohort (3.6% per year), but the benefit was more expensive ($18,900 per QALY). In the lowest-risk cohort (1.6% per year), cardioversion alone followed by aspirin therapy on relapse was optimal. The choice of optimal strategy and incremental cost-effectiveness was substantially influenced by the baseline risk for stroke, rate of stroke in sinus rhythm, efficacy of warfarin, and costs and utilities for long-term warfarin and amiodarone therapy. Cardioversion alone should be the initial management strategy for persistent nonvalvular atrial fibrillation. On relapse of arrhythmia, repeated cardioversion plus low-dose amiodarone is cost-effective for patients at moderate to high risk for ischemic stroke.

Effect of oxandrolone therapy on adult height in Turner syndrome patients treated with growth hormone: a meta-analysis.

PubMed

Sheanon, Nicole M; Backeljauw, Philippe F

2015-01-01

Turner syndrome is a chromosomal abnormality in which there is complete or partial absence of the X chromosome. Turner syndrome effects 1 in every 2000 live births. Short stature is a cardinal feature of Turner Syndrome and the standard treatment is recombinant human growth hormone. When growth hormone is started at an early age a normal adult height can be achieved. With delayed diagnosis young women with Turner Syndrome may not reach a normal height. Adjuvant therapy with oxandrolone is used but there is no consensus on the optimal timing of treatment, the duration of treatment and the long term adverse effects of treatment. The objective of this review and meta-analysis is to examine the effect of oxandrolone on adult height in growth hormone treated Turner syndrome patients. Eligible trials were identified by a literature search using the terms: Turner syndrome, oxandrolone. The search was limited to English language randomized-controlled trials after 1980. Twenty-six articles were reviewed and four were included in the meta-analysis. A random effects model was used to calculate an effect size and confidence interval. The pooled effect size of 2.0759 (95 % CI 0.0988 to 4.0529) indicates that oxandrolone has a positive effect on adult height in Turner syndrome when combined with growth hormone therapy. In conclusion, the addition of oxandrolone to growth hormone therapy for treatment of short stature in Turner syndrome improves adult height. Further studies are warranted to investigate if there is a subset of Turner syndrome patients that would benefit most from growth hormone plus oxandrolone therapy, and to determine the optimal timing and duration of such therapy.

Personalizing Drug Selection Using Advanced Clinical Decision Support

PubMed Central

Pestian, John; Spencer, Malik; Matykiewicz, Pawel; Zhang, Kejian; Vinks, Alexander A.; Glauser, Tracy

2009-01-01

This article describes the process of developing an advanced pharmacogenetics clinical decision support at one of the United States’ leading pediatric academic medical centers. This system, called CHRISTINE, combines clinical and genetic data to identify the optimal drug therapy when treating patients with epilepsy or Attention Deficit Hyperactivity Disorder. In the discussion a description of clinical decision support systems is provided, along with an overview of neurocognitive computing and how it is applied in this setting. PMID:19898682

Prevention and treatment of protein energy wasting in chronic kidney disease patients: a consensus statement by the International Society of Renal Nutrition and Metabolism.

PubMed

Ikizler, T Alp; Cano, Noel J; Franch, Harold; Fouque, Denis; Himmelfarb, Jonathan; Kalantar-Zadeh, Kamyar; Kuhlmann, Martin K; Stenvinkel, Peter; TerWee, Pieter; Teta, Daniel; Wang, Angela Yee-Moon; Wanner, Christoph

2013-12-01

Protein energy wasting (PEW) is common in patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes, especially in individuals receiving maintenance dialysis therapy. A multitude of factors can affect the nutritional and metabolic status of CKD patients requiring a combination of therapeutic maneuvers to prevent or reverse protein and energy depletion. These include optimizing dietary nutrient intake, appropriate treatment of metabolic disturbances such as metabolic acidosis, systemic inflammation, and hormonal deficiencies, and prescribing optimized dialytic regimens. In patients where oral dietary intake from regular meals cannot maintain adequate nutritional status, nutritional supplementation, administered orally, enterally, or parenterally, is shown to be effective in replenishing protein and energy stores. In clinical practice, the advantages of oral nutritional supplements include proven efficacy, safety, and compliance. Anabolic strategies such as anabolic steroids, growth hormone, and exercise, in combination with nutritional supplementation or alone, have been shown to improve protein stores and represent potential additional approaches for the treatment of PEW. Appetite stimulants, anti-inflammatory interventions, and newer anabolic agents are emerging as novel therapies. While numerous epidemiological data suggest that an improvement in biomarkers of nutritional status is associated with improved survival, there are no large randomized clinical trials that have tested the effectiveness of nutritional interventions on mortality and morbidity.

Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury

PubMed Central

Acosta, Sandra A.; Tajiri, Naoki; Shinozuka, Kazutaka; Ishikawa, Hiroto; Sanberg, Paul R.; Sanchez-Ramos, Juan; Song, Shijie; Kaneko, Yuji; Borlongan, Cesar V.

2014-01-01

Traumatic brain injury (TBI) is associated with neuro-inflammation, debilitating sensory-motor deficits, and learning and memory impairments. Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI. Here, we tested the potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model. Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function accompanied the combined therapy, which was either moderately or short-lived in the monotherapy conditions. These results suggest that combined treatment rather than monotherapy appears optimal for abrogating histophalogical and motor impairments in chronic TBI. PMID:24621603

Treatment of Helicobacter pylori infection: Current status and future concepts

PubMed Central

Yang, Jyh-Chin; Lu, Chien-Wei; Lin, Chun-Jung

2014-01-01

Helicobacter pylori (H. pylori) infection is highly associated with the occurrence of gastrointestinal diseases, including gastric inflammation, peptic ulcer, gastric cancer, and gastric mucosa-associated lymphoid-tissue lymphoma. Although alternative therapies, including phytomedicines and probiotics, have been used to improve eradication, current treatment still relies on a combination of antimicrobial agents, such as amoxicillin, clarithromycin, metronidazole, and levofloxacin, and antisecretory agents, such as proton pump inhibitors (PPIs). A standard triple therapy consisting of a PPI and two antibiotics (clarithromycin and amoxicillin/metronidazole) is widely used as the first-line regimen for treatment of infection, but the increased resistance of H. pylori to clarithromycin and metronidazole has significantly reduced the eradication rate using this therapy and bismuth-containing therapy or 10-d sequential therapy has therefore been proposed to replace standard triple therapy. Alternatively, levofloxacin-based triple therapy can be used as rescue therapy for H. pylori infection after failure of first-line therapy. The increase in resistance to antibiotics, including levofloxacin, may limit the applicability of such regimens. However, since resistance of H. pylori to amoxicillin is generally low, an optimized high dose dual therapy consisting of a PPI and amoxicillin can be an effective first-line or rescue therapy. In addition, the concomitant use of alternative medicine has the potential to provide additive or synergistic effects against H. pylori infection, though its efficacy needs to be verified in clinical studies. PMID:24833858

Boosted Hyperthermia Therapy by Combined AC Magnetic and Photothermal Exposures in Ag/Fe3O4 Nanoflowers.

PubMed

Das, R; Rinaldi-Montes, N; Alonso, J; Amghouz, Z; Garaio, E; García, J A; Gorria, P; Blanco, J A; Phan, M H; Srikanth, H

2016-09-28

Over the past two decades, magnetic hyperthermia and photothermal therapy are becoming very promising supplementary techniques to well-established cancer treatments such as radiotherapy and chemotherapy. These techniques have dramatically improved their ability to perform controlled treatments, relying on the procedure of delivering nanoscale objects into targeted tumor tissues, which can release therapeutic killing doses of heat either upon AC magnetic field exposure or laser irradiation. Although an intense research effort has been made in recent years to study, separately, magnetic hyperthermia using iron oxide nanoparticles and photothermal therapy based on gold or silver plasmonic nanostructures, the full potential of combining both techniques has not yet been systematically explored. Here we present a proof-of-principle experiment showing that designing multifunctional silver/magnetite (Ag/Fe3O4) nanoflowers acting as dual hyperthermia agents is an efficient route for enhancing their heating ability or specific absorption rate (SAR). Interestingly, the SAR of the nanoflowers is increased by at least 1 order of magnitude under the application of both an external magnetic field of 200 Oe and simultaneous laser irradiation. Furthermore, our results show that the synergistic exploitation of the magnetic and photothermal properties of the nanoflowers reduces the magnetic field and laser intensities that would be required in the case that both external stimuli were applied separately. This constitutes a key step toward optimizing the hyperthermia therapy through a combined multifunctional magnetic and photothermal treatment and improving our understanding of the therapeutic process to specific applications that will entail coordinated efforts in physics, engineering, biology, and medicine.

Optimizing topical therapies for treating psoriasis: a consensus conference.

PubMed

Zeichner, Joshua A; Lebwohl, Mark G; Menter, Alan; Bagel, Jerry; Del Rosso, James Q; Elewski, Boni E; Feldman, Steven R; Kircik, Leon H; Koo, John; Gold, Linda Stein; Tanghetti, Emil

2010-09-01

In 2010, an expert committee of physicians and researchers in the field of dermatology working together as the Psoriasis Process of Care Consensus Panel developed consensus guidelines for the treatment of psoriasis. As much as possible, the guidelines were evidence based but also included the extensive clinical experience of the dermatologists. Psoriasis is a lifelong disease that requires long-term treatment and 80% of psoriasis patients have mild to moderate disease. Topical therapies play an important role in the treatment of psoriasis, especially in patients with mild to moderate disease. Patients usually start with monotherapy; however, in more severe cases (> 10% body surface area [BSA], severely impaired quality of life [QOL], or recalcitrant psoriatic lesions), multiple treatment modalities may be used as part of combination, sequential, or rotational therapeutic regimens. Main treatment options include topical steroids, systemic therapies, topical vitamin D treatments such as vitamin D3 ointment, retinoids, phototherapy, and biologic therapies. Other topical therapies include the following steroid-sparing agents: coal tar, anthralin, calcineurin inhibitors, keratolytics, and emollients. Therapeutic considerations also should focus on adherence, improving QOL, and promoting a good patient-physician relationship.

Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives.

PubMed

Scomparin, Anna; Florindo, Helena F; Tiram, Galia; Ferguson, Elaine L; Satchi-Fainaro, Ronit

2017-09-01

Polymer-directed enzyme prodrug therapy (PDEPT) and polymer enzyme liposome therapy (PELT) are two-step therapies developed to provide anticancer drugs site-selective intratumoral accumulation and release. Nanomedicines, such as polymer-drug conjugates and liposomal drugs, accumulate in the tumor site due to extravasation-dependent mechanism (enhanced permeability and retention - EPR - effect), and further need to cross the cellular membrane and release their payload in the intracellular compartment. The subsequent administration of a polymer-enzyme conjugate able to accumulate in the tumor tissue and to trigger the extracellular release of the active drug showed promising preclinical results. The development of polymer-enzyme, polymer-drug conjugates and liposomal drugs had undergone a vast advancement over the past decades. Several examples of enzyme mimics for in vivo therapy can be found in the literature. Moreover, polymer therapeutics often present an enzyme-sensitive mechanism of drug release. These nanomedicines can thus be optimal substrates for PDEPT and this review aims to provide new insights and stimuli toward the future perspectives of this promising combination. Copyright © 2017 Elsevier B.V. All rights reserved.

Radiation therapy for primary breast lymphoma in male gynecomastia: a rare case report and review of the literature.

PubMed

Ishibashi, Naoya; Hata, Masaharu; Mochizuki, Takao; Ogawa, Kogi; Sugiura, Hiroaki; Takekawa, Yoshinori; Maebayashi, Toshiya; Aizawa, Takuya; Sakaguchi, Masakuni; Abe, Osamu

2016-10-01

Primary breast lymphoma is a rare type of non-Hodgkin lymphoma and usually affects women, although a few cases have been reported in men. Chemotherapy and radiation therapy, or a combination of both, are frequently administered for treatment of primary breast lymphoma, as local control by surgical resection is poor. No standard therapy has been established, and the optimal radiation dose and irradiation field for male patients are unknown. The present report describes a 75-year-old man with bilateral cirrhosis-induced gynecomastia who was diagnosed with primary breast lymphoma; specifically, diffuse large B-cell lymphoma. Because of his hepatic dysfunction, he was treated with radiation therapy alone. Radiation therapy was followed by eight cycles of rituximab monotherapy. Clinical response was good, with no signs of relapse. Clinicians may benefit from knowledge regarding effective treatment of primary breast lymphoma in male patients, which has been rarely reported owing to the low incidence of this condition. The outcome in the present case may help to establish effective treatment guidelines in similar cases.

Options for treating postherpetic neuralgia in the medically complicated patient

PubMed Central

Bruckenthal, Patricia; Barkin, Robert L

2013-01-01

Patients with postherpetic neuralgia (PHN) are often of advanced age or immunocompromised and likely to have ≥1 comorbid medical condition for which they receive ≥1 medication (polypharmacy). Comorbidities affecting renal or hepatic function can alter pharmacokinetics, thereby impacting the efficacy or tolerability of PHN analgesic therapies. Cardiovascular, cerebrovascular, or psychiatric comorbidities may increase patient vulnerability to potential adverse events associated with some PHN analgesic therapies. Because PHN is a localized condition, localized therapy with a topical analgesic (lidocaine patch 5% and capsaicin 8% patch or cream) may provide adequate efficacy while mitigating the risk of systemic adverse events compared with oral analgesics (eg, tricyclic antidepressants, anticonvulsants, opioids). However, combined therapy with a topical and an oral analgesic or with >1 oral analgesic may be needed for optimal pain management in some patients. This review summarizes how comorbidities and concomitant medications should be taken into account when selecting among available pharmacotherapies for PHN and provides recommendations for the selection of therapies that will provide analgesia while minimizing the risk of adverse events. PMID:23990726

Dispositional optimism as predictor of outcome in short- and long-term psychotherapy.

PubMed

Heinonen, Erkki; Heiskanen, Tiia; Lindfors, Olavi; Härkäpää, Kristiina; Knekt, Paul

2017-09-01

Dispositional optimism predicts various beneficial outcomes in somatic health and treatment, but has been little studied in psychotherapy. This study investigated whether an optimistic disposition differentially predicts patients' ability to benefit from short-term versus long-term psychotherapy. A total of 326 adult outpatients with mood and/or anxiety disorder were randomized into short-term (solution-focused or short-term psychodynamic) or long-term psychodynamic therapy and followed up for 3 years. Dispositional optimism was assessed by patients at baseline with the self-rated Life Orientation Test (LOT) questionnaire. Outcome was assessed at baseline and seven times during the follow-up, in terms of depressive (BDI, HDRS), anxiety (SCL-90-ANX, HARS), and general psychiatric symptoms (SCL-90-GSI), all seven follow-up points including patients' self-reports and three including interview-based measures. Lower dispositional optimism predicted faster symptom reduction in short-term than in long-term psychotherapy. Higher optimism predicted equally rapid and eventually greater benefits in long-term, as compared to short-term, psychotherapy. Weaker optimism appeared to predict sustenance of problems early in long-term therapy. Stronger optimism seems to best facilitate engaging in and benefiting from a long-term therapy process. Closer research might clarify the psychological processes responsible for these effects and help fine-tune both briefer and longer interventions to optimize treatment effectiveness for particular patients and their psychological qualities. Weaker dispositional optimism does not appear to inhibit brief therapy from effecting symptomatic recovery. Patients with weaker optimism do not seem to gain added benefits from long-term therapy, but instead may be susceptible to prolonged psychiatric symptoms in the early stages of long-term therapy. © 2016 The British Psychological Society.

Aggressive treatment of early rheumatoid arthritis: recognizing the window of opportunity and treating to target goals.

PubMed

Resman-Targoff, Beth H; Cicero, Marco P

2010-11-01

Evidence supports the use of aggressive therapy for patients with early rheumatoid arthritis (RA). Clinical outcomes in patients with early RA can improve with a treat-to-target approach that sets the goal at disease remission. The current selection of antirheumatic therapies, including conventional and biologic disease-modifying antirheumatic drugs (DMARDs), has made disease remission a realistic target for patients with early RA. The challenge is selecting the optimal antirheumatic drug or combination of drugs for initial and subsequent therapy to balance the clinical benefits, risks, and economic considerations. In some cases, the use of biologic agents as part of the treatment regimen has shown superior results compared with conventional DMARDs alone in halting the progression of disease, especially in reducing radiographic damage. However, the use of biologic agents as initial therapy is challenged by cost-effectiveness analyses, which favor the use of conventional DMARDs. The use of biologic agents may be justified in certain patients with poor prognostic factors or those who experience an inadequate response to conventional DMARDs as a means to slow or halt disease progression and its associated disability. In these cases, the higher cost of treatment with biologic agents may be offset by decreased societal costs, such as lost work productivity, and increased health-related quality of life. Further research is needed to understand optimal strategies for balancing costs, benefits, and risks of antirheumatic drugs. Some key questions are (1) when biologic agents are appropriate for initial therapy, and (2) when to conclude that response to conventional DMARDs is inadequate and biologic agents should be initiated.

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial.

PubMed

Busard, C I; Menting, S P; van Bezooijen, J S; van den Reek, J M; Hutten, B A; Prens, E P; de Jong, E M; van Doorn, M B; Spuls, P I

2017-02-02

The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. NTR4499 . Registered on 7 April 2014.

Aspergillus spondylodiscitis in solid organ transplant recipients.

PubMed

Li, X-F; Liu, Z-D; Xia, Q; Dai, L-Y

2010-12-01

Transplantation practices have had a significant effect on the epidemiology of invasive Aspergillosis. Aspergillus spondylodiscitis is rare in transplant recipients. The optimal treatment has yet to be defined because of the rarity of such cases. This article reviews the available literature on Aspergillus spondylodiscitis in solid organ transplant recipients and provides recommendations on its management. We identified 15 cases of Aspergillus spondylodiscitis in transplant recipients. Most patients were heart transplant recipients. Back pain was the mode of presentation in all patients. Most cases were afebrile. The dominant location was the lumbar spine. Aspergillus fumigatus was responsible for 84.62% of cases and A flavus for 15.38%. The overall recovery rate was 66.67%. Delay in diagnosis remained a major impediment to the successful treatment of spinal aspergillosis. Treatment included antifungal therapy alone or combined with surgery. Initial therapy with voriconazole could lead to better curative effects. Combined medical and operative interventions are recommended for treatment. Copyright © 2010 Elsevier Inc. All rights reserved.

Adverse effects of antiretroviral therapy for HIV infection.

PubMed

Montessori, Valentina; Press, Natasha; Harris, Marianne; Akagi, Linda; Montaner, Julio S G

2004-01-20

Long-term remission of HIV-1 disease can be readily achieved by combinations of antiretroviral agents. The suppression of plasma viral loads to less than the limit of quantification of the most sensitive commercially available assays (i.e., less than 50 copies/mL) and the coincident improvement in CD4 T cell counts is associated with resolution of established opportunistic infections and a decrease in the risk of new opportunistic infections. However, prolonged treatment with combination regimens can be difficult to sustain because of problems with adherence and toxic effects. All antiretroviral drugs can have both short-term and long-term adverse events. The risk of specific side effects varies from drug to drug, from drug class to drug class, and from patient to patient. A better understanding of the adverse effects of antiretroviral agents is of interest not only for HIV specialists as they try to optimize therapy, but also for other physicians who care for HIV-positive patients.

Adverse effects of antiretroviral therapy for HIV infection

PubMed Central

Montessori, Valentina; Press, Natasha; Harris, Marianne; Akagi, Linda; Montaner, Julio S.G.

2004-01-01

LONG-TERM REMISSION OF HIV-1 DISEASE CAN BE READILY ACHIEVED by combinations of antiretroviral agents. The suppression of plasma viral loads to less than the limit of quantification of the most sensitive commercially available assays (i.e., less than 50 copies/mL) and the coincident improvement in CD4 T cell counts is associated with resolution of established opportunistic infections and a decrease in the risk of new opportunistic infections. However, prolonged treatment with combination regimens can be difficult to sustain because of problems with adherence and toxic effects. All antiretroviral drugs can have both short-term and long-term adverse events. The risk of specific side effects varies from drug to drug, from drug class to drug class, and from patient to patient. A better understanding of the adverse effects of antiretroviral agents is of interest not only for HIV specialists as they try to optimize therapy, but also for other physicians who care for HIV-positive patients. PMID:14734438

Combinations of stroke neurorehabilitation to facilitate motor recovery: perspectives on Hebbian plasticity and homeostatic metaplasticity

PubMed Central

Takeuchi, Naoyuki; Izumi, Shin-Ichi

2015-01-01

Motor recovery after stroke involves developing new neural connections, acquiring new functions, and compensating for impairments. These processes are related to neural plasticity. Various novel stroke rehabilitation techniques based on basic science and clinical studies of neural plasticity have been developed to aid motor recovery. Current research aims to determine whether using combinations of these techniques can synergistically improve motor recovery. When different stroke neurorehabilitation therapies are combined, the timing of each therapeutic program must be considered to enable optimal neural plasticity. Synchronizing stroke rehabilitation with voluntary neural and/or muscle activity can lead to motor recovery by targeting Hebbian plasticity. This reinforces the neural connections between paretic muscles and the residual motor area. Homeostatic metaplasticity, which stabilizes the activity of neurons and neural circuits, can either augment or reduce the synergic effect depending on the timing of combination therapy and types of neurorehabilitation that are used. Moreover, the possibility that the threshold and degree of induced plasticity can be altered after stroke should be noted. This review focuses on the mechanisms underlying combinations of neurorehabilitation approaches and their future clinical applications. We suggest therapeutic approaches for cortical reorganization and maximal functional gain in patients with stroke, based on the processes of Hebbian plasticity and homeostatic metaplasticity. Few of the possible combinations of stroke neurorehabilitation have been tested experimentally; therefore, further studies are required to determine the appropriate combination for motor recovery. PMID:26157374

Development, validation, and implementation of a patient-specific Monte Carlo 3D internal dosimetry platform

NASA Astrophysics Data System (ADS)

Besemer, Abigail E.

Targeted radionuclide therapy is emerging as an attractive treatment option for a broad spectrum of tumor types because it has the potential to simultaneously eradicate both the primary tumor site as well as the metastatic disease throughout the body. Patient-specific absorbed dose calculations for radionuclide therapies are important for reducing the risk of normal tissue complications and optimizing tumor response. However, the only FDA approved software for internal dosimetry calculates doses based on the MIRD methodology which estimates mean organ doses using activity-to-dose scaling factors tabulated from standard phantom geometries. Despite the improved dosimetric accuracy afforded by direct Monte Carlo dosimetry methods these methods are not widely used in routine clinical practice because of the complexity of implementation, lack of relevant standard protocols, and longer dose calculation times. The main goal of this work was to develop a Monte Carlo internal dosimetry platform in order to (1) calculate patient-specific voxelized dose distributions in a clinically feasible time frame, (2) examine and quantify the dosimetric impact of various parameters and methodologies used in 3D internal dosimetry methods, and (3) develop a multi-criteria treatment planning optimization framework for multi-radiopharmaceutical combination therapies. This platform utilizes serial PET/CT or SPECT/CT images to calculate voxelized 3D internal dose distributions with the Monte Carlo code Geant4. Dosimetry can be computed for any diagnostic or therapeutic radiopharmaceutical and for both pre-clinical and clinical applications. In this work, the platform's dosimetry calculations were successfully validated against previously published reference doses values calculated in standard phantoms for a variety of radionuclides, over a wide range of photon and electron energies, and for many different organs and tumor sizes. Retrospective dosimetry was also calculated for various pre-clinical and clinical patients and large dosimetric differences resulted when using conventional organ-level methods and the patient-specific voxelized methods described in this work. The dosimetric impact of various steps in the 3D voxelized dosimetry process were evaluated including quantitative imaging acquisition, image coregistration, voxel resampling, ROI contouring, CT-based material segmentation, and pharmacokinetic fitting. Finally, a multi-objective treatment planning optimization framework was developed for multi-radiopharmaceutical combination therapies.

Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer.

PubMed

Li, Mengshi; Zhang, Xiuli; Quinn, Thomas P; Lee, Dongyoul; Liu, Dijie; Kunkel, Falk; Zimmerman, Brian E; McAlister, Daniel; Olewein, Keith; Menda, Yusuf; Mirzadeh, Saed; Copping, Roy; Johnson, Frances L; Schultz, Michael K

2017-09-01

A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85°C (45min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Strategies to Improve Cancer Photothermal Therapy Mediated by Nanomaterials.

PubMed

de Melo-Diogo, Duarte; Pais-Silva, Cleide; Dias, Diana R; Moreira, André F; Correia, Ilídio J

2017-05-01

The deployment of hyperthermia-based treatments for cancer therapy has captured the attention of different researchers worldwide. In particular, the application of light-responsive nanomaterials to mediate hyperthermia has revealed promising results in several pre-clinical assays. Unlike conventional therapies, these nanostructures can display a preferential tumor accumulation and thus mediate, upon irradiation with near-infrared light, a selective hyperthermic effect with temporal resolution. Different types of nanomaterials such as those based on gold, carbon, copper, molybdenum, tungsten, iron, palladium and conjugated polymers have been used for this photothermal modality. This progress report summarizes the different strategies that have been applied so far for increasing the efficacy of the photothermal therapeutic effect mediated by nanomaterials, namely those that improve the accumulation of nanomaterials in tumors (e.g. by changing the corona composition or through the functionalization with targeting ligands), increase nanomaterials' intrinsic capacity to generate photoinduced heat (e.g. by synthesizing new nanomaterials or assembling nanostructures) or by optimizing the parameters related to the laser light used in the irradiation process (e.g. by modulating the radiation wavelength). Overall, the development of new strategies or the optimization and combination of the existing ones will surely give a major contribution for the application of nanomaterials in cancer PTT. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Spectral matching technology for light-emitting diode-based jaundice photodynamic therapy device

NASA Astrophysics Data System (ADS)

Gan, Ru-ting; Guo, Zhen-ning; Lin, Jie-ben

2015-02-01

The objective of this paper is to obtain the spectrum of light-emitting diode (LED)-based jaundice photodynamic therapy device (JPTD), the bilirubin absorption spectrum in vivo was regarded as target spectrum. According to the spectral constructing theory, a simple genetic algorithm as the spectral matching algorithm was first proposed in this study. The optimal combination ratios of LEDs were obtained, and the required LEDs number was then calculated. Meanwhile, the algorithm was compared with the existing spectral matching algorithms. The results show that this algorithm runs faster with higher efficiency, the switching time consumed is 2.06 s, and the fitting spectrum is very similar to the target spectrum with 98.15% matching degree. Thus, blue LED-based JPTD can replace traditional blue fluorescent tube, the spectral matching technology that has been put forward can be applied to the light source spectral matching for jaundice photodynamic therapy and other medical phototherapy.

History of phototherapy in dermatology.

PubMed

Hönigsmann, Herbert

2013-01-01

Over many centuries, treatment with sunlight or "heliotherapy" was used in the treatment of skin diseases. More than 3500 years ago, ancient Egyptian and Indian healers used the ingestion of plant extracts or seeds in addition to sunlight for treating "leucoderma". Modern phototherapy began with Nobel Prize winner Niels Finsen who developed a "chemical rays" lamp with which he treated patients with skin tuberculosis. However, it took several decades until phototherapy was introduced anew into the dermatological armamentarium. It was the development of photochemotherapy (PUVA) in 1974 that marked the beginning of a huge upsurge in photodermatology. The subsequent development of high intensity UV sources with defined spectra facilitated an optimized therapy for psoriasis and led to an expansion of indications for photo(chemo)therapy also in combination with topical and systemic agents. The introduction of extracorporeal photopheresis in 1987 for cutaneous T-cell lymphoma and of topical photodynamic therapy widely expanded the therapeutic possibilities in dermato-oncology.

Paclitaxel targets VEGF-mediated angiogenesis in ovarian cancer treatment

PubMed Central

Ai, Bin; Bie, Zhixin; Zhang, Shuai; Li, Ailing

2016-01-01

Ovarian cancer is one of the gynecologic cancers with the highest mortality, wherein vascular endothelial growth factor (VEGF) is involved in regulating tumor vascularization, growth, migration, and invasion. VEGF-mediated angiogenesis in tumors has been targeted in various cancer treatments, and anti-VEGF therapy has been used clinically for treatment of several types of cancer. Paclitaxel is a natural antitumor agent in the standard front-line treatment that has significant efficiency to treat advanced cancers, including ovarian cancer. Although platinum/paclitaxel-based chemotherapy has good response rates, most patients eventually relapse because the disease develops drug resistance. We aim to review the recent advances in paclitaxel treatment of ovarian cancer via antiangiogenesis. Single-agent therapy may be used in selected cases of ovarian cancer. However, to prevent drug resistance, drug combinations should be identified for optimal effectiveness and existing therapies should be improved. PMID:27648354

Treatment with protein synthesis inhibitors improves outcomes from secondary bacterial pneumonia following influenza

PubMed Central

Karlström, Åsa; Boyd, Kelli L.; English, B. Keith; McCullers, Jonathan A.

2008-01-01

Pneumonia as a secondary infection after influenza is a major cause of excess morbidity and mortality despite the availability and use of antibiotics active against Streptococcus pneumoniae. We hypothesized that use of a bacteriostatic protein synthesis inhibitor would improve outcomes by reducing the inflammatory response. BALB/c mice infected with influenza virus and super-infected with Streptococcus pneumoniae were treated with either the cell wall active antibiotic ampicillin or protein synthesis inhibitors clindamycin or azithromycin. Ampicillin therapy performed significantly worse (56% survival) in the model compared to clindamycin therapy either alone (82%) or in combination with ampicillin (80%) and to azithromycin (92%). Improved survival appeared to be mediated by decreased inflammation manifested as lower levels of inflammatory cells and pro-inflammatory cytokines in the lungs, and less severe histopathology. These data suggest that beta-lactam therapy may not be optimal as first line treatment of community acquired pneumonia when it follows influenza. PMID:19113989

Recent advances in T-cell immunotherapy for haematological malignancies.

PubMed

Rouce, Rayne H; Sharma, Sandhya; Huynh, Mai; Heslop, Helen E

2017-03-01

In vitro discoveries have paved the way for bench-to-bedside translation in adoptive T cell immunotherapy, resulting in remarkable clinical responses in a variety of haematological malignancies. Adoptively transferred T cells genetically modified to express CD19 CARs have shown great promise, although many unanswered questions regarding how to optimize T-cell therapies for both safety and efficacy remain. Similarly, T cells that recognize viral or tumour antigens though their native receptors have produced encouraging clinical responses. Honing manufacturing processes will increase the availability of T-cell products, while combining T-cell therapies has the ability to increase complete response rates. Lastly, innovative mechanisms to control these therapies may improve safety profiles while genome editing offers the prospect of modulating T-cell function. This review will focus on recent advances in T-cell immunotherapy, highlighting both clinical and pre-clinical advances, as well as exploring what the future holds. © 2016 John Wiley & Sons Ltd.

Modulation of myocardial energetics: An important category of agents in the multimodal treatment of coronary artery disease and heart failure.

PubMed

Dalal, Jamshed J; Mishra, Sundeep

The combined and relative contribution of glucose and fatty acid oxidation generates myocardial energy, which regulates the cardiac function and efficiency. Any dysregulation in this metabolic homeostasis can adversely affect the function of heart and contribute to cardiac conditions such as angina and heart failure. Metabolic agents ameliorate this internal metabolic anomaly, by shifting the energy production pathway from free fatty acids to glucose, resulting in a better performance of the heart. Metabolic therapy is relatively a new modality, which functions through optimization of cardiac substrate metabolism. Among the metabolic therapies, trimetazidine and ranolazine are the agents presently available in India. In the present review, we would like to present the metabolic perspective of pathophysiology of coronary artery disease and heart failure, and metabolic therapy by using trimetazidine and ranolazine. Copyright © 2017. Published by Elsevier B.V.

Diagnosis and treatment of neuropathic pain.

PubMed

Chong, M Sam; Bajwa, Zahid H

2003-05-01

Currently, no consensus on the optimal management of neuropathic pain exists and practices vary greatly worldwide. Possible explanations for this include difficulties in developing agreed diagnostic protocols and the coexistence of neuropathic, nociceptive and, occasionally, idiopathic pain in the same patient. Also, neuropathic pain has historically been classified according to its etiology (e.g., painful diabetic neuropathy, trigeminal neuralgia, spinal cord injury) without regard for the presumed mechanism(s) underlying the specific symptoms. A combined etiologic/mechanistic classification might improve neuropathic pain management. The treatment of neuropathic pain is largely empirical, often relying heavily on data from small, generally poorly-designed clinical trials or anecdotal evidence. Consequently, diverse treatments are used, including non-invasive drug therapies (antidepressants, antiepileptic drugs and membrane stabilizing drugs), invasive therapies (nerve blocks, ablative surgery), and alternative therapies (e.g., acupuncture). This article reviews the current and historical practices in the diagnosis and treatment of neuropathic pain, and focuses on the USA, Europe and Japan.

Topical Vehicle Formulations in the Treatment of Acne.

PubMed

Hoffman, Lauren K; Bhatia, Neal; Zeichner, Joshua; Kircik, Leon H

2018-06-01

Topical treatment is the mainstay of acne therapy. The most commonly prescribed topical medications for acne include benzoyl peroxide, clindamycin, and retinoids. Despite their effectiveness in treating mild to moderate acne vulgaris, these topical medications are found to be irritating, and are historically associated with poor tolerability and diminished patient adherence. Thus, choosing the right formulation that will be effective and well tolerated is essential. Novel formulations that optimize drug concentration and utilize improved delivery vehicles have helped to enhance the tolerability and efficacy, and allow for less frequent application or co-application of drugs that were previously considered incompatible. This article will review the goals of topical therapy for the treatment of acne, in addition to common therapies and their challenges. Advanced formulations and combination formulations of benzoyl peroxide, clindamycin, and tretinoin will also be discussed. J Drugs Dermatol. 2018;17(6 Suppl):s6-10.

The role of chemotherapy in the treatment of malignant astrocytomas.

PubMed

Mathieu, David; Fortin, David

2006-05-01

Malignant astrocytomas are aggressive neoplasms with a dismal prognosis despite optimal treatment. Maximal resective surgery is traditionally complemented by radiation therapy. Chemotherapy is now used on patients as initial therapy when their functional status is congruent with further treatment. The classic agents used are nitrosoureas, but temozolomide has taken the front seat recently, with recent data demonstrating increased survival when this agent is used concurrently with radiation therapy in newly diagnosed glioblastoma patients. A new class of agents, refered to as biological modifiers, are increasingly used in clinical trials in an effort to affect the intrinsic biologic aberrations harboured by tumor cells. These drugs comprise differentiation agents, anti-angiogenic agents, matrix-metalloproteinase inhibitors and signal transduction inhibitors, among others. This article reviews the standard cytotoxic agents that have been used to treat malignant astrocytomas, and the different combination regimens offering promise. In addition, recent advances with biological modifiers are also discussed.

New protein kinase inhibitors in breast cancer: afatinib and neratinib.

PubMed

Zhang, Xiaosong; Munster, Pamela N

2014-06-01

Human epidermal growth factor receptor (HER) 2 is overexpressed in 20 - 25% of breast cancers, and has historically been a poor prognostic marker. The introduction of trastuzumab, the first fully humanized monoclonal antibody targeting HER2, has drastically changed the outcomes of metastatic breast cancers. However, despite initial response, most patients develop resistance. Recent data suggest that strategies targeting more than one member of HER family may circumvent trastuzumab resistance and confer synergistic effects. Following a literature search on PubMed, national meetings and clinicaltrials.gov using 'afatinib', 'neratinib', 'HER2' and 'breast cancer' as keywords, we critically analyzed the different HER2-targeted therapies for their drug development and evidence-based therapeutic strategies. Afatinib and neratinib, two second-generation tyrosine kinase inhibitors (TKIs) that irreversibly inhibit more than one HER family member, are being actively investigated in clinical trials either as monotherapy or in combination. We reviewed the efficacy and optimal use of these agents in various settings, such as systemic therapy for advanced breast cancer including brain metastases, and neoadjuvant therapy in early-stage breast cancer. HER2-targeted therapies have been widely used and greatly improved the outcome of HER2-positive breast cancer. Despite the accelerated advancement in recent years, several crucial questions remain unanswered, such as how to treat a prior resistance or affect a sanctuary site, that is, CNS metastasis. The novel next-generation TKIs, afatinib and neratinib, were rationally designed to overcome the resistance by targeting multiple HER family members and irreversibly binding the targets. In spite of the encouraging results of the afatinib and neratinib monotherapies, they have not been proven more efficacious in the combination therapies yet, even though multicenter international trials are still ongoing. The key tasks in the future are to study resistance pathways, design novel strategies to more efficiently test combinations for synergistic effects and identify biomarkers and novel imaging tools to guide individualized therapies.

Stigmatellin Y - An anti-biofilm compound from Bacillus subtilis BR4 possibly interferes in PQS-PqsR mediated quorum sensing system in Pseudomonas aeruginosa.

PubMed

Boopathi, Seenivasan; Vashisth, Rajesh; Manoharan, Prabu; Kandasamy, Ruckmani; Sivakumar, Natesan

2017-05-15

Hitherto this is the first report pertaining to production of biofilm inhibitory compound(s) (BIC) from Bacillus subtilis BR4 against Pseudomonas aeruginosa (ATCC 27853) coupled with production optimization. In order to achieve this, combinations of media components were formulated by employing statistical tools such as Plackett-Burman analysis and central composite rotatable design (CCRD). It was evident that at 35mlL -1 glycerol and 3.8gL -1 casamino acid, anti-biofilm activity and production of extracellular protein significantly increased by 1.5-fold and 1.2-fold, respectively. These results corroborate that the combination of glycerol and casamino acid plays a key role in the production of BIC. Further, metabolic profiling of BIC was carried out using liquid chromatography/tandem mass spectrometry (LC-MS/MS) based on m/z value. The presence of Stigmatellin Y was predicted with monoisotopic neutral mass of 484.2825Da. In support of optimization study, higher production of BIC was confirmed in the optimized-media-grown BR4 (OPT-BR4) than in the ideal-media-grown BR4 (ID-BR4) by LC-MS/MS analysis. PqsR in P. aeruginosa is a potential target for anti-virulent therapy. Molecular docking study has revealed that Stigmatellin Y interacts with PqsR in the similar orientation like a cognate signal (PQS) and synthetic inhibitor. In addition, Stigmatellin Y was found to exhibit interaction with four more amino acid residues of PqsR to establish strong affinity. Stigmatellin Y thus might play a role of competitor for PQS to distract PQS-PqsR mediated communication in P. aeruginosa. The present investigation thus paves new avenues to develop anti-Pseudomonas virulent therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cost-Effectiveness of Nivolumab-Ipilimumab Combination Therapy Compared with Monotherapy for First-Line Treatment of Metastatic Melanoma in the United States.

PubMed

Oh, Anna; Tran, Dang M; McDowell, Leann C; Keyvani, Dor; Barcelon, Jay Andrew; Merino, Oscar; Wilson, Leslie

2017-06-01

The approval of new immunotherapies has dramatically changed the treatment landscape of metastatic melanoma. These survival gains come with trade-offs in side effects and costs, as well as important considerations for third-party payer systems, physicians, and patients. To develop a Markov model to determine the cost-effectiveness of nivolumab, ipilimumab, and nivolumab-ipilimumab combination as firstline therapy in metastatic melanoma, while accounting for differential effectiveness in programmed death-ligand 1 (PD-L1) positive and negative patients. A 3-state Markov model (PD-L1 positive stable disease, PD-L1 negative stable disease, and progression and/or death) was developed using a U.S. societal perspective with a lifetime time horizon of 14.5 years. Transition probabilities were calculated from progression-free (PF) survival data reported in the CheckMate-067 trial. Costs were expressed in 2015 U.S. dollars and were determined using national sources. Adverse event (AE) management was determined using immune-related AE (irAE) data from CheckMate-067, irAE management guides for nivolumab and ipilimumab, and treatment guidelines. Utilities were obtained from published literature, using melanoma-specific studies when available, and were weighted based on incidence and duration of irAEs. Base case, one-way sensitivity, and probabilistic sensitivity analyses were conducted. Nivolumab-ipilimumab combination therapy was not the cost-effective choice ($454,092 per PF quality-adjusted life-year [QALY]) compared with nivolumab monotherapy in a base case analysis at a willingness-to-pay threshold of $100,000 per PFQALY. Combination therapy and nivolumab monotherapy were cost-effective choices compared with ipilimumab monotherapy. PD-L1 positive status, utility of nivolumab and combination therapy, and medication costs contributed the most uncertainty to the model. In a population of 100% PD-L1 negative patients, nivolumab was still the optimal treatment, but combination therapy had an improved incremental cost-effectiveness ratio (ICER) of $295,903 per PFQALY. Combination therapy became dominated by nivolumab, when 68% of the sample was PD-L1 positive. In addition, the cost of ipilimumab would have to decrease to < $21,555 per dose for combination therapy to have an ICER < $100,000 per PFQALY and to < $19,151 (a 42% reduction) to be more cost-effective than nivolumab monotherapy. Nivolumab-ipilimumab combination therapy was not cost-effective compared with nivolumab monotherapy, which was the most cost-effective option. Professionals in managed care settings should consider the pharmacoeconomic implications of these new immunotherapies as they make value-based formulary decisions, and future cost-effectiveness studies are completed. No funding supported this study. Merino was a contractor with EMD Serono at the time of this study but does not have any conflicts of interest and did not receive any funding related to this study. All other authors have no financial disclosures and no conflicts of interest. All the authors contributed to the study concept and design. Tran, McDowell, and Barcelon took the lead in data collection, along with Oh, Keyvani, and Merino. All authors except Merino contributed to data interpretation. The manuscript was written by Oh, Tran, McDowell, and Wilson and revised by Oh, Tran, McDowell, Wilson, and Keyvani. This analysis was presented at Academy of Managed Care Pharmacy Managed Care & Specialty Pharmacy Annual Meeting 2016, April 19-22, 2016, in San Francisco, California, and at the International Society for Pharmacoeconomics and Outcomes Research Annual International Meeting, May 21-25, 2016, in Washington DC.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beltran, C; Kamal, H

Purpose: To provide a multicriteria optimization algorithm for intensity modulated radiation therapy using pencil proton beam scanning. Methods: Intensity modulated radiation therapy using pencil proton beam scanning requires efficient optimization algorithms to overcome the uncertainties in the Bragg peaks locations. This work is focused on optimization algorithms that are based on Monte Carlo simulation of the treatment planning and use the weights and the dose volume histogram (DVH) control points to steer toward desired plans. The proton beam treatment planning process based on single objective optimization (representing a weighted sum of multiple objectives) usually leads to time-consuming iterations involving treatmentmore » planning team members. We proved a time efficient multicriteria optimization algorithm that is developed to run on NVIDIA GPU (Graphical Processing Units) cluster. The multicriteria optimization algorithm running time benefits from up-sampling of the CT voxel size of the calculations without loss of fidelity. Results: We will present preliminary results of Multicriteria optimization for intensity modulated proton therapy based on DVH control points. The results will show optimization results of a phantom case and a brain tumor case. Conclusion: The multicriteria optimization of the intensity modulated radiation therapy using pencil proton beam scanning provides a novel tool for treatment planning. Work support by a grant from Varian Inc.« less

Relationships among optimism, well-being, self-transcendence, coping, and social support in women during treatment for breast cancer.

PubMed

Matthews, Ellyn E; Cook, Paul F

2009-07-01

The impact of diagnosis and treatment for breast cancer, stressors that affect emotional well-being, is influenced by several psychosocial factors and the relationships among them. The purpose of this study was to investigate the relationship between optimism and emotional well-being (EWB) and the individual and combined mediation of this relationship by perceived social support (SS), problem focused coping (PFC), and self-transcendence in women with breast cancer during radiation therapy. Ninety-three women receiving radiation treatment for breast cancer completed questionnaires that measured EWB, optimism, SS, PFC, and self-transcendence. Correlational and multiple regression analysis revealed that optimism was positively related to EWB. Of the three mediators, self-transcendence alone was found to partially mediate the relationship between optimism and EWB. The relationship between optimism and PFC was not significant. Optimism was related to SS, but its indirect effect on EWB through SS did not reach significance. During breast cancer treatment, the positive effects of optimism on EWB are partially mediated by a woman's level of self-transcendence. Brief screening of women's optimism may help identify women at risk for psychological distress. Early detection and interventions to promote psychological adjustment throughout the cancer trajectory (e.g. enhancing self-transcendence) should receive attention in future research. (c) 2008 John Wiley & Sons, Ltd.

An automatic CFD-based flow diverter optimization principle for patient-specific intracranial aneurysms.

PubMed

Janiga, Gábor; Daróczy, László; Berg, Philipp; Thévenin, Dominique; Skalej, Martin; Beuing, Oliver

2015-11-05

The optimal treatment of intracranial aneurysms using flow diverting devices is a fundamental issue for neuroradiologists as well as neurosurgeons. Due to highly irregular manifold aneurysm shapes and locations, the choice of the stent and the patient-specific deployment strategy can be a very difficult decision. To support the therapy planning, a new method is introduced that combines a three-dimensional CFD-based optimization with a realistic deployment of a virtual flow diverting stent for a given aneurysm. To demonstrate the feasibility of this method, it was applied to a patient-specific intracranial giant aneurysm that was successfully treated using a commercial flow diverter. Eight treatment scenarios with different local compressions were considered in a fully automated simulation loop. The impact on the corresponding blood flow behavior was evaluated qualitatively as well as quantitatively, and the optimal configuration for this specific case was identified. The virtual deployment of an uncompressed flow diverter reduced the inflow into the aneurysm by 24.4% compared to the untreated case. Depending on the positioning of the local stent compression below the ostium, blood flow reduction could vary between 27.3% and 33.4%. Therefore, a broad range of potential treatment outcomes was identified, illustrating the variability of a given flow diverter deployment in general. This method represents a proof of concept to automatically identify the optimal treatment for a patient in a virtual study under certain assumptions. Hence, it contributes to the improvement of virtual stenting for intracranial aneurysms and can support physicians during therapy planning in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

Future Directions in Medical Physics

NASA Astrophysics Data System (ADS)

Jeraj, Robert

Medical Physics is a highly interdisciplinary field at the intersection between physics and medicine and biology. Medical Physics is aiming at development of novel applications of physical processes and techniques in various areas of medicine and biology. Medical Physics had and continues to have profound impact by developing improved imaging and treatment technologies, and helping to advance our understanding of the complexity of the disease. The general trend in medicine towards personalized therapy, and emphasis on accelerated translational research is having a profound impact on medical physics as well. In the traditional stronghold for medical physicists - radiation therapy - the new reality is shaping in the form of biologically conformal and combination therapies, as well as advanced particle therapy approaches, such as proton and ion therapies. Rapid increase in faster and more informative multi-modality medical imaging is bringing a wealth of information that is being complemented with data obtained from genomic profiling and other biomarkers. Novel data analysis and data mining approaches are proving grounds for employment of various artificial intelligence methods that will help further improving clinical decision making for optimization of various therapies as well as better understanding of the disease properties and disease evolution, ultimately leading to improved clinical outcomes.

Application of Pharmacokinetic and Pharmacodynamic Analysis to the Development of Liposomal Formulations for Oncology

PubMed Central

Ait-Oudhia, Sihem; Mager, Donald E.; Straubinger, Robert M.

2014-01-01

Liposomal formulations of anticancer agents have been developed to prolong drug circulating lifetime, enhance anti-tumor efficacy by increasing tumor drug deposition, and reduce drug toxicity by avoiding critical normal tissues. Despite the clinical approval of numerous liposome-based chemotherapeutics, challenges remain in the development and clinical deployment of micro- and nano-particulate formulations, as well as combining these novel agents with conventional drugs and standard-of-care therapies. Factors requiring optimization include control of drug biodistribution, release rates of the encapsulated drug, and uptake by target cells. Quantitative mathematical modeling of formulation performance can provide an important tool for understanding drug transport, uptake, and disposition processes, as well as their role in therapeutic outcomes. This review identifies several relevant pharmacokinetic/pharmacodynamic models that incorporate key physical, biochemical, and physiological processes involved in delivery of oncology drugs by liposomal formulations. They capture observed data, lend insight into factors determining overall antitumor response, and in some cases, predict conditions for optimizing chemotherapy combinations that include nanoparticulate drug carriers. PMID:24647104

Carbohydrate-Restriction with High-Intensity Interval Training: An Optimal Combination for Treating Metabolic Diseases?

PubMed Central

Francois, Monique E.; Gillen, Jenna B.; Little, Jonathan P.

2017-01-01

Lifestyle interventions incorporating both diet and exercise strategies remain cornerstone therapies for treating metabolic disease. Carbohydrate-restriction and high-intensity interval training (HIIT) have independently been shown to improve cardiovascular and metabolic health. Carbohydrate-restriction reduces postprandial hyperglycemia, thereby limiting potential deleterious metabolic and cardiovascular consequences of excessive glucose excursions. Additionally, carbohydrate-restriction has been shown to improve body composition and blood lipids. The benefits of exercise for improving insulin sensitivity are well known. In this regard, HIIT has been shown to rapidly improve glucose control, endothelial function, and cardiorespiratory fitness. Here, we report the available evidence for each strategy and speculate that the combination of carbohydrate-restriction and HIIT will synergistically maximize the benefits of both approaches. We hypothesize that this lifestyle strategy represents an optimal intervention to treat metabolic disease; however, further research is warranted in order to harness the potential benefits of carbohydrate-restriction and HIIT for improving cardiometabolic health. PMID:29075629

Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin.

PubMed

Elf, S; Lin, R; Xia, S; Pan, Y; Shan, C; Wu, S; Lonial, S; Gaddh, M; Arellano, M L; Khoury, H J; Khuri, F R; Lee, B H; Boggon, T J; Fan, J; Chen, J

2017-01-12

The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small-molecule 6PGD inhibitors Physcion and its derivative S3, shows anticancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase, exhibit non-immune hemolytic anemia upon exposure to aspirin and various antimalarial drugs. Inspired by these clinical observations, we examined the anticancer potential of combined treatment with 6PGD inhibitors and antimalarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to antimalarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel antileukemia treatment without inducing hemolysis.

Analysis of Defined Combinations of Monoclonal Antibodies in Anthrax Toxin Neutralization Assays and Their Synergistic Action

PubMed Central

Ngundi, Miriam M.; Meade, Bruce D.; Little, Stephen F.; Quinn, Conrad P.; Corbett, Cindi R.; Brady, Rebecca A.

2012-01-01

Antibodies against the protective antigen (PA) component of anthrax toxin play an important role in protection against disease caused by Bacillus anthracis. In this study, we examined defined combinations of PA-specific monoclonal antibodies for their ability to neutralize anthrax toxin in cell culture assays. We observed additive, synergistic, and antagonistic effects of the antibodies depending on the specific antibody combination examined and the specific assay used. Synergistic toxin-neutralizing antibody interactions were examined in more detail. We found that one mechanism that can lead to antibody synergy is the bridging of PA monomers by one antibody, with resultant bivalent binding of the second antibody. These results may aid in optimal design of new vaccines and antibody therapies against anthrax. PMID:22441391

The use of fillers and botulinum toxin type A in combination with superficial glycolic acid (alpha-hydroxy acid) peels: optimizing injection therapy with the skin-smoothing properties of peels.

PubMed

Rendon, Marta I; Effron, Cheryl; Edison, Brenda L

2007-01-01

There are many procedures that a physician may utilize to improve the appearance and quality of the skin. Combining procedures can enhance the overall result and lead to increased patient satisfaction. Thus, it is important to choose procedures that will complement each other. Fillers or botulinum toxin type A (BTX-A) can plump the skin and smooth lines and wrinkles but will do little for uneven tone, skin laxity, or radiance and clarity. These signs of aging can be addressed with superficial glycolic acid peels. Methods of combining injectable compounds with superficial glycolic acid peels were discussed at a dermatologist roundtable event and are summarized in this article.

[Clinical end-points and surrogate markers of pulmonary arterial hypertension in the light of evidence-based treatment].

PubMed

Can, Mehmet Mustafa; Kaymaz, Cihangir

2010-08-01

Pulmonary arterial hypertension (PAH) is a rare, fatal and progressive disease. There is an acceleration in the advent of new therapies in parallel to the development of the knowledge about etiogenesis and pathogenesis of PAH. Therefore, to optimize the goals of PAH-specific treatment and to determine the time to shift from monotherapy to combination therapy, simple, objective and reproducible end-points, which may predict the disease severity, progression rate and life expectancy are needed. The adventure of end points in PAH has started with six minute walk distance and functional capacity, and continues with new parameters (biochemical marker, time to clinical worsening, echocardiography and magnetic resonance imaging etc.), which can better reflect the clinical outcome.

The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC).

PubMed

Golding, Brandon; Luu, Anita; Jones, Robert; Viloria-Petit, Alicia M

2018-02-19

Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule ATP-competitive ALK inhibitor was proven to be more effective than chemotherapy in ALK-positive NSCLC patients. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, are approved for use as a first-line therapy in these patients, where ALK rearrangement is currently diagnosed by immunohistochemistry and in situ hybridization. The clinical success of these three ALK inhibitors has led to the development of next-generation ALK inhibitors with even greater potency and selectivity. However, patients inevitably develop resistance to ALK inhibitors leading to tumor relapse that commonly manifests in the form of brain metastasis. Several new approaches aim to overcome the various mechanisms of resistance that develop in ALK-positive NSCLC including the knowledge-based alternate and successive use of different ALK inhibitors, as well as combined therapies targeting ALK plus alternative signaling pathways. Key issues to resolve for the optimal implementation of established and emerging treatment modalities for ALK-rearranged NSCLC therapy include the high cost of the targeted inhibitors and the potential of exacerbated toxicities with combination therapies.

On the role of the optimization algorithm of RapidArc(®) volumetric modulated arc therapy on plan quality and efficiency.

PubMed

Vanetti, Eugenio; Nicolini, Giorgia; Nord, Janne; Peltola, Jarkko; Clivio, Alessandro; Fogliata, Antonella; Cozzi, Luca

2011-11-01

The RapidArc volumetric modulated arc therapy (VMAT) planning process is based on a core engine, the so-called progressive resolution optimizer (PRO). This is the optimization algorithm used to determine the combination of field shapes, segment weights (with dose rate and gantry speed variations), which best approximate the desired dose distribution in the inverse planning problem. A study was performed to assess the behavior of two versions of PRO. These two versions mostly differ in the way continuous variables describing the modulated arc are sampled into discrete control points, in the planning efficiency and in the presence of some new features. The analysis aimed to assess (i) plan quality, (ii) technical delivery aspects, (iii) agreement between delivery and calculations, and (iv) planning efficiency of the two versions. RapidArc plans were generated for four groups of patients (five patients each): anal canal, advanced lung, head and neck, and multiple brain metastases and were designed to test different levels of planning complexity and anatomical features. Plans from optimization with PRO2 (first generation of RapidArc optimizer) were compared against PRO3 (second generation of the algorithm). Additional plans were optimized with PRO3 using new features: the jaw tracking, the intermediate dose and the air cavity correction options. Results showed that (i) plan quality was generally improved with PRO3 and, although not for all parameters, some of the scored indices showed a macroscopic improvement with PRO3. (ii) PRO3 optimization leads to simpler patterns of the dynamic parameters particularly for dose rate. (iii) No differences were observed between the two algorithms in terms of pretreatment quality assurance measurements and (iv) PRO3 optimization was generally faster, with a time reduction of a factor approximately 3.5 with respect to PRO2. These results indicate that PRO3 is either clinically beneficial or neutral in terms of dosimetric quality while it showed significant advantages in speed and technical aspects.

Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

PubMed

Mori, Keiichiro; Kimura, Takahiro; Onuma, Hajime; Kimura, Shoji; Yamamoto, Toshihiro; Sasaki, Hiroshi; Miki, Jun; Miki, Kenta; Egawa, Shin

2017-07-01

An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS. © 2017 Wiley Periodicals, Inc.

Positioning Vascularized Composite Allotransplantation in the Spectrum of Transplantation

DTIC Science & Technology

2017-10-01

have now shown that the efficacy of both protocols is dependent upon a radiation-sensitive donor bone marrow (BM) cell type that is of T or B cell... dependent VCA survival. IL-2C Therapy Increases the Number but Not Function of Foxp3 CD4+ Treg Cells To test the effects of JES6-1 mAb-based IL-2C...which Treg cell- dependent immunoregulation has considerable potential. These IL-2C studies are now “in press” (4). TASK 5: OPTIMAL COMBINATION

Light-based therapies in acne treatment

PubMed Central

Pei, Susan; Inamadar, Arun C.; Adya, Keshavmurthy A.; Tsoukas, Maria M.

2015-01-01

The use of light and laser in the treatment of acne is increasing as these modalities are safe, effective, and associated with no or minimal complications when used appropriately. These light and laser sources are also being used in combination with pharmacological and/or physical measures to synergize their effects and optimize the therapeutic outcome. This review focuses on optical devices used in treating acne and serves to delineate the current application of various methods, including their utility and efficacy. PMID:26009707

Enhanced Growth and Hepatic Differentiation of Fetal Liver Epithelial Cells through Combinational and Temporal Adjustment of Soluble Factors

PubMed Central

Qian, Lichuan; Krause, Diane S.; Saltzman, W. Mark

2012-01-01

Fetal liver epithelial cells (FLEC) are valuable for liver cell therapy and tissue engineering, but methods for culture and characterization of these cells are not well developed. This work explores the influence of multiple soluble factors on FLEC, with the long-term goal of developing an optimal culture system to generate functional liver tissue. Our comparative analysis suggests hepatocyte growth factor (HGF) is required throughout the culture period. In the presence of HGF, addition of oncostatin M (OSM) at culture initiation results in concurrent growth and maturation, while constant presence of protective agents like ascorbic acid enhances cell survival. Study observations led to the development of a culture medium that provided optimal growth and hepatic differentiation conditions. FLEC expansion was observed to be ~2 fold of that under standard conditions, albumin secretion rate was 2 – 3 times greater than maximal values obtained with other media, and the highest level of glycogen accumulation among all conditions was observed with the developed medium. Our findings serve to advance culture methods for liver progenitors in cell therapy and tissue engineering applications. PMID:21922669

Challenges and opportunities in the manufacture and expansion of cells for therapy.

PubMed

Maartens, Joachim H; De-Juan-Pardo, Elena; Wunner, Felix M; Simula, Antonio; Voelcker, Nicolas H; Barry, Simon C; Hutmacher, Dietmar W

2017-10-01

Laboratory-based ex vivo cell culture methods are largely manual in their manufacturing processes. This makes it extremely difficult to meet regulatory requirements for process validation, quality control and reproducibility. Cell culture concepts with a translational focus need to embrace a more automated approach where cell yields are able to meet the quantitative production demands, the correct cell lineage and phenotype is readily confirmed and reagent usage has been optimized. Areas covered: This article discusses the obstacles inherent in classical laboratory-based methods, their concomitant impact on cost-of-goods and that a technology step change is required to facilitate translation from bed-to-bedside. Expert opinion: While traditional bioreactors have demonstrated limited success where adherent cells are used in combination with microcarriers, further process optimization will be required to find solutions for commercial-scale therapies. New cell culture technologies based on 3D-printed cell culture lattices with favourable surface to volume ratios have the potential to change the paradigm in industry. An integrated Quality-by-Design /System engineering approach will be essential to facilitate the scaled-up translation from proof-of-principle to clinical validation.

Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma.

PubMed

Tavera, René J; Forget, Marie-Andrée; Kim, Young Uk; Sakellariou-Thompson, Donastas; Creasy, Caitlin A; Bhatta, Ankit; Fulbright, Orenthial J; Ramachandran, Renjith; Thorsen, Shawne T; Flores, Esteban; Wahl, Arely; Gonzalez, Audrey M; Toth, Christopher; Wardell, Seth; Mansaray, Rahmatu; Radvanyi, Laszlo G; Gombos, Dan S; Patel, Sapna P; Hwu, Patrick; Amaria, Rodabe N; Bernatchez, Chantale; Haymaker, Cara

2018-05-11

In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy-the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8 TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8CD3 TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in <3 weeks. Finally, providing the 3 signals attributed to optimal T-cell activation led to expansion of TIL capable of recognizing their tumor counterpart in cutaneous and uveal melanoma. This new methodology for the initial phase of TIL expansion brings a new opportunity for translation of TIL therapy in challenging malignancies such as uveal melanoma.

Optimization of pressure settings during adaptive servo-ventilation support using real-time heart rate variability assessment: initial case report.

PubMed

Imamura, Teruhiko; Nitta, Daisuke; Kinugawa, Koichiro

2017-01-05

Adaptive servo-ventilation (ASV) therapy is a recent non-invasive positive pressure ventilation therapy that was developed for patients with heart failure (HF) refractory to optimal medical therapy. However, it is likely that ASV therapy at relatively higher pressure setting worsens some of the patients' prognosis compared with optimal medical therapy. Therefore, identification of optimal pressure settings of ASV therapy is warranted. We present the case of a 42-year-old male with HF, which was caused by dilated cardiomyopathy, who was admitted to our institution for evaluating his eligibility for heart transplantation. To identify the optimal pressure setting [peak end-expiratory pressure (PEEP) ramp test], we performed an ASV support test, during which the PEEP settings were set at levels ranging from 4 to 8 mmHg, and a heart rate variability (HRV) analysis using the MemCalc power spectral density method. Clinical parameters varied dramatically during the PEEP ramp test. Over incremental PEEP levels, pulmonary capillary wedge pressure, cardiac index and high-frequency level (reflecting parasympathetic activity) decreased; however, the low-frequency level increased along with increase in plasma noradrenaline concentrations. An inappropriately high PEEP setting may stimulate sympathetic nerve activity accompanied by decreased cardiac output. This was the first report on the PEEP ramp test during ASV therapy. Further research is warranted to determine whether use of optimal pressure settings using HRV analyses may improve the long-term prognosis of such patients.

[Diagnosis and treatment of metabolic syndrome combined with liver toxicity genesis in contract service officers].

PubMed

Semiserin, V A; Khritinin, D F; Maev, I V; Karakozov, A T; Eremin, M N; Olenicheva, E L

2012-01-01

In this paper is synthesized current and recent data on the problem of metabolic syndrome (MS) in combination with toxic liver injury (CCI). Statistical parameters of the last 15 years, the dynamics of alimentary-constitutional obesity (ABC) in patients from the officers contracted service of Defense Ministry of Russia are reflected. Two-year experience in the application of modern non-invasive methods of diagnosis of liver fibrosis with a reflection of its dynamics on the background of complex treatment of patients with MS in conjunction with the Chamber on the example of 57 patients is shown. Paid great attention to psychological and emotional adjustment of patients with ABC, given the complex survey design and treatment in violation of motivational and behavioral responses. High clinical efficiency of combination drug therapy of MS and CCI, the diagnostic value of modern non-invasive methods of diagnosis of hepatic fibrosis are reliably performed. Technique of elastography significantly improves the liver clinical evaluation of the effectiveness of the therapy, allows for early detect the presence of the initial degree of hepatic fibrosis, choose the optimal treatment regimen and to evaluate the results dynamically.

Open-loop-feedback control of serum drug concentrations: pharmacokinetic approaches to drug therapy.

PubMed

Jelliffe, R W

1983-01-01

Recent developments to optimize open-loop-feedback control of drug dosage regimens, generally applicable to pharmacokinetically oriented therapy with many drugs, involve computation of patient-individualized strategies for obtaining desired serum drug concentrations. Analyses of past therapy are performed by least squares, extended least squares, and maximum a posteriori probability Bayesian methods of fitting pharmacokinetic models to serum level data. Future possibilities for truly optimal open-loop-feedback therapy with full Bayesian methods, and conceivably for optimal closed-loop therapy in such data-poor clinical situations, are also discussed. Implementation of these various therapeutic strategies, using automated, locally controlled infusion devices, has also been achieved in prototype form.

Induction therapy with linezolid/clarithromycin combination for Mycobacterium chelonae skin infections in immunocompromised hosts.

PubMed

Parize, P; Hamelin, A; Veziris, N; Morand, P C; Guillemain, R; Lortholary, O; Dupin, N

2016-01-01

The optimal management of Mycobacterium chelonae disease in immunocompromised patients remains unclear. A combination of antimicrobial agents is recommended as monotherapy with clarithromycin has been associated with clinical failures due to acquired resistance. We aim to report the efficacy and tolerability of linezolid in association with clarithromycin for the treatment of M. chelonae infections in immunocompromised patients. We describe four immunocompromised patients treated by linezolid and clarithromycin for cutaneous M. chelonae disease. This combination was associated with rapid clinical efficacy in all patients with no relapse observed after a median follow-up of 2.25 years (1.4 years). However, this treatment was responsible for frequent adverse events including thrombocytopaenia, myalgia and mitochondrial toxicity. All adverse effects were reversible after linezolid discontinuation. We therefore suggest linezolid/clarithromycin combination as the initial therapeutic strategy for M. chelonae skin infections in immunocompromised patients. © 2015 European Academy of Dermatology and Venereology.

Hypertrichotic Becker's nevi treated with combination 1,550 nm non-ablative fractional photothermolysis and laser hair removal.

PubMed

Balaraman, Brundha; Friedman, Paul M

2016-04-01

The removal of Becker's nevi poses a significant challenge due to limited available therapeutic options and increased risk of adverse effects, including scarring and dyspigmentation. Herein, we present the use of the non-ablative fractional photothermolysis in combination with laser hair removal for the treatment of hypertrichotic Becker's nevi. Retrospective analysis of three patients with Becker's nevi revealed that two patients with hypertrichotic Becker's nevi had greater than 75% clearance with combination therapy, and one patient with atrichotic Becker's nevus had a similar result with monotherapy non-ablative fractional photothermolysis. This report demonstrates the utility and safety of combination non-ablative fractional resurfacing and laser hair removal for the treatment of hypertrichotic Becker's nevi, and monotherapy non-ablative fractional photothermolysis for atrichotic Becker's nevi. Further comparative studies are necessary to determine optimal laser parameters, treatment schedules, and response duration. © 2016 Wiley Periodicals, Inc.

Immunomodulatory therapies for acute pancreatitis

PubMed Central

Li, Jing; Yang, Wen-Juan; Huang, Lu-Ming; Tang, Cheng-Wei

2014-01-01

It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3rd d to the 14th d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis. PMID:25493006

Synergistic Killing of Multidrug-Resistant Pseudomonas aeruginosa at Multiple Inocula by Colistin Combined with Doripenem in an In Vitro Pharmacokinetic/Pharmacodynamic Model ▿

PubMed Central

Bergen, Phillip J.; Tsuji, Brian T.; Bulitta, Jurgen B.; Forrest, Alan; Jacob, Jovan; Sidjabat, Hanna E.; Paterson, David L.; Nation, Roger L.; Li, Jian

2011-01-01

Combination therapy may be required for multidrug-resistant (MDR) Pseudomonas aeruginosa. The aim of this study was to systematically investigate bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against MDR P. aeruginosa. Studies were conducted in a one-compartment in vitro pharmacokinetic/pharmacodynamic model for 96 h at two inocula (∼106 and ∼108 CFU/ml) against a colistin-heteroresistant reference strain (ATCC 27853) and a colistin-resistant MDR clinical isolate (19147 n/m). Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles. Colistin (constant concentrations of 0.5 or 2 mg/liter) plus doripenem (peaks of 2.5 or 25 mg/liter every 8 h; half-life, 1.5 h) substantially increased bacterial killing against both strains at the low inoculum, while combinations containing colistin at 2 mg/liter increased activity against ATCC 27853 at the high inoculum; only colistin at 0.5 mg/liter plus doripenem at 2.5 mg/liter failed to improve activity against 19147 n/m at the high inoculum. Combinations were additive or synergistic against ATCC 27853 in 16 and 11 of 20 cases (4 combinations across 5 sample points) at the 106- and 108-CFU/ml inocula, respectively; the corresponding values for 19147 n/m were 16 and 9. Combinations containing doripenem at 25 mg/liter resulted in eradication of 19147 n/m at the low inoculum and substantial reductions in regrowth (including to below the limit of detection at ∼50 h) at the high inoculum. Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations. PMID:21911563

Fighting Cancer with Mathematics and Viruses.

PubMed

Santiago, Daniel N; Heidbuechel, Johannes P W; Kandell, Wendy M; Walker, Rachel; Djeu, Julie; Engeland, Christine E; Abate-Daga, Daniel; Enderling, Heiko

2017-08-23

After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex antitumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these research fields to increase the value of the preclinical development and the therapeutic efficacy of the resulting treatments.

Fighting Cancer with Mathematics and Viruses

PubMed Central

Santiago, Daniel N.; Heidbuechel, Johannes P. W.; Kandell, Wendy M.; Walker, Rachel; Djeu, Julie; Abate-Daga, Daniel; Enderling, Heiko

2017-01-01

After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex antitumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these research fields to increase the value of the preclinical development and the therapeutic efficacy of the resulting treatments. PMID:28832539

The effect of nanoparticle size on theranostic systems: the optimal particle size for imaging is not necessarily optimal for drug delivery

NASA Astrophysics Data System (ADS)

Dreifuss, Tamar; Betzer, Oshra; Barnoy, Eran; Motiei, Menachem; Popovtzer, Rachela

2018-02-01

Theranostics is an emerging field, defined as combination of therapeutic and diagnostic capabilities in the same material. Nanoparticles are considered as an efficient platform for theranostics, particularly in cancer treatment, as they offer substantial advantages over both common imaging contrast agents and chemotherapeutic drugs. However, the development of theranostic nanoplatforms raises an important question: Is the optimal particle for imaging also optimal for therapy? Are the specific parameters required for maximal drug delivery, similar to those required for imaging applications? Herein, we examined this issue by investigating the effect of nanoparticle size on tumor uptake and imaging. Anti-epidermal growth factor receptor (EGFR)-conjugated gold nanoparticles (GNPs) in different sizes (diameter range: 20-120 nm) were injected to tumor bearing mice and their uptake by tumors was measured, as well as their tumor visualization capabilities as tumor-targeted CT contrast agent. Interestingly, the results showed that different particles led to highest tumor uptake or highest contrast enhancement, meaning that the optimal particle size for drug delivery is not necessarily optimal for tumor imaging. These results have important implications on the design of theranostic nanoplatforms.

ITALIAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS STATEMENT-REPLACEMENT THERAPY FOR PRIMARY HYPOTHYROIDISM: A BRIEF GUIDE FOR CLINICAL PRACTICE.

PubMed

Guglielmi, Rinaldo; Frasoldati, Andrea; Zini, Michele; Grimaldi, Franco; Gharib, Hossein; Garber, Jeffrey R; Papini, Enrico

2016-11-01

Hypothyroidism requires life-long thyroid hormone replacement therapy in most patients. Oral levothyroxine (LT4) is an established safe and effective treatment for hypothyroidism, but some issues remain unsettled. The Italian Association of Clinical Endocrinologists appointed a panel of experts to provide an updated statement for appropriate use of thyroid hormone formulations for hypothyroidism replacement therapy. The American Association of Clinical Endocrinologists' protocol for standardized production of clinical practice guidelines was followed. LT4 is the first choice in replacement therapy. Thyroid-stimulating hormone (TSH) should be maintained between 1.0 and 3.0 mIU/L in young subjects and at the upper normal limit in elderly or fragile patients. Achievement of biochemical targets, patient well-being, and adherence to treatment should be addressed. In patients with unstable serum TSH, a search for interfering factors and patient compliance is warranted. Liquid or gel formulations may be considered in subjects with hampered LT4 absorption or who do not allow sufficient time before or after meals and LT4 replacement. Replacement therapy with LT4 and L-triiodothyronine (LT3) combination is generally not recommended. A trial may be considered in patients with normal values of serum TSH who continue to complain of symptoms of hypothyroidism only after co-existent nonthyroid problems have been excluded or optimally managed. LT3 should be administered in small (LT4:LT3 ratio, 10:1 to 20:1) divided daily doses. Combined therapy should be avoided in elderly patients or those with cardiac risk factors and in pregnancy. LT4 therapy should be aimed at resolution of symptoms of hypothyroidism, normalization of serum TSH, and improvement of quality of life. In selected cases, the use of liquid LT4 formulations or combined LT4/LT3 treatment may be considered to improve adherence to treatment or patient well-being. AACE = American Association of Clinical Endocrinologists FT3 = free triiodothyronine FT4 = free thyroxine LT3 = levotriiodothyronine LT4 = levothyroxine MeSH = medicine medical subject headings QoL = quality of life TSH = thyroid-stimulating hormone.

Approaches to enhancing the quality of drug therapy. A joint statement by the CMA and the Canadian Pharmaceutical Association. Canadian Medical Association.

PubMed Central

1996-01-01

This joint statement was developed by the CMA and the Canadian Pharmaceutical Association, a national association of pharmacists, and includes the goal of drug therapy, strategies for collaboration to optimize drug therapy and physicians' and pharmacists' responsibilities in drug therapy. The statement recognizes the importance of patients, physicians and pharmacists working in close collaboration and partnership to achieve optimal outcomes from drug therapy. PMID:8823225

Clindamycin phosphate 1.2% / tretinoin 0.025%: a novel fixed-dose combination treatment for acne vulgaris.

PubMed

Ochsendorf, F

2015-06-01

The Global Alliance to Improve Outcomes in Acne Group recommends retinoid-based combination therapy as first-line therapy and the preferred treatment approach for almost all acne patients except those with the most severe disease. Clindamycin 1% (as clindamycin phosphate 1.2%)/tretinoin 0.025% (Clin-RA) is a new fixed-dose retinoid-based combination therapy. The aqueous-based gel formulation of Clin-RA was designed to minimize skin irritation and optimize adherence with the therapy. It contains both solubilized and crystalline tretinoin which allows the retinoid to be slowly released onto the skin surface and decreases the potential for cutaneous irritation. A pooled analysis of three pivotal studies involving 4550 acne patients showed that Clin-RA is well tolerated and effective at treating both inflammatory and non-inflammatory acne lesions. The onset of action of Clin-RA is rapid occurring within 2 weeks of treatment initiation. It is not associated with acne flaring or an increase in clindamycin-resistant Propionibacterium acnes counts. Clin-RA is considered as effective as adapalene 0.1%/benzoyl peroxide (BPO) 2.5%, whereas Clin-RA has a more favourable tolerability profile. Clin-RA may be more effective than clindamycin 1%/BPO 5% at treating non-inflammatory acne lesions since the latter does not contain a retinoid to target comedones. Clin-RA is also easy for patients to handle and apply, and has the advantage of not containing BPO which can bleach hair and fabrics. Taken together, the profile of Clin-RA suggests Clin-RA to be a first-line treatment for patients with facial acne. © 2015 European Academy of Dermatology and Venereology.

Combination L-T3 and L-T4 therapy for hypothyroidism.

PubMed

Wartofsky, Leonard

2013-10-01

Because of the longstanding controversy regarding whether hypothyroid patients can be optimally replaced by treatment with levothyroxine (L-T4) alone, numerous studies have addressed potential benefits of combined therapy of triiodothyronine (T3) with L-T4. Results of these studies have failed to support a potential benefit of combined therapy. A strong argument for the addition of L-T3 to L-T4 monotherapy has been lacking until recent genetic studies indicated a rationale for such therapy among a small fraction of the hypothyroid patient population. Interest in this issue has focused on the importance of the deiodinases in maintaining the euthyroid state and the role of genetic polymorphisms in the deiodinase genes that would affect thyroid hormone concentrations in both blood and tissues. One such polymorphism in the D2 gene, Thr92Ala, is associated with reduced T4 to T3 activation in skeletal muscle and thyroid, linked to obesity and alterations in thyroid-pituitary feedback, and in responses to thyroid hormone treatment. Although our professional organizations continue to recommend L-T4 alone for the treatment of hypothyroidism, the possibility of a D2 gene polymorphism should be considered in patients on L-T4 monotherapy who continue to complain of fatigue in spite of dosage achieving low normal serum thyroid stimulating hormone levels. A suggestive clue to the presence of this polymorphism could be a higher than normal free T4/free T3 ratio. Clinicians could consider adding T3 as a therapeutic trial in selected patients. Future well controlled clinical trials will be required to more fully resolve the controversy.

Defining and achieving treatment success in patients with type 2 diabetes mellitus.

PubMed

Stolar, Mark W

2010-12-01

Traditionally, successful treatment of patients with type 2 diabetes mellitus (DM) has been defined strictly by achievement of targeted glycemic control, primarily using a stepped-care approach that begins with changes in lifestyle combined with oral therapy that is slowly intensified as disease progression advances and β-cell function declines. However, stepped care is often adjusted without regard to the mechanism of hyperglycemia or without long-term objectives. A more comprehensive definition of treatment success in patients with type 2 DM should include slowing or stopping disease progression and optimizing the reduction of all risk factors associated with microvascular and macrovascular disease complications. To achieve these broader goals, it is important to diagnose diabetes earlier in the disease course and to consider use of more aggressive combination therapy much earlier with agents that have the potential to slow or halt the progressive β-cell dysfunction and loss characteristic of type 2 DM. A new paradigm for managing patients with type 2 DM should address the concomitant risk factors and morbidities of obesity, hypertension, and dyslipidemia with equal or occasionally even greater aggressiveness than for hyperglycemia. The use of antidiabetes agents that may favorably address cardiovascular risk factors should be considered more strongly in treatment algorithms, although no pharmacological therapy is likely to be ultimately successful without concomitant synergistic lifestyle changes. Newer incretin-based therapies, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, which appear to have a favorable cardiovascular safety profile as well as the mechanistic possibility for a favorable cardiovascular risk impact, are suitable for earlier inclusion as part of combination regimens aimed at achieving comprehensive treatment success in patients with type 2 DM.

Indirect radio-chemo-beta therapy: a targeted approach to increase biological efficiency of x-rays based on energy

NASA Astrophysics Data System (ADS)

Oktaria, Sianne; Corde, Stéphanie; Lerch, Michael L. F.; Konstantinov, Konstantin; Rosenfeld, Anatoly B.; Tehei, Moeava

2015-10-01

Despite the use of multimodal treatments incorporating surgery, chemotherapy and radiotherapy, local control of gliomas remains a major challenge. The potential of a new treatment approach called indirect radio-chemo-beta therapy using the synergy created by combining methotrexate (MTX) with bromodeoxyuridine (BrUdR) under optimum energy x-ray irradiation is assessed. 9L rat gliosarcoma cells pre-treated with 0.01 μM MTX and/or 10 μM BrUdR were irradiated in vitro with 50 kVp, 125 kVp, 250 kVp, 6 MV and 10 MV x-rays. The cytotoxicity was assessed using clonogenic survival as the radiobiological endpoint. The photon energy with maximum effect was determined using radiation sensitization enhancement factors at 10% clonogenic survival (SER10%). The cell cycle distribution was investigated using flow cytometric analysis with propidium iodide staining. Incorporation of BrUdR in the DNA was detected by the fluorescence of labelled anti-BrUdR antibodies. The radiation sensitization enhancement exhibits energy dependence with a maximum of 2.3 at 125 kVp for the combined drug treated cells. At this energy, the shape of the clonogenic survival curve of the pharmacological agents treated cells changes substantially. This change is interpreted as an increased lethality of the local radiation environment and is attributed to supplemented inhibition of DNA repair. Radiation induced chemo-beta therapy was demonstrated in vitro by the targeted activation of combined pharmacological agents with optimized energy tuning of x-ray beams on 9 L cells. Our results show that this is a highly effective form of chemo-radiation therapy.

Radiofrequency ablation combined with transcatheter arterial embolisation in rabbit liver: investigation of the ablation zone according to the time interval between the two therapies.

PubMed

Lee, I J; Kim, Y I; Kim, K W; Kim, D H; Ryoo, I; Lee, M W; Chung, J W

2012-11-01

This study was designed to evaluate the extent of the radiofrequency ablation zone in relation to the time interval between transcatheter arterial embolisation (TAE) and radiofrequency ablation (RFA) and, ultimately, to determine the optimal strategy of combining these two therapies for hepatocellular carcinoma. 15 rabbits were evenly divided into three groups: Group A was treated with RFA alone; Group B was treated with TAE immediately followed by RFA; and Group C was treated with TAE followed by RFA 5 days later. All animals underwent perfusion CT (PCT) scans immediately after RFA. Serum liver transaminases were measured to evaluate acute liver damage. Animals were euthanised for pathological analysis of ablated tissues 10 days after RFA. Non-parametric analyses were conducted to compare PCT indices, the RFA zone and liver transaminase levels among the three experimental groups. Group B showed a significantly larger ablation zone than the other two groups. Arterial liver perfusion and hepatic perfusion index represented well the perfusion decrease after TAE on PCT. Although Group B showed the most elevated liver transaminase levels at 1 day post RFA, the enzymes decreased to levels that were not different from the other groups at 10 days post-RFA. When combined TAE and RFA therapy is considered, TAE should be followed by RFA as quickly as possible, as it can be performed safely without serious hepatic deterioration, despite the short interval between the two procedures.

The synergistic effects of Apatinib combined with cytotoxic chemotherapeutic agents on gastric cancer cells and in a fluorescence imaging gastric cancer xenograft model.

PubMed

Feng, Jiuhuan; Qin, Shukui

2018-01-01

Methylsulfonic apatinib (hereinafter referred to as Apatinib) is a small-molecule angiogenesis inhibitor highly and selectively targeted to vascular endothelial growth factor receptor-2. At present, a series of basic and clinical studies have confirmed that Apatinib mono-therapy can inhibit the growth of different carcinomas. Our experiment aimed to determine whether there is a synergistic effect between the combination of the traditional cytotoxic chemotherapy drugs paclitaxel (TAX), oxaliplatin (L-OHP), 5-fluorouracil (5-FU), and Apatinib. We evaluated the combined effect using cytological experiments and a fluorescence imaging xenograft model. In vitro, the inhibition of cell proliferation increased notably when Apatinib was combined with TAX, L-OHP, and 5-FU. Then, for the mechanistic research, we selected the optimal dose of drugs that also had a synergistic effect. Apatinib combined with the aforementioned drugs, especially the combination of Apatinib and 5-FU, decreased the invasion and migration ability of the cells and increased the apoptosis ratio; expression of the anti-apoptotic protein Bcl-2 significantly decreased, and expression of the pro-apoptotic protein Bax increased. In vivo, when Apatinib was combined with TAX, L-OHP, and 5-FU, the volume of the xenograft model was significantly inhibited, the strength of the green fluorescence was weakened and the microvessel density decreased. The combination of Apatinib with TAX and 5-FU was synergistic (coefficient of drug interaction <1); the combination effect of Apatinib and L-OHP was only additive, with a shorter associated survival time. The combination of Apatinib and classical chemotherapy drugs may be an optimal choice for gastric cancer treatment.

The synergistic effects of Apatinib combined with cytotoxic chemotherapeutic agents on gastric cancer cells and in a fluorescence imaging gastric cancer xenograft model

PubMed Central

Feng, Jiuhuan; Qin, Shukui

2018-01-01

Introduction Methylsulfonic apatinib (hereinafter referred to as Apatinib) is a small-molecule angiogenesis inhibitor highly and selectively targeted to vascular endothelial growth factor receptor-2. At present, a series of basic and clinical studies have confirmed that Apatinib mono-therapy can inhibit the growth of different carcinomas. Our experiment aimed to determine whether there is a synergistic effect between the combination of the traditional cytotoxic chemotherapy drugs paclitaxel (TAX), oxaliplatin (L-OHP), 5-fluorouracil (5-FU), and Apatinib. Materials and methods We evaluated the combined effect using cytological experiments and a fluorescence imaging xenograft model. In vitro, the inhibition of cell proliferation increased notably when Apatinib was combined with TAX, L-OHP, and 5-FU. Then, for the mechanistic research, we selected the optimal dose of drugs that also had a synergistic effect. Apatinib combined with the aforementioned drugs, especially the combination of Apatinib and 5-FU, decreased the invasion and migration ability of the cells and increased the apoptosis ratio; expression of the anti-apoptotic protein Bcl-2 significantly decreased, and expression of the pro-apoptotic protein Bax increased. In vivo, when Apatinib was combined with TAX, L-OHP, and 5-FU, the volume of the xenograft model was significantly inhibited, the strength of the green fluorescence was weakened and the microvessel density decreased. Results The combination of Apatinib with TAX and 5-FU was synergistic (coefficient of drug interaction <1); the combination effect of Apatinib and L-OHP was only additive, with a shorter associated survival time. Conclusion The combination of Apatinib and classical chemotherapy drugs may be an optimal choice for gastric cancer treatment. PMID:29872316

The effect of a dual or a triple antithrombotic therapy with apixaban on thrombus formation in vivo and in an ex vivo perfusion chamber model

PubMed Central

Weisshaar, Stefan; Litschauer, Brigitte; Bucher, Sebastian; Riesenhuber, Martin; Kapiotis, Stylianos; Kyrle, Paul Alexander; Wolzt, Michael

2016-01-01

Abstract Background: There is a need to optimize pharmacological treatment in patients with acute coronary syndrome and concomitant atrial fibrillation, in particular with newer antithrombotic medicines. We have therefore studied if dual or triple combination of antithrombotic agents exert similar effects on coagulation activation in an in vivo model in the skin microvasculature and in an ex vivo perfusion chamber. Methods and Results: Shed blood platelet activation (β-thromboglobulin [β-TG]), thrombin generation (thrombin-antithrombin complex [TAT]) and volume as well as markers of thrombus size (D-dimer) and its platelet content (P-selectin) in a perfusion chamber were studied in a sequential, open-label, parallel group trial in 40 healthy male volunteers (n = 20 per group). Subjects received ticagrelor and apixaban without or with acetylsalicylic acid (ASA). Outcome parameters were assessed at 3 hours after therapy dosing, and at steady-state trough and peak conditions. A triple or dual therapy induced a comparable decrease in shed blood β-TG at 3 hours after therapy dosing but was more pronounced at steady-state conditions with the more intense treatment combination. During both antithrombotic regimens a similarly sustained inhibition in thrombin generation was observed which was accompanied by comparable increases in shed blood volume. In contrast, no treatment effect could be observed in the perfusion chamber experiment. Conclusion: Ticagrelor and apixaban with or without ASA inhibit platelet activation and thrombin formation in vivo in healthy subjects. Platelet inhibition was greater at steady-state conditions after triple therapy administration. PMID:27399131

Upfront Androgen Deprivation Therapy With Salvage Radiation May Improve Biochemical Outcomes in Prostate Cancer Patients With Post-Prostatectomy Rising PSA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jang, Joanne W.; Hwang, Wei-Ting; Guzzo, Thomas J.

2012-08-01

Purpose: The addition of androgen deprivation therapy (ADT) to definitive external beam radiation therapy (RT) improves outcomes in higher-risk prostate cancer patients. However, the benefit of ADT with salvage RT in post-prostatectomy patients is not clearly established. Our study compares biochemical outcomes in post-prostatectomy patients who received salvage RT with or without concurrent ADT. Methods and Materials: Of nearly 2,000 post-prostatectomy patients, we reviewed the medical records of 191 patients who received salvage RT at University of Pennsylvania between 1987 and 2007. Follow-up data were obtained by chart review and electronic polling of the institutional laboratory database and Social Securitymore » Death Index. Biochemical failure after salvage RT was defined as a prostate-specific antigen of 2.0 ng/mL above the post-RT nadir or the initiation of ADT after completion of salvage RT. Results: One hundred twenty-nine patients received salvage RT alone, and 62 patients received combined ADT and salvage RT. Median follow-up was 5.4 years. Patients who received combined ADT and salvage RT were younger, had higher pathologic Gleason scores, and higher rates of seminal vesicle invasion, lymph node involvement, and pelvic nodal irradiation compared with patients who received salvage RT alone. Patients who received combined therapy had improved biochemical progression-free survival (bPFS) compared with patients who received RT alone (p = 0.048). For patients with pathologic Gleason scores {<=}7, combined RT and ADT resulted in significantly improved bPFS compared to RT alone (p = 0.013). Conclusions: These results suggest that initiating ADT during salvage RT in the post-prostatectomy setting may improve bPFS compared with salvage RT alone. However, prospective randomized data are necessary to definitively determine whether hormonal manipulation should be used with salvage RT. Furthermore, the optimal nature and duration of ADT and the patient subgroups in which ADT could provide the most benefit remain open questions.« less

Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway

PubMed Central

Benson, Helen E; Sharman, Joanna L; Mpamhanga, Chido P; Parton, Andrew; Southan, Christopher; Harmar, Anthony J; Ghazal, Peter

2017-01-01

Background and Purpose An ever‐growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single‐drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway. Experimental Approach Using open online resources, we assembled a computational model of the mevalonate pathway and compiled a set of inhibitors directed against targets in this pathway. We used computational optimization to identify combination and dose options that show not only maximal efficacy of inhibition on the cholesterol producing branch but also minimal impact on the geranylation branch, known to mediate the side effects of pharmaceutical treatment. Key Results We describe serious impediments to systems pharmacology studies arising from limitations in the data, incomplete coverage and inconsistent reporting. By curating a more complete dataset, we demonstrate the utility of computational optimization for identifying multi‐drug treatments with high efficacy and minimal off‐target effects. Conclusion and Implications We suggest solutions that facilitate systems pharmacology studies, based on the introduction of standards for data capture that increase the power of experimental data. We propose a systems pharmacology workflow for the refinement of data and the generation of future therapeutic hypotheses. PMID:28910500

Radiotherapy before and after radical prostatectomy for high-risk and locally advanced prostate cancer.

PubMed

Perez, Bradford A; Koontz, Bridget F

2015-05-01

Men with localized high-risk prostate cancer carry significant risk of prostate cancer-specific mortality. The best treatment approach to minimize this risk is unclear. In this review, we evaluate the role of radiation before and after radical prostatectomy. A critical review of the literature was performed regarding the application of external radiation therapy (RT) in combination with prostatectomy for high-risk localized prostate cancer. Up to 70% of men with high-risk localized disease may require adjuvant therapy because of adverse pathologic features or biochemical recurrence in the absence of systemic disease. The utility of adjuvant RT among men with adverse pathologic features are well established at least regarding minimizing biochemical recurrence risk. The optimal timing of salvage radiation is the subject of ongoing studies. Neoadjuvant RT requires further study but is a potentially attractive method because of decreased radiation field sizes and potential radiobiologic benefits of delivering RT before surgery. Salvage prostatectomy is effective at treating local recurrence after radiation but is associated with significant surgical morbidity. Combining local therapies including radical prostatectomy and RT can be a reasonable approach. Care should be taken at the initial presentation of high-risk localized prostate cancer to consider and plan for the likelihood of multimodality care. Copyright © 2015 Elsevier Inc. All rights reserved.

Management of multidrug-resistant Pseudomonas aeruginosa in the intensive care unit: state of the art.

PubMed

Maraolo, Alberto Enrico; Cascella, Marco; Corcione, Silvia; Cuomo, Arturo; Nappa, Salvatore; Borgia, Guglielmo; De Rosa, Francesco Giuseppe; Gentile, Ivan

2017-09-01

Pseudomonas aeruginosa (PA) is one of the most important causes of healthcare-related infections among Gram-negative bacteria. The best therapeutic approach is controversial, especially for multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains as well as in the setting of most severe patients, such as in the intensive care unit (ICU). Areas covered: This article addresses several points. First, the main microbiological aspects of PA, focusing on its wide array of resistance mechanisms. Second, risk factors and the worse outcome linked to MDR-PA infection. Third, the pharmacological peculiarity of ICU patients, that makes the choice of a proper antimicrobial therapy difficult. Eventually, the current therapeutic options against MDR-PA are reviewed, taking into account the main variables that drive antimicrobial optimization in critically ill patients. Literature search was carried out using Pubmed and Web of Science. Expert commentary: Methodologically rigorous studies are urgently needed to clarify crucial aspects of the treatment against MDR-PA, namely monotherapy versus combination therapy in empiric and targeted settings. In the meanwhile, useful options are represented by newly approved drugs, such as ceftolozane/tazobactam and ceftazidime/avibactam. In critically ill patients, at least as empirical approach, a combination therapy is a prudent choice when a MDR-PA strain is suspected.

Slow continuous renal replacement therapies: an update.

PubMed

Kes, P

2000-01-01

Continuous renal replacement therapies (CRRT) are now being used by nephrologists, intensivists, and anesthesiologists. The various CRRT modalities differ in the kind of vascular access, the application of diffusive or convective clearances (or a combination of both), and in the location where the replacement fluid enters the circuit. CRRTs have certainly made the management of critically ill patients with acute renal failure (ARF) combined with cardiovascular instability, severe fluid overload, hypercatabolism, cerebral edema, adult respiratory distress syndrome, lactic acidosis, sepsis or other inflammatory syndromes, crush syndrome, congestive heart failure, and cardiopulmonary bypass easier. Continuous therapies incorporate several advantages including improved hemodynamic stability, optimal fluid balance, gradual urea removal, elimination of septic mediators, and the possibility of unlimited parenteral nutrition. Major difficulties and unsolved problems of CRRT are the ongoing necessity of continuous anticoagulation, considerable loss of amino acids, vitamins, trace elements, potassium, phosphate, and some drugs, as well as immobilization of the patient. The advantages of CRRT should theoretically translate into improved outcomes of critically ill ARF patients, but the superiority of continuous modalities in terms of outcome is still controversial, despite encouraging results in some clinical trials. Currently used CRRT with sophisticated treatment devices has become more expensive than hemodialysis, but the cost cannot be used as an argument against the continuous treatment modalities.

Lung tumor diagnosis and subtype discovery by gene expression profiling.

PubMed

Wang, Lu-yong; Tu, Zhuowen

2006-01-01

The optimal treatment of patients with complex diseases, such as cancers, depends on the accurate diagnosis by using a combination of clinical and histopathological data. In many scenarios, it becomes tremendously difficult because of the limitations in clinical presentation and histopathology. To accurate diagnose complex diseases, the molecular classification based on gene or protein expression profiles are indispensable for modern medicine. Moreover, many heterogeneous diseases consist of various potential subtypes in molecular basis and differ remarkably in their response to therapies. It is critical to accurate predict subgroup on disease gene expression profiles. More fundamental knowledge of the molecular basis and classification of disease could aid in the prediction of patient outcome, the informed selection of therapies, and identification of novel molecular targets for therapy. In this paper, we propose a new disease diagnostic method, probabilistic boosting tree (PB tree) method, on gene expression profiles of lung tumors. It enables accurate disease classification and subtype discovery in disease. It automatically constructs a tree in which each node combines a number of weak classifiers into a strong classifier. Also, subtype discovery is naturally embedded in the learning process. Our algorithm achieves excellent diagnostic performance, and meanwhile it is capable of detecting the disease subtype based on gene expression profile.

Socially assistive robotics for stroke and mild TBI rehabilitation.

PubMed

Matarić, Maja; Tapus, Adriana; Winstein, Carolee; Eriksson, Jon

2009-01-01

This paper describes an interdisciplinary research project aimed at developing and evaluating effective and user-friendly non-contact robot-assisted therapy, aimed at in-home use. The approach stems from the emerging field of social cognitive neuroscience that seeks to understand phenomena in terms of interactions between the social, cognitive, and neural levels of analysis. This technology-assisted therapy is designed to be safe and affordable, and relies on novel human-robot interaction methods for accelerated recovery of upper-extremity function after lesion-induced hemiparesis. The work is based on the combined expertise in the science and technology of non-contact socially assistive robotics and the clinical science of neurorehabilitation and motor learning, brought together to study how to best enhance recovery after stroke and mild traumatic brain injury. Our approach is original and promising in that it combines several ingredients that individually have been shown to be important for learning and long-term efficacy in motor neurorehabilitation: (1) intensity of task specific training and (2) engagement and self-management of goal-directed actions. These principles motivate and guide the strategies used to develop novel user activity sensing and provide the rationale for development of socially assistive robotics therapy for monitoring and coaching users toward personalized and optimal rehabilitation programs.

Dyslipidemia: management using optimal lipid-lowering therapy.

PubMed

Ito, Matthew K

2012-10-01

To evaluate current approaches and explore emerging research related to dyslipidemia management. MEDLINE (2004-April 2012) was searched for randomized controlled trials using the terms dyslipidemia and lipid-lowering therapy or statin (>1000 hits). Separate searches (MEDLINE, Google) identified meta-analyses (2010-2011), disease prevalence statistics, and current consensus guidelines (2004-July 2011). Additional references were identified from the publications reviewed. English-language articles on large multicenter trials were evaluated. National Cholesterol Education Program Adult Treatment Panel III guidelines for the reduction of cardiovascular risk recommend the attainment of specific low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) target values, based on an individual's 10-year risk of coronary heart disease or global risk. For most patients unable to achieve recommended lipid level goals with therapeutic lifestyle changes, statins are the first option for treatment. Results of large, well-controlled clinical trials have demonstrated that statins are effective in primary and secondary prevention of cardiovascular disease in diverse populations, including patients with diabetes and the elderly, and that intensive statin therapy provides more effective lipid goal attainment and significantly greater risk reduction in patients with coronary artery disease. Statin therapy is generally well tolerated but may increase the risk of myopathy. Statin use has been associated with increases in hepatic transaminases and an increased risk of diabetes, although the absolute risk of diabetes is low compared with the risk reduction benefit. Combination therapy including a statin may be appropriate for certain populations, but the risk reduction benefits of combination therapy remain unclear. Ezetimibe is an important treatment option for patients with hypercholesterolemia who do not tolerate intensive statin therapy. Although fibrates or niacin improves overall lipid profiles in patients with hypertriglyceridemia or dyslipidemia who are receiving statin therapy, their efficacy in reducing cardiovascular risk remains questionable and their use raises safety and tolerability concerns. Intensifying lifestyle changes and statin dose should be utilized first in patients not achieving their LDL-C and non-HDL-C goals.

SU-D-BRC-01: An Automatic Beam Model Commissioning Method for Monte Carlo Simulations in Pencil-Beam Scanning Proton Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qin, N; Shen, C; Tian, Z

Purpose: Monte Carlo (MC) simulation is typically regarded as the most accurate dose calculation method for proton therapy. Yet for real clinical cases, the overall accuracy also depends on that of the MC beam model. Commissioning a beam model to faithfully represent a real beam requires finely tuning a set of model parameters, which could be tedious given the large number of pencil beams to commmission. This abstract reports an automatic beam-model commissioning method for pencil-beam scanning proton therapy via an optimization approach. Methods: We modeled a real pencil beam with energy and spatial spread following Gaussian distributions. Mean energy,more » and energy and spatial spread are model parameters. To commission against a real beam, we first performed MC simulations to calculate dose distributions of a set of ideal (monoenergetic, zero-size) pencil beams. Dose distribution for a real pencil beam is hence linear superposition of doses for those ideal pencil beams with weights in the Gaussian form. We formulated the commissioning task as an optimization problem, such that the calculated central axis depth dose and lateral profiles at several depths match corresponding measurements. An iterative algorithm combining conjugate gradient method and parameter fitting was employed to solve the optimization problem. We validated our method in simulation studies. Results: We calculated dose distributions for three real pencil beams with nominal energies 83, 147 and 199 MeV using realistic beam parameters. These data were regarded as measurements and used for commission. After commissioning, average difference in energy and beam spread between determined values and ground truth were 4.6% and 0.2%. With the commissioned model, we recomputed dose. Mean dose differences from measurements were 0.64%, 0.20% and 0.25%. Conclusion: The developed automatic MC beam-model commissioning method for pencil-beam scanning proton therapy can determine beam model parameters with satisfactory accuracy.« less

Estimating Tissue Iron Burden: Current Status and Future Prospects

PubMed Central

Wood, John C.

2015-01-01

SUMMARY Iron overload is becoming an increasing problem as haemoglobinopathy patients gain greater access to good medical care and as therapies for myelodysplastic syndromes improve. Therapeutic options for iron chelation therapy have increased and many patients now receive combination therapies. However, optimal utilization of iron chelation therapy requires knowledge not only of the total body iron burden but the relative iron distribution among the different organs. The physiological basis for extrahepatic iron deposition is presented in order to help identify patients at highest risk for cardiac and endocrine complications. This manuscript reviews the current state of the art for monitoring global iron overload status as well as its compartmentalization. Plasma markers, computerized tomography, liver biopsy, magnetic susceptibility devices and magnetic resonance imaging (MRI) techniques are all discussed but MRI has come to dominate clinical practice. The potential impact of recent pancreatic and pituitary MRI studies on clinical practice are discussed as well as other works-in-progress. Clinical protocols are derived from experience in haemoglobinopathies but may provide useful guiding principles for other iron overload disorders, such as myelodysplastic syndromes. PMID:25765344

Adaptive non-linear control for cancer therapy through a Fokker-Planck observer.

PubMed

Shakeri, Ehsan; Latif-Shabgahi, Gholamreza; Esmaeili Abharian, Amir

2018-04-01

In recent years, many efforts have been made to present optimal strategies for cancer therapy through the mathematical modelling of tumour-cell population dynamics and optimal control theory. In many cases, therapy effect is included in the drift term of the stochastic Gompertz model. By fitting the model with empirical data, the parameters of therapy function are estimated. The reported research works have not presented any algorithm to determine the optimal parameters of therapy function. In this study, a logarithmic therapy function is entered in the drift term of the Gompertz model. Using the proposed control algorithm, the therapy function parameters are predicted and adaptively adjusted. To control the growth of tumour-cell population, its moments must be manipulated. This study employs the probability density function (PDF) control approach because of its ability to control all the process moments. A Fokker-Planck-based non-linear stochastic observer will be used to determine the PDF of the process. A cost function based on the difference between a predefined desired PDF and PDF of tumour-cell population is defined. Using the proposed algorithm, the therapy function parameters are adjusted in such a manner that the cost function is minimised. The existence of an optimal therapy function is also proved. The numerical results are finally given to demonstrate the effectiveness of the proposed method.

Cardiac surgery antibiotic prophylaxis and calculated empiric antibiotic therapy.

PubMed

Gorski, Armin; Hamouda, Khaled; Özkur, Mehmet; Leistner, Markus; Sommer, Sebastian-Patrick; Leyh, Rainer; Schimmer, Christoph

2015-03-01

Ongoing debate exists concerning the optimal choice and duration of antibiotic prophylaxis as well as the reasonable calculated empiric antibiotic therapy for hospital-acquired infections in critically ill cardiac surgery patients. A nationwide questionnaire was distributed to all German heart surgery centers concerning antibiotic prophylaxis and the calculated empiric antibiotic therapy. The response to the questionnaire was 87.3%. All clinics that responded use antibiotic prophylaxis, 79% perform it not longer than 24 h (single-shot: 23%; 2 doses: 29%; 3 doses: 27%; 4 doses: 13%; and >5 doses: 8%). Cephalosporin was used in 89% of clinics (46% second-generation, 43% first-generation cephalosporin). If sepsis is suspected, the following diagnostics are performed routinely: wound inspection 100%; white blood cell count 100%; radiography 99%; C-reactive protein 97%; microbiological testing of urine 91%, blood 81%, and bronchial secretion 81%; procalcitonin 74%; and echocardiography 75%. The calculated empiric antibiotic therapy (depending on the suspected focus) consists of a multidrug combination with broad-spectrum agents. This survey shows that existing national guidelines and recommendations concerning perioperative antibiotic prophylaxis and calculated empiric antibiotic therapy are well applied in almost all German heart centers. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Image-guided ultrasound phased arrays are a disruptive technology for non-invasive therapy

NASA Astrophysics Data System (ADS)

Hynynen, Kullervo; Jones, Ryan M.

2016-09-01

Focused ultrasound offers a non-invasive way of depositing acoustic energy deep into the body, which can be harnessed for a broad spectrum of therapeutic purposes, including tissue ablation, the targeting of therapeutic agents, and stem cell delivery. Phased array transducers enable electronic control over the beam geometry and direction, and can be tailored to provide optimal energy deposition patterns for a given therapeutic application. Their use in combination with modern medical imaging for therapy guidance allows precise targeting, online monitoring, and post-treatment evaluation of the ultrasound-mediated bioeffects. In the past there have been some technical obstacles hindering the construction of large aperture, high-power, densely-populated phased arrays and, as a result, they have not been fully exploited for therapy delivery to date. However, recent research has made the construction of such arrays feasible, and it is expected that their continued development will both greatly improve the safety and efficacy of existing ultrasound therapies as well as enable treatments that are not currently possible with existing technology. This review will summarize the basic principles, current statures, and future potential of image-guided ultrasound phased arrays for therapy.

Image-guided ultrasound phased arrays are a disruptive technology for non-invasive therapy.

PubMed

Hynynen, Kullervo; Jones, Ryan M

2016-09-07

Focused ultrasound offers a non-invasive way of depositing acoustic energy deep into the body, which can be harnessed for a broad spectrum of therapeutic purposes, including tissue ablation, the targeting of therapeutic agents, and stem cell delivery. Phased array transducers enable electronic control over the beam geometry and direction, and can be tailored to provide optimal energy deposition patterns for a given therapeutic application. Their use in combination with modern medical imaging for therapy guidance allows precise targeting, online monitoring, and post-treatment evaluation of the ultrasound-mediated bioeffects. In the past there have been some technical obstacles hindering the construction of large aperture, high-power, densely-populated phased arrays and, as a result, they have not been fully exploited for therapy delivery to date. However, recent research has made the construction of such arrays feasible, and it is expected that their continued development will both greatly improve the safety and efficacy of existing ultrasound therapies as well as enable treatments that are not currently possible with existing technology. This review will summarize the basic principles, current statures, and future potential of image-guided ultrasound phased arrays for therapy.

Rechallenge and maintenance therapy using cetuximab and chemotherapy administered to a patient with metastatic colorectal cancer.

PubMed

Ma, Jian; Yang, Quan-Liang; Ling, Yang

2017-02-14

Cetuximab combined with chemotherapy is one of the first-line treatments of metastatic colorectal cancer. Although disease progression inevitably occurs, rechallenge and maintenance therapies using cetuximab-based regimens may be beneficial, particularly for patients with wild-type (WT) KRAS. A 47-year-old female patient who underwent right hemicolectomy presented with an ulcerative adenocarcinoma (grade 2) revealed by histopathological analysis. The patient received three cycles of adjuvant chemotherapy, but disease recurred 15 months later. Cetuximab and a FOLFOX-4 regimen were administered, followed by surgery and adjuvant chemotherapy that was administered for approximately one year. Three years after completing adjuvant therapy, her serum carcinoembryonic antigen levels rapidly increased, and enhanced computed tomography showed widespread metastases. Rechallenge with cetuximab and the FOLFIRI regimen was then initiated, and after 12 cycles, lesions in the lung and liver shrank significantly, and serum CEA levels dramatically declined. Maintenance therapy with cetuximab and capecitabine was then administered for 10 months until the metastatic lesions in the lung and liver enlarged. Rechallenge and maintenance therapy with cetuximab-based chemotherapy were relatively effective for managing a female patient with WT KRAS. Optimization of this strategy requires further in-depth investigations of more patients.

Image-guided ultrasound phased arrays are a disruptive technology for non-invasive therapy

PubMed Central

Hynynen, Kullervo; Jones, Ryan M.

2016-01-01

Focused ultrasound offers a non-invasive way of depositing acoustic energy deep into the body, which can be harnessed for a broad spectrum of therapeutic purposes, including tissue ablation, the targeting of therapeutic agents, and stem cell delivery. Phased array transducers enable electronic control over the beam geometry and direction, and can be tailored to provide optimal energy deposition patterns for a given therapeutic application. Their use in combination with modern medical imaging for therapy guidance allows precise targeting, online monitoring, and post-treatment evaluation of the ultrasound-mediated bioeffects. In the past there have been some technical obstacles hindering the construction of large aperture, high-power, densely-populated phased arrays and, as a result, they have not been fully exploited for therapy delivery to date. However, recent research has made the construction of such arrays feasible, and it is expected that their continued development will both greatly improve the safety and efficacy of existing ultrasound therapies as well as enable treatments that are not currently possible with existing technology. This review will summarize the basic principles, current statures, and future potential of image-guided ultrasound phased arrays for therapy. PMID:27494561

Role of NK cells in immunotherapy and virotherapy of solid tumors.

PubMed

Cantoni, Claudia; Grauwet, Korneel; Pietra, Gabriella; Parodi, Monica; Mingari, Maria Cristina; Maria, Andrea De; Favoreel, Herman; Vitale, Massimo

2015-01-01

Although natural killer (NK) cells are endowed with powerful cytolytic activity against cancer cells, their role in different therapies against solid tumors has not yet been fully elucidated. Their interactions with various elements of the tumor microenvironment as well as their possible effects in contributing to and/or limiting oncolytic virotherapy render this potential immunotherapeutic tool still difficult to exploit at the bedside. Here, we will review the current literature with the aim of providing new hints to manage this powerful cell type in future innovative therapies, such as the use of NK cells in combination with new cytokines, specific mAbs (inducing ADCC), Tyr-Kinase inhibitors, immunomodulatory drugs and/or the design of oncolytic viruses aimed at optimizing the effect of NK cells in virotherapy.

Analgesics for orthopedic postoperative pain.

PubMed

Bourne, Michael H

2004-03-01

Postoperative pain management is critical for optimal care of orthopedic surgery patients. Opioids, administered intramuscularly, as epidurals, or IV as patient-controlled analgesia, are effective for severe pain. Adjunctive therapy and preemptive analgesia such as nerve blocks, and methods of delivery such as infusion pumps, may be used after total knee arthroplasty and anterior cruciate ligament (ACL) reconstruction. Oral opioids are effective for moderate to severe pain, and tramadol, with efficacy comparable to morphine but with fewer severe side effects, is selected for moderate to moderately severe pain. Opioid-sparing NSAIDs, such as ketorolac, and COX-2-specific NSAIDS have use in pain management of hip, knee, and ACL procedures. An individualized regimen of appropriate analgesics, combined with nonpharmacologic treatments such as physical therapy or cryotherapy and patient education, can aid orthopedic surgery patients' recovery.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swanson, K; Corwin, D; Rockne, R

Purpose: To demonstrate a method of generating patient-specific, biologically-guided radiation therapy (RT) plans and to quantify and predict response to RT in glioblastoma. We investigate the biological correlates and imaging physics driving T2-MRI based response to radiation therapy using an MRI simulator. Methods: We have integrated a patient-specific biomathematical model of glioblastoma proliferation, invasion and radiotherapy with a multiobjective evolutionary algorithm for intensity-modulated RT optimization to construct individualized, biologically-guided plans. Patient-individualized simulations of the standard-of-care and optimized plans are compared in terms of several biological metrics quantified on MRI. An extension of the PI model is used to investigate themore » role of angiogenesis and its correlates in glioma response to therapy with the Proliferation-Invasion-Hypoxia- Necrosis-Angiogenesis model (PIHNA). The PIHNA model is used with a brain tissue phantom to predict tumor-induced vasogenic edema, tumor and tissue density that is used in a multi-compartmental MRI signal equation for generation of simulated T2- weighted MRIs. Results: Applying a novel metric of treatment response (Days Gained) to the patient-individualized simulation results predicted that the optimized RT plans would have a significant impact on delaying tumor progression, with Days Gained increases from 21% to 105%. For the T2- MRI simulations, initial validation tests compared average simulated T2 values for white matter, tumor, and peripheral edema to values cited in the literature. Simulated results closely match the characteristic T2 value for each tissue. Conclusion: Patient-individualized simulations using the combination of a biomathematical model with an optimization algorithm for RT generated biologically-guided doses that decreased normal tissue dose and increased therapeutic ratio with the potential to improve survival outcomes for treatment of glioblastoma. Simulated T2-MRI is shown to be consistent with known physics of MRI and can be used to further investigate biological drivers of imaging-based response to RT.« less

Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study

PubMed Central

Martin, N K; Robey, I F; Gaffney, E A; Gillies, R J; Gatenby, R A; Maini, P K

2012-01-01

Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts. Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies. Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2. Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising. PMID:22382688

Relationships among optimism, well-being, self-transcendence, coping, and social support in women during treatment for breast cancer

PubMed Central

Matthews, Ellyn E.; Cook, Paul F.

2011-01-01

Objective The impact of diagnosis and treatment for breast cancer, stressors that affect emotional well-being, is influenced by several psychosocial factors and the relationships among them. The purpose of this study was to investigate the relationship between optimism and emotional well-being (EWB) and the individual and combined mediation of this relationship by perceived social support (SS), problem focused coping (PFC), and self-transcendence in women with breast cancer during radiation therapy. Methods Ninety-three women receiving radiation treatment for breast cancer completed questionnaires that measured EWB, optimism, SS, PFC, and self-transcendence. Results Correlational and multiple regression analysis revealed that optimism was positively related to EWB. Of the three mediators, self-transcendence alone was found to partially mediate the relationship between optimism and EWB. The relationship between optimism and PFC was not significant. Optimism was related to SS, but its indirect effect on EWB through SS did not reach significance. Conclusions and implications During breast cancer treatment, the positive effects of optimism on EWB are partially mediated by a woman’s level of self-transcendence. Brief screening of women’s optimism may help identify women at risk for psychological distress. Early detection and interventions to promote psychological adjustment throughout the cancer trajectory (e.g. enhancing self-transcendence) should receive attention in future research. PMID:19034884

Machine learning-based patient specific prompt-gamma dose monitoring in proton therapy

NASA Astrophysics Data System (ADS)

Gueth, P.; Dauvergne, D.; Freud, N.; Létang, J. M.; Ray, C.; Testa, E.; Sarrut, D.

2013-07-01

Online dose monitoring in proton therapy is currently being investigated with prompt-gamma (PG) devices. PG emission was shown to be correlated with dose deposition. This relationship is mostly unknown under real conditions. We propose a machine learning approach based on simulations to create optimized treatment-specific classifiers that detect discrepancies between planned and delivered dose. Simulations were performed with the Monte-Carlo platform Gate/Geant4 for a spot-scanning proton therapy treatment and a PG camera prototype currently under investigation. The method first builds a learning set of perturbed situations corresponding to a range of patient translation. This set is then used to train a combined classifier using distal falloff and registered correlation measures. Classifier performances were evaluated using receiver operating characteristic curves and maximum associated specificity and sensitivity. A leave-one-out study showed that it is possible to detect discrepancies of 5 mm with specificity and sensitivity of 85% whereas using only distal falloff decreases the sensitivity down to 77% on the same data set. The proposed method could help to evaluate performance and to optimize the design of PG monitoring devices. It is generic: other learning sets of deviations, other measures and other types of classifiers could be studied to potentially reach better performance. At the moment, the main limitation lies in the computation time needed to perform the simulations.

Prophylaxis versus treatment: Is there a better way to manage radiotherapy-induced nausea and vomiting?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Horiot, Jean-Claude

Nausea and vomiting are two of the most distressing side effects of radiotherapy and cytotoxic drugs, which currently are often combined to treat moderately advanced and advanced solid tumors. Inadequate control of these symptoms may result in significant patient suffering and decrease in the patient's quality of life, which has been shown to decrease patients' compliance to treatment, with potential impact on disease outcome. It is, therefore, important that radiation oncologists recognize the need for adequate prophylactic treatment of radiation-induced nausea and vomiting (RINV) to avoid the detrimental effects on patients' quality of life, and optimize chances for cure. Themore » 5-hydroxytryptamine type 3 (5-HT{sub 3})-receptor antagonists have been proved to provide effective antiemetic therapy in patients undergoing highly emetogenic radiotherapy. Nevertheless, several large surveys have shown that optimal treatments are not always used. Hence, a risk exists that waiting for RINV symptoms rather than prescribing prophylactic antiemetic treatment may lead to increased patient suffering, poorer disease control, and less cost-effective therapy options. Prophylactic management with an effective 5-HT{sub 3}-receptor antagonist should offer a better treatment option for patients at high to moderate risk of RINV. Adequate control of RINV should contribute to patient compliance to treatment, improved therapy outcomes, and decreased burdens on nursing and health care resources.« less

Non-surgical treatments for the management of early osteoarthritis.

PubMed

Filardo, Giuseppe; Kon, Elizaveta; Longo, Umile Giuseppe; Madry, Henning; Marchettini, Paolo; Marmotti, Antonio; Van Assche, Dieter; Zanon, Giacomo; Peretti, Giuseppe M

2016-06-01

Non-surgical treatments are usually the first choice for the management of knee degeneration, especially in the early osteoarthritis (OA) phase when no clear lesions or combined abnormalities need to be addressed surgically. Early OA may be addressed by a wide range of non-surgical approaches, from non-pharmacological modalities to dietary supplements and pharmacological therapies, as well as physical therapies and novel biological minimally invasive procedures involving injections of various substances to obtain a clinical improvement and possibly a disease-modifying effect. Numerous pharmaceutical agents are able to provide clinical benefit, but no one has shown all the characteristic of an ideal treatment, and side effects have been reported at both systemic and local level. Patients and physicians should have realistic outcome goals in pharmacological treatment, which should be considered together with other conservative measures. Among these, exercise is an effective conservative approach, while physical therapies lack literature support. Even though a combination of these therapeutic options might be the most suitable strategy, there is a paucity of studies focusing on combining treatments, which is the most common clinical scenario. Further studies are needed to increase the limited evidence on non-surgical treatments and their combination, to optimize indications, application modalities, and results with particular focus on early OA. In fact, most of the available evidence regards established OA. Increased knowledge about degeneration mechanisms will help to better target the available treatments and develop new biological options, where preliminary results are promising, especially concerning early disease phases. Specific treatments aimed at improving joint homoeostasis, or even counteracting tissue damage by inducing regenerative processes, might be successful in early OA, where tissue loss and anatomical changes are still at very initial stages.

A combination therapy of neural and glial restricted precursor cells and chronic quipazine treatment paired with passive cycling promotes quipazine-induced stepping in adult spinalized rats.

PubMed

Dugan, Elizabeth A; Shumsky, Jed S

2015-11-01

In order to develop optimal treatments to promote recovery from complete spinal cord injury (SCI), we examined the combination of: (1) a cellular graft of neural and glial restricted precursor (NRP/GRP) cells, (2) passive exercise, and (3) chronic quipazine treatment on behavioral outcomes and compared them with the individual treatment elements. NRP/GRP cells were transplanted at the time of spinalization. Daily passive exercise began 1 week after injury to give sufficient time for the animals to recover. Chronic quipazine administration began 2 weeks after spinalization to allow for sufficient receptor upregulation permitting the expression of its behavioral effects. Behavioral measures consisted of the Basso, Beattie, and Bresnahan (BBB) locomotor score and percent of weight-supported steps and hops on a treadmill. Rats displayed an increased response to quipazine (BBB ≥ 9) beginning at 8 weeks post-injury in all the animals that received the combination therapy. This increase in BBB score was persistent through the end of the study (12 weeks post-injury). Unlike the individual treatment groups which never achieved weight support, the combination therapy animals were able to perform uncoordinated weight-supported stepping without a body weight support system while on a moving treadmill (6.5 m per minute) and were capable of supporting their own weight in stance during open field locomotion testing. No regeneration of descending serotonergic projections into and through the lesion cavity was observed. Furthermore, these results are a testament to the capacity of the lumbar spinal cord, when properly stimulated, to sustain functioning locomotor circuitry following complete SCI.

Optimal use of novel agents in chronic lymphocytic leukemia.

PubMed

Smith, Mitchell R; Weiss, Robert F

2018-05-07

Novel agents are changing therapy for patients with CLL, but their optimal use remains unclear. We model the clinical situation in which CLL responds to therapy, but resistant clones, generally carrying del17p, progress and lead to relapse. Sub-clones of varying growth rates and treatment sensitivity affect predicted therapy outcomes. We explore effects of different approaches to starting novel agent in relation to bendamustine-rituximab induction therapy: at initiation of therapy, at the end of chemo-immunotherapy, at molecular relapse, or at clinical detection of relapse. The outcomes differ depending on the underlying clonal architecture, raising the concept that personalized approaches based on clinical evaluation of each patient's clonal architecture might optimize outcomes while minimizing toxicity and cost. Copyright © 2018 Elsevier Ltd. All rights reserved.

Real-Time Dosimetry and Optimization of Prostate Photodynamic Therapy

DTIC Science & Technology

2006-09-01

photodynamic therapy in patients with prostate cancer,” IPA 9th World Congress of Photodynamic Medicine, (2003). 2. Zhu TC, Diana S, Dimofte A...photodynamic therapy,” IPA 9th World Congress of Photodynamic Medicine, (2003). 3. Zhu TC, Altschuler M, Xiao Y, Finlay J, Dimofte A, Hahn SM, “Light...Optimization of treatment plan using Cimmino algorithm in prostate photodynamic therapy,” IPA 10th World Congress of Photodynamic Medicine, Munich

Optimizing Tumor Microenvironment for Cancer Immunotherapy: β-Glucan-Based Nanoparticles

PubMed Central

Zhang, Mei; Kim, Julian A.; Huang, Alex Yee-Chen

2018-01-01

Immunotherapy is revolutionizing cancer treatment. Recent clinical success with immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and adoptive immune cellular therapies has generated excitement and new hopes for patients and investigators. However, clinically efficacious responses to cancer immunotherapy occur only in a minority of patients. One reason is the tumor microenvironment (TME), which potently inhibits the generation and delivery of optimal antitumor immune responses. As our understanding of TME continues to grow, strategies are being developed to change the TME toward one that augments the emergence of strong antitumor immunity. These strategies include eliminating tumor bulk to provoke the release of tumor antigens, using adjuvants to enhance antigen-presenting cell function, and employ agents that enhance immune cell effector activity. This article reviews the development of β-glucan and β-glucan-based nanoparticles as immune modulators of TME, as well as their potential benefit and future therapeutic applications. Cell-wall β-glucans from natural sources including plant, fungi, and bacteria are molecules that adopt pathogen-associated molecular pattern (PAMP) known to target specific receptors on immune cell subsets. Emerging data suggest that the TME can be actively manipulated by β-glucans and their related nanoparticles. In this review, we discuss the mechanisms of conditioning TME using β-glucan and β-glucan-based nanoparticles, and how this strategy enables future design of optimal combination cancer immunotherapies. PMID:29535722

Plan averaging for multicriteria navigation of sliding window IMRT and VMAT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Craft, David, E-mail: dcraft@partners.org; Papp, Dávid; Unkelbach, Jan

2014-02-15

Purpose: To describe a method for combining sliding window plans [intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT)] for use in treatment plan averaging, which is needed for Pareto surface navigation based multicriteria treatment planning. Methods: The authors show that by taking an appropriately defined average of leaf trajectories of sliding window plans, the authors obtain a sliding window plan whose fluence map is the exact average of the fluence maps corresponding to the initial plans. In the case of static-beam IMRT, this also implies that the dose distribution of the averaged plan is the exact dosimetricmore » average of the initial plans. In VMAT delivery, the dose distribution of the averaged plan is a close approximation of the dosimetric average of the initial plans. Results: The authors demonstrate the method on three Pareto optimal VMAT plans created for a demanding paraspinal case, where the tumor surrounds the spinal cord. The results show that the leaf averaged plans yield dose distributions that approximate the dosimetric averages of the precomputed Pareto optimal plans well. Conclusions: The proposed method enables the navigation of deliverable Pareto optimal plans directly, i.e., interactive multicriteria exploration of deliverable sliding window IMRT and VMAT plans, eliminating the need for a sequencing step after navigation and hence the dose degradation that is caused by such a sequencing step.« less

Co-delivery of chemotherapeutics and proteins for synergistic therapy.

PubMed

He, Chaoliang; Tang, Zhaohui; Tian, Huayu; Chen, Xuesi

2016-03-01

Combination therapy with chemotherapeutics and protein therapeutics, typically cytokines and antibodies, has been a type of crucial approaches for synergistic cancer treatment. However, conventional approaches by simultaneous administration of free chemotherapeutic drugs and proteins lead to limitations for further optimizing the synergistic effects, due to the distinct in vivo pharmacokinetics and distribution of small drugs and proteins, insufficient tumor selectivity and tumor accumulation, unpredictable drug/protein ratios at tumor sites, short half-lives, and serious systemic adverse effects. Consequently, to obtain optimal synergistic anti-tumor efficacy, considerable efforts have been devoted to develop the co-delivery systems for co-incorporating chemotherapeutics and proteins into a single carrier system and subsequently releasing the dual or multiple payloads at desired target sites in a more controllable manner. The co-delivery systems result in markedly enhanced blood stability and in vivo half-lives of the small drugs and proteins, elevated tumor accumulation, as well as the capability of delivering the multiple agents to the same target sites with rational drug/protein ratios, which may facilitate maximizing the synergistic effects and therefore lead to optimal antitumor efficacy. This review emphasizes the recent advances in the co-delivery systems for chemotherapeutics and proteins, typically cytokines and antibodies, for systemic or localized synergistic cancer treatment. Moreover, the proposed mechanisms responsible for the synergy of chemotherapeutic drugs and proteins are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Selectivity and Efficiency of Late Transgene Expression by Transcriptionally Targeted Oncolytic Adenoviruses Are Dependent on the Transgene Insertion Strategy

PubMed Central

Quirin, Christina; Rohmer, Stanimira; Fernández-Ulibarri, Inés; Behr, Michael; Hesse, Andrea; Engelhardt, Sarah; Erbs, Philippe; Enk, Alexander H.

2011-01-01

Abstract Key challenges facing cancer therapy are the development of tumor-specific drugs and potent multimodal regimens. Oncolytic adenoviruses possess the potential to realize both aims by restricting virus replication to tumors and inserting therapeutic genes into the virus genome, respectively. A major effort in this regard is to express transgenes in a tumor-specific manner without affecting virus replication. Using both luciferase as a sensitive reporter and genetic prodrug activation, we show that promoter control of E1A facilitates highly selective expression of transgenes inserted into the late transcription unit. This, however, required multistep optimization of late transgene expression. Transgene insertion via internal ribosome entry site (IRES), splice acceptor (SA), or viral 2A sequences resulted in replication-dependent expression. Unexpectedly, analyses in appropriate substrates and with matching control viruses revealed that IRES and SA, but not 2A, facilitated indirect transgene targeting via tyrosinase promoter control of E1A. Transgene expression via SA was more selective (up to 1,500-fold) but less effective than via IRES. Notably, we also revealed transgene-dependent interference with splicing. Hence, the prodrug convertase FCU1 (a cytosine deaminase–uracil phosphoribosyltransferase fusion protein) was expressed only after optimizing the sequence surrounding the SA site and mutating a cryptic splice site within the transgene. The resulting tyrosinase promoter-regulated and FCU1-encoding adenovirus combined effective oncolysis with targeted prodrug activation therapy of melanoma. Thus, prodrug activation showed potent bystander killing and increased cytotoxicity of the virus up to 10-fold. We conclude that armed oncolytic viruses can be improved substantially by comparing and optimizing strategies for targeted transgene expression, thereby implementing selective and multimodal cancer therapies. PMID:20939692

Conceptuation, formulation and evaluation of sustained release floating tablets of captopril compression coated with gastric dispersible hydrochlorothiazide using 23 factorial design

PubMed Central

Sirisha, Pathuri Lakshmi; Babu, Govada Kishore; Babu, Puttagunta Srinivasa

2014-01-01

Ambulatory blood pressure monitoring is regarded as the gold standard for hypertensive therapy in non-dipping hypertension patients. A novel compression coated formulation of captopril and hydrochlorothiazide (HCTZ) was developed in order to improve the efficacy of antihypertensive therapy considering the half-life of both drugs. The synergistic action using combination therapy can be effectively achieved by sustained release captopril (t1/2= 2.5 h) and fast releasing HCTZ (average t1/2= 9.5 h). The sustained release floating tablets of captopril were prepared by using 23 factorial design by employing three polymers i.e., ethyl cellulose (EC), carbopol and xanthan gum at two levels. The formulations (CF1-CF8) were optimized using analysis of variance for two response variables, buoyancy and T50%. Among the three polymers employed, the coefficients and P values for the response variable buoyancy and T50% using EC were found to be 3.824, 0.028 and 0.0196, 0.046 respectively. From the coefficients and P values for the two response variables, formulation CF2 was optimized, which contains EC polymer alone at a high level. The CF2 formulation was further compression coated with optimized gastric dispersible HCTZ layer (HF9). The compression coated tablet was further evaluated using drug release kinetics. The Q value of HCTZ layer is achieved within 20 min following first order release whereas the Q value of captopril was obtained at 6.5 h following Higuchi model, from which it is proved that rapid release HCTZ and slow release of captopril is achieved. The mechanism of drug release was analyzed using Peppas equation, which showed an n >0.90 confirming case II transportation mechanism for drug release. PMID:25006552

Hormone therapy in acne.

PubMed

Lakshmi, Chembolli

2013-01-01

Underlying hormone imbalances may render acne unresponsive to conventional therapy. Relevant investigations followed by initiation of hormonal therapy in combination with regular anti-acne therapy may be necessary if signs of hyperandrogenism are present. In addition to other factors, androgen-stimulated sebum production plays an important role in the pathophysiology of acne in women. Sebum production is also regulated by other hormones, including estrogens, growth hormone, insulin, insulin-like growth factor-1, glucocorticoids, adrenocorticotropic hormone, and melanocortins. Hormonal therapy may also be beneficial in female acne patients with normal serum androgen levels. An understanding of the sebaceous gland and the hormonal influences in the pathogenesis of acne would be essential for optimizing hormonal therapy. Sebocytes form the sebaceous gland. Human sebocytes express a multitude of receptors, including receptors for peptide hormones, neurotransmitters and the receptors for steroid and thyroid hormones. Various hormones and mediators acting through the sebocyte receptors play a role in the orchestration of pathogenetic lesions of acne. Thus, the goal of hormonal treatment is a reduction in sebum production. This review shall focus on hormonal influences in the elicitation of acne via the sebocyte receptors, pathways of cutaneous androgen metabolism, various clinical scenarios and syndromes associated with acne, and the available therapeutic armamentarium of hormones and drugs having hormone-like actions in the treatment of acne.

Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome

PubMed Central

Raghavendran, Krishnan; Pryhuber, Gloria S.; Chess, Patricia R.; Davidson, Bruce A.; Knight, Paul R.; Notter, Robert H.

2009-01-01

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article. PMID:18691048

Maraviroc (Celsentri) for multidrug-resistant human immunodeficiency virus (HIV)-1.

PubMed

Ndegwa, S

2007-12-01

(1) Maraviroc belongs to a new class of antiretroviral drugs designed to block entry of HIV-1 into CD4+ T-cells via the CCR5 coreceptor. It is indicated for combination therapy in treatment-experienced adults infected with CCR5-tropic HIV-1 that is resistant to multiple antiretroviral agents. (2) Results from two randomized controlled trials (RCTs) indicate that in treatment experienced patients, maraviroc, combined with optimized background therapy (OBT), significantly decreases the level of HIV-1 RNA in the blood (viral load) when compared with OBT alone. The number of patients achieving undetectable viral loads and CD4+ cell count increases were also significantly higher in those receiving maraviroc. (3) Most patients experiencing treatment failure with maraviroc exhibit tropism changes from CCR5-tropic to CXCR4-using virus, but there is no evidence of disease progression. (4) Adverse effects reported with maraviroc include cough, fever, upper respiratory tract infections, rash, muscle and joint pain, abdominal pain, and postural hypotension (dizziness). No significant increases in cardiovascular events, hepatotoxicity, infections or malignancies have been reported with short-term maraviroc therapy. Several post-marketing studies will assess maraviroc's long-term safety for immune function, liver function, malignancy, cardiac events, and risks associated with changes in tropism. (5) Results from an ongoing trial in treatment naive patients suggest that maraviroc may not be superior in terms of viral suppression to standard therapy, but may significantly increase the number of CD4+ T-cells.

Effect of Combined Manual Acupuncture and Massage on Body Weight and Body Mass Index Reduction in Obese and Overweight Women: A Randomized, Short-term Clinical Trial.

PubMed

He, Junfeng; Zhang, Xing; Qu, Yating; Huang, Huiyong; Liu, Xia; Du, Jia; Guo, Shengtong

2015-04-01

Obesity is one of the leading health risk factors worldwide and is associated with several other risk factors and health problems. Acupuncture is utilized to treat a variety of health problems, one of which is obesity. Fifty-six obese women with body mass index (BMI) ≥25 kg/m(2) were recruited for this trial and were randomly divided into two groups, one with combined manual acupuncture and massage therapy (MAMT), and the other with only manual acupuncture therapy (MAT). In addition, 40 overweight women with BMI 23-25 kg/m(2) were randomly divided into two groups, one with MAMT and the other with MAT. Therapy was carried out once per day for 21 days, and the body weights and the BMIs were recorded every day. The results showed that both MAMT and MAT could reduce body weight and BMI significantly, compared with the pretreatment values, for all the participants (p < 0.001); however, the differences in body weight and BMI reductions between pre- and posttreatment for the MAMT and the MAT groups were not statistically significant. The optimal periods for reductions in both body weight and in BMI were the first 4 days. Accounting for the economic strategy (time and money) in alternative therapy, MAT alone may present a reasonable option in the treatment of overweight and obesity in adults. Copyright © 2015. Published by Elsevier B.V.

Multidisciplinary, multimodal approach for a child with a traumatic facial scar.

PubMed

Admani, Shehla; Gertner, Jeffrey W; Grosman, Amanda; Shumaker, Peter R; Uebelhoer, Nathan S; Krakowski, Andrew C

2015-03-01

The treatment of disfiguring and disabling scars remains a field of active study, reinvigorated with recent advances in techniques and technologies. A variety of approaches can be utilized depending on scar characteristics, location, degree of tissue loss, and associated contractures. Just as traumatic scars can be complex and heterogeneous, the corresponding paradigm for treatment must also be flexible and multimodal for optimal improvement. This report describes a 3-year-old girl with a "mixed" (atrophic/hypertrophic), violaceous, contracted facial scar from a dog bite. It was treated with a novel approach utilizing a multidisciplinary pediatric scar team to combine autologous fat grafting, ablative fractional laser resurfacing, pulsed-dye laser, and laser-assisted delivery of a corticosteroid as concurrent, multimodal therapy to optimize the outcome. ©2015 Frontline Medical Communications.

Treatment strategy for a multidrug-resistant Klebsiella UTI.

PubMed

Fleming, Erin; Heil, Emily L; Hynicka, Lauren M

2014-01-01

To describe the management strategy for a multidrug-resistant (MDR) Klebsiella urinary tract infection (UTI). A 69-year-old Caucasian woman with a past medical history of recurrent UTIs and a right-lung transplant presented with fever to 101.4°F, chills, malaise, and cloudy, foul-smelling urine for approximately 1 week. She was found to have a MDR Klebsiella UTI that was sensitive to tigecycline and cefepime. To further evaluate the degree of resistance Etest minimum inhibitory concentrations were requested for cefepime, amikacin, meropenem, and ertapenem. The patient received a 14-day course of amikacin, which resulted in resolution of her symptoms. One month later, the patient's UTI symptoms returned. The urine culture again grew MDR Klebsiella, sensitive only to tigecycline. Fosfomycin was initiated and resulted in limited resolution of her symptoms. Colistin was started, however, therapy was discontinued on day 5 secondary to the development of acute kidney injury. Despite the short course of therapy, the patient's symptoms resolved. The case presented lends itself well to numerous discussion items that are important to consider when determining optimal treatment for MDR Gram-negative bacilli (GNBs). Susceptibility testing is an important tool for optimizing antibiotic therapy, however, automated systems may overestimate the susceptibility profile for a MDR GNB. Treatment strategies evaluated to treat MDR GNB, include combination therapy with a carbepenem and synergy using polymyxin. We have described the management strategy for a MDR Klebsiella UTI, the consequences of the initial management strategy, and potential strategies to manage these types of infections in future patients.

Research on NC laser combined cutting optimization model of sheet metal parts

NASA Astrophysics Data System (ADS)

Wu, Z. Y.; Zhang, Y. L.; Li, L.; Wu, L. H.; Liu, N. B.

2017-09-01

The optimization problem for NC laser combined cutting of sheet metal parts was taken as the research object in this paper. The problem included two contents: combined packing optimization and combined cutting path optimization. In the problem of combined packing optimization, the method of “genetic algorithm + gravity center NFP + geometric transformation” was used to optimize the packing of sheet metal parts. In the problem of combined cutting path optimization, the mathematical model of cutting path optimization was established based on the parts cutting constraint rules of internal contour priority and cross cutting. The model played an important role in the optimization calculation of NC laser combined cutting.

Fasudil Enhances Therapeutic Efficacy of Neural Stem Cells in the Mouse Model of MPTP-Induced Parkinson's Disease.

PubMed

Li, Yan-Hua; Yu, Jing-Wen; Xi, Jian-Yin; Yu, Wen-Bo; Liu, Jian-Chun; Wang, Qing; Song, Li-Juan; Feng, Ling; Yan, Ya-Ping; Zhang, Guang-Xian; Xiao, Bao-Guo; Ma, Cun-Gen

2017-09-01

Bone marrow-derived neural stem cells (NSCs) are ideal cells for cellular therapy because of their therapeutic potential for repairing and regenerating damaged neurons. However, the optimization of implanted cells and the improvement of microenvironment in the central nervous system (CNS) are still two critical elements for enhancing therapeutic effect. In the current study, we observed the combined therapeutic effect of NSCs with fasudil in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model and explored the possible cellular and molecular mechanisms. The results clearly show that combined treatment of NSCs with fasudil further improves motor capacity of PD mice, thus exerting double effect in treating MPTP-PD. The combined intervention more effectively protected dopaminergic (DA) neurons from loss in the substantia nigra pars compacta (SNpc), which may be associated with the increased number and survival of transplanted NSCs in the brain. Compared with the treatment of fasudil or NSCs alone, the combined intervention more effectively inhibited the activation and aggregation of microglia and astrocytes, displayed stronger anti-inflammatory and antioxidant effects, induced more neurotrophic factor NT-3, and affected the dynamic homeostasis of NMDA and AMPA receptors in MPTP-PD mice. Our study demonstrates that intranasal administration of NSCs, followed by fasudil administration, is a promising cell-based therapy for neuronal lesions.

Calcium channel blockers in hypertension. Is there still a controversy?

PubMed

Izzo, Joseph L

2005-08-01

There are several reasons why no single antihypertensive drug class is ideal in all clinical situations. First, pathophysiologic heterogeneity in hypertension and diversity of mechanisms of antihypertensive drugs dictate that no single drug class can be optimally effective in all subpopulations. Second, sustained blood pressure control generally requires combination therapy to block the reflex stimulation of physiologic mechanisms that attempt to restore blood pressure to pretreatment levels. Third, while effective blood pressure control is more important than choice of initial drug in the prevention of hypertension-related morbidity and mortality, specific drug classes are indicated for optimal treatment of complications of hypertension (e.g. heart failure, kidney disease). Fourth, although antihypertensive drug side effects are uncommon, alternative strategies are required in some patients. Given these principles, past controversies regarding whether calcium channel blockers (CCBs) should be used in the treatment of hypertension become moot. CCBs are extremely effective in lowering blood pressure and in preventing stroke and cardiovascular disease. When additional blood pressure lowering is necessary to meet strict targets, CCBs may be added, even in heart failure or chronic kidney disease, where CCBs alone may not achieve optimal outcomes. Combinations of CCBs with "anti-neurohumoral" drugs such as ACE inhibitors are particularly useful to achieve sustained blood pressure control, reduce adverse effects such as edema, and improve outcomes.

I-SWOT as instrument to individually optimize therapy of thoracoabdominal aortic aneurysms: Effective, norm-compliant and meeting the needs.

PubMed

Sachweh, A; von Kodolitsch, Y; Kölbel, T; Larena-Avellaneda, A; Wipper, S; Bernhardt, A M; Girdauskas, E; Detter, C; Reichenspurner, H; Blankart, C R; Debus, E S

2017-01-01

Guidelines summarize medical evidence, they identify the most efficient therapy under study conditions and recommend this therapy for use. The physician now has the challenge to translate a therapy that is efficient under laboratory conditions to a patient who is an individual person. To accomplish this task the physician has to make sure that (I) the ideal typical therapy is applicable and effective in this individual patient taking the special features into consideration, that (II) therapy is compliant with the norm including guidelines, laws and ethical requirements (conformity) and that (III) the therapy meets the patient's needs. How can physicians together with the patients translate the medical evidence into an individually optimized therapy? At the German Aortic Center in Hamburg we use I‑SWOT as an instrument to identify such individually optimized therapy. With I‑SWOT, we present an instrument with which we have developed an (I) efficient, (II) conform and (III) needs-oriented therapeutic strategy for individual patients. I-SWOT cross-tabulates strengths (S) and weaknesses (W) related to therapy with opportunities (O) and threats (T) related to individual patients. This I‑SWOT matrix identifies four fundamental types of strategy, which comprise "SO" maximizing strengths and opportunities, "WT" minimizing weaknesses and threats, "WO" minimizing weaknesses and maximizing opportunities and "ST" maximizing strengths and minimizing threats. We discuss the case of a patient with asymptomatic thoracoabdominal aneurysm to show how I‑SWOT is used to identify an individually optimized therapy strategy.

Clinical feasibility of exercise-based A-V interval optimization for cardiac resynchronization: a pilot study.

PubMed

Choudhuri, Indrajit; MacCarter, Dean; Shaw, Rachael; Anderson, Steve; St Cyr, John; Niazi, Imran

2014-11-01

One-third of eligible patients fail to respond to cardiac resynchronization therapy (CRT). Current methods to "optimize" the atrio-ventricular (A-V) interval are performed at rest, which may limit its efficacy during daily activities. We hypothesized that low-intensity cardiopulmonary exercise testing (CPX) could identify the most favorable physiologic combination of specific gas exchange parameters reflecting pulmonary blood flow or cardiac output, stroke volume, and left atrial pressure to guide determination of the optimal A-V interval. We assessed relative feasibility of determining the optimal A-V interval by three methods in 17 patients who underwent optimization of CRT: (1) resting echocardiographic optimization (the Ritter method), (2) resting electrical optimization (intrinsic A-V interval and QRS duration), and (3) during low-intensity, steady-state CPX. Five sequential, incremental A-V intervals were programmed in each method. Assessment of cardiopulmonary stability and potential influence on the CPX-based method were assessed. CPX and determination of a physiological optimal A-V interval was successfully completed in 94.1% of patients, slightly higher than the resting echo-based approach (88.2%). There was a wide variation in the optimal A-V delay determined by each method. There was no observed cardiopulmonary instability or impact of the implant procedure that affected determination of the CPX-based optimized A-V interval. Determining optimized A-V intervals by CPX is feasible. Proposed mechanisms explaining this finding and long-term impact require further study. ©2014 Wiley Periodicals, Inc.

The clinical benefit of cardiac resynchronization therapy optimization using a device-based hemodynamic sensor in a patient with dilated cardiomyopathy: a case report.

PubMed

Volpicelli, Mario; Covino, Gregorio; Capogrosso, Paolo

2015-12-19

Results on the evolution of the clinical status of patients undergoing cardiac resynchronization therapy with a defibrillator after automatic optimization of their cardiac resynchronization therapy are scarce. We observed a rapid and important change in the clinical status of our non-responding patient following activation of a sensor capable of weekly atrioventricular and interventricular delays' optimization. A 78-year-old Caucasian man presented with dilated cardiomyopathy, left bundle branch block, a left ventricular ejection fraction of 35 %, New York Heart Association class III/IV heart failure, and paroxysmal atrial fibrillation. Our patient was implanted with a cardiac resynchronization device with a defibrillator and the SonRtip atrial lead. Right ventricular and left ventricular leads were also implanted. Because of the recurrence of atrial fibrillation, the automatic optimization was set off at discharge. Consequently, the device did not optimize atrioventricular and interventricular delays (programming at discharge: 125 ms for the atrioventricular delay and 0 ms for the interventriculardelay). Our patient was treated with an anti-arrhythmic drug. Five months after implantation, his clinical status remained impaired (left ventricular ejection fraction = 30 %). The SonR signal amplitude had also decreased from 0.52 g to 0.29 g. Nevertheless, because our patient was no longer presenting with atrial fibrillation, the anti-arrhythmic treatment was stopped and the SonR optimization system was activated. After 2 months of automatic cardiac resynchronization therapy with defibrillator optimization, our patient's clinical status had significantly improved (left ventricular ejection fraction = 60 %, New York Heart Association class II) and the SonR signal amplitude had doubled shortly after the first weekly automatic optimization. In this non-responding patient, device-based automatic cardiac resynchronization therapy optimization was shown to significantly improve his clinical status.

Optimal Management of Metastatic Melanoma: Current Strategies and Future Directions

PubMed Central

Batus, Marta; Waheed, Salman; Ruby, Carl; Petersen, Lindsay; Bines, Steven D.; Kaufman, Howard L.

2013-01-01

Melanoma is increasing in incidence and remains a major public health threat. Although the disease may be curable when identified early, advanced melanoma is characterized by widespread metastatic disease and a median survival of less than 10 months. In recent years, however, major advances in our understanding of the molecular nature of melanoma and the interaction of melanoma cells with the immune system have resulted in several new therapeutic strategies that are showing significant clinical benefit. Current therapeutic approaches include surgical resection of metastatic disease, chemotherapy, immunotherapy, and targeted therapy. Dacarbazine, interleukin-2, ipilimumab, and vemurafenib are now approved for the treatment of advanced melanoma. In addition, new combination chemotherapy regimens, monoclonal antibodies blocking the programmed death-1 (PD-1)/PD-ligand 1 pathway, and targeted therapy against CKIT, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and other putative signaling pathways in melanoma are beginning to show promise in early-phase clinical trials. Further research on these modalities alone and in combination will likely be the focus of future clinical investigation and may impact the outcomes for patients with advanced melanoma. PMID:23677693

Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies

PubMed Central

Steckel, Michael; Molina-Arcas, Miriam; Weigelt, Britta; Marani, Michaela; Warne, Patricia H; Kuznetsov, Hanna; Kelly, Gavin; Saunders, Becky; Howell, Michael; Downward, Julian; Hancock, David C

2012-01-01

Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy. PMID:22613949

Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer.

PubMed

Lousberg, Laurence; Jerusalem, Guy

2016-01-01

Everolimus combined with exemestane is an important treatment option for patients suffering from estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (ABC) who have been previously treated with a nonsteroidal aromatase inhibitor (NSAI). After presentation of phase III registration trial BOLERO-2, several phase IIIb trials have been started to evaluate this regimen in a more real-world setting. Here, we review the efficacy and safety data published or presented at selected international meetings. These studies confirmed the outcome observed in the BOLERO-2 trial. Patient acceptance rate is also discussed by focusing on the permanent everolimus discontinuation rate in these trials. Factors influencing the safety profile are also reported, including the impact of age. The optimal sequence of combined therapy approaches associating targeted and endocrine therapy (ET) has yet to be determined as new treatment options such as cyclin-dependent kinase inhibitors become available. However, everolimus-exemestane remains an important treatment option with a major impact on progression-free survival (PFS) and an acceptable safety profile.

Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer

PubMed Central

Lousberg, Laurence; Jerusalem, Guy

2016-01-01

Everolimus combined with exemestane is an important treatment option for patients suffering from estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (ABC) who have been previously treated with a nonsteroidal aromatase inhibitor (NSAI). After presentation of phase III registration trial BOLERO-2, several phase IIIb trials have been started to evaluate this regimen in a more real-world setting. Here, we review the efficacy and safety data published or presented at selected international meetings. These studies confirmed the outcome observed in the BOLERO-2 trial. Patient acceptance rate is also discussed by focusing on the permanent everolimus discontinuation rate in these trials. Factors influencing the safety profile are also reported, including the impact of age. The optimal sequence of combined therapy approaches associating targeted and endocrine therapy (ET) has yet to be determined as new treatment options such as cyclin-dependent kinase inhibitors become available. However, everolimus–exemestane remains an important treatment option with a major impact on progression-free survival (PFS) and an acceptable safety profile. PMID:28096680

Early, structured disease modifying anti-rheumatic drug (DMARD) therapy reduces cardiovascular risk in rheumatoid arthritis--a single centre study using non-biologic drugs.

PubMed

Chatterjee, Sumit; Sarkate, Pankaj; Ghosh, Sudip; Biswas, Monodeep; Ghosh, Alakendu

2013-08-01

Rheumatoid arthritis, being a chronic disease requires long-term management of patients with drugs. The increasing cost of biologics in this era of disease management led us to devise a treatment regime, optimal for use in a developing country like India, which was economical as well as effective in controlling disease activity. To investigate if combination therapy with DMARDs can reduce cardiovascular risk in early Rheumatoid Arthritis, besides controlling disease activity. A small cohort of early Rheumatoid subjects with disease duration less than 1 year were treated with a structured DMARD regime and were followed up over a year. Disease activity score, C-reactive protein (CRP) and cardiac risk markers like lipid panel and carotid intima-medial thickness were monitored at 6 months and 1 year. A significant reduction (p < 0.001) of disease activity as well as cardiac risk parameters were observed. Our study showed that treatment of early rheumatoid arthritis with a combination regime of traditional DMARDs is highly effective in controlling disease activity as well as cardiovascular risk.

Hemiplegic shoulder pain: implications for occupational therapy treatment.

PubMed

Gilmore, Paula E; Spaulding, Sandi J; Vandervoort, Anthony A

2004-02-01

Hemiplegic shoulder pain is common after stroke causing hemiplegia. It adversely affects the recovery of arm function and independence in activities of daily living. Subluxation, abnormal tone and limited range of motion or capsular constrictions have been reported as potential causes. Other factors such as rotator cuff tears, brachial plexus injury, shoulder-hand syndrome and other pre-existing pathological conditions may also be associated with hemiplegic shoulder pain. The etiology remains unclear, but hemiplegic shoulder pain may result from a combination of the above factors. This literature review examines the possible causes of hemiplegic shoulder pain and discusses the implications for occupational therapy treatment. Occupational therapy interventions include proper positioning, facilitation of movement through purposeful therapeutic activities, increasing passive range of motion, implementation of external supports and treatment of shoulder-hand syndrome. Understanding the processes involved will assist with effective assessment, treatment and prevention of hemiplegic shoulder pain. This will facilitate clients' participation in rehabilitation programs and move them towards attainment of optimal function.

MIRD Pamphlet No. 23: Quantitative SPECT for Patient-Specific 3-Dimensional Dosimetry in Internal Radionuclide Therapy

PubMed Central

Dewaraja, Yuni K.; Frey, Eric C.; Sgouros, George; Brill, A. Bertrand; Roberson, Peter; Zanzonico, Pat B.; Ljungberg, Michael

2012-01-01

In internal radionuclide therapy, a growing interest in voxel-level estimates of tissue-absorbed dose has been driven by the desire to report radiobiologic quantities that account for the biologic consequences of both spatial and temporal nonuniformities in these dose estimates. This report presents an overview of 3-dimensional SPECT methods and requirements for internal dosimetry at both regional and voxel levels. Combined SPECT/CT image-based methods are emphasized, because the CT-derived anatomic information allows one to address multiple technical factors that affect SPECT quantification while facilitating the patient-specific voxel-level dosimetry calculation itself. SPECT imaging and reconstruction techniques for quantification in radionuclide therapy are not necessarily the same as those designed to optimize diagnostic imaging quality. The current overview is intended as an introduction to an upcoming series of MIRD pamphlets with detailed radionuclide-specific recommendations intended to provide best-practice SPECT quantification–based guidance for radionuclide dosimetry. PMID:22743252

The management of severe community acquired pneumonia in the intensive care unit.

PubMed

Liapikou, Adamantia; Rosales-Mayor, Edmundo; Torres, Antoni

2014-06-01

Severe CAP (SCAP), accounting for 6% of admissions to intensive care units (ICUs) needs early diagnosis and aggressive interventions at the most proximal point of disease presentation. The prognostic scores as the ATS/IDSA rule, the systolic blood pressure, multilobar infiltrates, albumin, respiratory rate, tachycardia, confusion, oxygen and pH or SCAP system are appropriate in early identification of eligible patients requiring admission to ICU. Then the recommended initial resuscitation in SCAP in the ICU consists of fluid volume intake titrated to specific goals after a fluid challenge and hemodynamic optimization. The first selection of antimicrobial therapy should be started in the first hour and would be broad enough to cover all likely pathogens. Combination therapy may be useful in patients with non refractory septic shock and severe sepsis pneumococcal bacteremia as well. After 6 hours the patient would be reevaluated in terms of hemodynamic stability and antibiotic and therapy. Future developments will focus on sepsis biomarkers, molecular diagnostic techniques and the development of novel therapeutic immunomodulaty agents.

Numerical simulation of high intensity focused ultrasound temperature distribution for transcranial brain therapy

NASA Astrophysics Data System (ADS)

Zhang, Qian; Wang, Yizhe; Zhou, Wenzheng; Zhang, Ji; Jian, Xiqi

2017-03-01

To provide a reference for the HIFU clinical therapeutic planning, the temperature distribution and lesion volume are analyzed by the numerical simulation. The adopted numerical simulation is based on a transcranial ultrasound therapy model, including an 8 annular-element curved phased array transducer. The acoustic pressure and temperature elevation are calculated by using the approximation of Westervelt Formula and the Pennes Heat Transfer Equation. In addition, the Time Reversal theory and eliminating hot spot technique are combined to optimize the temperature distribution. With different input powers and exposure times, the lesion volume is evaluated based on temperature threshold theory. The lesion region could be restored at the expected location by the time reversal theory. Although the lesion volume reduces after eliminating the peak temperature in the skull and more input power and exposure time is required, the injury of normal tissue around skull could be reduced during the HIFU therapy. The prediction of thermal deposition in the skull and the lesion region could provide a reference for clinical therapeutic dose.

A distance learning model in a physical therapy curriculum.

PubMed

English, T; Harrison, A L; Hart, A L

1998-01-01

In response to the rural health initiative established in 1991, the University of Kentucky has developed an innovative distance learning program of physical therapy instruction that combines classroom lecture and discussion via compressed video technology with laboratory experiences. The authors describe the process of planning, implementing, and evaluating a specific distance learning course in pathomechanics for the professional-level master's-degree physical therapy students at the University of Kentucky. This presentation may serve as a model for teaching distance learning. Descriptions of optimal approaches to preclass preparation, scheduling, course delivery, use of audiovisual aids, use of handout material, and video production are given. Special activities that may enhance or deter the achievement of the learning objectives are outlined, and a problem-solving approach to common problems encountered is presented. An approach to evaluating and comparing course outcomes for the distance learnere is presented. For this particular course, there was no statistically significant difference in the outcome measures utilized to compare the distance learners with the on-site learners.

Development of high yielding photonic light delivery system for photodynamic therapy of esophageal carcinomas

NASA Astrophysics Data System (ADS)

Premasiri, Amaranath; Happawana, Gemunu; Rosen, Arye

2007-02-01

Photodynamic therapy (PDT) is an approved treatment modality for Barrett's and invasive esophageal carcinoma. Proper Combination of photosentizing agent, oxygen, and a specific wavelength of light to activate the photosentizing agents is necessary for the cytotoxic destruction of cancerous cells by PDT. As a light source expensive solid-state laser sources currently are being used for the treatment. Inexpensive semiconductor lasers have been suggested for the light delivery system, however packaging of semiconductor lasers for optimal optical power output is challenging. In this paper, we present a multidirectional direct water-cooling of semiconductor lasers that provides a better efficiency than the conventional unidirectional cooling. AlGaAsP lasers were tested under de-ionized (DI) water and it is shown that the optical power output of the lasers under the DI water is much higher than that of the uni-directional cooling of lasers. Also, in this paper we discuss how direct DI water-cooling can optimize power output of semiconductor lasers. Thereafter an optimal design of the semiconductor laser package is shown with the DI water-cooling system. Further, a microwave antenna is designed which is to be imprinted on to a balloon catheter in order to provide local heating of esophagus, leading to an increase in local oxygenation of the tumor to generate an effective level of singlet oxygen for cellular death. Finally the optimal level of light energy that is required to achieve the expected level of singlet oxygen is modeled to design an efficient PDT protocol.

Irreversible electroporation of stage 3 locally advanced pancreatic cancer: optimal technique and outcomes

PubMed Central

2015-01-01

Objective Irreversible electroporation (IRE) of stage 3 pancreatic adenocarcinoma has been used to provide quality of life time in patients who have undergone appropriate induction therapy. The optimal technique has been reported within the literature, but not in video form. IRE of locally advanced pancreatic cancer is technically demanding requiring precision ultrasound use for continuous imaging in multiple needle placements and during IRE energy delivery. Methods Appropriate patients with locally advanced pancreatic cancer should have undergone appropriate induction chemotherapy for a reasonable duration. The safe and effective technique for irreversible electroporation is preformed through an open approach with the emphasis on intra-operative ultrasound and intra-operative electroporation management. Results The technique of open irreversible electroporation of the pancreas involves bracketing the target tumor with IRE probes and any and all invaded vital structures including the celiac axis, superior mesenteric artery (SMA), superior mesenteric-portal vein, and bile duct with continuous intraoperative ultrasound imaging through a caudal to cranial approach. Optimal IRE delivery requires a change in amperage of at least 12 amps from baseline tissue conductivity in order to achieve technical success. Multiple pull-backs are necessary since the IRE ablation probe lengths are 1 cm and thus needed to achieve technical success along the caudal to cranial plane. Conclusions Irreversible electroporation in combination with multi-modality therapy for locally advanced pancreatic carcinoma is feasible for appropriate patients with locally advanced cancer. Technical demands are high and require the highest quality ultrasound for precise spacing measurements and optimal delivery to ensure adequate change in tissue resistance. PMID:29075594

[Prospect and Current Situation of Immune Checkpoint Inhibitors 
in First-line Treatment in Advanced Non-small Cell Lung Cancer Patients].

PubMed

Wang, Haiyang; Yu, Xiaoqing; Fan, Yun

2017-06-20

With the breakthroughs achieved of programmed death-1 (PD-1)/PD-L1 inhibitors monotherapy as first-line and second-line treatment in advanced non-small cell lung cancer (NSCLC), the treatment strategy is gradually evolving and optimizing. Immune combination therapy expands the benefit population and improves the curative effect. A series of randomized phase III trials are ongoing. In this review, we discuss the prospect and current situation of immune checkpoint inhibitors in first-line treatment in advanced NSCLC patients.

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

PubMed Central

Blasco, Benjamin; Leroy, Didier; Fidock, David A

2017-01-01

The global adoption of artemisinin-based combination therapies (ACTs) in the early 2000s heralded a new era in effectively treating drug-resistant Plasmodium falciparum malaria. However, several Southeast Asian countries have now reported the emergence of parasites that have decreased susceptibility to artemisinin (ART) derivatives and ACT partner drugs, resulting in increasing rates of treatment failures. Here we review recent advances in understanding how antimalarials act and how resistance develops, and discuss new strategies for effectively combatting resistance, optimizing treatment and advancing the global campaign to eliminate malaria. PMID:28777791

[The problems of antihypertensive balneotherapy].

PubMed

Vladimirskiĭ, E V; Fil'tsagina, T N

2013-01-01

This review is devoted to the challenging problems of balneotherapeutics, such as the mechanisms of antihypertensive balneotherapy and its optimization. The experience of the authors with the practical application of chloride - sodium, iodine - bromide, and hydrogen sulfide mineral baths is analysed in comparison with the literature data. The role, dosage regimen, and duration of balneotherapeutic treatment as well as the effectiveness of its combination with medicamental therapy are considered. The authors hope that the discussion of these issues will be conducive to the solution of problems currently facing modern antihypertensive balneotherapy.

Juvenile Macular Degenerations

PubMed Central

Altschwager, Pablo; Ambrosio, Lucia; Swanson, Emily A.; Moskowitz, Anne; Fulton, Anne B.

2017-01-01

In this paper we review three common juvenile macular degenerations: Stargardt disease, X-linked retinoschisis, and Best vitelliform macular dystrophy. These are inherited disorders that typically present during childhood, when vision is still developing. They are sufficiently common that they should be included in the differential diagnosis of visual loss in pediatric patients. Diagnosis is secured by a combination of clinical findings, optical coherence tomography (OCT) imaging, and genetic testing. Early diagnosis promotes optimal management. While there is currently no definitive cure for these conditions, therapeutic modalities under investigation include pharmacologic treatment, gene therapy, and stem cell transplantation. PMID:28941524

TH-AB-BRB-01: Trajectory Modulated Arc Therapy: Application to Partial Breast Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hristov, D.

2016-06-15

Current state-of-the art digital C-arm medical linear accelerators are capable of delivering radiation treatments with high level of automation, which affords coordinated motions of gantry, couch, and multileaf collimator (MLC) with dose rate modulations. The new machine capacity has shown the potential to bring substantially improved radiation dosimetry and/or delivery efficiency to many challenging diseases. Combining an integrated beam orientation optimization algorithm with automated machine navigation, markedly improved dose conformity has been achieved using 4ρ therapy. Trajectory modulated radiation therapy (TMAT) can be used to deliver highly conformal dose to partial breast or to carve complex dose distribution for therapymore » involving extended volumes such as total marrow and total lymph node treatment. Dynamic electron arc radiotherapy (DEAR) not only overcomes the deficiencies of conventional electron therapy in dose conformity and homogeneity but also achieves so without patient-specific shields. The combination of MLC and couch tracking provides improved motion management of thoracic and abdominal tumors. A substantial body of work has been done in these technological advances for clinical translation. The proposed symposium will provide a timely review of these exciting opportunities. Learning Objectives: Recognize the potential of using digitally controlled linacs for clinically significant improvements in delivered dose distributions for various treatment sites. Identify existing approaches to treatment planning, optimization and delivery for treatment techniques utilizing the advanced functions of digital linacs and venues for further development and improvement. Understand methods for testing and validating delivery system performance. Identify tools available on current delivery systems for implementation and control for such treatments. Obtain the update in clinical applications, trials and regulatory approval. K. Sheng, NIH U19AI067769, NIH R43CA183390, NIH R01CA188300, Varian Medical Systems V. Yu, Varian Medical Systems, AAPM Summer Undergraduate Fellowship, NSF graduate fellowship S. Nill, Elekta AB. Cancer Research UK under Programme C33589/A19727, NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research.« less

Use of allopurinol with low-dose 6-mercaptopurine in inflammatory bowel disease to achieve optimal active metabolite levels: A review of four cases and the literature

PubMed Central

Witte, Todd N; Ginsberg, Allen L

2008-01-01

BACKGROUND: At least one-third of patients with inflammatory bowel disease do not respond or are intolerant to therapy with 6-mercaptopurine (6-MP). A subgroup fails to attain optimal levels of 6-thioguanine nucleotide (6-TGN) and instead shunts to 6-methylmercaptopurine nucleotide (6-MMPN). PATIENTS AND METHODS: A retrospective chart review was conducted, and four patients are described who had been previously unable to achieve optimal 6-TGN metabolite levels until allopurinol was added to their treatment. RESULTS: All four patients achieved optimal 6-TGN levels and undetectable 6-MMPN with a mean 6-MP dose of 0.49 mg/kg. Three achieved steroid-free clinical remission. Two of those three patients had normalization of liver enzymes; one patient had baseline normal liver enzymes despite an initial 6-MMPN level of 27,369 pmol/8×108 red blood cells. Two patients experienced reversible leukopenia. CONCLUSIONS: Combination allopurinol and low-dose 6-MP is an effective means to achieve optimal metabolite levels and steroid-free clinical remission in previously refractory patients. Caution is advised. PMID:18299738

Stem cell gene therapy for fanconi anemia: report from the 1st international Fanconi anemia gene therapy working group meeting.

PubMed

Tolar, Jakub; Adair, Jennifer E; Antoniou, Michael; Bartholomae, Cynthia C; Becker, Pamela S; Blazar, Bruce R; Bueren, Juan; Carroll, Thomas; Cavazzana-Calvo, Marina; Clapp, D Wade; Dalgleish, Robert; Galy, Anne; Gaspar, H Bobby; Hanenberg, Helmut; Von Kalle, Christof; Kiem, Hans-Peter; Lindeman, Dirk; Naldini, Luigi; Navarro, Susana; Renella, Raffaele; Rio, Paula; Sevilla, Julián; Schmidt, Manfred; Verhoeyen, Els; Wagner, John E; Williams, David A; Thrasher, Adrian J

2011-07-01

Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA.

The role of basal insulin and GLP-1 receptor agonist combination products in the management of type 2 diabetes

PubMed Central

Inman, Taylor R.; Plyushko, Erika; Austin, Nicholas P.; Johnson, Jeremy L.

2018-01-01

The prevalence of type 2 diabetes necessitates the development of new treatment options to individualize therapy. Basal insulin has been a standard treatment option for years, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have grown in use over the past decade due to glucose-lowering efficacy and weight loss potential. There are two new combination injectable products that have recently been approved combining basal insulins with GLP-1 RAs in single pen-injector devices. United States guidelines recently emphasize the option to use combination injectable therapy with GLP-1 RAs and basal insulin once the basal insulin has been optimally titrated as a second- or third-line agent in addition to metformin without reaching the goal A1c. Insulin glargine/lixisenatide 100/33 (IGlarLixi) can be dosed between 15 and 60 units once daily from a single pen-injector device. Insulin degludec/liraglutide 100/3.6 (IDegLira) can be dosed between 10 and 50 units once daily, also from a single pen-injector device. Maximum doses, while measured in units, correspond to limits defined by each individual GLP-1 RA. The dual use of basal insulin plus GLP-1 RA is non-inferior compared with basal insulin plus a single injection of prandial insulin at the largest meal and compared with twice daily-dosed premixed insulins; and this combination is associated with weight loss and less hypoglycemia. These new combination products could help providers effectively and efficiently follow clinical practice guidelines while enhancing patient adherence with injectable medications. PMID:29796245

The role of basal insulin and GLP-1 receptor agonist combination products in the management of type 2 diabetes.

PubMed

Inman, Taylor R; Plyushko, Erika; Austin, Nicholas P; Johnson, Jeremy L

2018-05-01

The prevalence of type 2 diabetes necessitates the development of new treatment options to individualize therapy. Basal insulin has been a standard treatment option for years, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have grown in use over the past decade due to glucose-lowering efficacy and weight loss potential. There are two new combination injectable products that have recently been approved combining basal insulins with GLP-1 RAs in single pen-injector devices. United States guidelines recently emphasize the option to use combination injectable therapy with GLP-1 RAs and basal insulin once the basal insulin has been optimally titrated as a second- or third-line agent in addition to metformin without reaching the goal A1c. Insulin glargine/lixisenatide 100/33 (IGlarLixi) can be dosed between 15 and 60 units once daily from a single pen-injector device. Insulin degludec/liraglutide 100/3.6 (IDegLira) can be dosed between 10 and 50 units once daily, also from a single pen-injector device. Maximum doses, while measured in units, correspond to limits defined by each individual GLP-1 RA. The dual use of basal insulin plus GLP-1 RA is non-inferior compared with basal insulin plus a single injection of prandial insulin at the largest meal and compared with twice daily-dosed premixed insulins; and this combination is associated with weight loss and less hypoglycemia. These new combination products could help providers effectively and efficiently follow clinical practice guidelines while enhancing patient adherence with injectable medications.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

PubMed

Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules

PubMed Central

Liu, Qian; Sun, Jessica D.; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F.; Cranmer, Lee D.; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W. Steve; Curd, John G.; Matteucci, Mark D.

2014-01-01

Purpose Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2–8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302. PMID:22382881

A user’s guide to cannabinoid therapies in oncology

PubMed Central

Maida, V.; Daeninck, P.J.

2016-01-01

“Cannabinoid” is the collective term for a group of chemical compounds that either are derived from the Cannabis plant, are synthetic analogues, or occur endogenously. Although cannabinoids interact mostly at the level of the currently recognized cannabinoid receptors, they might have cross reactivity, such as at opioid receptors. Patients with malignant disease represent a cohort within health care that have some of the greatest unmet needs despite the availability of a plethora of guideline-driven disease-modulating treatments and pain and symptom management options. Cannabinoid therapies are varied and versatile, and can be offered as pharmaceuticals (nabilone, dronabinol, and nabiximols), dried botanical material, and edible organic oils infused with cannabis extracts. Cannabinoid therapy regimens can be creative, involving combinations of all of the aforementioned modalities. Patients with malignant disease, at all points of their disease trajectory, could be candidates for cannabinoid therapies whether as monotherapies or as adjuvants. The most studied and established roles for cannabinoid therapies include pain, chemotherapy-induced nausea and vomiting, and anorexia. Moreover, given their breadth of activity, cannabinoids could be used to concurrently optimize the management of multiple symptoms, thereby reducing overall polypharmacy. The use of cannabinoid therapies could be effective in improving quality of life and possibly modifying malignancy by virtue of direct effects and in improving compliance or adherence with disease-modulating treatments such as chemotherapy and radiation therapy. PMID:28050136

Unresolved antiretroviral treatment management issues in HIV-infected children.

PubMed

Heidari, Shirin; Mofenson, Lynne M; Hobbs, Charlotte V; Cotton, Mark F; Marlink, Richard; Katabira, Elly

2012-02-01

Antiretroviral therapy in children has expanded dramatically in low-income and middle-income countries. The World Health Organization revised its pediatric HIV guidelines to recommend initiation of antiretroviral therapy in all HIV-infected children younger than 2 years, regardless of CD4 count or clinical stage. The number of children starting life-long antiretroviral therapy should therefore expand dramatically over time. The early initiation of antiretroviral therapy has indisputable benefits for children, but there is a paucity of definitive information on the potential adverse effects. In this review, a comprehensive literature search was conducted to provide an overview of our knowledge about the complications of treating pediatric HIV. Antiretroviral therapy in children, as in adults, is associated with enhanced survival, reduction in opportunistic infections, improved growth and neurocognitive function, and better quality of life. Despite antiretroviral therapy, HIV-infected children may continue to lag behind their uninfected peers in growth and development. In addition, epidemic concurrent conditions, such as tuberculosis, malaria, and malnutrition, can combine with HIV to yield more rapid disease progression and poor treatment outcomes. Additional studies are required to evaluate the long-term effects of antiretroviral therapy in HIV-infected infants, children, and adolescents, particularly in resource-limited countries where concomitant infections and conditions may enhance the risk of adverse effects. There is an urgent need to evaluate drug-drug interactions in children to determine optimal treatment regimens for both HIV and coinfections.

Optimized S-Trityl-l-cysteine-Based Inhibitors of Kinesin Spindle Protein with Potent in Vivo Antitumor Activity in Lung Cancer Xenograft Models

PubMed Central

2013-01-01

The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-l-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (Kiapp < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacokinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies. PMID:23394180

Optimal medical treatment versus carotid endarterectomy: the rationale and design of the Aggressive Medical Treatment Evaluation for Asymptomatic Carotid Artery Stenosis (AMTEC) study.

PubMed

Kolos, Igor; Loukianov, Mikhail; Dupik, Nikolay; Boytsov, Sergey; Deev, Alexandr

2015-02-01

Carotid endarterectomy and medical therapy (aspirin) were shown superior to medical therapy alone for asymptomatic (≥ 60%) carotid stenosis. The role of modern medical therapy (statins, antihypertensive treatment, and aspirin) in the treatment of such patients is undefined. Establishing the safety, efficacy, and durability of optimal medical therapy and lifestyle modification requires rigorous comparison with carotid endarterectomy in asymptomatic patients. The objective is to compare the efficacy of carotid endarterectomy + optimal medical therapy versus optimal medical therapy alone in patients with asymptomatic (70-79%) extracranial carotid stenosis. The Aggressive Medical Treatment Evaluation for Asymptomatic Carotid Artery Stenosis study is a prospective, randomized, parallel, two-arm, multicenter trial. Primary end-points will be analyzed using standard time-to-event statistical modeling with adjustment for major baseline covariates. The primary analysis is on an intent-to-treat basis. The primary outcome is nonfatal stroke, nonfatal myocardial infarction, and death during follow-up of up to five-years, and the secondary outcome includes death from any cause and stroke. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.

Combination of SLC administration and Tregs depletion is an attractive strategy for targeting hepatocellular carcinoma

PubMed Central

2013-01-01

Background Secondary lymphoid tissue chemokine (SLC) is a key CC chemokine for chemotaxis of immune cells and has been an attractive candidate for anti-tumor treatments. However, among the immune cells recruited by SLC to tumors, the CD25+ Foxp3+ regulatory T cells (Tregs) compromise the anti-tumor effects. In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). We hypothesized that the intratumoral injections of SLC and depletion of Tregs would have stronger inhibition effects on the progression of hepatocellular carcinoma (HCC) in mice. Methods C57BL/6 mice were inoculated subcutaneously with the murine HCC cell line, and mice with visible tumors were treated intratumorally with SLC, SLC plus anti-CD25 mAbs or the control antibodies. The percentages of Tregs, effector CD8+ T cells and CD4+ T cells were checked in the tumors, lymph nodes, spleen and liver at regular intervals. The levels of intratumoral IL-12, IFN-γ, IL-10 and TGF-β1 were evaluated. The final anti-tumor effects were measured by the tumor volume and weight as well as the intratumoral activity of MMP2 and MMP9. Bone-marrow-derived dendritic cells were used to explore the mechanisms of maturation induced by SLC in vitro. Results Our experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Unexpectedly, we observed a significantly decreased percentage of Tregs, and increased CD8+ T cells and CD4+ T cells in the lymph nodes, spleen and liver after the combination therapy. The growth and invasiveness of HCC was also maximally inhibited in the combination therapy compared with the SLC alone. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy. Conclusions Our data demonstrated that intratumoral co-administration of SLC and anti-CD25 mAbs was an effective treatment for HCC, which was correlated with the altered tumor microenvironment and systemically optimized percentages of Tregs, CD8+ T cells and CD4+ T cells in peripheral immune organs. PMID:24304581

Glycolytic inhibitors 2-deoxyglucose and 3-bromopyruvate synergize with photodynamic therapy respectively to inhibit cell migration.

PubMed

Feng, Xiaolan; Wang, Pan; Liu, Quanhong; Zhang, Ting; Mai, Bingjie; Wang, Xiaobing

2015-06-01

Most cancer cells have the specially increased glycolytic phenotype, which makes this pathway become an attractive therapeutic target. Although glycolytic inhibitor 2-deoxyglucose (2-DG) has been demonstrated to potentiate the cytotoxicity of photodynamic therapy (PDT), the impacts on cell migration after the combined treatment has never been reported yet. The present study aimed to analyze the influence of glycolytic inhibitors 2-DG and 3-bromopyruvate (3-BP) combined with Ce6-PDT on cell motility of Triple Negative Breast Cancer MDA-MB-231 cells. As determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium-bromide-Tetraz-olium (MTT) assay, more decreased cell viability was observed in 2-DG + PDT and 3-BP + PDT groups when compared with either monotherapy. Under optimal conditions, synergistic potentiation on cell membrane destruction and the decline of cell adhesion and cells migratory ability were observed in both 2-DG + PDT and 3-BP + PDT by electron microscope observation (SEM), wound healing and trans-well assays. Besides, serious microfilament network collapses as well as impairment of matrix metalloproteinases-9 (MMP-9) were notably improved after the combined treatments by immunofluorescent staining. These results suggest that 2-DG and 3-BP can both significantly potentiated Ce6-PDT efficacy of cell migration inhibition.

Combination of active targeting, enzyme-triggered release and fluorescent dye into gold nanoclusters for endomicroscopy-guided photothermal/photodynamic therapy to pancreatic ductal adenocarcinoma.

PubMed

Li, Hui; Wang, Ping; Deng, Yunxiang; Zeng, Meiying; Tang, Yan; Zhu, Wei-Hong; Cheng, Yingsheng

2017-09-01

Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating malignancies in patients, and there is an urgent need for an effective treatment method. Herein, we report a novel gold nanocluster-based platform for confocal laser endomicroscopy-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for PDAC, which consists of four components: the PTT-carrier gold nanocluster, an active targeting ligand U11 peptide, a Cathepsin E (CTSE)-sensitive PDT therapy prodrug, and a CTSE-sensitive imaging agent (cyanine dye Cy5.5). Due to the strong coupling among cross-linked gold nanoparticles (AuNPs), the surface plasmon resonance peak of nanoclusters shifts to the near-infrared (NIR) region, thus making the nanoclusters useful in the effective PTT therapy. In the system, the labeling of nanoclusters with U11 peptide can distinctly increase their affinity and accelerate their uptake by pancreatic cancer cells. Cell apoptosis staining demonstrates that, upon incorporation of the uPAR-targeted unit, the antitumor efficacy of CTSE-sensitive nanocluster AuS-U11 is significantly enhanced with respect to that of the non-targeted nanocluster AuS-PEG and the insensitive nanocluster AuC-PEG. In vivo and ex vivo optical imaging confirms the high accumulation of AuS-U11 in the in situ pancreatic tumor model. Therapeutic studies further show that the combination of active targeting for tumor tissue, enzyme-triggered drug release of 5-ALA and fluorescent dye Cy5.5 in nanoclusters AuS-U11 could achieve optimal therapeutic efficacy with endomicroscopy-guided photothermal/photodynamic therapy with minimal side effects. As a consequence, the delicate gold nanocluster concept provides a promising strategy to enhance the therapy efficiency in the most challenging PDAC treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

COMBIT: protocol of a randomised comparison trial of COMbined modified constraint induced movement therapy and bimanual intensive training with distributed model of standard upper limb rehabilitation in children with congenital hemiplegia.

PubMed

Boyd, Roslyn N; Ziviani, Jenny; Sakzewski, Leanne; Miller, Laura; Bowden, Joanne; Cunnington, Ross; Ware, Robert; Guzzetta, Andrea; Al Macdonell, Richard; Jackson, Graeme D; Abbott, David F; Rose, Stephen

2013-06-28

Children with congenital hemiplegia often present with limitations in using their impaired upper limb which impacts on independence in activities of daily living, societal participation and quality of life. Traditional therapy has adopted a bimanual training approach (BIM) and more recently, modified constraint induced movement therapy (mCIMT) has emerged as a promising unimanual approach. Evidence of enhanced neuroplasticity following mCIMT suggests that the sequential application of mCIMT followed by bimanual training may optimise outcomes (Hybrid CIMT). It remains unclear whether more intensely delivered group based interventions (hCIMT) are superior to distributed models of individualised therapy. This study aims to determine the optimal density of upper limb training for children with congenital hemiplegia. A total of 50 children (25 in each group) with congenital hemiplegia will be recruited to participate in this randomized comparison trial. Children will be matched in pairs at baseline and randomly allocated to receive an intensive block group hybrid model of combined mCIMT followed by intensive bimanual training delivered in a day camp model (COMBiT; total dose 45 hours direct, 10 hours of indirect therapy), or a distributed model of standard occupational therapy and physiotherapy care (SC) over 12 weeks (total 45 hours direct and indirect therapy). Outcomes will be assessed at 13 weeks after commencement, and retention of effects tested at 26 weeks. The primary outcomes will be bimanual coordination and unimanual upper-limb capacity. Secondary outcomes will be participation and quality of life. Advanced brain imaging will assess neurovascular changes in response to treatment. Analysis will follow standard principles for RCTs, using two-group comparisons on all participants on an intention-to-treat basis. Comparisons will be between treatment groups using generalized linear models. ACTRN12613000181707.

The importance of Zebrafish in biomedical research.

PubMed

Tavares, Bárbara; Santos Lopes, Susana

2013-01-01

Zebrafish (Danio rerio) is an ideal model organism for the study of vertebrate development. This is due to the large clutches that each couple produces, with up to 200 embryos every 7 days, and to the fact that the embryos and larvae are small, transparent and undergo rapid external development. Using scientific literature research tools available online and the keywords Zebrafish, biomedical research, human disease, and drug screening, we reviewed original studies and reviews indexed in PubMed. In this review we summarized work conducted with this model for the advancement of our knowledge related to several human diseases. We also focused on the biomedical research being performed in Portugal with the zebrafish model. Powerful live imaging and genetic tools are currently available for zebrafish making it a valuable model in biomedical research. The combination of these properties with the optimization of automated systems for drug screening has transformed the zebrafish into "a top model" in biomedical research, drug discovery and toxicity testing. Furthermore, with the optimization of xenografts technology it will be possible to use zebrafish to aide in the choice of the best therapy for each patient. Zebrafish is an excellent model organism in biomedical research, drug development and in clinical therapy.

Systems oncology: towards patient-specific treatment regimes informed by multiscale mathematical modelling.

PubMed

Powathil, Gibin G; Swat, Maciej; Chaplain, Mark A J

2015-02-01

The multiscale complexity of cancer as a disease necessitates a corresponding multiscale modelling approach to produce truly predictive mathematical models capable of improving existing treatment protocols. To capture all the dynamics of solid tumour growth and its progression, mathematical modellers need to couple biological processes occurring at various spatial and temporal scales (from genes to tissues). Because effectiveness of cancer therapy is considerably affected by intracellular and extracellular heterogeneities as well as by the dynamical changes in the tissue microenvironment, any model attempt to optimise existing protocols must consider these factors ultimately leading to improved multimodal treatment regimes. By improving existing and building new mathematical models of cancer, modellers can play important role in preventing the use of potentially sub-optimal treatment combinations. In this paper, we analyse a multiscale computational mathematical model for cancer growth and spread, incorporating the multiple effects of radiation therapy and chemotherapy in the patient survival probability and implement the model using two different cell based modelling techniques. We show that the insights provided by such multiscale modelling approaches can ultimately help in designing optimal patient-specific multi-modality treatment protocols that may increase patients quality of life. Copyright © 2014 Elsevier Ltd. All rights reserved.

The effect of RAAS blockade on the progression of diabetic nephropathy.

PubMed

Roscioni, Sara S; Heerspink, Hiddo J Lambers; de Zeeuw, Dick

2014-02-01

The renin-angiotensin-aldosterone system (RAAS) has a key role in the regulation of blood pressure, sodium and water balance, and cardiovascular and renal homeostasis. In diabetic nephropathy, excessive activation of the RAAS results in progressive renal damage. RAAS blockade using angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers is the cornerstone of treatment of diabetic renal disease. Alternative RAAS-blockade strategies include renin inhibition and aldosterone blockade. Data from small initial studies of these agents are promising. However, single-agent interventions do not fully block the RAAS and patients treated with these therapies remain at high residual renal risk. Approaches to optimize drug responses include dietary changes and increasing dosages. The theoretically attractive option of combining different RAAS interventions has also been tested in clinical trials but long-term outcomes were disappointing. However, dual RAAS blockade might represent a good therapeutic option for specific patients. A better knowledge of the pathophysiology of the RAAS is crucial to fully understand the mechanisms of action of RAAS blockers and to exploit their renoprotective effects. Moreover, lifestyle interventions or diagnostic tools might be used to optimize RAAS blockade and identify those patients who are most likely to benefit from the therapy.

FAST INdiCATE Trial protocol. Clinical efficacy of functional strength training for upper limb motor recovery early after stroke: neural correlates and prognostic indicators.

PubMed

Pomeroy, Valerie M; Ward, Nick S; Johansen-Berg, Heidi; van Vliet, Paulette; Burridge, Jane; Hunter, Susan M; Lemon, Roger N; Rothwell, John; Weir, Christopher J; Wing, Alan; Walker, Andrew A; Kennedy, Niamh; Barton, Garry; Greenwood, Richard J; McConnachie, Alex

2014-02-01

Functional strength training in addition to conventional physical therapy could enhance upper limb recovery early after stroke more than movement performance therapy plus conventional physical therapy. To determine (a) the relative clinical efficacy of conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy for upper limb recovery; (b) the neural correlates of response to conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy; (c) whether any one or combination of baseline measures predict motor improvement in response to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. Randomized, controlled, observer-blind trial. The sample will consist of 288 participants with upper limb paresis resulting from a stroke that occurred within the previous 60 days. All will be allocated to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. Functional strength training and movement performance therapy will be undertaken for up to 1·5 h/day, five-days/week for six-weeks. Measurements will be undertaken before randomization, six-weeks thereafter, and six-months after stroke. Primary efficacy outcome will be the Action Research Arm Test. Explanatory measurements will include voxel-wise estimates of brain activity during hand movement, brain white matter integrity (fractional anisotropy), and brain-muscle connectivity (e.g. latency of motor evoked potentials). The primary clinical efficacy analysis will compare treatment groups using a multilevel normal linear model adjusting for stratification variables and for which therapist administered the treatment. Effect of conventional physical therapy combined with functional strength training versus conventional physical therapy combined with movement performance therapy will be summarized using the adjusted mean difference and 95% confidence interval. To identify the neural correlates of improvement in both groups, we will investigate associations between change from baseline in clinical outcomes and each explanatory measure. To identify baseline measurements that independently predict motor improvement, we will develop a multiple regression model. © 2013 The Authors. International Journal of Stroke published by John Wiley & Sons Ltd on behalf of World Stroke Organization.

Moving Beyond Maximum Tolerated Dose for Targeted Oncology Drugs: Use of Clinical Utility Index to Optimize Venetoclax Dosage in Multiple Myeloma Patients.

PubMed

Freise, K J; Jones, A K; Verdugo, M E; Menon, R M; Maciag, P C; Salem, A H

2017-12-01

Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a phase Ib venetoclax dose-ranging study. Logistic regression models were utilized to determine relationships, identify subpopulations with different responses, and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment. Higher venetoclax exposures were estimated to increase the probability of achieving a very good partial response (VGPR) or better through venetoclax doses of 1,200 mg. However, the probability of neutropenia (grade ≥3) was estimated to increase at doses >800 mg. Using a clinical utility index, a venetoclax dosage of 800 mg daily was selected to optimally balance the VGPR or better rates and neutropenia rates in MM patients administered 1-3 prior lines of therapy and nonrefractory to bortezomib. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement

PubMed Central

Bianco, Antonio C.; Bauer, Andrew J.; Burman, Kenneth D.; Cappola, Anne R.; Celi, Francesco S.; Cooper, David S.; Kim, Brian W.; Peeters, Robin P.; Rosenthal, M. Sara; Sawka, Anna M.

2014-01-01

Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. Results: We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non–levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones. Conclusions: We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine–liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile. PMID:25266247

Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement.

PubMed

Jonklaas, Jacqueline; Bianco, Antonio C; Bauer, Andrew J; Burman, Kenneth D; Cappola, Anne R; Celi, Francesco S; Cooper, David S; Kim, Brian W; Peeters, Robin P; Rosenthal, M Sara; Sawka, Anna M

2014-12-01

A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones. We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile.

Treatment planning, optimization, and beam delivery technqiues for intensity modulated proton therapy

NASA Astrophysics Data System (ADS)

Sengbusch, Evan R.

Physical properties of proton interactions in matter give them a theoretical advantage over photons in radiation therapy for cancer treatment, but they are seldom used relative to photons. The primary barriers to wider acceptance of proton therapy are the technical feasibility, size, and price of proton therapy systems. Several aspects of the proton therapy landscape are investigated, and new techniques for treatment planning, optimization, and beam delivery are presented. The results of these investigations suggest a means by which proton therapy can be delivered more efficiently, effectively, and to a much larger proportion of eligible patients. An analysis of the existing proton therapy market was performed. Personal interviews with over 30 radiation oncology leaders were conducted with regard to the current and future use of proton therapy. In addition, global proton therapy market projections are presented. The results of these investigations serve as motivation and guidance for the subsequent development of treatment system designs and treatment planning, optimization, and beam delivery methods. A major factor impacting the size and cost of proton treatment systems is the maximum energy of the accelerator. Historically, 250 MeV has been the accepted value, but there is minimal quantitative evidence in the literature that supports this standard. A retrospective study of 100 patients is presented that quantifies the maximum proton kinetic energy requirements for cancer treatment, and the impact of those results with regard to treatment system size, cost, and neutron production is discussed. This study is subsequently expanded to include 100 cranial stereotactic radiosurgery (SRS) patients, and the results are discussed in the context of a proposed dedicated proton SRS treatment system. Finally, novel proton therapy optimization and delivery techniques are presented. Algorithms are developed that optimize treatment plans over beam angle, spot size, spot spacing, beamlet weight, the number of delivered beamlets, and the number of delivery angles. These methods are evaluated via treatment planning studies including left-sided whole breast irradiation, lung stereotactic body radiotherapy, nasopharyngeal carcinoma, and whole brain radiotherapy with hippocampal avoidance. Improvements in efficiency and efficacy relative to traditional proton therapy and intensity modulated photon radiation therapy are discussed.

An approach to multiobjective optimization of rotational therapy. II. Pareto optimal surfaces and linear combinations of modulated blocked arcs for a prostate geometry.

PubMed

Pardo-Montero, Juan; Fenwick, John D

2010-06-01

The purpose of this work is twofold: To further develop an approach to multiobjective optimization of rotational therapy treatments recently introduced by the authors [J. Pardo-Montero and J. D. Fenwick, "An approach to multiobjective optimization of rotational therapy," Med. Phys. 36, 3292-3303 (2009)], especially regarding its application to realistic geometries, and to study the quality (Pareto optimality) of plans obtained using such an approach by comparing them with Pareto optimal plans obtained through inverse planning. In the previous work of the authors, a methodology is proposed for constructing a large number of plans, with different compromises between the objectives involved, from a small number of geometrically based arcs, each arc prioritizing different objectives. Here, this method has been further developed and studied. Two different techniques for constructing these arcs are investigated, one based on image-reconstruction algorithms and the other based on more common gradient-descent algorithms. The difficulty of dealing with organs abutting the target, briefly reported in previous work of the authors, has been investigated using partial OAR unblocking. Optimality of the solutions has been investigated by comparison with a Pareto front obtained from inverse planning. A relative Euclidean distance has been used to measure the distance of these plans to the Pareto front, and dose volume histogram comparisons have been used to gauge the clinical impact of these distances. A prostate geometry has been used for the study. For geometries where a blocked OAR abuts the target, moderate OAR unblocking can substantially improve target dose distribution and minimize hot spots while not overly compromising dose sparing of the organ. Image-reconstruction type and gradient-descent blocked-arc computations generate similar results. The Pareto front for the prostate geometry, reconstructed using a large number of inverse plans, presents a hockey-stick shape comprising two regions: One where the dose to the target is close to prescription and trade-offs can be made between doses to the organs at risk and (small) changes in target dose, and one where very substantial rectal sparing is achieved at the cost of large target underdosage. Plans computed following the approach using a conformal arc and four blocked arcs generally lie close to the Pareto front, although distances of some plans from high gradient regions of the Pareto front can be greater. Only around 12% of plans lie a relative Euclidean distance of 0.15 or greater from the Pareto front. Using the alternative distance measure of Craft ["Calculating and controlling the error of discrete representations of Pareto surfaces in convex multi-criteria optimization," Phys. Medica (to be published)], around 2/5 of plans lie more than 0.05 from the front. Computation of blocked arcs is quite fast, the algorithms requiring 35%-80% of the running time per iteration needed for conventional inverse plan computation. The geometry-based arc approach to multicriteria optimization of rotational therapy allows solutions to be obtained that lie close to the Pareto front. Both the image-reconstruction type and gradient-descent algorithms produce similar modulated arcs, the latter one perhaps being preferred because it is more easily implementable in standard treatment planning systems. Moderate unblocking provides a good way of dealing with OARs which abut the PTV. Optimization of geometry-based arcs is faster than usual inverse optimization of treatment plans, making this approach more rapid than an inverse-based Pareto front reconstruction.

The application of prodrug-based nano-drug delivery strategy in cancer combination therapy.

PubMed

Ge, Yanxiu; Ma, Yakun; Li, Lingbing

2016-10-01

Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology. Copyright © 2016 Elsevier B.V. All rights reserved.

Receipt of Medication and Behavioral Therapy Among a National Sample of School-Age Children Diagnosed With Attention-Deficit/Hyperactivity Disorder.

PubMed

Walls, Morgan; Allen, Caitlin G; Cabral, Howard; Kazis, Lewis E; Bair-Merritt, Megan

2018-04-01

In 2011, the American Academy of Pediatrics published practice guidelines for attention-deficit/hyperactivity disorder (ADHD), recommending both medication and behavioral therapy for school-age children. The current study examines associations between child/family characteristics and ADHD medication, behavioral, and combined therapy. This study used data from the 2014 National Survey of the Diagnosis and Treatment of ADHD and Tourette syndrome, a nationally representative follow-up survey to the 2011-2012 National Survey of Children's Health. Descriptive statistics were used to estimate frequencies of ADHD treatments and multivariable logistic regression to examine child/family characteristics associated with parent-reported medication use, classroom management, and parent training for children aged 8 to 17 diagnosed with ADHD (n = 2401). Black and Hispanic children were less likely than white children to have ever received ADHD medication. Hispanic children were less likely than white children to be currently receiving medications (adjusted odds ratio, 0.49; 95% confidence interval, 0.30-0.80). No differences were found in current medication use for black children compared to white children. Thirty-percent of parents reported that their child was currently receiving classroom management, and 31% reported having ever received parent training for ADHD. Children whose ADHD medication was managed by a primary care physician were less likely to receive combined medication and behavioral therapy compared to children managed by specialty physicians (adjusted odds ratio, 2.58; 95% confidence interval, 1.75-3.79). Most school-age children reported receiving medication for ADHD; however, medication disparities persist. Parent-reported use of behavioral therapies are low. Future research should examine reasons for observed variation in treatment and interventions to optimize ADHD care. Copyright © 2018 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype-4 chronic hepatitis C patients.

PubMed

Helal, Gouda Kamel; Gad, Magdy Abdelmawgoud; Abd-Ellah, Mohamed Fahmy; Eid, Mahmoud Saied

2016-12-01

The therapeutic effect of pegylated interferon (peg-IFN) alfa-2a combined with ribavirin (RBV) on chronic hepatitis C Egyptian patients is low and further efforts are required to optimize this therapy for achievement of higher rates of virological response. This study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) in combination with pegylated interferon plus ribavirin on early virological response (EVR) in chronic hepatitis C Egyptian patients. Naïve 120 Egyptian patients with chronic hepatitis C virus infection were divided into two groups. Group 1 have administered the standard of care therapy (pegylated interferon alfa-2a plus ribavirin) for 12 weeks, (n = 60). Group 2 have administered hydroxychloroquine plus standard of care therapy for 12 weeks, (n = 60). Therapeutics included hydroxychloroquine (200 mg) oral twice daily, peginterferon alfa-2a (160 μg) subcutaneous once weekly and oral weight-based ribavirin (1000-1200 mg/day). Baseline characteristics were similar in the two groups. The percentage of early virological response was significantly more in patients given the triple therapy than in patients given the standard of care [54/60 (90%) vs. 43/60 (71.7%); P = 0.011; respectively]. Biochemical response at week 12 was also significantly higher in patients given the triple therapy compared with the standard of care [58/60 (96.7%) vs. 42/60 (70%); P < 0.001; respectively]. Along the study, the observed adverse events were mild and similar across treatment groups. Addition of hydroxychloroquine to pegylated interferon plus ribavirin improves the rate of early virological and biochemical responses in chronic hepatitis C Egyptian patients without an increase in adverse events. J. Med. Virol. 88:2170-2178, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Survival After Neoadjuvant and Adjuvant Treatments Compared to Surgery Alone for Resectable Esophageal Carcinoma: A Network Meta-analysis.

PubMed

Pasquali, Sandro; Yim, Guang; Vohra, Ravinder S; Mocellin, Simone; Nyanhongo, Donald; Marriott, Paul; Geh, Ju Ian; Griffiths, Ewen A

2017-03-01

This network meta-analysis compared overall survival after neoadjuvant or adjuvant chemotherapy (CT), radiotherapy (RT), or combinations of both (chemoradiotherapy, CRT) or surgery alone to identify the most effective approach. The optimal treatment for resectable esophageal cancer is unknown. A search for randomized controlled trials reporting on neoadjuvant and adjuvant therapies was conducted. Using a network meta-analysis, treatments were ranked based on their effectiveness for improving survival. In 33 eligible randomized controlled trials, 6072 patients were randomized to receive either surgery alone (N = 2459) or neoadjuvant CT (N = 1332), RT (N = 58), and CRT (N = 1196) followed by surgery or surgery followed by adjuvant CT (N = 542), RT (N = 383), and CRT (N = 102). Twenty-one comparisons were generated. Neoadjuvant CRT followed by surgery compared with surgery alone was the only treatment to significantly improve survival [hazard ratio (HR) = 0.77, 95% confidence interval (CI): 0.68-0.87]. When trials were grouped considering neoadjuvant and adjuvant therapies and surgery alone, neoadjuvant therapies combined with surgery compared with surgery alone showed a survival advantage (HR = 0.83, 95% CI 0.76-0.90), whereas surgery along with adjuvant therapies showed no significant survival advantage (HR = 0.87, 95% CI 0.67-1.14). A subgroup analysis of neoadjuvant therapies showed a superior effectiveness of neoadjuvant CRT and surgery compared with surgery alone (HR = 0.77, 95% CI 0.68-0.87). This network meta-analysis showed neoadjuvant CRT followed by surgery to be the most effective strategy in improving survival of resectable esophageal cancer. Resources should be focused on developing the most effective neoadjuvant CRT regimens for both adenocarcinomas and squamous cell carcinomas of the esophagus.

Comparative activity of tedizolid and glycopeptide combination therapies for the treatment of Staphylococcus aureus infections: an in vitro and in vivo evaluation against strains with reduced susceptibility to glycopeptides.

PubMed

Betts, J W; Abdul Momin, H F; Phee, L M; Wareham, D W

2018-02-01

Glycopeptides are widely used for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections. Although difficult to detect, isolates with reduced (GISA), hetero (hGISA) or complete (GRSA) resistance to glycopeptides are increasingly reported. Optimal therapy for such strains is unknown. We compared the in vitro and in vivo activity of tedizolid (TED), a recently licensed oxazolidonone, with vancomycin (VAN) and teicoplanin (TEIC) combined with fusidic acid (FD) or rifampicin (RIF) against S. aureus (SA) with reduced susceptibility to glycopeptides. Susceptibility was determined for six (GISA, hGISA and GRSA) reference strains and 72 clinical MRSA isolates screened for hGISA/GISA-like phenotypes. Synergy and bactericidal activity were assessed using chequerboard and time-kill assays. The G. mellonella wax moth caterpillar model was used to measure the activity of TED and the combinations in vivo. Glycopeptide MICs (VAN/TEIC) ranged from 0.5-8/4 and 0.125-1 for TED. No significant synergy was noted when VAN/TEIC were combined with either RIF or FD. Time-kill assays confirmed that TED was bacteriostatic but superior to VAN and TEIC against GISA strains. In G. mellonella TED was more effective than TEIC monotherapy versus GISA strains. The combination of TEIC with RIF was the most effective combination overall, both in vitro and in vivo. TED had good in vitro activity versus MRSA including those with reduced susceptibility to glycopeptides. Although bacteriostatic, it was effective in the G. mellonella model and superior to TEIC in the treatment of GISA. Although this supports the use of TED for MRSA and GISA, the TEIC/RIF combination also warrants further study.

Analysis of the antinociceptive interactions in two-drug combinations of gabapentin, oxcarbazepine and amitriptyline in streptozotocin-induced diabetic mice.

PubMed

Tomić, Maja A; Vucković, Sonja M; Stepanović-Petrović, Radica M; Micov, Ana M; Ugresić, Nenad D; Prostran, Milica S; Bosković, Bogdan

2010-02-25

Antiepileptic and antidepressant drugs are the primary treatments for pain relief in diabetic neuropathy. Combination therapy is a valid approach in pain treatment, where a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of two-drug combinations of gabapentin, oxcarbazepine, and amitriptyline on nociception in diabetic mice and aimed to determine the type of interaction between components. The nociceptive responses in normal and diabetic mice were assessed by the tail-flick test. The testing was performed before and three weeks after the diabetes induction with streptozotocin (150mg/kg; i.p.), when the antinociceptive effects of gabapentin, oxcarbazepine, amitriptyline and their two-drug combinations were examined. Gabapentin (10-40mg/kg; p.o.) and oxcarbazepine (20-80mg/kg; p.o.) produced a significant, dose-dependent antinociception in diabetic mice while amitriptyline (5-60mg/kg; p.o.) produced weak antinociceptive effect. In normal mice, neither of the drugs produced antinociception. Gabapentin and oxcarbazepine, co-administered in fixed-dose fractions of the ED(50) to diabetic mice, induced significant, dose-dependent antinociception. Isobolographic analysis revealed synergistic interaction. Oxcarbazepine (10-60mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) and gabapentin (10-30mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) combinations significantly and dose-dependently reduced nociception in diabetic mice. Analysis of the log dose-response curves for oxcarbazepine or gabapentin in a presence of amitriptyline and oxcarbazepine or gabapentin applied alone, revealed a synergism in oxcarbazepine-amitriptyline and additivity in gabapentin-amitriptyline combination. These findings provide new information about the combination therapy of painful diabetic neuropathy and should be explored further in patients with diabetic neuropathy.

TH-AB-BRB-04: Quality Assurance for Advanced Digital Linac Implementations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, V.

2016-06-15

Current state-of-the art digital C-arm medical linear accelerators are capable of delivering radiation treatments with high level of automation, which affords coordinated motions of gantry, couch, and multileaf collimator (MLC) with dose rate modulations. The new machine capacity has shown the potential to bring substantially improved radiation dosimetry and/or delivery efficiency to many challenging diseases. Combining an integrated beam orientation optimization algorithm with automated machine navigation, markedly improved dose conformity has been achieved using 4ρ therapy. Trajectory modulated radiation therapy (TMAT) can be used to deliver highly conformal dose to partial breast or to carve complex dose distribution for therapymore » involving extended volumes such as total marrow and total lymph node treatment. Dynamic electron arc radiotherapy (DEAR) not only overcomes the deficiencies of conventional electron therapy in dose conformity and homogeneity but also achieves so without patient-specific shields. The combination of MLC and couch tracking provides improved motion management of thoracic and abdominal tumors. A substantial body of work has been done in these technological advances for clinical translation. The proposed symposium will provide a timely review of these exciting opportunities. Learning Objectives: Recognize the potential of using digitally controlled linacs for clinically significant improvements in delivered dose distributions for various treatment sites. Identify existing approaches to treatment planning, optimization and delivery for treatment techniques utilizing the advanced functions of digital linacs and venues for further development and improvement. Understand methods for testing and validating delivery system performance. Identify tools available on current delivery systems for implementation and control for such treatments. Obtain the update in clinical applications, trials and regulatory approval. K. Sheng, NIH U19AI067769, NIH R43CA183390, NIH R01CA188300, Varian Medical Systems V. Yu, Varian Medical Systems, AAPM Summer Undergraduate Fellowship, NSF graduate fellowship S. Nill, Elekta AB. Cancer Research UK under Programme C33589/A19727, NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research.« less

TH-AB-BRB-00: Research Opportunities with Digital Linear Accelerators

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

2016-06-15

Current state-of-the art digital C-arm medical linear accelerators are capable of delivering radiation treatments with high level of automation, which affords coordinated motions of gantry, couch, and multileaf collimator (MLC) with dose rate modulations. The new machine capacity has shown the potential to bring substantially improved radiation dosimetry and/or delivery efficiency to many challenging diseases. Combining an integrated beam orientation optimization algorithm with automated machine navigation, markedly improved dose conformity has been achieved using 4ρ therapy. Trajectory modulated radiation therapy (TMAT) can be used to deliver highly conformal dose to partial breast or to carve complex dose distribution for therapymore » involving extended volumes such as total marrow and total lymph node treatment. Dynamic electron arc radiotherapy (DEAR) not only overcomes the deficiencies of conventional electron therapy in dose conformity and homogeneity but also achieves so without patient-specific shields. The combination of MLC and couch tracking provides improved motion management of thoracic and abdominal tumors. A substantial body of work has been done in these technological advances for clinical translation. The proposed symposium will provide a timely review of these exciting opportunities. Learning Objectives: Recognize the potential of using digitally controlled linacs for clinically significant improvements in delivered dose distributions for various treatment sites. Identify existing approaches to treatment planning, optimization and delivery for treatment techniques utilizing the advanced functions of digital linacs and venues for further development and improvement. Understand methods for testing and validating delivery system performance. Identify tools available on current delivery systems for implementation and control for such treatments. Obtain the update in clinical applications, trials and regulatory approval. K. Sheng, NIH U19AI067769, NIH R43CA183390, NIH R01CA188300, Varian Medical Systems V. Yu, Varian Medical Systems, AAPM Summer Undergraduate Fellowship, NSF graduate fellowship S. Nill, Elekta AB. Cancer Research UK under Programme C33589/A19727, NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research.« less

Effect of first-line endocrine therapy in patients with hormone-sensitive advanced breast cancer: a network meta-analysis.

PubMed

Zhang, Tingting; Feng, Fubin; Zhao, Wenge; Tian, Jinhui; Yao, Yan; Zhou, Chao; Dong, Shengjie; Wang, Congcong; Zang, Chuanxin; Lv, Qingliang; Sun, Changgang

2018-01-01

Endocrine therapy is the cornerstone treatment for patients with hormone receptor-positive advanced breast cancer. We aimed to assess the effectiveness of various first-line endocrine monotherapies or combinations to determine the optimal sequence in a network meta-analysis. We searched PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) from inception up to November 21, 2017. We included only RCTs that assessed the effectiveness of the following treatments as a monotherapy or in combination as the first-line treatment: tamoxifen, anastrozole, letrozole, exemestane, fulvestrant, palbociclib, and ribociclib. The results were presented with pooled odds ratio or hazard ratio (HR), and 95% credible interval (CrI). The primary outcomes were objective response rate (ORR) and progression-free survival/time to progression. A total of 16 eligible articles (14 RCTs) involving 6,602 patients treated with 10 different first-line endocrine therapies were assessed in our network meta-analysis. Palbociclib plus letrozole was superior to anastrozole, letrozole, exemestane, fulvestrant 500 mg, and anastrozole plus fulvestrant (loading dose) (HR=0.44, 95% CrI: 0.33-0.58; HR=0.56, 95% CrI: 0.45-0.68; HR=0.45, 95% CrI: 0.32-0.61; HR=0.58, 95% CrI: 0.42-0.81; HR=0.50, 95% CrI: 0.37-0.68; respectively). However, there is no significant advantage compared with ribociclib plus letrozole (HR=1.00, 95% CrI: 0.72-1.39). In terms of ORR, ribociclib plus letrozole is more effective than palbociclib plus letrozole (odds ratio=1.30, 95% CrI: 0.83-2.02). Palbociclib plus letrozole and ribociclib plus letrozole might be the optimal first-line endocrine therapeutic choices for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer due to a longer progression-free survival/time to progression and a more efficacious ORR.

Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes.

PubMed

Moses, R; Slobodniuk, R; Boyages, S; Colagiuri, S; Kidson, W; Carter, J; Donnelly, T; Moffitt, P; Hopkins, H

1999-01-01

To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes. A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period. In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05). Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy.

The Relationship Between Heart Rate Reserve and Oxygen Uptake Reserve in Heart Failure Patients on Optimized and Non-Optimized Beta-Blocker Therapy

PubMed Central

Carvalho, Vitor Oliveira; Guimarães, Guilherme Veiga; Bocchi, Edimar Alcides

2008-01-01

BACKGROUND The relationship between the percentage of oxygen consumption reserve and percentage of heart rate reserve in heart failure patients either on non-optimized or off beta-blocker therapy is known to be unreliable. The aim of this study was to evaluate the relationship between the percentage of oxygen consumption reserve and percentage of heart rate reserve in heart failure patients receiving optimized and non-optimized beta-blocker treatment during a treadmill cardiopulmonary exercise test. METHODS A total of 27 sedentary heart failure patients (86% male, 50±12 years) on optimized beta-blocker therapy with a left ventricle ejection fraction of 33±8% and 35 sedentary non-optimized heart failure patients (75% male, 47±10 years) with a left ventricle ejection fraction of 30±10% underwent the treadmill cardiopulmonary exercise test (Naughton protocol). Resting and peak effort values of both the percentage of oxygen consumption reserve and percentage of heart rate reserve were, by definition, 0 and 100, respectively. RESULTS The heart rate slope for the non-optimized group was derived from the points 0.949±0.088 (0 intercept) and 1.055±0.128 (1 intercept), p<0.0001. The heart rate slope for the optimized group was derived from the points 1.026±0.108 (0 intercept) and 1.012±0.108 (1 intercept), p=0.47. Regression linear plots for the heart rate slope for each patient in the non-optimized and optimized groups revealed a slope of 0.986 (almost perfect) for the optimized group, but the regression analysis for the non-optimized group was 0.030 (far from perfect, which occurs at 1). CONCLUSION The relationship between the percentage of oxygen consumption reserve and percentage of heart rate reserve in patients on optimized beta-blocker therapy was reliable, but this relationship was unreliable in non-optimized heart failure patients. PMID:19060991

Losartan/hydrochlorothiazide combination is safe and effective for morning hypertension in Very-Elderly patients.

PubMed

Uchiwa, Hiroki; Kai, Hisashi; Iwamoto, Yoshiko; Anegawa, Takahiro; Kajimoto, Hidemi; Fukuda, Kenji; Imaizumi, Tsutomu; Fukumoto, Yoshihiro

2018-01-01

Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the prevalence of morning hypertension increases with age, treatment of morning hypertension has not been established, particularly in Very-Elderly patients. We compared the safety and efficacy of a losartan/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension between Very-Elderly (≥75 years) and Young/Elderly patients (<75 years). This study was a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy study, in which patients with morning hypertension (≥135/85 mmHg) received a 50-mg losartan/12.5-mg HCTZ combination tablet (combination therapy) or 100-mg losartan (high-dose therapy) for 3 months. High adherence rates and few adverse effects were observed in Very-Elderly patients receiving combination (n = 32) and high-dose (n = 34) therapies and in Young/Elderly patients receiving combination (n = 69) and high-dose (n = 66) therapies. Baseline morning systolic BP (SBP) was similar in both age groups receiving either therapy. Morning SBP was reduced by 20.2 and 18.1 mmHg with combination therapy and by 7.1 and 9.1 mmHg with high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Morning BP target (<135/85 mmHg) was achieved in 40.6% and 55.1% by combination therapy and in 14.7% and 24.2% by high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Neither therapy changed renal function and serum potassium in Very-Elderly patients. In conclusion, the losartan/HCTZ combination was safe and effective in controlling morning hypertension in Very-Elderly as well as Young/Elderly patients. In addition, combination therapy was also superior to high-dose therapy for lowering morning SBP in Very-Elderly patients.

Managing Severe Community-Acquired Pneumonia Due to Community Methicillin-Resistant Staphylococcus aureus (MRSA).

PubMed

Kwong, Jason C; Chua, Kyra; Charles, Patrick G P

2012-06-01

Community-associated methicillin-resistant Staphylococcus aureus (MRSA) is a rare, but significant cause of community-acquired pneumonia (CAP). A number of virulence determinants have been implicated in the development of severe community MRSA pneumonia, characterized by multilobar cavitating necrosis in patients without usual risk-factors for pneumonia. Optimal management is uncertain, and is extrapolated from anecdotal experiences with small case series, randomized studies of hospital-acquired pneumonia, and laboratory investigations using in vitro experiments and animal models of MRSA pneumonia. Adequate clinical suspicion, early diagnosis and administration of appropriate antibiotics are necessary for best patient outcomes, although some patients will still do badly even with early anti-MRSA therapy. Vancomycin or linezolid have been recommended as first-line therapy, possibly in combination with other antibiotics. Newer antibiotics such as ceftaroline are still being evaluated.

Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila

NASA Astrophysics Data System (ADS)

Agrawal, Namita; Pallos, Judit; Slepko, Natalia; Apostol, Barbara L.; Bodai, Laszlo; Chang, Ling-Wen; Chiang, Ann-Shyn; Michels Thompson, Leslie; Marsh, J. Lawrence

2005-03-01

We explore the hypothesis that pathology of Huntington's disease involves multiple cellular mechanisms whose contributions to disease are incrementally additive or synergistic. We provide evidence that the photoreceptor neuron degeneration seen in flies expressing mutant human huntingtin correlates with widespread degenerative events in the Drosophila CNS. We use a Drosophila Huntington's disease model to establish dose regimens and protocols to assess the effectiveness of drug combinations used at low threshold concentrations. These proof of principle studies identify at least two potential combinatorial treatment options and illustrate a rapid and cost-effective paradigm for testing and optimizing combinatorial drug therapies while reducing side effects for patients with neurodegenerative disease. The potential for using prescreening in Drosophila to inform combinatorial therapies that are most likely to be effective for testing in mammals is discussed. combinatorial treatments | neurodegeneration

Nanomedicine of synergistic drug combinations for cancer therapy – strategies and perspectives

PubMed Central

Xue, Hui Yi; Eoh, June Young; Wu, Xiao Yu

2016-01-01

Nanomedicine of synergistic drug combinations has shown increasing significance in cancer therapy due to its promise in providing superior therapeutic benefits to the current drug combination therapy used in clinical practice. In this article, we will examine the rationale, principles, and advantages of applying nanocarriers to improve anticancer drug combination therapy, review the use of nanocarriers for delivery of a variety of combinations of different classes of anticancer agents including small molecule drugs and biologics, and discuss the challenges and future perspectives of the nanocarrier-based combination therapy. The goal of this review is to provide better understanding of this increasingly important new paradigm of cancer treatment and key considerations for rational design of nanomedicine of synergistic drug combinations for cancer therapy. PMID:27287891

Design of a fast multileaf collimator for radiobiological optimized IMRT with scanned beams of photons, electrons, and light ions.

PubMed

Svensson, Roger; Larsson, Susanne; Gudowska, Irena; Holmberg, Rickard; Brahme, Anders

2007-03-01

Intensity modulated radiation therapy is rapidly becoming the treatment of choice for most tumors with respect to minimizing damage to the normal tissues and maximizing tumor control. Today, intensity modulated beams are most commonly delivered using segmental multileaf collimation, although an increasing number of radiation therapy departments are employing dynamic multileaf collimation. The irradiation time using dynamic multileaf collimation depends strongly on the nature of the desired dose distribution, and it is difficult to reduce this time to less than the sum of the irradiation times for all individual peak heights using dynamic leaf collimation [Svensson et al., Phys. Med. Biol. 39, 37-61 (1994)]. Therefore, the intensity modulation will considerably increase the total treatment time. A more cost-effective procedure for rapid intensity modulation is using narrow scanned photon, electron, and light ion beams in combination with fast multileaf collimator penumbra trimming. With this approach, the irradiation time is largely independent of the complexity of the desired intensity distribution and, in the case of photon beams, may even be shorter than with uniform beams. The intensity modulation is achieved primarily by scanning of a narrow elementary photon pencil beam generated by directing a narrow well focused high energy electron beam onto a thin bremsstrahlung target. In the present study, the design of a fast low-weight multileaf collimator that is capable of further sharpening the penumbra at the edge of the elementary scanned beam has been simulated, in order to minimize the dose or radiation response of healthy tissues. In the case of photon beams, such a multileaf collimator can be placed relatively close to the bremsstrahlung target to minimize its size. It can also be flat and thin, i.e., only 15-25 mm thick in the direction of the beam with edges made of tungsten or preferably osmium to optimize the sharpening of the penumbra. The low height of the collimator will minimize edge scatter from glancing incidence. The major portions of the collimator leafs can then be made of steel or even aluminum, so that the total weight of the multileaf collimator will be as low as 10 kg, which may even allow high-speed collimation in real time in synchrony with organ movements. To demonstrate the efficiency of this collimator design in combination with pencil beam scanning, optimal radiobiological treatments of an advanced cervix cancer were simulated. Different geometrical collimator designs were tested for bremsstrahlung, electron, and light ion beams. With a 10 mm half-width elementary scanned photon beam and a steel collimator with tungsten edges, it was possible to make as effective treatments as obtained with intensity modulated beams of full resolution, i.e., here 5 mm resolution in the fluence map. In combination with narrow pencil beam scanning, such a collimator may provide ideal delivery of photons, electrons, or light ions for radiation therapy synchronized to breathing and other organ motions. These high-energy photon and light ion beams may allow three-dimensional in vivo verification of delivery and thereby clinical implementation of the BioArt approach using Biologically Optimized three-dimensional in vivo predictive Assay based adaptive Radiation Therapy [Brahme, Acta Oncol. 42, 123-126 (2003)].

Profile of clindamycin phosphate 1.2%/benzoyl peroxide 3.75% aqueous gel for the treatment of acne vulgaris

PubMed Central

Nguyen, Tuyet A; Eichenfield, Lawrence F

2015-01-01

Acne vulgaris is a common and chronic skin disease, and is a frequent source of morbidity for affected patients. Treatment of acne vulgaris is often difficult due to the multifactorial nature of this disease. Combination therapy, such as that containing clindamycin and benzoyl peroxide, has become the standard of care. Several fixed formulations of clindamycin 1% and benzoyl peroxide of varying concentrations are available and have been used with considerable success. The major limitation is irritation and dryness from higher concentrations of benzoyl peroxide, and a combination providing optimal efficacy and tolerability has yet to be determined. Recently, a clindamycin and benzoyl peroxide 3.75% fixed combination formulation was developed. Studies have suggested that this formulation may be a safe and effective treatment regimen for patients with acne vulgaris. Here, we provide a brief review of acne pathogenesis, benzoyl peroxide and clindamycin, and profile a new Clindamycin-BP 3.75% fixed combination gel for the treatment of moderate-to-severe acne vulgaris. PMID:26604811

A study of the treatment of cutaneous fungal infection in animal model using photoactivated composite of methylene blue and gold nanoparticle.

PubMed

Tawfik, Abeer Attia; Noaman, Islam; El-Elsayyad, Hasan; El-Mashad, Noha; Soliman, Mona

2016-09-01

Onychomycosis is a widespread public health problem, in which T. rubrum and T. mentagrophytes is the commenest causative organisms. Current medical therapy has many drawbacks and side effects. Methylene blue (m.b) photodynamic therapy (pdt) proved efficacy but with lengthy sessions. Optimizing methylene blue photodynamic therapy by combination of methylene blue photosensitizer and gold nanoparticles (aunps) in a composite as gold nanoparticles are efficient delivery systems and efficient enhancers of photosensitizers for antifungal photodynamic therapy. Eighty newzealand rabbit (Oryctolagus cuniculus) were used and categorized in eight equal groups as follows; healthy and infection control, composite photodynamic therapy and five comparative groups. Photodynamic therapy was initiated at day three to five post inoculation, for four sessions forty eight hours apart. Each group divided and light exposure at two fluencies; 80J and 100J. All groups were investigated macroscopically and microscopically (histopathology and scanning electron microscope) also flowcytometry assessment for cell death and X-ray analysis for gold nanoparticles accumulation in brain and liver tissues were determined. Recovery from infection approaching 96% in gold nanoparticles+light group, around 40% in methylene blue photodynamic therapy and 34% in composite photodynamic therapy. The observed findings confirmed by apparent decrease of apoptosis, however small amounts of gold nanoparticles detected in brain and liver. Light stimulated gold nanoparticles is a promising tool in treatment of onychomycosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Combined Therapies of Modified Taiyi Miraculous Moxa Roll and Cupping for Patients with Lumbar Intervertebral Disc Herniation

PubMed Central

Dong, Dayong; Xue, Jinbiao; Zheng, Xiaoting

2018-01-01

Lumbar intervertebral disc herniation is a kind of syndrome caused by stimulation or pressure of nerve root and cauda equina due to intervertebral disc disorder, fibrous ring rupture, and pulpiform nucleus protrusion. Application of traditional Chinese medicine (TCM) including acupuncture therapy and cupping therapy is unique and effective treatment for lumbar intervertebral disc herniation in China. Hence, we try to investigate the combined clinical efficacy of modified Taiyi miraculous moxa roll and cupping therapy on patients with lumbar intervertebral disc herniation. Seventy patients were randomly assigned into combined treatment group (n = 35) and control group (n = 35). The treatment group received combined therapy of modified Taiyi miraculous moxa roll and cupping therapy, while control group received acupuncture therapy alone. Diagnostic criteria of TCM syndrome, Japanese Orthopedic Association (JOA) score, and simplified McGill pain questionnaire (MPQ) were used to evaluate the therapy. 11 and 13 out of 35 subjects in the combined treatment group had improvement > 75% and between 50% and 75%, respectively. The corresponding number was 2 and 22 of 35 subjects in the acupuncture group. There was significant difference in the clinical efficacy between the treatment group and control group (P = 0.036). The scores of JOA and MPQ detected in the patients of the two groups (P < 0.05) also showed statistically significant differences. Moreover, no serious adverse events occurred in the patients, who received cupping therapy or acupuncture. The combined or alone therapies can effectively improve the treatment efficacy in the patients with lumbar intervertebral disc herniation, while the combined therapies show more comparative effectiveness. Furthermore, the combined therapies are potentially safe and cost-effective and also benefit the improvement of short-term pain. Therefore, the combined therapies of the two ancient TCM deserve further clinical applications. PMID:29785195

Combined Therapies of Modified Taiyi Miraculous Moxa Roll and Cupping for Patients with Lumbar Intervertebral Disc Herniation.

PubMed

Cai, Chunyue; Gong, Yuefeng; Dong, Dayong; Xue, Jinbiao; Zheng, Xiaoting; Zhong, Zhangfeng; Shao, Jialong; Mi, Daguo

2018-01-01

Lumbar intervertebral disc herniation is a kind of syndrome caused by stimulation or pressure of nerve root and cauda equina due to intervertebral disc disorder, fibrous ring rupture, and pulpiform nucleus protrusion. Application of traditional Chinese medicine (TCM) including acupuncture therapy and cupping therapy is unique and effective treatment for lumbar intervertebral disc herniation in China. Hence, we try to investigate the combined clinical efficacy of modified Taiyi miraculous moxa roll and cupping therapy on patients with lumbar intervertebral disc herniation. Seventy patients were randomly assigned into combined treatment group ( n = 35) and control group ( n = 35). The treatment group received combined therapy of modified Taiyi miraculous moxa roll and cupping therapy, while control group received acupuncture therapy alone. Diagnostic criteria of TCM syndrome, Japanese Orthopedic Association (JOA) score, and simplified McGill pain questionnaire (MPQ) were used to evaluate the therapy. 11 and 13 out of 35 subjects in the combined treatment group had improvement > 75% and between 50% and 75%, respectively. The corresponding number was 2 and 22 of 35 subjects in the acupuncture group. There was significant difference in the clinical efficacy between the treatment group and control group ( P = 0.036). The scores of JOA and MPQ detected in the patients of the two groups ( P < 0.05) also showed statistically significant differences. Moreover, no serious adverse events occurred in the patients, who received cupping therapy or acupuncture. The combined or alone therapies can effectively improve the treatment efficacy in the patients with lumbar intervertebral disc herniation, while the combined therapies show more comparative effectiveness. Furthermore, the combined therapies are potentially safe and cost-effective and also benefit the improvement of short-term pain. Therefore, the combined therapies of the two ancient TCM deserve further clinical applications.

What is the role of combination drug therapy in the treatment of overactive bladder? ICI-RS 2014.

PubMed

Visco, Anthony G; Fraser, Matthew O; Newgreen, Donald; Oelke, Matthias; Cardozo, Linda

2016-02-01

The role of combination therapy using oral antimuscarinic medications for the treatment of overactive bladder was proposed at the 2014 International Consultation on Incontinence-Research Society in Bristol, UK to identify key factors to consider when making clinical decisions and to guide future research design. Combination therapy is justified if monotherapy is associated with suboptimal efficacy or bothersome side effects. Combination therapy has the potential to improve efficacy with fewer side effects than monotherapy. Two Phase 2 studies comparing combination therapy that included an antimuscarinic demonstrated improvement in mean voided volume, the primary outcome chosen, with some combinations showing improved micturition frequency and quality of life. The two studies found no evidence of an increased safety risk with combination therapy compared to monotherapy. Future studies should use clinically meaningful or patient reported outcomes such as incontinence episodes when comparing efficacy. If surrogate measures are used, a clear justification should be provided. Cost analyses should be planned for clinical research trials evaluating combination drug therapy. Combination therapy is reasonable when monotherapy has suboptimal efficacy or bothersome side effects. Future research studies evaluating combination therapy for urgency urinary incontinence should ideally(1) be performed as part of a randomized clinical trial,(2) evaluate non-responders to monotherapy,(3) evaluate combination therapy using medications with different mechanisms of action,(4) include clinically meaningful and patient reported outcomes when evaluating efficacy, and(5) include cost-effectiveness analyses to justify any increased cost by showing improvement in efficacy or reduction in side effects. © 2016 Wiley Periodicals, Inc.

The Addition of an Immunosuppressant After Loss of Response to Anti-TNFα Monotherapy in Inflammatory Bowel Disease: A 2-Year Study.

PubMed

Macaluso, Fabio Salvatore; Sapienza, Chiara; Ventimiglia, Marco; Renna, Sara; Rizzuto, Giulia; Orlando, Rosalba; Di Pisa, Marta; Affronti, Marco; Orlando, Emanuele; Cottone, Mario; Orlando, Ambrogio

2018-01-18

The addition of an immunosuppressant (IM) after loss of response to anti-TNFα monotherapy is an emerging strategy of therapeutic optimization in patients with inflammatory bowel disease (IBD). However, few clinical data have been reported to date. We aimed to evaluate the efficacy and safety of this selective combination therapy in patients with IBD. All consecutive patients with loss of response to anti-TNFα monotherapy despite an intensive dose optimization who added an IM from October 2014 to October 2016 were entered into a prospective database. Among 630 patients treated with anti-TNFα agents during the study period, 46 (7.3%) added an IM. A total of 31 patients (67.4%) were treated with an intravenous anti-TNFα (infliximab, as originator or biosimilar), while 15 (32.6%) were treated with a subcutaneous anti-TNFα agent (10 adalimumab and 5 golimumab). The mean duration of follow-up was 12.8 ± 7.3 months. Twenty-one patients (45.7%) remained on combination therapy at the end of follow-up: 15 (32.6%) maintained a steroid-free remission, and 6 (13.0%) achieved a clinical response. In patients who experienced treatment success, the median value of C-reactive protein decreased from baseline to the end of follow-up (13.2 vs 3.0, P = 0.01; normal values <5 mg/L). Adverse events leading to treatment discontinuation were reported in 8 out of 46 patients (17.4%). In the largest cohort on this argument reported to date, the addition of an IM was an effective and safe optimization strategy after loss of response to anti-TNFα monotherapy. Low doses of IM were sufficient to achieve a clinical response. © 2018 Crohn’s & Colitis Foundation of America. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Optimizing the management of depression: primary care experience.

PubMed

Cameron, Catherine; Habert, Jeff; Anand, Leena; Furtado, Melissa

2014-12-01

This article is intended to identify some of the most important challenges faced by family physicians when treating MDD and to provide practical solutions. Key issues, reviewed from a primary care view point will include: treating to remission (and not just response), identification of high-risk groups, diagnosis, acute treatment approaches (including pharmacotherapy and the management of related side effects), the use of psychotherapy and somatic therapies, assessment of the adequacy of treatment including the assessment of remission, response measurement, optimal follow-up care throughout the phase of treatment, the key components of patient education and strategies for partial/limited response to the first-line antidepressant (switching, augmentation and combination strategies), how to provide support for improved treatment adherence, and approaches to prevent the recurrence of depressive episodes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Stem Cell Gene Therapy for Fanconi Anemia: Report from the 1st International Fanconi Anemia Gene Therapy Working Group Meeting

PubMed Central

Tolar, Jakub; Adair, Jennifer E; Antoniou, Michael; Bartholomae, Cynthia C; Becker, Pamela S; Blazar, Bruce R; Bueren, Juan; Carroll, Thomas; Cavazzana-Calvo, Marina; Clapp, D Wade; Dalgleish, Robert; Galy, Anne; Gaspar, H Bobby; Hanenberg, Helmut; Von Kalle, Christof; Kiem, Hans-Peter; Lindeman, Dirk; Naldini, Luigi; Navarro, Susana; Renella, Raffaele; Rio, Paula; Sevilla, Julián; Schmidt, Manfred; Verhoeyen, Els; Wagner, John E; Williams, David A; Thrasher, Adrian J

2011-01-01

Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA. PMID:21540837

Portopulmonary hypertension: state of the art.

PubMed

Porres-Aguilar, Mateo; Zuckerman, Marc J; Figueroa-Casas, Juan B; Krowka, Michael J

2008-01-01

Portopulmonary hypertension is an uncommon but treatable pulmonary vascular consequence of portal hypertension, which can lead to significant morbidity and mortality. Portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodeling that eventually leads to right-heart failure and death if left untreated. Although pulmonary vascular disease in these patients may be asymptomatic or associated with subtle and nonspecific symptoms (dyspnea, fatigue and lower extremity swelling), it should be looked for especially if patients are potential candidates for liver transplantation. Patients with clinical suspicion of portopulmonary hypertension should undergo screening testing, specifically echocardiography. Right heart catheterization remains the gold standard for the diagnosis. The existence of moderate to severe disease poses higher risks and challenges for liver transplantation. The disease has a substantial impact on survival and requires focused pharmacological therapy. New and evolving medical therapies, such as prostanoids (intravenous, inhaled or oral), endothelin receptors antagonists, phosphodiesterases inhibitors, combination therapy and other experimental drugs might change the natural course of the disease. Case reports and cases series have been published regarding the efficacy and safety of pharmacological therapy, but randomized, controlled multicenter trials are urgently needed. Liver transplantation is not the treatment of choice for portopulmonary hypertension, but after optimal hemodynamic and clinical improvement with medical therapy as a bridge, liver transplant can be considered an option in selected patients.

Pharmacogenetics of the β2-Adrenergic Receptor Gene

PubMed Central

Ortega, Victor E.; Hawkins, Gregory A.; Peters, Stephen P.; Bleecker, Eugene R.

2009-01-01

Asthma is a complex genetic disease with multiple genetic and environmental determinants contributing to the observed variability in response to common anti-asthma therapies. Asthma pharmacogenetic research has focused on multiple candidate genes including the β2-adrenergic receptor gene (ADRβ2) and its effect on individual responses to beta agonist therapy. At present, knowledge about the effects of ADRβ2 variation on therapeutic responses is evolving and should not alter current Asthma Guideline approaches consisting of the use of short acting beta agonists for as-needed symptom based therapy and the use of a regular long-acting beta agonist in combination with inhaled corticosteroid therapy for optimal control of asthma symptoms in those asthmatics who are not controlled on inhaled corticosteroid alone. This approach is based upon studies showing a consistent pharmacogenetic response to regular use of short acting beta agonists (SABA) and less consistent findings in studies evaluating long acting beta agonist (LABA). While emerging pharmacogenetic studies are provocative and should lead to functional approaches, conflicting data with responses to LABA therapy may be caused by factors that include small sample sizes of study populations and differences in experimental design that may limit the conclusions that may be drawn from these clinical trials at the present time. PMID:17996583

Epidemiology and therapies for metastatic sarcoma

PubMed Central

Amankwah, Ernest K; Conley, Anthony P; Reed, Damon R

2013-01-01

Sarcomas are cancers arising from the mesenchymal layer that affect children, adolescents, young adults, and adults. Although most sarcomas are localized, many display a remarkable predilection for metastasis to the lungs, liver, bones, subcutaneous tissue, and lymph nodes. Additionally, many sarcoma patients presenting initially with localized disease may relapse at metastatic sites. While localized sarcomas can often be cured through surgery and often radiation, controversies exist over optimal management of patients with metastatic sarcoma. Combinations of chemotherapy are the most effective in many settings, and many promising new agents are under active investigation or are being explored in preclinical models. Metastatic sarcomas are excellent candidates for novel approaches with additional agents as they have demonstrated chemosensitivity and affect a portion of the population that is motivated toward curative therapy. In this paper, we provide an overview on the common sarcomas of childhood (rhabdomyosarcoma), adolescence, and young adults (osteosarcoma, Ewing sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor) and older adults (leiomyosarcoma, liposarcoma, and undifferentiated high grade sarcoma) in terms of the epidemiology, current therapy, promising therapeutic directions and outcome with a focus on metastatic disease. Potential advances in terms of promising therapy and biologic insights may lead to more effective and safer therapies; however, more clinical trials and research are needed for patients with metastatic sarcoma. PMID:23700373

[Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015].

PubMed

Vanacker, Hélène; Bally, Olivia; Kassem, Loay; Tredan, Olivier; Heudel, Pierre; Bachelot, Thomas

2015-06-01

Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.