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Sample records for minimal disease application

  1. Minimal Residual Disease Assessment in Lymphoma: Methods and Applications.

    PubMed

    Herrera, Alex F; Armand, Philippe

    2017-09-21

    Standard methods for disease response assessment in patients with lymphoma, including positron emission tomography and computed tomography scans, are imperfect. In other hematologic malignancies, particularly leukemias, the ability to detect minimal residual disease (MRD) is increasingly influencing treatment paradigms. However, in many subtypes of lymphoma, the application of MRD assessment techniques, like flow cytometry or polymerase chain reaction-based methods, has been challenging because of the absence of readily detected circulating disease or canonic chromosomal translocations. Newer MRD detection methods that use next-generation sequencing have yielded promising results in a number of lymphoma subtypes, fueling the hope that MRD detection may soon be applicable in clinical practice for most patients with lymphoma. MRD assessment can provide real-time information about tumor burden and response to therapy, noninvasive genomic profiling, and monitoring of clonal dynamics, allowing for many possible applications that could significantly affect the care of patients with lymphoma. Further validation of MRD assessment methods, including the incorporation of MRD assessment into clinical trials in patients with lymphoma, will be critical to determine how best to deploy MRD testing in routine practice and whether MRD assessment can ultimately bring us closer to the goal of personalized lymphoma care. In this review article, we describe the methods available for detecting MRD in patients with lymphoma and their relative advantages and disadvantages. We discuss preliminary results supporting the potential applications for MRD testing in the care of patients with lymphoma and strategies for including MRD assessment in lymphoma clinical trials.

  2. Minimal Residual Disease in Acute Myeloid Leukemia of Adults: Determination, Prognostic Impact and Clinical Applications.

    PubMed

    Del Principe, Maria Ilaria; Buccisano, Francesco; Maurillo, Luca; Sconocchia, Giuseppe; Cefalo, Mariagiovanna; Consalvo, Maria Irno; Sarlo, Chiara; Conti, Consuelo; De Santis, Giovanna; De Bellis, Eleonora; Di Veroli, Ambra; Palomba, Patrizia; Attrotto, Cristina; Zizzari, Annagiulia; Paterno, Giovangiacinto; Voso, Maria Teresa; Del Poeta, Giovanni; Lo-Coco, Francesco; Arcese, William; Amadori, Sergio; Venditti, Adriano

    2016-01-01

    Pretreatment assessment of cytogenetic/genetic signature of acute myeloid leukemia (AML) has been consistently shown to play a major prognostic role but also to fail at predicting outcome on individual basis, even in low-risk AML. Therefore, we are in need of further accurate methods to refine the patients' risk allocation process, distinguishing more adequately those who are likely to recur from those who are not. In this view, there is now evidence that the submicroscopic amounts of leukemic cells (called minimal residual disease, MRD), measured during the course of treatment, indicate the quality of response to therapy. Therefore, MRD might serve as an independent, additional biomarker to help to identify patients at higher risk of relapse. Detection of MRD requires the use of highly sensitive ancillary techniques, such as polymerase chain reaction (PCR) and multiparametric flow cytometry(MPFC). In the present manuscript, we will review the current approaches to investigate MRD and its clinical applications in AML management.

  3. Minimal Change Disease.

    PubMed

    Vivarelli, Marina; Massella, Laura; Ruggiero, Barbara; Emma, Francesco

    2017-02-07

    Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15% of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%-90% in children >1 year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immunosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis. Copyright © 2017 by the American Society of Nephrology.

  4. Minimal Residual Disease in Acute Myeloid Leukemia of Adults: Determination, Prognostic Impact and Clinical Applications

    PubMed Central

    Del Principe, Maria Ilaria; Buccisano, Francesco; Maurillo, Luca; Sconocchia, Giuseppe; Cefalo, Mariagiovanna; Consalvo, Maria Irno; Sarlo, Chiara; Conti, Consuelo; De Santis, Giovanna; De Bellis, Eleonora; Di Veroli, Ambra; Palomba, Patrizia; Attrotto, Cristina; Zizzari, Annagiulia; Paterno, Giovangiacinto; Voso, Maria Teresa; Del Poeta, Giovanni; Lo-Coco, Francesco; Arcese, William; Amadori, Sergio; Venditti, Adriano

    2016-01-01

    Pretreatment assessment of cytogenetic/genetic signature of acute myeloid leukemia (AML) has been consistently shown to play a major prognostic role but also to fail at predicting outcome on individual basis, even in low-risk AML. Therefore, we are in need of further accurate methods to refine the patients’ risk allocation process, distinguishing more adequately those who are likely to recur from those who are not. In this view, there is now evidence that the submicroscopic amounts of leukemic cells (called minimal residual disease, MRD), measured during the course of treatment, indicate the quality of response to therapy. Therefore, MRD might serve as an independent, additional biomarker to help to identify patients at higher risk of relapse. Detection of MRD requires the use of highly sensitive ancillary techniques, such as polymerase chain reaction (PCR) and multiparametric flow cytometry(MPFC). In the present manuscript, we will review the current approaches to investigate MRD and its clinical applications in AML management. PMID:27872732

  5. Monitoring Minimal Residual Disease in the Myeloproliferative Neoplasms: Current Applications and Emerging Approaches

    PubMed Central

    2016-01-01

    The presence of acquired mutations within the JAK2, CALR, and MPL genes in the majority of patients with myeloproliferative neoplasms (MPN) affords the opportunity to utilise these mutations as markers of minimal residual disease (MRD). Reduction of the mutated allele burden has been reported in response to a number of therapeutic modalities including interferon, JAK inhibitors, and allogeneic stem cell transplantation; novel therapies in development will also require assessment of efficacy. Real-time quantitative PCR has been widely adopted for recurrent point mutations with assays demonstrating the specificity, sensitivity, and reproducibility required for clinical utility. More recently, approaches such as digital PCR have demonstrated comparable, if not improved, assay characteristics and are likely to play an increasing role in MRD monitoring. While next-generation sequencing is increasingly valuable as a tool for diagnosis of MPN, its role in the assessment of MRD requires further evaluation. PMID:27840830

  6. Minimally Invasive Surgery for Inflammatory Bowel Disease

    PubMed Central

    Holder-Murray, Jennifer; Marsicovetere, Priscilla

    2015-01-01

    Abstract: Surgical management of inflammatory bowel disease is a challenging endeavor given infectious and inflammatory complications, such as fistula, and abscess, complex often postoperative anatomy, including adhesive disease from previous open operations. Patients with Crohn's disease and ulcerative colitis also bring to the table the burden of their chronic illness with anemia, malnutrition, and immunosuppression, all common and contributing independently as risk factors for increased surgical morbidity in this high-risk population. However, to reduce the physical trauma of surgery, technologic advances and worldwide experience with minimally invasive surgery have allowed laparoscopic management of patients to become standard of care, with significant short- and long-term patient benefits compared with the open approach. In this review, we will describe the current state-of the-art for minimally invasive surgery for inflammatory bowel disease and the caveats inherent with this practice in this complex patient population. Also, we will review the applicability of current and future trends in minimally invasive surgical technique, such as laparoscopic “incisionless,” single-incision laparoscopic surgery (SILS), robotic-assisted, and other techniques for the patient with inflammatory bowel disease. There can be no doubt that minimally invasive surgery has been proven to decrease the short- and long-term burden of surgery of these chronic illnesses and represents high-value care for both patient and society. PMID:25989341

  7. Quantification of the Mutant CALR Allelic Burden by Digital PCR: Application to Minimal Residual Disease Evaluation after Bone Marrow Transplantation.

    PubMed

    Mansier, Olivier; Migeon, Marina; Saint-Lézer, Arnaud; James, Chloé; Verger, Emmanuelle; Robin, Marie; Socié, Gérard; Bidet, Audrey; Mahon, François-Xavier; Cassinat, Bruno; Lippert, Eric

    2016-01-01

    With the recent discovery of CALR mutations, >80% of patients with myeloproliferative neoplasms carry a phenotype-driving mutation. For JAK2 V617F, the most frequent mutation in myeloproliferative neoplasms, accurate determination of mutational loads is of interest at diagnosis, for phenotypic and prognostic purposes, and during follow-up for minimal residual disease assessment. We developed a digital PCR technique that allowed the accurate determination of CALR allelic burdens for the main mutations (types 1 and 2). Compared with the commonly used fluorescent PCR product analysis, digital PCR is more precise, reproducible, and accurate. Furthermore, this method reached a very high sensitivity. We detected at least 0.025% CALR mutants. It can thus be used for patient characterization at diagnosis and for minimal residual disease monitoring. When applied to patients with primary myelofibrosis who underwent hematopoietic stem cell transplant, the digital PCR detected low levels of minimal residual disease. After negativation of the mutational load in all patients, the disease reappeared at a low level in one patient, preceding hematologic relapse. In conclusion, digital PCR adapted to type 1 and 2 CALR mutations is an inexpensive, highly precise, and sensitive technique suitable for evaluation of myeloproliferative neoplasm patients during follow-up.

  8. The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications.

    PubMed

    Anderson, Kenneth C; Auclair, Daniel; Kelloff, Gary J; Sigman, Caroline C; Avet-Loiseau, Hervé; Farrell, Ann T; Gormley, Nicole J; Kumar, Shaji K; Landgren, Ola; Munshi, Nikhil C; Cavo, Michele; Davies, Faith E; Di Bacco, Alessandra; Dickey, Jennifer S; Gutman, Steven I; Higley, Howard R; Hussein, Mohamad A; Jessup, J Milburn; Kirsch, Ilan R; Little, Richard F; Loberg, Robert D; Lohr, Jens G; Mukundan, Lata; Omel, James L; Pugh, Trevor J; Reaman, Gregory H; Robbins, Michael D; Sasser, A Kate; Valente, Nancy; Zamagni, Elena

    2017-08-01

    Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10(-5) to 10(-6) cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980-93. ©2017 AACR. ©2017 American Association for Cancer Research.

  9. Multiple myeloma, immunotherapy and minimal residual disease.

    PubMed

    Kusenda, J; Kovarikova, A

    2016-01-01

    Multiple myeloma (MM) is an incurable heterogeneous hematological malignancy in which relapse is characterized by re-growth of residual tumor and immune suppression with a complex biology that affects many aspects of the disease and its response to treatment. The bone marrow microenvironment, including immune cells, plays a central role in MM pathogenesis, survival, and drug resistance. The advances in basic and translational research, introduction of novel agents, particularly combination therapies, improved indicators of quality of life and survival. Minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) has revolutionized monitoring of treatment response in MM. The importance of MFC methodology will be further strengthened by the ongoing international standardization efforts. Results of MRD testing provide unique and clinically important information and demonstrated the prognostic significance of MRD in patients, leading to regulate treatment intensity in many contemporary protocols. In this review, we will summarize the principal approaches in MM immunotherapy, focusing how new agents have potential in the treatment of MM and application of MRD detection by MFC as a surrogate endpoint would allow quicker evaluation of treatment outcomes and rapid identification of effective new therapies.

  10. Immunoglobulin light chain gene rearrangements in precursor-B-acute lymphoblastic leukemia: characteristics and applicability for the detection of minimal residual disease.

    PubMed

    van der Velden, Vincent H J; de Bie, Maaike; van Wering, Elisabeth R; van Dongen, Jacques J M

    2006-05-01

    We analyzed the frequency and characteristics of Vk-Jk and Vlambda-Jlambda rearrangements inpatients with precursor-B-acute lymphoblastic leukemia (ALL) and evaluated the applicability of these rearrangements as targets for minimal residual disease (MRD) detection. Using the BIOMED-2 primer sets, Vk-Jk and Vlambda-Jlambda rearrangements were detected in 30% and 17% of patients, respectively. Vk-Jk rearrangements were particularly frequent in common-ALL, children between 5-10 years, and TEL-AML1-positive patients. Vk-Jk and Vlambda-Jlambda rearrangements showed a good stability between diagnosis and relapse and reached good sensitivities in real-time quantitative polymerase chain reaction analysis. Our data show that Vk-Jk and Vlambda-Jlambda rearrangements can be successfully applied for MRD detection in a subset of patients with precursor-B-ALL.

  11. [Minimally Invasive Treatment of Esophageal Benign Diseases].

    PubMed

    Inoue, Haruhiro

    2016-07-01

    As a minimally invasive treatment of esophageal achalasia per-oral endoscopic myotomy( POEM) was developed in 2008. More than 1,100 cases of achalasia-related diseases received POEM. Success rate of the procedure was more than 95%(Eckerdt score improvement 3 points and more). No serious( Clavian-Dindo classification III b and more) complication was experienced. These results suggest that POEM becomes a standard minimally invasive treatment for achalasia-related diseases. As an off-shoot of POEM submucosal tumor removal through submucosal tunnel (per-oral endoscopic tumor resection:POET) was developed and safely performed. Best indication of POET is less than 5 cm esophageal leiomyoma. A novel endoscopic treatment of gastroesophageal reflux disease (GERD) was developed. Anti-reflux mucosectomy( ARMS) is nearly circumferential mucosal reduction of gastric cardia mucosa. ARMS is performed in 56 consecutive cases of refractory GERD. No major complications were encountered and excellent clinical results. Best indication of ARMS is a refractory GERD without long sliding hernia. Longest follow-up case is more than 10 years. Minimally invasive treatments for esophageal benign diseases are currently performed by therapeutic endoscopy.

  12. The Challenge of Producing Skin Test Antigens with Minimal Resources Suitable for Human Application against a Neglected Tropical Disease; Leprosy

    PubMed Central

    Rivoire, Becky L.; TerLouw, Stephen; Groathouse, Nathan A.; Brennan, Patrick J.

    2014-01-01

    True incidence of leprosy and its impact on transmission will not be understood until a tool is available to measure pre-symptomatic infection. Diagnosis of leprosy disease is currently based on clinical symptoms, which on average take 3–10 years to manifest. The fact that incidence, as defined by new case detection, equates with prevalence, i.e., registered cases, suggests that the cycle of transmission has not been fully intercepted by implementation of multiple drug therapy. This is supported by a high incidence of childhood leprosy. Epidemiological screening for pre-symptomatic leprosy in large endemic populations is required to facilitate targeted chemoprophylactic interventions. Such a test must be sensitive, specific, simple to administer, cost-effective, and easy to interpret. The intradermal skin test method that measures cell-mediated immunity was explored as the best option. Prior knowledge on skin testing of healthy subjects and leprosy patients with whole or partially fractionated Mycobacterium leprae bacilli, such as Lepromin or the Rees' or Convit' antigens, has established an acceptable safety and potency profile of these antigens. These data, along with immunoreactivity data, laid the foundation for two new leprosy skin test antigens, MLSA-LAM (M. leprae soluble antigen devoid of mycobacterial lipoglycans, primarily lipoarabinomannan) and MLCwA (M. leprae cell wall antigens). In the absence of commercial interest, the challenge was to develop these antigens under current good manufacturing practices in an acceptable local pilot facility and submit an Investigational New Drug to the Food and Drug Administration to allow a first-in-human phase I clinical trial. PMID:24874086

  13. Technology applications for radioactive waste minimization

    SciTech Connect

    Devgun, J.S.

    1994-07-01

    The nuclear power industry has achieved one of the most successful examples of waste minimization. The annual volume of low-level radioactive waste shipped for disposal per reactor has decreased to approximately one-fifth the volume about a decade ago. In addition, the curie content of the total waste shipped for disposal has decreased. This paper will discuss the regulatory drivers and economic factors for waste minimization and describe the application of technologies for achieving waste minimization for low-level radioactive waste with examples from the nuclear power industry.

  14. Minimally invasive technology in the management of breast disease.

    PubMed

    Hung, W K; Ying, M; Chan, C M; Lam, H S; Mak, K L

    2009-01-01

    Minimally invasive surgery is gaining popularity around the world because it achieves the same or even superior results when compared to standard surgery but with less morbidity. Minimally invasive breast surgery is a broad concept encompassing new developments in the field of breast surgery that work on this minimally invasive principle. In this regard, breast-conserving surgery and sentinel lymph node biopsy are good illustrations of this concept. There are three major areas of progress in the minimally invasive management of breast disease. First, percutaneous excisional devices are now available that can replace the surgical excision of breast mass lesions. Second, various ablative treatments are capable of destroying breast cancers in situ instead of surgical excision. Third, mammary ductoscopy provides a new approach to the investigation of mammary duct pathology. Clinical experience and potential applications of these new technologies are reviewed.

  15. Minimally invasive surgery for thyroid eye disease

    PubMed Central

    Naik, Milind Neilkant; Nair, Akshay Gopinathan; Gupta, Adit; Kamal, Saurabh

    2015-01-01

    Thyroid eye disease (TED) can affect the eye in myriad ways: proptosis, strabismus, eyelid retraction, optic neuropathy, soft tissue changes around the eye and an unstable ocular surface. TED consists of two phases: active, and inactive. The active phase of TED is limited to a period of 12–18 months and is mainly managed medically with immunosuppression. The residual structural changes due to the resultant fibrosis are usually addressed with surgery, the mainstay of which is orbital decompression. These surgeries are performed during the inactive phase. The surgical rehabilitation of TED has evolved over the years: not only the surgical techniques, but also the concepts, and the surgical tools available. The indications for decompression surgery have also expanded in the recent past. This article discusses the technological and conceptual advances of minimally invasive surgery for TED that decrease complications and speed up recovery. Current surgical techniques offer predictable, consistent results with better esthetics. PMID:26669337

  16. Minimal residual disease in chronic lymphocytic leukaemia.

    PubMed

    García Vela, José Antonio; García Marco, José Antonio

    2017-08-29

    Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  17. Minimally invasive surgery for thyroid eye disease.

    PubMed

    Naik, Milind Neilkant; Nair, Akshay Gopinathan; Gupta, Adit; Kamal, Saurabh

    2015-11-01

    Thyroid eye disease (TED) can affect the eye in myriad ways: proptosis, strabismus, eyelid retraction, optic neuropathy, soft tissue changes around the eye and an unstable ocular surface. TED consists of two phases: active, and inactive. The active phase of TED is limited to a period of 12-18 months and is mainly managed medically with immunosuppression. The residual structural changes due to the resultant fibrosis are usually addressed with surgery, the mainstay of which is orbital decompression. These surgeries are performed during the inactive phase. The surgical rehabilitation of TED has evolved over the years: not only the surgical techniques, but also the concepts, and the surgical tools available. The indications for decompression surgery have also expanded in the recent past. This article discusses the technological and conceptual advances of minimally invasive surgery for TED that decrease complications and speed up recovery. Current surgical techniques offer predictable, consistent results with better esthetics.

  18. Waste minimization applications at a remediation site

    SciTech Connect

    Allmon, L.A.

    1995-01-23

    The Fernald Environmental Management Project (FEMP) owned by the Department of Energy was used for the processing of uranium. In 1989 Fernald suspended production of uranium metals and was placed on the National Priorities List (NPL). The site`s mission has changed from one of production to environmental restoration. Many groups necessary for producing a product were deemed irrelevant for remediation work, including Waste Minimization. Waste Minimization does not readily appear to be applicable to remediation work. Environmental remediation is designed to correct adverse impacts to the environment from past operations and generates significant amounts of waste requiring management. The premise of pollution prevention is to avoid waste generation, thus remediation is in direct conflict with this premise. Although greater amounts of waste will be generated during environmental remediation, treatment capacities are not always available and disposal is becoming more difficult and costly. This creates the need for pollution prevention and waste minimization. Applying waste minimization principles at a remediation site is an enormous challenge. If the remediation site is also radiologically contaminated it is even a bigger challenge. Innovative techniques and ideas must be utilized to achieve reductions in the amount of waste that must be managed or dispositioned. At Fernald the waste minimization paradigm was shifted from focusing efforts on source reduction to focusing efforts on recycle/reuse by inverting the EPA waste management hierarchy. A fundamental difference at remediation sites is that source reduction has limited applicability to legacy wastes but can be applied successfully on secondary waste generation. The bulk of measurable waste reduction will be achieved by the recycle/reuse of primary wastes and by segregation and decontamination of secondary wastestreams. Each effort must be measured in terms of being economically and ecologically beneficial.

  19. Minimal Residual Disease in Acute Myeloid Leukemia

    PubMed Central

    Hourigan, Christopher S.; Karp, Judith E.

    2014-01-01

    Technological advances in the laboratory have lead to substantial improvements in clinical decision-making by the use of pre-treatment prognostic risk stratification factors in acute myeloid leukemia (AML). Unfortunately similar progress has not been made in treatment response criteria, with the definition of “complete remission” in AML largely unchanged for over half a century. Several recent clinical trials have demonstrated that higher sensitivity measurements of residual disease burden during or after treatment can be performed, that results are predictive for clinical outcome and can be used to improve outcomes by guiding additional therapeutic intervention to patients in clinical complete remission but at increased relapse risk. We review here these recent trials, the characteristics and challenges of the modalities currently used to detect minimal residual disease (MRD), and outline opportunities to both refine detection and better clinically utilize MRD measurements. MRD measurement is already the standard of care in other myeloid malignancies such as chronic myelogenous leukemia (CML) and acute promyelocytic leukemia (APL). It is our belief that response criteria for non-APL AML should be updated to include assessment for molecular complete remission (mCR) and that recommendations for post-consolidation surveillance should include regular monitoring for molecular relapse as a standard of care. PMID:23799371

  20. Modeling minimal residual disease (MRD)-testing.

    PubMed

    Butturini, Anna; Klein, John; Gale, Robert Peter

    2003-04-01

    There is considerable effort to develop more sensitive methods to detect minimal residual disease (MRD) in bone marrow and blood samples of persons with cancer. Results of MRD-testing are used to predict clinical outcome and determine if more anti-cancer therapy is needed. Mathematical models were developed to assess factors affecting sensitivity and specificity of MRD-testing at diverse cancer cell prevalences. Modeling results and predictions were compared to results of large published studies.Accuracy of MRD-testing depends on cancer cell prevalence and distribution in the blood or bone marrow of the subject, sensitivity and specificity of the MRD-test and sample size. In subjects with low cancer cell prevalences (< or = 10(-4)) results of MRD testing are likely inaccurate. Increasingly sensitive MRD-tests are only marginally useful; the major obstacle to accuracy is inadequate sampling. Increasing sensitivity of methods to detect MRD is unlikely sufficient to increase accuracy of MRD-testing. In contrast, increased sampling (size and frequency) and assigning a high cut-off value (for example, > or = 10(-3)) to declare a MRD-test positive will increase sensitivity and specificity, respectively.

  1. Minimally symptomatic hypocalcaemia unmasking celiac disease.

    PubMed

    Lazaridis, A; Drosou, M E; Fontalis, A; Prousali, E; Hadwe, S E; Giouleme, O; Petidis, K

    2016-11-01

    Celiac disease is an autoimmune disease of the small intestine which occurs in genetically predisposed people of all ages. A large clinical spectrum of manifestations accompanies the onset of the disease with diarrhoea, flatulence and weight loss being the most common. However, findings like osteoporosis, iron deficiency, anaemia and hypocalcaemia could also insinuate the existence of the disease. We report the case of a 55-year-old man with numbness and tingling of the upper extremities due to hypocalcaemia that proved to be an uncommon case of celiac disease. A non-negligible number of adult patients with celiac disease can present with only minor and subclinical manifestations of the disease. As such, hypocalcaemia may be the sole manifestation of celiac disease. A high index of suspicion is needed for prompt diagnosis. © The Author(s) 2016.

  2. Eliminating Hairy Cell Leukemia Minimal Residual Disease

    Cancer.gov

    In this trial, patients with hairy cell leukemia who have disease-related symptoms that require treatment will be randomly assigned to receive cladribine with either concurrent rituximab or rituximab at least 6 months after completing cladribine therapy.

  3. Application of minimal important differences in degenerative knee disease outcomes: a systematic review and case study to inform BMJ Rapid Recommendations.

    PubMed

    Devji, Tahira; Guyatt, Gordon H; Lytvyn, Lyubov; Brignardello-Petersen, Romina; Foroutan, Farid; Sadeghirad, Behnam; Buchbinder, Rachelle; Poolman, Rudolf W; Harris, Ian A; Carrasco-Labra, Alonso; Siemieniuk, Reed A C; Vandvik, Per O

    2017-05-11

    To identify the most credible anchor-based minimal important differences (MIDs) for patient important outcomes in patients with degenerative knee disease, and to inform BMJ Rapid Recommendations for arthroscopic surgery versus conservative management DESIGN: Systematic review. Estimates of anchor-based MIDs, and their credibility, for knee symptoms and health-related quality of life (HRQoL). MEDLINE, EMBASE and PsycINFO. We included original studies documenting the development of anchor-based MIDs for patient-reported outcomes (PROs) reported in randomised controlled trials included in the linked systematic review and meta-analysis and judged by the parallel BMJ Rapid Recommendations panel as critically important for informing their recommendation: measures of pain, function and HRQoL. 13 studies reported 95 empirically estimated anchor-based MIDs for 8 PRO instruments and/or their subdomains that measure knee pain, function or HRQoL. All studies used a transition rating (global rating of change) as the anchor to ascertain the MID. Among PROs with more than 1 estimated MID, we found wide variation in MID values. Many studies suffered from serious methodological limitations. We identified the following most credible MIDs: Western Ontario and McMaster University Osteoarthritis Index (WOMAC; pain: 12, function: 13), Knee injury and Osteoarthritis Outcome Score (KOOS; pain: 12, activities of daily living: 8) and EuroQol five dimensions Questionnaire (EQ-5D; 0.15). We were able to distinguish between more and less credible MID estimates and provide best estimates for key instruments that informed evidence presentation in the associated systematic review and judgements made by the Rapid Recommendation panel. CRD42016047912. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  4. Prognostic relevance of minimal residual disease in colorectal cancer

    PubMed Central

    Bork, Ulrich; Grützmann, Robert; Rahbari, Nuh N; Schölch, Sebastian; Distler, Marius; Reissfelder, Christoph; Koch, Moritz; Weitz, Jürgen

    2014-01-01

    Presence of occult minimal residual disease in patients with colorectal cancer (CRC) has a strong prognostic impact on survival. Minimal residual disease plays a major role in disease relapse and formation of metastases in CRC. Analysis of circulating tumor cells (CTC) in the blood is increasingly used in clinical practice for disease monitoring of CRC patients. In this review article the role of CTC, disseminated tumor cells (DTC) in the bone marrow and micrometastases and isolated tumor cells (ITC) in the lymph nodes will be discussed, including literature published until September 2013. Occult disease is a strong prognostic marker for patient survival in CRC and defined by the presence of CTC in the blood, DTC in the bone marrow and/or micrometastases and ITC in the lymph nodes. Minimal residual disease could be used in the future to identify patient groups at risk, who might benefit from individualized treatment options. PMID:25132746

  5. A Minimal Periods Algorithm with Applications

    NASA Astrophysics Data System (ADS)

    Xu, Zhi

    Kosaraju in "Computation of squares in a string" briefly described a linear-time algorithm for computing the minimal squares starting at each position in a word. Using the same construction of suffix trees, we generalize his result and describe in detail how to compute the minimal α power, with a period of length longer than s, starting at each position in a word w for arbitrary exponent α> 1 and integer s ≥ 0. The algorithm runs in O(α|w|)-time for s = 0 and in O(|w|2)-time otherwise. We provide a complete proof of the correctness and computational complexity of the algorithm. The algorithm can be used to detect certain types of pseudo-patterns in words, which was our original goal in studying this generalization.

  6. Minimal Technologies Application Project: Planning and installation

    SciTech Connect

    Zellmer, S.D.; Hinchman, R.R.; Severinghaus, W.D.; Johnson, D.O.; Brent, J.J.

    1989-03-01

    Intensive and continuous tactical training during the last 35 years at the Hohenfels Training Area in West Germany has caused the loss of vegetative ground cover and has accelerated soil erosion rates, resulting in extensive environmental damage, safety hazards, and unrealistic training habitats. The objectives of this project are to develop and evaluate revegetation procedures for establishing adequate vegetative cover to control erosion at minimal costs and disruption to training activities. This project involved the development and installation of 12 revegetation procedures that combined four seedbed preparation methods and seeding options with three site-closure periods. In March 1987, the four seedbed preparation/seeding options and closure periods were selected, a study site design and location chosen, and specifications for the revegetation procedures developed. A German rehabilitation contractor attempted the specified seedbed preparation and seeding on the 13.5-ha site in June, but abnormally high rainfall, usually wet site conditions, and lack of adequate equipment prevented the contractor from completing six of the 12 planned procedures. Planning and execution of the project has nonetheless provided valuable information on the importance and use of soil analytical results, seed availability and cost data, contractor equipment requirements, and time required for planning future revegetation efforts. Continued monitoring of vegetative ground cover at the site for the next two years, combined with cost information, will provide necessary data to determine which of the six revegetation procedures is the most effective. These data will be used in planning future rehabilitation efforts on tactical training areas.

  7. [Kimura's disease: an unrecognized cause of adult-onset nephrotic syndrome with minimal change disease].

    PubMed

    Shehwaro, N; Langlois, A-L; Gueutin, V; Debchi, L; Charlotte, F; Rouvier, P; Rottembourg, J; Izzedine, H

    2014-02-01

    Kimura's disease (KD) is an angiolymphoid proliferative disorder of soft tissue with eosinophilia, with a predilection for head and neck regions in young Oriental men. Kidney disease is thought to be rare in KD. About a case of adult-onset nephrotic syndrome with minimal change disease, we comment Kimura's disease and its associated kidney damage. Kimura disease should be suspected and included in the diagnosis of adult-onset nephrotic syndrome with minimal change disease.

  8. Minimal residual disease studies by flow cytometry in acute leukemia.

    PubMed

    Campana, Dario; Coustan-Smith, Elaine

    2004-01-01

    Minimal residual disease (MRD) assays are increasingly important in the clinical management of patients with acute leukemia. Among the methods available for monitoring MRD, flow cytometry holds great promise for clinical application because of its simplicity and wide availability. Several studies have demonstrated strong correlations between MRD levels by flow cytometry during clinical remission and treatment outcome, lending support to the reliability of this approach. Flow-cytometric detection of MRD is based on the identification of immunophenotypic combinations expressed on leukemic cells but not on normal hematopoietic cells. Its sensitivity depends on the specificity of the immunophenotypes used to track leukemic cells and on the number of cells available for study. Immunophenotypes that allow detection of 1 leukemic cell in 10,000 normal cells can be identified in at least 90% of patients with acute lymphoblastic leukemia; immunophenotypes that allow detection of 1 leukemic cell in 1,000-10,000 normal cells can be identified in at least 85% of patients with acute myeloid leukemia. Identification of new markers of leukemia by gene array technology should lead to the design of simple and reliable antibody panels for universal monitoring of MRD. Here we review the relative advantages and disadvantages of flow cytometry for MRD studies, as well as results obtained in correlative studies with treatment outcome. Copyright 2004 S. Karger AG, Basel

  9. Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?

    PubMed Central

    Mosna, Federico; Capelli, Debora; Gottardi, Michele

    2017-01-01

    Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of the disease, as the final product of the drug schedule, dose intensity, biodistribution, and the pharmakogenetic profile of the patient. There is now consistent evidence for the prognostic power of minimal residual disease evaluation in acute myeloid leukemia, which is complementary to the baseline prognostic assessment of the disease. The focus for its use is therefore shifting to individualize treatment based on a deeper evaluation of chemosensitivity and residual tumor burden. In this review, we will summarize the results of the major clinical studies evaluating minimal residual disease in acute myeloid leukemia in adults in recent years and address the technical and practical issues still hampering the spread of these techniques outside controlled clinical trials. We will also briefly speculate on future developments and offer our point of view, and a word of caution, on the present use of minimal residual disease measurements in “real-life” practice. Still, as final standardization and diffusion of the methods are sorted out, we believe that minimal residual disease will soon become the new standard for evaluating response in the treatment of acute myeloid leukemia. PMID:28587190

  10. Assessment of Minimal Residual Disease in Standard-Risk AML.

    PubMed

    Ivey, Adam; Hills, Robert K; Simpson, Michael A; Jovanovic, Jelena V; Gilkes, Amanda; Grech, Angela; Patel, Yashma; Bhudia, Neesa; Farah, Hassan; Mason, Joanne; Wall, Kerry; Akiki, Susanna; Griffiths, Michael; Solomon, Ellen; McCaughan, Frank; Linch, David C; Gale, Rosemary E; Vyas, Paresh; Freeman, Sylvie D; Russell, Nigel; Burnett, Alan K; Grimwade, David

    2016-02-04

    Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations

  11. Minimally invasive surgical treatment of valvular heart disease.

    PubMed

    Goldstone, Andrew B; Joseph Woo, Y

    2014-01-01

    Cardiac surgery is in the midst of a practice revolution. Traditionally, surgery for valvular heart disease consisted of valve replacement via conventional sternotomy using cardiopulmonary bypass. However, over the past 20 years, the increasing popularity of less-invasive procedures, accompanied by advancements in imaging, surgical instrumentation, and robotic technology, has motivated and enabled surgeons to develop and perform complex cardiac surgical procedures through small incisions, often eliminating the need for sternotomy or cardiopulmonary bypass. In addition to the benefits of improved cosmesis, minimally invasive mitral valve surgery was pioneered with the intent of reducing morbidity, postoperative pain, blood loss, hospital length of stay, and time to return to normal activity. This article reviews the current state-of-the-art of minimally invasive approaches to the surgical treatment of valvular heart disease.

  12. Detection of minimal residual disease in acute myelogenous leukemia.

    PubMed

    Raanani, P; Ben-Bassat, I

    2004-01-01

    Acute myelogenous leukemia (AML) is considered to be in complete remission when fewer than 5% of the cells in bone marrow are blasts. Nevertheless, approximately two thirds of patients relapse due to persisting leukemic blasts. The persistence of these cells, below the threshold of morphological detection, is termed minimal residual disease (MRD) and various methods are used for its detection. These methods include classical cytogenetics, fluorescence in situ hybridization, qualitative and quantitative RT-PCR and multiparametric flow cytometry. Currently, less than half of the AML patients have a specific marker detectable by RT-PCR techniques. The major specific molecular markers are involvement of the MLL gene with up to 50 different partners and partial tandem duplications, the core binding factor leukemias with AML1/ETO and CBFbeta/MYH11 rearrangements, PML/RARalpha in acute promyelocytic leukemia, internal tandem duplications and mutations of FLT3 and some other rare translocations. In addition, several other genes show abnormal expression levels in AML, including the Wilms tumor gene, the PRAME gene and Ig/TCR rearrangements. Most of these genetic abnormalities can be detected by qualitative but more importantly by quantitative RT-PCR. The kinetics of disappearance of molecular markers in AML differs between the various types of leukemias, although at least a 2 log reduction of transcript after induction chemotherapy is necessary for long-term remission in all types. Conversely, the change of PCR from negativity to positivity is highly predictive of relapse. Whereas in acute lymphoblastic leukemia, multiparametric flow cytometry is an established method for MRD detection, this is less so in AML. The reason is the absence of well-characterized leukemia-specific antigens and the existence of phenotypic changes at relapse. On the other hand, this method is convenient due to its simplicity and universal applicability. In conclusion, several methods can be used

  13. [Minimally invasive video-assisted operations for heart disease].

    PubMed

    Pojar, M; Vojáček, J; Harrer, J; Turek, Z; Samek, J; Omran, N; Volt, M

    2013-11-01

    Minimally invasive surgical access for the treatment of mitral and tricuspid valves has become an alternative method to the conventional approach via median sternotomy. The aim of this paper is to evaluate our experience and results with minimally invasive approach in cardiac surgery at our institution. A total of 52 patients underwent minimally invasive cardiac surgery between November 2011 and March 2013. Right lateral minithoracotomy and femoral vessels cannulation for cardiopulmonary bypass was used. Follow-up data was collected in a prospective database and analysed retrospectively. The mean age of patients was 60.9 ± 11.6 years (female patients accounted for 63.5%). The procedures performed included mitral valve repair in 44 (85%) patients and tricuspid valve repair in 25 (48%). Atrial septal defect closure was performed in 8 (15%) patients and cryoablation of atrial fibrillation in 26 (50%) patients. There were 75% combined procedures. The median duration of the operation was 235 (155-315) minutes. The median length of cardiopulmonary bypass and crossclamp time was 139 (89-225) and 92 (51-168) minutes, respectively. The median duration of postoperative hospital stay was 12.5 (6-34) days. Hospital and 30-day mortality was 0%. At follow-up (121.3 ± 32.72 days), two patients (3.8%) required reoperation (1 for right haemothorax, 1 for aortic valve insufficiency). Minimally invasive access has been adopted as a routine method for the therapy of valve disease. The minithoracotomy approach is a safe and feasible technique with comparable mortality and in-hospital morbidity.

  14. Minimal cut-set methodology for artificial intelligence applications

    SciTech Connect

    Weisbin, C.R.; de Saussure, G.; Barhen, J.; Oblow, E.M.; White, J.C.

    1984-01-01

    This paper reviews minimal cut-set theory and illustrates its application with an example. The minimal cut-set approach uses disjunctive normal form in Boolean algebra and various Boolean operators to simplify very complicated tree structures composed of AND/OR gates. The simplification process is automated and performed off-line using existing computer codes to implement the Boolean reduction on the finite, but large tree structure. With this approach, on-line expert diagnostic systems whose response time is critical, could determine directly whether a goal is achievable by comparing the actual system state to a concisely stored set of preprocessed critical state elements.

  15. Minimal disease activity for rheumatoid arthritis: a preliminary definition.

    PubMed

    Wells, George A; Boers, Maarten; Shea, Beverley; Brooks, Peter M; Simon, Lee S; Strand, C Vibeke; Aletaha, Daniel; Anderson, Jennifer J; Bombardier, Claire; Dougados, Maxime; Emery, Paul; Felson, David T; Fransen, Jaap; Furst, Dan E; Hazes, Johanna M W; Johnson, Kent R; Kirwan, John R; Landewé, Robert B M; Lassere, Marissa N D; Michaud, Kaleb; Suarez-Almazor, Maria; Silman, Alan J; Smolen, Josef S; Van der Heijde, Desiree M F M; van Riel, Piet L C M; Wolfe, Fred; Tugwell, Peter S

    2005-10-01

    Agreement on response criteria in rheumatoid arthritis (RA) has allowed better standardization and interpretation of clinical trial reports. With recent advances in therapy, the proportion of patients achieving a satisfactory state of minimal disease activity (MDA) is becoming a more important measure with which to compare different treatment strategies. The threshold for MDA is between high disease activity and remission and, by definition, anyone in remission will also be in MDA. True remission is still rare in RA; in addition, the American College of Rheumatology definition is difficult to apply in the context of trials. Participants at OMERACT 6 in 2002 agreed on a conceptual definition of minimal disease activity (MDA): "that state of disease activity deemed a useful target of treatment by both the patient and the physician, given current treatment possibilities and limitations." To prepare for a preliminary operational definition of MDA for use in clinical trials, we asked rheumatologists to assess 60 patient profiles describing real RA patients seen in routine clinical practice. Based on their responses, several candidate definitions for MDA were designed and discussed at the OMERACT 7 in 2004. Feedback from participants and additional on-site analyses in a cross-sectional database allowed the formulation of 2 preliminary, equivalent definitions of MDA: one based on the Disease Activity Score 28 (DAS28) index, and one based on meeting cutpoints in 5 out the 7 WHO/ILAR core set measures. Researchers applying these definitions first need to choose whether to use the DAS28 or the core set definition, because although each selects a similar proportion in a population, these are not always the same patients. In both MDA definitions, an initial decision node places all patients in MDA who have a tender joint count of 0 and a swollen joint count of 0, and an erythrocyte sedimentation rate (ESR) no greater than 10 mm. If this condition is not met: * The DAS28

  16. Minimizing the risk of disease transmission during corneal tissue processing.

    PubMed

    Lindquist, Thomas D; Miller, Thomas D; Elsen, Jennifer L; Lignoski, Paul J

    2009-06-01

    Corneal transplantation is undergoing significant change because the dysfunctional portion of the cornea may now be selectively transplanted. After recovery of corneoscleral tissue, further processing of such tissue as in microkeratome preparation of endothelial keratoplasty lenticules is defined as "open-container processing" by the Eye Bank Association of America. Airborne bacterial contamination during preparation of corneal tissue is a potential source of postoperative infection. This review addresses ways to minimize the risk of disease transmission as corneal tissue is processed for lamellar keratoplasty, endothelial keratoplasty, or femtosecond laser-assisted penetrating keratoplasty and to minimize risk to eye bank personnel or physicians preparing the tissue. Secondly, quality assurance measures are described that qualify the environment in which corneal tissue is being processed. We propose that the environment in which corneal tissue is being processed must be able to demonstrate acceptable levels of airborne microbial contamination annually as measured by settle plates to estimate airborne bacterial sedimentation. It is recommended that any environment where corneal tissue is prepared should meet the minimum standard of a conventional operating room which is <25 colony-forming unit per 90-mm settle plate per 1-hour exposure.

  17. Minimally invasive surgical treatment for kidney stone disease.

    PubMed

    Rodríguez, Dayron; Sacco, Dianne E

    2015-07-01

    Minimally invasive interventions for stone disease in the United States are mainly founded on 3 surgical procedures: extracorporeal shock wave lithotripsy, ureteroscopic lithotripsy, and percutaneous nephrolithotomy. With the advancement of technology, treatment has shifted toward less invasive strategies and away from open or laparoscopic surgery. The treatment chosen for a patient with stones is based on the stone and patient characteristics. Each of the minimally invasive techniques uses an imaging source, either fluoroscopy or ultrasound, to localize the stone and an energy source to fragment the stone. Extracorporeal shock wave lithotripsy uses a shock wave energy source generated outside the body to fragment the stone. In contrast, with ureteroscopy, laser energy is placed directly on the stone using a ureteroscope that visualizes the stone. Percutaneous nephrolithotomy requires dilation of a tract through the back into the renal pelvis so that instruments can be inserted directly onto the stone to fragment or pulverize it. The success of the surgical intervention relies on performing the least invasive technique with the highest success of stone removal.

  18. Minimal Residual Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Kröger, Nicolaus; Miyamura, Koichi; Bishop, Michael R.

    2010-01-01

    Minimal residual disease (MRD), both before and after transplant, is a clinically important yet relatively poorly defined aspect of allogeneic hematopoietic stem cell transplantation (alloHSCT). The clinical relevance of MRD in the context of alloHSCT has been demonstrated by its association with the development of clinical relapse. However, with the possible exception of chronic myeloid leukemia, the specific techniques, timing, frequency and clinical utility, relative to improvement in patient outcomes, for monitoring MRD in the setting of alloHSCT has yet to be clearly defined. A concise overview of monitoring techniques for detecting MRD, as well as treatment strategies and biologic and clinical research initiatives for MRD suggested by the National Cancer Institute 1st International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation, is covered in this paper. PMID:21047560

  19. Application of trajectory optimization principles to minimize aircraft operating costs

    NASA Technical Reports Server (NTRS)

    Sorensen, J. A.; Morello, S. A.; Erzberger, H.

    1979-01-01

    This paper summarizes various applications of trajectory optimization principles that have been or are being devised by both government and industrial researchers to minimize aircraft direct operating costs (DOC). These costs (time and fuel) are computed for aircraft constrained to fly over a fixed range. Optimization theory is briefly outlined, and specific algorithms which have resulted from application of this theory are described. Typical results which demonstrate use of these algorithms and the potential savings which they can produce are given. Finally, need for further trajectory optimization research is presented.

  20. Energy minimization in medical image analysis: Methodologies and applications.

    PubMed

    Zhao, Feng; Xie, Xianghua

    2016-02-01

    Energy minimization is of particular interest in medical image analysis. In the past two decades, a variety of optimization schemes have been developed. In this paper, we present a comprehensive survey of the state-of-the-art optimization approaches. These algorithms are mainly classified into two categories: continuous method and discrete method. The former includes Newton-Raphson method, gradient descent method, conjugate gradient method, proximal gradient method, coordinate descent method, and genetic algorithm-based method, while the latter covers graph cuts method, belief propagation method, tree-reweighted message passing method, linear programming method, maximum margin learning method, simulated annealing method, and iterated conditional modes method. We also discuss the minimal surface method, primal-dual method, and the multi-objective optimization method. In addition, we review several comparative studies that evaluate the performance of different minimization techniques in terms of accuracy, efficiency, or complexity. These optimization techniques are widely used in many medical applications, for example, image segmentation, registration, reconstruction, motion tracking, and compressed sensing. We thus give an overview on those applications as well.

  1. [Minimal Residual Disease (MRD) in gastric carcinoma--an overview].

    PubMed

    Garlipp, B; Steinert, R; Lippert, H; Meyer, F

    2011-02-01

    Despite recent developments in therapy for gastric cancer, the prognosis of this disease remains poor in advanced stages. In many cases even curatively treated patients without any residual tumour develop metachronous metastases. As in other solid tumours, adjuvant therapies can reduce the metastatic risk, which implies that some of these patients harbour isolated tumour cells or micrometastases (minimal residual disease, MRD) that are undetectable by radiological imaging and conventional histopathology but can still be the cause of tumour recurrence. Therefore, reliable methods for diagnosing MRD would be desirable for individually tailoring therapy for these patients. Unfortunately, testing methods for MRD and interpretation of their results are not standardised and studies published on this topic are difficult to interpret due to methodological differences and small sample sizes. As of now, testing for MRD has not become relevant in clinical routine for any of the anatomic compartments lymph nodes, peritoneal lavage fluid, peripheral blood, and bone marrow in the Western hemisphere. Most reliable data on MRD in gastric cancer patients have been reported for peritoneal lavage fluid. In some centres in Japan, this test is routinely being used for making therapeutic decisions, e. g., on the use of intraperitoneal chemotherapy. MRD in resected lymph nodes will be further evaluated in the context of the sentinel lymph node concept and possibly be employed for designing individualised therapy for patients in early disease stages who are not routinely candidates for multimodal treatment. As for tumour cells in peripheral blood and in bone marrow, studies suggest that these cells are only able to form metastases in the presence of certain molecular factors. Therefore, rather than simply confirming the existence of isolated tumour cells in blood or bone marrow, future studies should concentrate on defining their molecular characteristics and the conditions required for

  2. Minimal residual disease monitoring by 8-color flow cytometry in mantle cell lymphoma: an EU-MCL and LYSA study

    PubMed Central

    Cheminant, Morgane; Derrieux, Coralie; Touzart, Aurore; Schmit, Stéphanie; Grenier, Adrien; Trinquand, Amélie; Delfau-Larue, Marie-Hélène; Lhermitte, Ludovic; Thieblemont, Catherine; Ribrag, Vincent; Cheze, Stéphane; Sanhes, Laurence; Jardin, Fabrice; Lefrère, François; Delarue, Richard; Hoster, Eva; Dreyling, Martin; Asnafi, Vahid; Hermine, Olivier; Macintyre, Elizabeth

    2016-01-01

    Quantification of minimal residual disease may guide therapeutic strategies in mantle cell lymphoma. While multiparameter flow cytometry is used for diagnosis, the gold standard method for minimal residual disease analysis is real-time quantitative polymerase chain reaction (RQ-PCR). In this European Mantle Cell Lymphoma network (EU-MCL) pilot study, we compared flow cytometry with RQ-PCR for minimal residual disease detection. Of 113 patients with at least one minimal residual disease sample, RQ-PCR was applicable in 97 (86%). A total of 284 minimal residual disease samples from 61 patients were analyzed in parallel by flow cytometry and RQ-PCR. A single, 8-color, 10-antibody flow cytometry tube allowed specific minimal residual disease assessment in all patients, with a robust sensitivity of 0.01%. Using this cut-off level, the true-positive-rate of flow cytometry with respect to RQ-PCR was 80%, whereas the true-negative-rate was 92%. As expected, RQ-PCR frequently detected positivity below this 0.01% threshold, which is insufficiently sensitive for prognostic evaluation and would ideally be replaced with robust quantification down to a 0.001% (10-5) threshold. In 10 relapsing patients, the transition from negative to positive by RQ-PCR (median 22.5 months before relapse) nearly always preceded transition by flow cytometry (4.5 months), but transition to RQ-PCR positivity above 0.01% (5 months) was simultaneous. Pre-emptive rituximab treatment of 2 patients at minimal residual disease relapse allowed re-establishment of molecular and phenotypic complete remission. Flow cytometry minimal residual disease is a complementary approach to RQ-PCR and a promising tool in individual mantle cell lymphoma therapeutic management. PMID:26703963

  3. Minimal residual disease monitoring by 8-color flow cytometry in mantle cell lymphoma: an EU-MCL and LYSA study.

    PubMed

    Cheminant, Morgane; Derrieux, Coralie; Touzart, Aurore; Schmit, Stéphanie; Grenier, Adrien; Trinquand, Amélie; Delfau-Larue, Marie-Hélène; Lhermitte, Ludovic; Thieblemont, Catherine; Ribrag, Vincent; Cheze, Stéphane; Sanhes, Laurence; Jardin, Fabrice; Lefrère, François; Delarue, Richard; Hoster, Eva; Dreyling, Martin; Asnafi, Vahid; Hermine, Olivier; Macintyre, Elizabeth

    2016-03-01

    Quantification of minimal residual disease may guide therapeutic strategies in mantle cell lymphoma. While multiparameter flow cytometry is used for diagnosis, the gold standard method for minimal residual disease analysis is real-time quantitative polymerase chain reaction (RQ-PCR). In this European Mantle Cell Lymphoma network (EU-MCL) pilot study, we compared flow cytometry with RQ-PCR for minimal residual disease detection. Of 113 patients with at least one minimal residual disease sample, RQ-PCR was applicable in 97 (86%). A total of 284 minimal residual disease samples from 61 patients were analyzed in parallel by flow cytometry and RQ-PCR. A single, 8-color, 10-antibody flow cytometry tube allowed specific minimal residual disease assessment in all patients, with a robust sensitivity of 0.01%. Using this cut-off level, the true-positive-rate of flow cytometry with respect to RQ-PCR was 80%, whereas the true-negative-rate was 92%. As expected, RQ-PCR frequently detected positivity below this 0.01% threshold, which is insufficiently sensitive for prognostic evaluation and would ideally be replaced with robust quantification down to a 0.001% (10-5) threshold. In 10 relapsing patients, the transition from negative to positive by RQ-PCR (median 22.5 months before relapse) nearly always preceded transition by flow cytometry (4.5 months), but transition to RQ-PCR positivity above 0.01% (5 months) was simultaneous. Pre-emptive rituximab treatment of 2 patients at minimal residual disease relapse allowed re-establishment of molecular and phenotypic complete remission. Flow cytometry minimal residual disease is a complementary approach to RQ-PCR and a promising tool in individual mantle cell lymphoma therapeutic management. (clinicaltrials identifiers: 00209209 and 00209222).

  4. Monitoring minimal residual disease in acute myeloid leukaemia: a review of the current evolving strategies

    PubMed Central

    Ommen, Hans Beier

    2016-01-01

    Several disease-monitoring techniques are available for the physician treating acute myeloid leukaemia (AML). Besides immunohistochemistry assisted light microscopy, the past 20 years have seen the development and preclinical perfection of a number of techniques, most notably quantitative polymerase chain reaction (PCR) and multicolor flow cytometry. Late additions to the group of applicable assays include next generation sequencing and digital PCR. In this review the principles of use of these modalities at three different time points during the AML disease course are discussed, namely at the time of treatment evaluation, pretransplantation and postconsolidation. The drawbacks and pitfalls of each different technique are delineated. The evidence or lack of evidence for minimal residual disease guided treatment decisions is discussed. Lastly, future strategies in the MRD field are suggested and commented upon. PMID:26834951

  5. Proposal for the standardization of flow cytometry protocols to detect minimal residual disease in acute lymphoblastic leukemia

    PubMed Central

    Ikoma, Maura Rosane Valério; Beltrame, Miriam Perlingeiro; Ferreira, Silvia Inês Alejandra Cordoba Pires; Souto, Elizabeth Xisto; Malvezzi, Mariester; Yamamoto, Mihoko

    2015-01-01

    Minimal residual disease is the most powerful predictor of outcome in acute leukemia and is useful in therapeutic stratification for acute lymphoblastic leukemia protocols. Nowadays, the most reliable methods for studying minimal residual disease in acute lymphoblastic leukemia are multiparametric flow cytometry and polymerase chain reaction. Both provide similar results at a minimal residual disease level of 0.01% of normal cells, that is, detection of one leukemic cell in up to 10,000 normal nucleated cells. Currently, therapeutic protocols establish the minimal residual disease threshold value at the most informative time points according to the appropriate methodology employed. The expertise of the laboratory in a cancer center or a cooperative group could be the most important factor in determining which method should be used. In Brazil, multiparametric flow cytometry laboratories are available in most leukemia treatment centers, but multiparametric flow cytometry processes must be standardized for minimal residual disease investigations in order to offer reliable and reproducible results that ensure quality in the clinical application of the method. The Minimal Residual Disease Working Group of the Brazilian Society of Bone Marrow Transplantation (SBTMO) was created with that aim. This paper presents recommendations for the detection of minimal residual disease in acute lymphoblastic leukemia based on the literature and expertise of the laboratories who participated in this consensus, including pre-analytical and analytical methods. This paper also recommends that both multiparametric flow cytometry and polymerase chain reaction are complementary methods, and so more laboratories with expertise in immunoglobulin/T cell receptor (Ig/TCR) gene assays are necessary in Brazil. PMID:26670404

  6. 78 FR 36196 - Draft Guidance for Industry: Biologics License Applications for Minimally Manipulated, Unrelated...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-17

    ... for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for...: Biologics License Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord.../umbilical cord blood, for hematopoietic and immunologic reconstitution. The guidance document is intended to...

  7. Treatment of patients with minimal stage IIIA Hodgkin's disease

    SciTech Connect

    Powlis, W.D.; Mauch, P.; Goffman, T.; Goodman, R.L.

    1987-10-01

    Treatment recommendations for patients with upper abdominal Stage IIIA Hodgkin's (III1A) disease have varied widely. The current study reports on a combined institutional retrospective review of 85 patients with surgically staged III1A Hodgkin's disease. Twenty-two patients received combined modality therapy (CMT), 36 patients were treated initially with total nodal irradiation (TNI), and 27 with mantle and para-aortic radiotherapy (MPA). Patients treated with CMT had an actuarial 8-year freedom from relapse (FFR) of 96% as compared to a FFR of 51% in TNI treated patients (p = 0.002), and a FFR of 54% in MPA treated patients (p = 0.004). Of the 11 relapses in MPA treated patients, 7 had a component of their failure in the untreated pelvic or inguinal nodes. The patients treated with CMT had an 8-year actuarial survival of 100% as compared to 79% in TNI treated patients (p = 0.055) and 78% in patients treated with MPA (p = 0.025). Histology and the number of splenic nodules were the most important prognostic variables. Patients with MC/LD histology and greater than or equal to 5 splenic nodules have a high risk of relapse (10/13) when treated with radiation alone (TNI or MPA). We recommend CMT for this group of patients. Patients with NS/LP histology and 1-4 splenic nodules represent a favorable subset of Stage III1A patients. Only 4/21 patients have relapsed and all 21 patients are currently alive without disease regardless of treatment. We currently feel that patients with Stage III1A Hodgkin's disease with NS/LP histology and splenic disease limited to 1-4 nodules are good candidates for MPA as an alternative to TNI or CMT.

  8. Minimizing right ventricular pacing in sinus node disease: Sometimes the cure is worse than the disease

    PubMed Central

    De Maria, Elia; Olaru, Alina; Cappelli, Stefano

    2015-01-01

    Traditional right ventricular (RV) apical pacing has been associated with heart failure, atrial fibrillation and increased mortality. To avoid the negative consequences of RV apical pacing different strategies have been developed, among these a series of pacing algorithms designed to minimize RV pacing. These functions are particularly useful when there is not the need for continuous RV pacing: intermittent atrio-ventricular blocks and, mainly, sinus node disease. However, in order to avoid RV pacing, the operational features of these algorithms may lead to adverse (often under-appreciated) consequences in some patients. We describe a case of a patient with sinus node disease, in whom right atrial only pacing involved long atrio-ventricular delay to allow intrinsic ventricular conduction, which led to symptomatic hypotension that could be overcome only by “forcing” also right ventricular apical pacing. We subsequently discuss this case in the context of current available literature. PMID:25789293

  9. Minimal residual disease and circulating tumor cells in breast cancer

    PubMed Central

    2011-01-01

    Tumor cell dissemination in bone marrow or other organs is thought to represent an important step in the metastatic process. The detection of bone marrow disseminated tumor cells is associated with worse outcome in early breast cancer. Moreover, the detection of peripheral blood circulating tumor cells is an adverse prognostic factor in metastatic breast cancer, and emerging data suggest that this is also true for early disease. Beyond enumeration, the characterization of these cells has the potential to improve risk assessment, treatment selection and monitoring, and the development of novel therapeutic agents, and to advance our understanding of the biology of metastasis. PMID:22078011

  10. Minimal residual disease and circulating tumor cells in breast cancer.

    PubMed

    Ignatiadis, Michail; Reinholz, Monica

    2011-10-25

    Tumor cell dissemination in bone marrow or other organs is thought to represent an important step in the metastatic process. The detection of bone marrow disseminated tumor cells is associated with worse outcome in early breast cancer. Moreover, the detection of peripheral blood circulating tumor cells is an adverse prognostic factor in metastatic breast cancer, and emerging data suggest that this is also true for early disease. Beyond enumeration, the characterization of these cells has the potential to improve risk assessment, treatment selection and monitoring, and the development of novel therapeutic agents, and to advance our understanding of the biology of metastasis.

  11. Monitoring of minimal residual disease in acute leukemia by multiparametric flow cytometry.

    PubMed

    Kusenda, J; Fajtova, M; Kovarikova, A

    2014-01-01

    In this review, we discuss methodological principles and clinical applications of minimal residual disease (MRD) assays based on multiparameter flow cytometry (MFC). The introduction of methods for MRD detection has revolutionized monitoring of treatment response in acute leukemia. Great progress has been made in the development of wide array of flow cytometric techniques for rare event detection. This advance was accompanied by increasingly greater understanding of the immunophenotypic features of leukemic and normal lymphoid cells, and of the antigenic differences that make MRD studies possible. Immunologic testing of MRD relies on "leukemia-associated" immunophenotypes which can be identified by MFC in the most of acute leukemia cases. The recent technical innovations in routine MFC (3 lasers and≥8 colors) and the new developments in software for data analysis make this technology the most attractive for MRD diagnostics. The importance of MFC methodology will be further strengthened by the ongoing international standardization efforts. Results of MRD testing provide unique and clinically important information. The systematic application of immunologic techniques to study MRD in clinical samples has demonstrated the prognostic significance of MRD in patients, leading to the use of MRD to regulate treatment intensity in many contemporary protocols. The identification of new markers of MRD should increase the sensitivity of MRD testing by MFC and is required to widen the applicability of MRD studies.

  12. Minimally Invasive Procedures - Direct and Video-Assisted Forms in the Treatment of Heart Diseases

    PubMed Central

    Castro, Josué Viana; Melo, Emanuel Carvalho; Silva, Juliana Fernandes; Rebouças, Leonardo Lemos; Corrêa, Larissa Chagas; Germano, Amanda de Queiroz; Machado, João José Aquino

    2014-01-01

    Background Minimally invasive cardiovascular procedures have been progressively used in heart surgery. Objective To describe the techniques and immediate results of minimally invasive procedures in 5 years. Methods Prospective and descriptive study in which 102 patients were submitted to minimally invasive procedures in direct and video-assisted forms. Clinical and surgical variables were evaluated as well as the in hospital follow-up of the patients. Results Fourteen patients were operated through the direct form and 88 through the video-assisted form. Between minimally invasive procedures in direct form, 13 had aortic valve disease. Between minimally invasive procedures in video-assisted forms, 43 had mitral valve disease, 41 atrial septal defect and four tumors. In relation to mitral valve disease, we replaced 26 and reconstructed 17 valves. Aortic clamp, extracorporeal and procedure times were, respectively, 91,6 ± 21,8, 112,7 ± 27,9 e 247,1 ± 20,3 minutes in minimally invasive procedures in direct form. Between minimally invasive procedures in video-assisted forms, 71,6 ± 29, 99,7 ± 32,6 e 226,1 ± 42,7 minutes. Considering intensive care and hospitalization times, these were 41,1 ± 14,7 hours and 4,6 ± 2 days in minimally invasive procedures in direct and 36,8 ± 16,3 hours and 4,3 ± 1,9 days in minimally invasive procedures in video-assisted forms procedures. Conclusion Minimally invasive procedures were used in two forms - direct and video-assisted - with safety in the surgical treatment of video-assisted, atrial septal defect and tumors of the heart. These procedures seem to result in longer surgical variables. However, hospital recuperation was faster, independent of the access or pathology. PMID:24553983

  13. Chronic Lyme borreliosis associated with minimal change glomerular disease: a case report.

    PubMed

    Florens, N; Lemoine, S; Guebre-Egziabher, F; Valour, F; Kanitakis, J; Rabeyrin, M; Juillard, L

    2017-02-06

    There are only few cases of renal pathology induced by Lyme borreliosis in the literature, as this damage is rare and uncommon in humans. This patient is the first case of minimal change glomerular disease associated with chronic Lyme borreliosis. A 65-year-old Caucasian woman was admitted for an acute edematous syndrome related to a nephrotic syndrome. Clinical examination revealed violaceous skin lesions of the right calf and the gluteal region that occurred 2 years ago. Serological tests were positive for Lyme borreliosis and skin biopsy revealed lesions of chronic atrophic acrodermatitis. Renal biopsy showed minimal change glomerular disease. The skin lesions and the nephrotic syndrome resolved with a sequential treatment with first ceftriaxone and then corticosteroids. We report here the first case of minimal change disease associated with Lyme borreliosis. The pathogenesis of minimal change disease in the setting of Lyme disease is discussed but the association of Lyme and minimal change disease may imply a synergistic effect of phenotypic and bacterial factors. Regression of proteinuria after a sequential treatment with ceftriaxone and corticosteroids seems to strengthen this conceivable association.

  14. Minimally invasive surgery for inflammatory bowel disease: Review of current developments and future perspectives

    PubMed Central

    Neumann, Philipp-Alexander; Rijcken, Emile

    2016-01-01

    Patients with inflammatory bowel disease (IBD) comprise a population of patients that have a high likelihood of both surgical treatment at a young age and repetitive operative interventions. Therefore surgical procedures need to aim at minimizing operative trauma with best postoperative recovery. Minimally invasive techniques have been one of the major advancements in surgery in the last decades and are nowadays almost routinely performed in colorectal resections irrespective of underlying disease. However due to special disease related characteristics such as bowel stenosis, interenteric fistula, abscesses, malnutrition, repetitive surgeries, or immunosuppressive medications, patients with IBD represent a special cohort with specific needs for surgery. This review summarizes current evidence of minimally invasive surgery for patients with Crohn’s disease or ulcerative colitis and gives an outlook on the future perspective of technical advances in this highly moving field with its latest developments in single port surgery, robotics and trans-anal techniques. PMID:27158537

  15. Minimally invasive surgery for inflammatory bowel disease: Review of current developments and future perspectives.

    PubMed

    Neumann, Philipp-Alexander; Rijcken, Emile

    2016-05-06

    Patients with inflammatory bowel disease (IBD) comprise a population of patients that have a high likelihood of both surgical treatment at a young age and repetitive operative interventions. Therefore surgical procedures need to aim at minimizing operative trauma with best postoperative recovery. Minimally invasive techniques have been one of the major advancements in surgery in the last decades and are nowadays almost routinely performed in colorectal resections irrespective of underlying disease. However due to special disease related characteristics such as bowel stenosis, interenteric fistula, abscesses, malnutrition, repetitive surgeries, or immunosuppressive medications, patients with IBD represent a special cohort with specific needs for surgery. This review summarizes current evidence of minimally invasive surgery for patients with Crohn's disease or ulcerative colitis and gives an outlook on the future perspective of technical advances in this highly moving field with its latest developments in single port surgery, robotics and trans-anal techniques.

  16. Development of minimal-change glomerular disease and Hashimoto's thyroiditis during the treatment of sarcoidosis.

    PubMed

    Ando, Fumiaki; Okado, Tomokazu; Sohara, Eisei; Rai, Tatemitsu; Uchida, Shinichi; Sasaki, Sei

    2013-11-01

    Minimal-change glomerular disease, sarcoidosis and autoimmune thyroid disease rarely occur in the same patient. We herein report a patient in which minimal-change glomerular disease and Hashimoto's thyroiditis developed during the treatment of sarcoidosis with steroids. A 66-year-old female was admitted to our hospital with symptoms of nephrotic syndrome. Nine months before admission, she was diagnosed as having ocular and pulmonary sarcoidosis, for which prednisolone at an initial dose of 40 mg/day was started. When the dose of prednisolone was tapered to 20 mg/day, she noticed swelling of the lower extremities. Examination confirmed the simultaneous occurrence of minimal-change glomerular disease and Hashimoto's thyroiditis, which were diagnosed based on kidney histology, ultrasonography of the thyroid gland and positive antithyroglobulin antibodies. We used intravenous methylprednisolone pulse therapy followed by 40 mg/day oral prednisolone. The patient achieved complete remission of nephrotic syndrome and steroids were tapered without relapse.

  17. Minimizing masses in explosively driven two-shockwave physics applications

    NASA Astrophysics Data System (ADS)

    Buttler, William; Cherne, Frank; Furlanetto, Michael; Payton, Jeremy; Stone, Joseph; Tabaka, Leonard; Vincent, Samuel

    2015-06-01

    We have experimentally investigated different two-shockwave high-explosives (HE) physics package designs to maximize the variability of the second shockwave peak stress, while minimizing the total HE load of the physics tool. A critical requirement is to also have a large radial diameter of the second shockwave to maintain its value as an HE driven two-shockwave drive. We have previously shown that we could vary the peak-stress of the second-shockwave with a 76 mm diameter HE lens driving different composite boosters of PBX 9501 and TNT. Here we report on our results with a 56- and 50-mm diameter HE lens driving Baritol. The results indicate that the 56-mm diameter HE lens works well, as does the Baritol, giving total HE loads of about 250 mg TNT equivalent explosives.

  18. [Research progress on multiple myeloma immunophenotyping and minimal residual disease detected by flow cytometry].

    PubMed

    Li, Han-Qing; Zhai, Yong-Ping

    2015-02-01

    Multiple myeloma (MM) is a haematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow and remained incurable. Flow cytometry has been widely used in the detection of immunophenotype and minimal residual disease, diagnosis, monitoring and prognosis of MM. Normal plasma cells and malignant plasma cells can be distinguished according to different cell surface antigen expression. The clinical significane of many immune markes has been elucidated. However, the clinical significance of some phenotype remains controversial, the detection scheme and gating strategy are not unified. This review discusses the recent research progress on detection of MM immunophenotype and minimal residual disease by flow cytovetry.

  19. Selecting Map Projections in Minimizing Area Distortions in GIS Applications

    PubMed Central

    Yildirim, Faruk; Kaya, Ahmet

    2008-01-01

    Various software for Geographical Information Systems (GISs) have been developed and used in many different engineering projects. In GIS applications, map coverage is important in terms of performing reliable and meaningful queries. Map projections can be conformal, equal-area and equidistant. The goal of an application plays an important role in choosing one of those projections. Choosing the equal-area projection for an application in which area information is used (forestry, agriculture, ecosystem etc) reduces the amount of distortion on the area, but many users using GIS ignore this fact and continue to use applications with present map sheets no matter in what map projection it is. For example, extracting area information from data whose country system's map sheet is in conformal projection is relatively more distorted, compared to an equal-area projection one. The goal of this study is to make the best decision in choosing the most proper equal-area projection among the choices provided by ArcGIS 9.0, which is a popular GIS software package, and making a comparison on area errors when conformal projection is used. In this study, the area of parcels chosen in three different regions and geographic coordinates and whose sizes vary between 0.01 to 1,000,000 ha are calculated according to Transversal Mercator (TM, 3°), Universal Transversal Mercator (UTM, 6°) and 14 different equal-area projections existing in the ArcGIS 9.0 GIS software package. The parcel areas calculated with geographical coordinates are accepted as definite. The difference between the sizes calculated according to projection coordinates and real sizes of the parcels are determined. Consequently, the appropriate projections are decided for the areas smaller and equal than 1,000 ha and greater than 1,000 ha in the GIS software package. PMID:27873959

  20. Selecting Map Projections in Minimizing Area Distortions in GIS Applications.

    PubMed

    Yildirim, Faruk; Kaya, Ahmet

    2008-12-03

    Varioussoftware for Geographical Information Systems (GISs) have been developed and used in many different engineering projects. In GIS applications, map coverage is important in terms of performing reliable and meaningful queries. Map projections can be conformal, equal-area and equidistant. The goal of an application plays an important role in choosing one of those projections. Choosing the equal-area projection for an application in which area information is used (forestry, agriculture, ecosystem etc) reduces the amount of distortion on the area, but many users using GIS ignore this fact and continue to use applications with present map sheets no matter in what map projection it is. For example, extracting area information from data whose country system's map sheet is in conformal projection is relatively more distorted, compared to an equal-area projection one. The goal of this study is to make the best decision in choosing the most proper equal-area projection among the choices provided by ArcGIS 9.0, which is a popular GIS software package, and making a comparison on area errors when conformal projection is used. In this study, the area of parcels chosen in three different regions and geographic coordinates and whose sizes vary between 0.01 to 1,000,000 ha are calculated according to Transversal Mercator (TM, 3°), Universal Transversal Mercator (UTM, 6°) and 14 different equal-area projections existing in the ArcGIS 9.0 GIS software package. The parcel areas calculated with geographical coordinates are accepted as definite. The difference between the sizes calculated according to projection coordinates and real sizes of the parcels are determined. Consequently, the appropriate projections are decided for the areas smaller and equal than 1,000 ha and greater than 1,000 ha in the GIS software package.

  1. 78 FR 36194 - Draft Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-17

    ... New Drug Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood..., Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic... Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications...

  2. Minimal Technologies Application Project, Hohenfels Training Area, Germany: Final report

    SciTech Connect

    Zellmer, S.D.; Hinchman, R.R.; Johnson, D.O. . Energy Systems Div.); Severinghaus, W.D. ); Brent, J.J. )

    1991-12-01

    At the US Army Hohenfels Training Area in Germany, more than 30 years of continuous and intensive tactical training has caused extensive environmental damage because of the loss of vegetative cover and accelerated soil erosion. A project was conducted to evaluate the cost-effectiveness and relative benefits of various revegetation procedures. These procedures involved amendment and seedbed preparation options that were combined with three different durations of site closure. The point-intercept method was used to measure the types and amounts of vegetation established and changes in the vegetative community. Over three growing seasons, applications of fertilizer and seed increased the percent grass, legume, and total vegetative cover. The duration of site closure had no influence on the types or amounts of ground cover established. Materials made up only 10% of the total cost of the fertilization and seeding operations. The results of the research indicate that less expensive methods of amendment application should be evaluated. The data also show that site closure is not practical, economical, or necessary. The results of this project suggest that a regular maintenance program consisting of seeding and fertilization is required to maintain adequate vegetative cover and control erosion on tactical training areas.

  3. Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia.

    PubMed

    Karawajew, Leonid; Dworzak, Michael; Ratei, Richard; Rhein, Peter; Gaipa, Giuseppe; Buldini, Barbara; Basso, Giuseppe; Hrusak, Ondrej; Ludwig, Wolf-Dieter; Henze, Günter; Seeger, Karl; von Stackelberg, Arend; Mejstrikova, Ester; Eckert, Cornelia

    2015-07-01

    Multiparametric flow cytometry is an alternative approach to the polymerase chain reaction method for evaluating minimal residual disease in treatment protocols for primary acute lymphoblastic leukemia. Given considerable differences between primary and relapsed acute lymphoblastic leukemia treatment regimens, flow cytometric assessment of minimal residual disease in relapsed leukemia requires an independent comprehensive investigation. In the present study we addressed evaluation of minimal residual disease by flow cytometry in the clinical trial for childhood relapsed acute lymphoblastic leukemia using eight-color flow cytometry. The major challenge of the study was to reliably identify low amounts of residual leukemic cells against the complex background of regeneration, characteristic of follow-up samples during relapse treatment. In a prospective study of 263 follow-up bone marrow samples from 122 patients with B-cell precursor acute lymphoblastic leukemia, we tested various B-cell markers, adapted the antibody panel to the treatment protocol, and evaluated its performance by a blinded parallel comparison with the polymerase chain reaction data. The resulting eight-color single-tube panel showed a consistently high overall concordance (P<0.001) and, under optimal conditions, sensitivity similar to that of the reference polymerase chain reaction method. Overall, evaluation of minimal residual disease by flow cytometry can be successfully integrated into the clinical management of relapsed childhood acute lymphoblastic leukemia either as complementary to the polymerase chain reaction or as an independent risk stratification tool. ALL-REZ BFM 2002 clinical trial information: NCT00114348.

  4. Insights into spared memory capacity in amnestic MCI and Alzheimer's Disease via minimal interference.

    PubMed

    Dewar, Michaela; Pesallaccia, Martina; Cowan, Nelson; Provinciali, Leandro; Della Sala, Sergio

    2012-04-01

    Impairment on standard tests of delayed recall is often already maximal in the aMCI stage of Alzheimer's Disease. Neuropathological work shows that the neural substrates of memory function continue to deteriorate throughout the progression of the disease, hinting that further changes in memory performance could be tracked by a more sensitive test of delayed recall. Recent work shows that retention in aMCI patients can be raised well above floor when the delay period is devoid of further material - 'Minimal Interference'. This memory enhancement is thought to be the result of improved memory consolidation. Here we used the minimal interference/interference paradigm (word list retention following 10 min of quiet resting vs. picture naming) in a group of 17 AD patients, 25 aMCI patients and 25 controls. We found (1) that retention can be improved significantly by minimal interference in patients with aMCI and patients with mild to moderate AD; (2) that the minimal interference paradigm is sensitive to decline in memory function with disease severity, even when performance on standard tests has reached floor; and (3) that this paradigm can differentiate well (80% sensitivity and 100% specificity) between aMCI patients who progress and do not progress to AD within 2 years. Our findings support the notion that the early memory dysfunction in AD is associated with an increased susceptibility to memory interference and are suggestive of a gradual decline in consolidation capacity with disease progression.

  5. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma

    PubMed Central

    Lahuerta, Juan J.; Pepin, François; González, Marcos; Barrio, Santiago; Ayala, Rosa; Puig, Noemí; Montalban, María A.; Paiva, Bruno; Weng, Li; Jiménez, Cristina; Sopena, María; Moorhead, Martin; Cedena, Teresa; Rapado, Immaculada; Mateos, María Victoria; Rosiñol, Laura; Oriol, Albert; Blanchard, María J.; Martínez, Rafael; Bladé, Joan; San Miguel, Jesús; Faham, Malek; García-Sanz, Ramón

    2014-01-01

    We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma (MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD– by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P < .0001) and overall survival (median not reached vs 81 months; P = .02), compared with patients who were MRD+. When stratifying patients by different levels of MRD, the respective TTP medians were: MRD ≥10−3 27 months, MRD 10−3 to 10−5 48 months, and MRD <10−5 80 months (P = .003 to .0001). Ninety-two percent of VGPR patients were MRD+. In complete response patients, the TTP remained significantly longer for MRD– compared with MRD+ patients (131 vs 35 months; P = .0009). PMID:24646471

  6. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma.

    PubMed

    Martinez-Lopez, Joaquin; Lahuerta, Juan J; Pepin, François; González, Marcos; Barrio, Santiago; Ayala, Rosa; Puig, Noemí; Montalban, María A; Paiva, Bruno; Weng, Li; Jiménez, Cristina; Sopena, María; Moorhead, Martin; Cedena, Teresa; Rapado, Immaculada; Mateos, María Victoria; Rosiñol, Laura; Oriol, Albert; Blanchard, María J; Martínez, Rafael; Bladé, Joan; San Miguel, Jesús; Faham, Malek; García-Sanz, Ramón

    2014-05-15

    We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma (MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD(-) by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P < .0001) and overall survival (median not reached vs 81 months; P = .02), compared with patients who were MRD(+). When stratifying patients by different levels of MRD, the respective TTP medians were: MRD ≥10(-3) 27 months, MRD 10(-3) to 10(-5) 48 months, and MRD <10(-5) 80 months (P = .003 to .0001). Ninety-two percent of VGPR patients were MRD(+). In complete response patients, the TTP remained significantly longer for MRD(-) compared with MRD(+) patients (131 vs 35 months; P = .0009).

  7. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies.

    PubMed

    van Dongen, Jacques J M; van der Velden, Vincent H J; Brüggemann, Monika; Orfao, Alberto

    2015-06-25

    Monitoring of minimal residual disease (MRD) has become routine clinical practice in frontline treatment of virtually all childhood acute lymphoblastic leukemia (ALL) and in many adult ALL patients. MRD diagnostics has proven to be the strongest prognostic factor, allowing for risk group assignment into different treatment arms, ranging from significant treatment reduction to mild or strong intensification. Also in relapsed ALL patients and patients undergoing stem cell transplantation, MRD diagnostics is guiding treatment decisions. This is also why the efficacy of innovative drugs, such as antibodies and small molecules, are currently being evaluated with MRD diagnostics within clinical trials. In fact, MRD measurements might well be used as a surrogate end point, thereby significantly shortening the follow-up. The MRD techniques need to be sensitive (≤10(-4)), broadly applicable, accurate, reliable, fast, and affordable. Thus far, flow cytometry and polymerase chain reaction (PCR) analysis of rearranged immunoglobulin and T-cell receptor genes (allele-specific oligonucleotide [ASO]-PCR) are claimed to meet these criteria, but classical flow cytometry does not reach a solid 10(-4), whereas classical ASO-PCR is time-consuming and labor intensive. Therefore, 2 high-throughput technologies are being explored, ie, high-throughput sequencing and next-generation (multidimensional) flow cytometry, both evaluating millions of sequences or cells, respectively. Each of them has specific advantages and disadvantages.

  8. Minimal residual disease in canine lymphoma: An objective marker to assess tumour cell burden in remission.

    PubMed

    Sato, Masahiko; Yamazaki, Jumpei; Goto-Koshino, Yuko; Setoguchi, Asuka; Takahashi, Masashi; Baba, Kenji; Fujino, Yasuhito; Ohno, Koichi; Tsujimoto, Hajime

    2016-09-01

    Lymphoma is the most common haematopoietic malignancy in dogs. Since a high proportion of dogs with lymphoma achieve remission soon after initiation of chemotherapy, an objective marker assessing treatment efficacy is required. Following clinical remission, the residual population of tumour cells can be referred to as the minimal residual disease (MRD). MRD traditionally has been detected by cytology and flow cytometry; however, if the burden of malignant cells is low, these methods might not be sufficiently sensitive to detect MRD. As an extension of the development of PCR for antigen receptor gene rearrangements (PARR) in dogs, there has been recent progress in the application of real-time quantitative PCR (RT-qPCR) to canine lymphoma. With the RT-qPCR system, a very high sensitivity (1 cell per 10,000 cells) has been achieved by preparing allele-specific oligonucleotide primers and probes designed from neoplastic clones of each dog. A series of MRD diagnostics studies employing the RT-qPCR system has revealed its usefulness as a prognostic indicator, an objective marker of treatment efficacy and a predictor of relapse for dogs with lymphoma receiving chemotherapy. Introduction of the MRD monitoring system will provide an innovative scientific tool in the development of superior treatments and monitoring strategies for canine lymphoma. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies

    PubMed Central

    van der Velden, Vincent H. J.; Brüggemann, Monika; Orfao, Alberto

    2015-01-01

    Monitoring of minimal residual disease (MRD) has become routine clinical practice in frontline treatment of virtually all childhood acute lymphoblastic leukemia (ALL) and in many adult ALL patients. MRD diagnostics has proven to be the strongest prognostic factor, allowing for risk group assignment into different treatment arms, ranging from significant treatment reduction to mild or strong intensification. Also in relapsed ALL patients and patients undergoing stem cell transplantation, MRD diagnostics is guiding treatment decisions. This is also why the efficacy of innovative drugs, such as antibodies and small molecules, are currently being evaluated with MRD diagnostics within clinical trials. In fact, MRD measurements might well be used as a surrogate end point, thereby significantly shortening the follow-up. The MRD techniques need to be sensitive (≤10−4), broadly applicable, accurate, reliable, fast, and affordable. Thus far, flow cytometry and polymerase chain reaction (PCR) analysis of rearranged immunoglobulin and T-cell receptor genes (allele-specific oligonucleotide [ASO]-PCR) are claimed to meet these criteria, but classical flow cytometry does not reach a solid 10−4, whereas classical ASO-PCR is time-consuming and labor intensive. Therefore, 2 high-throughput technologies are being explored, ie, high-throughput sequencing and next-generation (multidimensional) flow cytometry, both evaluating millions of sequences or cells, respectively. Each of them has specific advantages and disadvantages. PMID:25999452

  10. Is there a role for retinoids to treat minimal residual disease in neuroblastoma?

    PubMed Central

    Matthay, K K; Reynolds, C P

    2000-01-01

    A variety of pre-clinical and clinical data point toward high drug levels of retinoids being required to achieve optimal efficacy against neuroblastoma. The results of the Kohler trial reported in this issue demonstrate that low-dose 13-cis-RA does not have clinical efficacy against neuroblastoma in a setting of minimal residual disease. A comparison of the Kohler trial with the US CCG trial provides clinical evidence that high-dose levels of retinoids are optimal for treating minimal residual disease in neuroblastoma. The comparison of high-dose and low-dose 13-cis-RA studies in neuroblastoma suggests the intriguing possibility that high dose, pulse schedules of other retinoids could be effective as therapeutic and chemopreventive agents in diseases where low-dose, chronic retinoid administration was not effective. Pre-clinical and perhaps clinical studies of the latter concept should be considered. © 2000 Cancer Research Campaign PMID:11027422

  11. Importance of minimal residual disease in hairy cell leukemia: monoclonal antibodies as a therapeutic strategy

    PubMed Central

    THOMAS, DEBORAH A.; RAVANDI, FARHAD; KEATING, MICHAEL; KANTARJIAN, HAGOP M.

    2014-01-01

    With the use of nucleoside analogs as frontline therapy, the prognosis of hairy cell leukemia (HCL) has improved dramatically. Unfortunately, disease recurrence remains problematic. Eradication of minimal residual disease (MRD) persisting after therapy may further improve outcome. The evolution of available techniques used to assess MRD, and the potential incorporation of novel agents such as monoclonal antibodies (MoAbs) into the treatment armamentarium for HCL mandate that MRD analyses be performed concurrently with routine assessments of disease status. Herein, the available data regarding the prevalence and clinical relevance of MRD after therapy for HCL is reviewed. PMID:19814695

  12. NOVP: a novel chemotherapeutic regimen with minimal toxicity for treatment of Hodgkin's disease

    SciTech Connect

    Hagemeister, F.B.; Cabanillas, F.; Velasquez, W.S.; Meistrich, M.L.; Liang, J.C.; McLaughlin, P.; Redman, J.R.; Romaguera, J.E.; Rodriguez, M.A.; Swan, F. Jr. )

    1990-12-01

    Patients with early-staged Hodgkin's disease have had a higher relapse rate following radiotherapy alone if they have B symptoms, large mediastinal masses, hilar involvement, or stage III disease. From June 1988 to December 1989, 27 previously untreated patients with early-staged Hodgkin's disease with adverse features for disease-free survival received combined-modality therapy. Seventeen patients had stage I or II disease, 10 had stage III, 5 had B symptoms, 13 had large mediastinal masses, and 6 had peripheral masses measuring 10 cm or more in diameter. All patients initially received three cycles of a novel chemotherapeutic regimen combining Novantrone (mitoxantrone, American Cyanamid Company), vincristine, vinblastine, and prednisone (NOVP). Twenty-four patients with clinically staged I or II disease with adverse features or stage III disease did not undergo laparotomy; three patients had favorable stage I or II disease and at laparotomy had stage III disease. Radiotherapy-treatment fields depended on the extent of nodal involvement. Twenty-six patients completed all therapy as planned to complete remission (CR) and one of these has had progression; she is in second CR following additional radiotherapy. With a median follow-up of 12 months, all patients are alive. Tolerance to treatment was excellent with only grade 1 or 2 nausea, alopecia and myalgias, and brief myelosuppression. NOVP is an effective adjuvant chemotherapy regimen for inducing responses, with minimal toxicity, prior to definitive radiotherapy for patients with early-staged Hodgkin's disease.

  13. Renal manifestations of human brucellosis: First report of minimal change disease.

    PubMed

    Sabanis, Nikolaos; Gavriilaki, Eleni; Paschou, Eleni; Tsotsiou, Eleni; Kalaitzoglou, Asterios; Kavlakoudis, Christos; Vasileiou, Sotirios

    2016-05-01

    Human brucellosis is considered a great example of the complexity of clinical manifestations possibly affecting multiple organs or systems. Renal manifestations of human brucellosis have been documented in few case reports and one case series. Herein, we present a case of Nephrotic syndrome (NS) due to minimal change disease in the course of acute brucellosis. A 53-year-old male farmer was admitted to our department with acute brucellosis and NS. Renal biopsy revealed minimal change disease. Combined treatment with prednisone (1 mg/kg), rifampicin (600 mg/day), and doxycycline (200 mg/day) was initiated. Complete remission of NS was achieved at the end of the fourth week. One year later, the patient remained in complete remission of NS without any sign of relapse of brucellosis.

  14. [Molecular detection of minimal residual disease in melanoma and solid tumors].

    PubMed

    Vázquez, Valeria; Otero, Laura L; Laurent, Viviana E; Gabri, Mariano R; Gómez, Daniel E; Alonso, Daniel F

    2009-01-01

    The availability of highly sensitive and specific methods for the detection of minimal residual disease in patients with solid tumors may have important prognostic and therapeutic implications. One of the most widely used methods for the molecular detection of cancer cells is the RT-PCR technique, which leads to the amplification of tissue-specific mRNA. It was firstly applied in the detection of circulating tumor cells in peripheral blood of patients with advanced melanoma; and soon it was adapted for the detection of minimal residual disease in other solid tumors. The aim of the present review is to evaluate the published data since the first study in 1991 and to analyze the clinical value of the findings obtained. The importance of sample handling and standardization of RT-PCR procedures is also discussed.

  15. [Molecular genetic detection of minimal residual disease (MRD) in children with acute lymphoblastic leukemia].

    PubMed

    Koehler, R; Bartram, C R

    2013-05-01

    The treatment of acute lymphoblastic leukemia (ALL) in childhood and adolescence achieves nowadays cure rates of more than 80%. The detection of minimal residual disease (MRD) via molecular genetic methods provides - in comparison with conventional clinical and biological parameters - much more sensitive approaches to monitor individual treatment response. Here we will discuss the molecular background and technical developments in the framework of the BFM-study group.

  16. A Novel Tandem Duplication Assay to Detect Minimal Residual Disease in FLT3/ITD AML

    PubMed Central

    Lin, Ming-Tseh; Tseng, Li-Hui; Dudley, Jonathan C.; Riel, Stacey; Tsai, Harrison; Zheng, Gang; Pratz, Keith W.; Levis, Mark J.; Gocke, Christopher D.

    2015-01-01

    Background Internal tandem duplication (ITD) of the FLT3 gene is associated with poor prognosis in acute myeloid leukemia (AML) patients with a normal karyotype. The current standard PCR assay for FLT3/ITD detection is not sufficiently sensitive to monitor minimal residual disease (MRD). Clone-specific assays may have sufficient sensitivity but are not practical to implement, since each clone-specific primer/probe requires clinical validation. Objective To develop an assay for clinical molecular diagnostics laboratories to monitor MRD in FLT3/ITD AMLs. Methods We designed a simple novel assay, tandem duplication PCR (TD-PCR), and tested its sensitivity, specificity and clinical utility in FLT3/ITD AML patients. Results TD-PCR was capable of detecting a single ITD molecule and was applicable to 75% of ITD mutants tested. TD-PCR detected MRD in bone marrow prior to patient relapse. TD-PCR also identified low level ITD mutants not only in FLT3/ITD AMLs but also in initial diagnostic specimens reportedly negative by the standard assay in patients who progressed with the same ITDs detected by the TD-PCR assay. Conclusion Detection of MRD by TD-PCR may guide patient selection for early clinical intervention. In contrast to clone-specific approaches, TD-PCR assay can be more easily validated for MRD detection in clinical laboratories due to standardized primers and a universal positive control. In addition, our results on multi-clonality and low-level ITDs suggest that further studies are warranted to elucidate their clinical/biological significance. PMID:26446915

  17. [Application progress of minimally invasive technique in treatment of calcaneus fractures].

    PubMed

    Yu, Tao; Yang, Yunfeng; Yu, Guangrong

    2013-02-01

    To review the application progress of minimally invasive technique in the treatment of calcaneus fractures and to analyze the advantages and disadvantages of each method as well as to predict the trend of development in the field. Domestic and abroad literature concerning the minimally invasive technique applied in calcaneus fractures in recent years was reviewed extensively and analyzed thoroughly. There are both advantages and limitations of each minimally invasive technique including percutaneous reduction and fixation, limited incision, external fixator, arthroscopic assisted reduction, and balloon expansion reduction. But every technique is developing rapidly and becoming more and more effective. A variety of minimally invasive technique can not only be used independently but also can be applied jointly to complement one another. It needs further study how to improve the effectiveness and expand the indications. And the theoretical basis of evidence-based medicine needs to be provided more.

  18. Minimally invasive transcatheter aortic valve implantation for the treatment of rheumatic heart disease in developing countries.

    PubMed

    Saidi, Trust; Douglas, Tania S

    2016-10-01

    The treatment of rheumatic heart disease presents a medical and surgical challenge, particularly in developing countries, where the disease is prevalent. Most of these countries find it prohibitively expensive to import heart valve prostheses that are required for treatment and are largely manufactured in the United States and Europe. Even if the valves were available, the absence of facilities to conduct open-heart surgery for valve replacement results in many people from developing countries dying needlessly of the disease. To address this problem, transcatheter aortic valve implantation, an emerging, minimally invasive, treatment strategy for rheumatic heart disease, has been proposed. Areas covered: This paper reviews the literature on current valve technologies in use globally, and focuses on a minimally invasive transcatheter aortic valve implantation device and aortic valve prosthesis that have been developed by Strait Access Technologies Holdings in South Africa. Expert commentary: This new technology holds the potential of making available heart valve replacements to millions of patients in the developing world who would otherwise have no recourse to treatment.

  19. Bootstrap imputation with a disease probability model minimized bias from misclassification due to administrative database codes.

    PubMed

    van Walraven, Carl

    2017-04-01

    Diagnostic codes used in administrative databases cause bias due to misclassification of patient disease status. It is unclear which methods minimize this bias. Serum creatinine measures were used to determine severe renal failure status in 50,074 hospitalized patients. The true prevalence of severe renal failure and its association with covariates were measured. These were compared to results for which renal failure status was determined using surrogate measures including the following: (1) diagnostic codes; (2) categorization of probability estimates of renal failure determined from a previously validated model; or (3) bootstrap methods imputation of disease status using model-derived probability estimates. Bias in estimates of severe renal failure prevalence and its association with covariates were minimal when bootstrap methods were used to impute renal failure status from model-based probability estimates. In contrast, biases were extensive when renal failure status was determined using codes or methods in which model-based condition probability was categorized. Bias due to misclassification from inaccurate diagnostic codes can be minimized using bootstrap methods to impute condition status using multivariable model-derived probability estimates. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. An Efficient Augmented Lagrangian Method with Applications to Total Variation Minimization

    DTIC Science & Technology

    2012-08-17

    history. It was introduced into imaging denoising problems by Rudin , Osher and Fatemi in 1992 [30]. From then on, TV minimizing models have become one 3...Powell applied to convex program- ming, Journal of Optimization Theory and Applications, vol. 12, no. 6, pp. 555–562, 1973. [30] L. Rudin , S. Osher and E

  1. Trust Management in Mobile Ad Hoc Networks for Bias Minimization and Application Performance Maximization

    DTIC Science & Technology

    2014-02-26

    analysis Application-level trust optimization Reliability assessment a b s t r a c t Trust management for mobile ad hoc networks ( MANETs ) has emerged as...this paper we address the performance issue of trust management protocol design for MANETs in two important areas: trust bias minimization and...application performance maximization. By means of a novel model- based approach to model the ground truth status of mobile nodes in MANETs as the basis for

  2. Clinical value of pre-transplant minimal residual disease in childhood lymphoblastic leukaemia: the results of the French minimal residual disease-guided protocol.

    PubMed

    Gandemer, Virginie; Pochon, Cécile; Oger, Emmanuel; Dalle, Jean-Hugues H; Michel, Gérard; Schmitt, Claudine; de Berranger, Eva; Galambrun, Claire; Cavé, Hélène; Cayuela, Jean-Michel; Grardel, Nathalie; Macintyre, Elizabeth; Margueritte, Geneviève; Méchinaud, Françoise; Rorhlich, Pierre; Lutz, Patrick; Demeocq, François; Schneider, Pascale; Plantaz, Dominique; Poirée, Marilyne; Bordigoni, Pierre

    2014-05-01

    Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD <10(-3) and the 27 with MRD ≥10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10(-3) compromised the 5-year cumulative incidence of relapse (43·6 vs. 16·7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72·3% of patients with MRD<10(-3) and 40·4% of those with MRD ≥10(-3). © 2014 John Wiley & Sons Ltd.

  3. Pre-transplantation minimal residual disease with cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid leukemia

    PubMed Central

    Oran, Betül; Jorgensen, Jeff L.; Marin, David; Wang, Sa; Ahmed, Sairah; Alousi, Amin M.; Andersson, Borje S.; Bashir, Qaiser; Bassett, Roland; Lyons, Genevieve; Chen, Julianne; Rezvani, Katy; Popat, Uday; Kebriaei, Partow; Patel, Keyur; Rondon, Gabriela; Shpall, Elizabeth J.; Champlin, Richard E.

    2017-01-01

    Our aim was to improve outcome prediction after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia by combining cytogenetic and molecular data at diagnosis with minimal residual disease assessment by multicolor flow-cytometry at transplantation. Patients with acute myeloid leukemia in first complete remission in whom minimal residual disease was assessed at transplantation were included and categorized according to the European LeukemiaNet classification. The primary outcome was 1-year relapse incidence after transplantation. Of 152 patients eligible, 48 had minimal residual disease at the time of their transplant. Minimal residual disease-positive patients were older, required more therapy to achieve first remission, were more likely to have incomplete recovery of blood counts and had more adverse risk features by cytogenetics. Relapse incidence at 1 year was higher in patients with minimal residual disease (32.6% versus 14.4%, P=0.002). Leukemia-free survival (43.6% versus 64%, P=0.007) and overall survival (48.8% versus 66.9%, P=0.008) rates were also inferior in patients with minimal residual disease. In multivariable analysis, minimal residual disease status at transplantation independently predicted 1-year relapse incidence, identifying a subgroup of intermediate-risk patients, according to the European LeukemiaNet classification, with a particularly poor outcome. Assessment of minimal residual disease at transplantation in combination with cytogenetic and molecular findings provides powerful independent prognostic information in acute myeloid leukemia, lending support to the incorporation of minimal residual disease detection to refine risk stratification and develop a more individualized approach during hematopoietic stem cell transplantation. PMID:27540139

  4. Minimal-change disease as a paraneoplastic syndrome in a patient with ovarian carcinoma.

    PubMed

    González-Fontal, Guido R; Restrepo, Juan G; Henao-Martínez, Andrés F

    2011-12-01

    Minimal-change disease (MCD) is an exceptional paraneoplastic presentation. We are describing the case of an ovarian paraneoplastic nephrotic syndrome. The kidney biopsy was consistent with MCD. Steroids and immunosuppressive therapy were given with no change in the nephrotic-range proteinuria. A complete resolution of the nephrotic syndrome was soon observed with improvement of her clinical condition after five cycles of chemotherapy with paclitaxel and carboplatin and tumor-debulking surgery. Ovarian carcinoma paraneoplastic nephrotic syndrome secondary to MCD is an extremely rare event, which is important to recognize since it is responsive to the standard chemotherapy.

  5. MINIMAL RESIDUAL DISEASE IN AML: WHY HAS IT LAGGED BEHIND PEDIATRIC ALL?

    PubMed Central

    Paietta, Elisabeth

    2015-01-01

    Although the concept of minimal residual disease (MRD) as an indicator for the quality of treatment response is the same in acute myeloid (AML) and acute lymphoid leukemia (ALL), the practice of measuring MRD levels for monitoring response and guiding post-induction therapy has been implemented much more rapidly in ALL, particularly pediatric ALL, than in AML. This perspective will look at the facts and discuss why ALL appears to be more amenable to MRD-shaped risk-allocation and a revised definition of complete remission. PMID:26297274

  6. Minimal Clinically Important Difference on Parkinson's Disease Sleep Scale 2nd Version

    PubMed Central

    Horváth, Krisztina; Aschermann, Zsuzsanna; Ács, Péter; Deli, Gabriella; Janszky, József; Komoly, Sámuel; Karádi, Kázmér; Kovács, Márton; Makkos, Attila; Faludi, Béla; Kovács, Norbert

    2015-01-01

    Background and Aims. The aim of the present study was to determine the estimates of minimal clinically important difference for Parkinson's Disease Sleep Scale 2nd version (PDSS-2) total score and dimensions. Methods. The subject population consisted of 413 PD patients. At baseline, MDS-UPDRS, Hoehn-Yahr Scale, Mattis Dementia Rating Scale, and PDSS-2 were assessed. Nine months later the PDSS-2 was reevaluated with the Patient-Reported Global Impression Improvement Scale. Both anchor-based techniques (within patients' score change method and sensitivity- and specificity-based method by receiver operating characteristic analysis) and distribution-based approaches (effect size calculations) were utilized to determine the magnitude of minimal clinically important difference. Results. According to our results, any improvements larger than −3.44 points or worsening larger than 2.07 points can represent clinically important changes for the patients. These thresholds have the effect size of 0.21 and −0.21, respectively. Conclusions. Minimal clinically important differences are the smallest change of scores that are subjectively meaningful to patients. Studies using the PDSS-2 as outcome measure should utilize the threshold of −3.44 points for detecting improvement or the threshold of 2.07 points for observing worsening. PMID:26539303

  7. New approaches to manipulate minimal residual disease after allogeneic stem cell transplantation

    PubMed Central

    Rein, Lindsay AM; Sung, Anthony D; Rizzieri, David A

    2013-01-01

    SUMMARY Minimal residual disease (MRD) is a complex topic that has been studied extensively in hematologic malignancies given its clinical implications related to prognosis. However, methods to monitor and treat MRD, especially after stem cell transplantation, are not well defined and vary in different disease processes. Alternative transplant strategies, such as reduced-intensity conditioning, have altered the way we assess and address MRD after transplantation. Development of new diagnostic tools have allowed for higher sensitivity and specificity of testing. Both targeted chemotherapeutic agents and immunotherapies have been developed to treat MRD in hopes of improving patient outcomes. This article aims to address ways to define and manipulate MRD specifically after stem cell transplantation. PMID:24303095

  8. Phenotypic changes in acute myeloid leukaemia: implications in the detection of minimal residual disease.

    PubMed Central

    Macedo, A; San Miguel, J F; Vidriales, M B; López-Berges, M C; García-Marcos, M A; Gonzalez, M; Landolfi, C; Orfão, A

    1996-01-01

    AIM: To explore the role of phenotypic changes as possible limiting factors in the immunological detection of minimal residual disease in patients with acute myeloid leukaemia (AML). METHODS: 20 relapses were evaluated, with special attention to changes in the criteria used for the definition of a phenotype as "aberrant". In all cases the same monoclonal antibody and fluorochrome were used at diagnosis and in relapse. RESULTS: Six out of the 16 patients showed aberrant phenotypes at diagnosis. At relapse, no changes in the aberrant phenotypes were detected in most of the patients; nevertheless, in two of the four patients with asynchronous antigen expression this aberration disappeared at relapse. At diagnosis in both cases there were already small blast cell subpopulations showing the phenotype of leukaemic cells at relapse. Ten out of the 16 cases analysed showed significant changes in the expression of at least one of the markers analysed. CONCLUSIONS: At relapse in AML the "leukaemic phenotypes" usually remained unaltered, while other phenotypic features--not relevant for distinguishing leukaemic blast cells among normal progenitors--changed frequently; however, they were not a major limitation in the immunological detection of minimal residual disease. PMID:8666678

  9. Precision and prognostic value of clone-specific minimal residual disease in acute myeloid leukemia.

    PubMed

    Hirsch, Pierre; Tang, Ruoping; Abermil, Nassera; Flandrin, Pascale; Moatti, Hannah; Favale, Fabrizia; Suner, Ludovic; Lorre, Florence; Marzac, Christophe; Fava, Fanny; Mamez, Anne-Claire; Lapusan, Simona; Isnard, Françoise; Mohty, Mohamad; Legrand, Ollivier; Douay, Luc; Bilhou-Nabera, Chrystele; Delhommeau, François

    2017-03-16

    The genetic landscape of adult acute myeloid leukemias has been recently unraveled. However, due to their genetic heterogeneity, only a handful of markers are currently used for the evaluation of minimal residual disease. Recent studies using multi-target strategies indicate that detection of residual mutations in less than 5% of cells in complete remission is associated with a better survival. Here, in a series of 69 acute myeloid leukemias with known clonal architecture, we design a clone-specific strategy based on fluorescent in situ hybridization and high-sensitivity next generation sequencing to detect chromosomal aberrations and mutations, respectively, in follow-up samples. The combination of these techniques allows tracking chromosomal and genomic lesions down to 0.5-0.4% of the cell population in remission samples. By testing all lesions in follow-up samples from 65/69 evaluable patients, we find that initiating events often persist, and appear to be, alone, inappropriate markers to predict short term relapse. In contrast, the persistence of two or more lesions in more than 0.4% of the cells from remission samples is strongly associated with lower leukemia-free and overall survivals in univariate and multivariate analyses. Although larger prospective studies are needed to extend these results, our data show that a personalized, clone-specific, minimal residual disease follow-up strategy is feasible in the vast majority of acute myeloid leukemia cases.

  10. Minimal residual disease detection in Tunisian B-acute lymphoblastic leukemia based on immunoglobulin gene rearrangements

    PubMed Central

    Besbes, S.; Hamadou, W.S.; Boulland, M.L.; Youssef, Y.B.; Achour, B.; Regaieg, H.; Khelif, A.; Fest, T.; Soua, Z.

    2017-01-01

    IGH gene rearrangement and IGK-Kde gene deletion can be used as molecular markers for the assessment of B lineage acute lymphoblastic leukemia (B-ALL). Minimal residual disease detected based on those markers is currently the most reliable prognosis factor in B-ALL. The aim of this study was to use clonal IGH/IGK-Kde gene rearrangements to confirm B-ALL diagnosis and to evaluate the treatment outcome of Tunisian leukemic patients by monitoring the minimal residual disease (MRD) after induction chemotherapy. Seventeen consecutive newly diagnosed B-ALL patients were investigated by multiplex PCR assay and real time quantitative PCR according to BIOMED 2 conditions. The vast majority of clonal VH-JH rearrangements included VH3 gene. For IGK deletion, clonal VK1f/6-Kde recombinations were mainly identified. These rearrangements were quantified to follow-up seven B-ALL after induction using patient-specific ASO. Four patients had an undetectable level of MRD with a sensitivity of up to 10-5. This molecular approach allowed identification of prognosis risk group and adequate therapeutic decision. The IGK-Kde and IGH gene rearrangements might be used for diagnosis and MRD monitoring of B-ALL, introduced for the first time in Tunisian laboratories. PMID:28099581

  11. The bone marrow microenvironment as a sanctuary for minimal residual disease in CML

    PubMed Central

    Nair, Rajesh R.; Tolentino, Joel; Hazlehurst, Lori A.

    2012-01-01

    Bcr-abl kinase inhibitors have provided proof of principal that targeted therapy holds great promise for the treatment of cancer. However, despite the success of these agents in treating chronic myelogenous leukemia (CML), the majority of patients continue to present with minimal residual disease contained within the bone marrow microenvironment. These clinical observations suggest that the bone marrow microenvironment may provide survival signals that contribute to the failure to eliminate minimal residual disease. The bone marrow microenvironment is comprised of multiple sub-domains which vary in cellular composition and gradients of soluble factors and matrix composition. Experimental evidence indicates that exposure of tumor cells to either bone marrow derived soluble factors or matrixes can confer a multi-drug resistance phenotype. Together, these data indicate that targeting such pathways may be a viable approach for increasing the efficacy of chemotherapy. Moreover, we propose that personalized medicine must go beyond understanding predictive models inherent to tumors but rather build predictive models that consider diversity in response due to interactions with the tumor microenvironment. This review will focus on CML, however, understanding the contribution of the bone marrow microenvironment could contribute to rationale combination therapy in other types of leukemia, multiple myeloma and solid tumors which metastasize to the bone. PMID:20382130

  12. The prognostic impact of minimal residual disease in patients with chronic lymphocytic leukemia requiring first-line therapy.

    PubMed

    Santacruz, Rodrigo; Villamor, Neus; Aymerich, Marta; Martínez-Trillos, Alejandra; López, Cristina; Navarro, Alba; Rozman, María; Beà, Sílvia; Royo, Cristina; Cazorla, Maite; Colomer, Dolors; Giné, Eva; Pinyol, Magda; Puente, Xose S; López-Otín, Carlos; Campo, Elías; López-Guillermo, Armando; Delgado, Julio

    2014-05-01

    A proportion of patients with chronic lymphocytic leukemia achieve a minimal residual disease negative status after therapy. We retrospectively evaluated the impact of minimal residual disease on the outcome of 255 consecutive patients receiving any front-line therapy in the context of a detailed prognostic evaluation, including assessment of IGHV, TP53, NOTCH1 and SF3B1 mutations. The median follow-up was 73 months (range, 2-202) from disease evaluation. The median treatment-free survival durations for patients achieving a complete response without or with minimal residual disease, a partial response and no response were 76, 40, 11 and 11 months, respectively (P<0.001). Multivariate analysis revealed that three variables had a significant impact on treatment-free survival: minimal residual disease (P<0.001), IGHV status (P<0.001) and β2-microglobulin levels (P=0.012). With regards to overall survival, factors predictive of an unfavorable outcome were minimal residual disease positivity (P=0.014), together with advanced age (P<0.001), unmutated IGHV status (P=0.001), TP53 mutations (P<0.001) and elevated levels of β2-microglobulin (P=0.003). In conclusion, for patients requiring front-line therapy, achievement of minimal residual disease negativity is associated with significantly prolonged treatment-free and overall survival irrespective of other prognostic markers or treatment administered.

  13. Psychoneuroimmunology: application to ocular diseases.

    PubMed

    Ventura, Lori M

    2009-06-01

    Psychoneuroimmunology (PNI) is a relatively new discipline within the field of neuroscience which researches the relationship between emotional states, the central and peripheral nervous systems, and the endocrine and immune systems. Negative psychological states, such as stress, anxiety, and depression, may alter immune system regulation and modulation of peripheral cytokines. A plethora of PNI studies have shown that increased psychological stress and depression are associated with an alteration of immune functioning and worsened health outcomes for many conditions. To date, application of PNI methodology has not been reported for ocular diseases. This article provides an historical perspective on the origins of the rift between the emotional and spiritual from physical aspects of disease. A review of how stress is mediated through sympathetic adrenomedullary and hypothalamic pituitary axis activation with shifts in immunity is provided. The literature which supports spirituality in healing is presented. Finally, ocular diseases which would be most amenable to a PNI approach are discussed.

  14. Minimally Invasive Treatment of Pilonidal Disease: Crystallized Phenol and Laser Depilation

    PubMed Central

    Girgin, Mustafa; Kanat, Burhan Hakan; Ayten, Refik; Cetinkaya, Ziya; Kanat, Zekiye; Bozdağ, Ahmet; Turkoglu, Ahmet; Ilhan, Yavuz Selim

    2012-01-01

    Pilonidal disease has been treated surgically and by various other methods for many years. The most important problem associated with such treatment is recurrence, but cosmetic outcome is another important issue that cannot be ignored. Today, crystallized phenol is recognized as a treatment option associated with good medical and cosmetic outcomes. We hypothesized that the addition of laser depilation to crystallized phenol treatment of pilonidal disease might increase the rate of success, and this study aimed to determine if the hypothesis was true. Patients who were treated with crystallized phenol and 755-nm alexandrite laser depilation were retrospectively analyzed. In total, 42 (31 male and 11 female) patients were treated with crystallized phenol and alexandrite laser depilation and were followed up between January 2009 and January 2012. In all, 38 patients (90.5%) had chronic disease and 4 (9.5%) had recurrent disease. Among the patients, 26 (61.9%) recovered following 1 crystallized phenol treatment, and the remaining patients had complete remission following repeated treatment. Some patients needed multiple treatments, even up to 8 times. None of the patients had a recurrence during a mean 24 months (range, 6–30 months) of follow-up. Whatever method of treatment is used for pilonidal disease, hair cleaning positively affects treatment outcome. The present results support the hypothesis that the addition of laser depilation (which provides more permanent and effective depilation than other methods) to crystallized phenol treatment (a non-radical, minimally invasive method associated with very good cosmetic results) can increase the effectiveness of the treatment and also reduce the recurrence rate of the disease. PMID:23294066

  15. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL

    PubMed Central

    Thompson, Philip A.

    2016-01-01

    Deep remission and prolonged disease-free survival can be achieved with first-line chemoimmunotherapy (CIT), such as combined fludarabine, cyclophosphamide, and rituximab, in the majority of patients with chronic lymphocytic leukemia (CLL). More modest results are reported with less intense regimens like obinutuzumab plus chlorambucil. Clinical assessment has limited sensitivity in detecting residual disease responsible for subsequent relapse, even including morphologic bone marrow (BM) evaluation. Multicolor flow cytometry and polymerase chain reaction (PCR)-based methods can detect minimal residual disease (MRD) to a sensitivity of ≥1:10 000 (10−4). Achieving BM MRD-negative complete remission (CR) is associated with superior progression-free survival (PFS) and overall survival; MRD status is the single best posttreatment predictor of long-term outcomes after CIT. Newer oral B-cell receptor signaling pathway inhibitors are highly effective at controlling disease, but best monotherapy responses are typically partial remission, and patients must remain on treatment to maintain disease control. Therapeutic progress is still needed for CLL. We propose that targeting MRD provides opportunity to realize this progress. Achieving BM MRD-negative CR is a prerequisite for long-term unmaintained disease-free survival and potential for cure. We review available methodologies for detecting MRD and correlations with posttreatment outcomes. We discuss the potential utility of MRD to direct individualized therapy. Finally, we discuss the importance of MRD-negative status as a surrogate marker for longer PFS in clinical studies to allow more rapid determination of clinical benefit. PMID:26576865

  16. Application of a narrow-surface cage in full endoscopic minimally invasive transforaminal lumbar interbody fusion.

    PubMed

    He, Er-Xing; Guo, Jing; Ling, Qin-Jie; Yin, Zhi-Xun; Wang, Ying; Li, Ming

    2017-06-01

    Spinal endoscopy has been widely applied in lumbar discectomy and decompression. However, endoscopic lumbar interbody fusion still remains a technical challenge due to the limited space within the working trocar for cage implantation. The purpose of this study was to investigate the feasibility and effectiveness of using a narrow-surface fusion cage in full endoscopic minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) for the treatment of lumbar degenerative disease. From Jun 2013 to Dec 2014, a total of 42 patients (23 males, 19 females) underwent full endoscopic MIS-TLIF at our hospital was recruited. An 8-mm-wide narrow-surface fusion cage was selected for all cases. Perioperative parameters and complications were recorded. Comparisons on visual analog scale (VAS) and oswestry disability index (ODI) scores before and after surgery were performed. At the last follow-up, Nakai grading system was applied to assess patients' satisfaction; meanwhile, interbody fusion was evaluated by computed tomography. Mean operation time was 233.1 ± 69.5 min, and mean blood loss during surgery was 221.8 ± 98.5 ml. Two patients (4.8%) developed neurological complications. Postoperative follow-up ranged from 24 to 36 months (mean 27.6 ± 3.8 months). VAS and ODI scores were significantly improved 3 months after surgery and at the final follow-up, respectively (P < 0.05). Outcome of surgery was graded as excellent for 32 patients, good for 8 patients, and acceptable for 2 patients, corresponding to a success rate ("good" and "excellent") of 95.2%. Thirty-nine of the 42 patients demonstrated solid interbody fusion at the last follow-up, indicating a fusion rate of 92.9%. Application of a narrow-surface fusion cage in full endoscopic MIS-TLIF for the treatment of lumbar degenerative disease is feasible and effective. The clinical outcome and fusion success of this procedure were acceptable and promising. Copyright © 2017 IJS Publishing Group Ltd

  17. Consensus guidelines on plasma cell myeloma minimal residual disease analysis and reporting.

    PubMed

    Arroz, Maria; Came, Neil; Lin, Pei; Chen, Weina; Yuan, Constance; Lagoo, Anand; Monreal, Mariela; de Tute, Ruth; Vergilio, Jo-Anne; Rawstron, Andy C; Paiva, Bruno

    2016-01-01

    Major heterogeneity between laboratories in flow cytometry (FC) minimal residual disease (MRD) testing in multiple myeloma (MM) must be overcome. Cytometry societies such as the International Clinical Cytometry Society and the European Society for Clinical Cell Analysis recognize a strong need to establish minimally acceptable requirements and recommendations to perform such complex testing. A group of 11 flow cytometrists currently performing FC testing in MM using different instrumentation, panel designs (≥ 6-color) and analysis software compared the procedures between their respective laboratories and reviewed the literature to propose a consensus guideline on flow-MRD analysis and reporting in MM. Consensus guidelines support i) the use of minimum of five initial gating parameters (CD38, CD138, CD45, forward, and sideward light scatter) within the same aliquot for accurate identification of the total plasma cell compartment; ii) the analysis of potentially aberrant phenotypic markers and to report the antigen expression pattern on neoplastic plasma cells as being reduced, normal or increased, when compared to a normal reference plasma cell immunophenotype (obtained using the same instrument and parameters); and iii) the percentage of total bone marrow plasma cells plus the percentages of both normal and neoplastic plasma cells within the total bone marrow plasma cell compartment, and over total bone marrow cells. Consensus guidelines on minimal current and future MRD analyses should target a lower limit of detection of 0.001%, and ideally a limit of quantification of 0.001%, which requires at least 3 × 10(6) and 5 × 10(6) bone marrow cells to be measured, respectively. © 2015 International Clinical Cytometry Society.

  18. Timing of foliar Zn application plays a vital role in minimizing Cd accumulation in wheat.

    PubMed

    Saifullah; Javed, Hina; Naeem, Asif; Rengel, Zed; Dahlawi, Saad

    2016-08-01

    Due to chemical and biochemical similarities between cadmium (Cd) and zinc (Zn), application of Zn may minimize Cd uptake by plants and ameliorate its toxicity. However, there is poor understanding of the comparative effectiveness of the foliar Zn application at different growth stages on Cd toxicity and accumulation in wheat. The present study was carried out to compare the effectiveness of foliarly applied Zn at different stages of plant growth to minimize Cd accumulation in wheat grains. Wheat (cv AARI-2011) was grown at three levels of soil Cd (0, 2.5, and 5.0 mg kg(-1)). Foliar application of Zn was carried out at either tillering, jointing, booting, heading, or grain filling stage using 0.05 % w/v aqueous solution of ZnSO4 · 7H2O. Increasing soil Cd had a negative effect on growth and yield attributes, including tiller production, root length and dry weight, plant height, 100-grain weight and grain and straw yield. Zinc foliar spray increased grain yield by increasing tiller production; importantly, an application at booting was more effective than at other stages. Foliarly applied Zn decreased Cd concentration in the roots, straw, and grain. Similar to grain yield, the largest decrease (74 %) in Cd concentration was associated with Zn foliar spray at booting. Grain yield was negatively related to grain Cd concentration which in turn showed a negative relationship with Zn concentration in leaves and grains. It is concluded that the booting stage is the suitable time for foliar application of Zn to (i) effectively minimize a Cd-induced loss in grain yield and (ii) decrease grain Cd concentration.

  19. Accurate Sample Assignment in a Multiplexed, Ultrasensitive, High-Throughput Sequencing Assay for Minimal Residual Disease.

    PubMed

    Bartram, Jack; Mountjoy, Edward; Brooks, Tony; Hancock, Jeremy; Williamson, Helen; Wright, Gary; Moppett, John; Goulden, Nick; Hubank, Mike

    2016-07-01

    High-throughput sequencing (HTS) (next-generation sequencing) of the rearranged Ig and T-cell receptor genes promises to be less expensive and more sensitive than current methods of monitoring minimal residual disease (MRD) in patients with acute lymphoblastic leukemia. However, the adoption of new approaches by clinical laboratories requires careful evaluation of all potential sources of error and the development of strategies to ensure the highest accuracy. Timely and efficient clinical use of HTS platforms will depend on combining multiple samples (multiplexing) in each sequencing run. Here we examine the Ig heavy-chain gene HTS on the Illumina MiSeq platform for MRD. We identify errors associated with multiplexing that could potentially impact the accuracy of MRD analysis. We optimize a strategy that combines high-purity, sequence-optimized oligonucleotides, dual indexing, and an error-aware demultiplexing approach to minimize errors and maximize sensitivity. We present a probability-based, demultiplexing pipeline Error-Aware Demultiplexer that is suitable for all MiSeq strategies and accurately assigns samples to the correct identifier without excessive loss of data. Finally, using controls quantified by digital PCR, we show that HTS-MRD can accurately detect as few as 1 in 10(6) copies of specific leukemic MRD. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  20. The minimal important difference for measures of urticaria disease activity: Updated findings.

    PubMed

    Mathias, Susan D; Crosby, Ross D; Rosén, Karin E; Zazzali, James L

    2015-01-01

    The Urticaria Patient Daily Diary (UPDD) is a validated patient-reported outcome that captures key measures of urticaria disease activity. To update estimates of the minimal important difference (MID) for urticaria disease activity measures in the UPDD, including the weekly itch severity score, weekly number of hives score, weekly average size of largest hive score, and the composite measure of itch severity and number of hives over 7 days, or urticaria activity score 7 (UAS7). A total of 975 subjects with chronic idiopathic urticaria from three randomized, double-blind, placebo-controlled studies completed the UPDD and other patient-reported outcome assessments (the Dermatology Life Quality Index, Medical Outcomes Study Sleep Scale, the Chronic Urticaria Quality-of-Life Questionnaire, the EuroQoL-5 Dimension Questionnaire) multiple times. MIDs were estimated through a combination of distribution- and anchor-based methods. MID estimates ranged from 4.5 to 5.0 for the weekly itch severity score, 5.0 to 5.5 for weekly hives count score, 9.5 to 10.5 for the UAS7, and 4.0 to 4.5 for the weekly size of the largest hive score. This analysis provided confirmation of the previous MID estimates for the urticaria disease activity measures in the UPDD.

  1. Automated analysis of acute myeloid leukemia minimal residual disease using a support vector machine

    PubMed Central

    Ni, Wanmao; Hu, Beili; Zheng, Cuiping; Tong, Yin; Wang, Lei; Li, Qing-qing; Tong, Xiangmin; Han, Yong

    2016-01-01

    We investigated the ability of support vector machines (SVM) to analyze minimal residual disease (MRD) in flow cytometry data from patients with acute myeloid leukemia (AML) automatically, objectively and standardly. The initial disease data and MRD review data in the form of 159 flow cytometry standard 3.0 files from 36 CD7-positive AML patients in whom MRD was detected more than once were exported. SVM was used for training with setting the initial disease data to 1 as the flag and setting 15 healthy persons to set 0 as the flag. Based on the two training groups, parameters were optimized, and a predictive model was built to analyze MRD data from each patient. The automated analysis results from the SVM model were compared to those obtained through conventional analysis to determine reliability. Automated analysis results based on the model did not differ from and were correlated with results obtained through conventional analysis (correlation coefficient c = 0.986, P > 0.05). Thus the SVM model could potentially be used to analyze flow cytometry-based AML MRD data automatically, objectively, and in a standardized manner. PMID:27713120

  2. Minimal clinically important difference in Parkinson's disease as assessed in pivotal trials of pramipexole extended release.

    PubMed

    Hauser, Robert A; Gordon, Mark Forrest; Mizuno, Yoshikuni; Poewe, Werner; Barone, Paolo; Schapira, Anthony H; Rascol, Olivier; Debieuvre, Catherine; Fräßdorf, Mandy

    2014-01-01

    Background. The minimal clinically important difference (MCID) is the smallest change in an outcome measure that is meaningful for patients. Objectives. To calculate the MCID for Unified Parkinson's Disease Rating Scale (UPDRS) scores in early Parkinson's disease (EPD) and for UPDRS scores and "OFF" time in advanced Parkinson's disease (APD). Methods. We analyzed data from two pivotal, double-blind, parallel-group trials of pramipexole ER that included pramipexole immediate release (IR) as an active comparator. We calculated MCID as the mean change in subjects who received active treatment and rated themselves "a little better" on patient global impression of improvement (PGI-I) minus the mean change in subjects who received placebo and rated themselves unchanged. Results. MCIDs in EPD (pramipexole ER, pramipexole IR) for UPDRS II were -1.8 and -2.0, for UPDRS III -6.2 and -6.1, and for UPDRS II + III -8.0 and -8.1. MCIDs in APD for UPDRS II were -1.8 and -2.3, for UPDRS III -5.2 and -6.5, and for UPDRS II + III -7.1 and -8.8. MCID for "OFF" time (pramipexole ER, pramipexole IR) was -1.0 and -1.3 hours. Conclusions. A range of MCIDs is emerging in the PD literature that provides the basis for power calculations and interpretation of clinical trials.

  3. Methods of minimal residual disease (MRD) detection in childhood haematological malignancies.

    PubMed

    Jółkowska, Justyna; Derwich, Katarzyna; Dawidowska, Małgorzata

    2007-01-01

    The appropriate management of haematological disorders must rely on a precise and long-term monitoring of the patient's response to chemotherapy and radiotherapy. Clinical data are not sufficient and that is why in the last decade it became the most important to improve the knowledge of haematological diseases on the basis of molecular techniques and molecular markers. The presence of residual malignant cells among normal cells is termed minimal residual disease (MRD). Nowadays a great progress has been made in the treatment of malignant diseases and in the development of reliable molecular techniques, which are characterised by high sensitivity (10-3- 10-6) and ability to distinguish between normal and malignant cells at diagnosis and during follow-up. Especially, MRD data based on quantitative analysis (RQ-PCR, RT-RQ-PCR) appear to be crucial for appropriate evaluation of treatment response in many haematological malignancies. Implementation of standardized approaches for MRD assessment into routine molecular diagnostics available in all oncohaematological centres should be regarded nowadays a crucial point in further MRD study development.

  4. Rifampicin-induced minimal change disease is improved after cessation of rifampicin without steroid therapy.

    PubMed

    Park, Dong Hyuk; Lee, Sul A; Jeong, Hyeon Joo; Yoo, Tae-Hyun; Kang, Shin-Wook; Oh, Hyung Jung

    2015-03-01

    There are several reports to demonstrate that rifampicin, a major anti-tuberculosis agent, is associated with some adverse renal effects, with a few cases of rifampicin-induced minimal change disease (MCD). In the present case, a 68-year-old female presented with nausea, vomiting, foamy urine, general weakness and edema. She had been taking rifampicin for 4 weeks due to pleural tuberculosis. The patient had no proteinuria before the anti-tuberculosis agents were started, but urine tests upon admission showed heavy proteinuria with a 24-h urinary protein of 9.2 g/day, and serum creatinine, albumin, and total cholesterol levels were 1.36 mg/dL, 2.40 g/dL, and 283 mg/dL, respectively. MCD was diagnosed, and the patient achieved complete remission after cessation of rifampicin without undergoing steroid therapy.

  5. Rifampicin-Induced Minimal Change Disease Is Improved after Cessation of Rifampicin without Steroid Therapy

    PubMed Central

    Park, Dong Hyuk; Lee, Sul A; Jeong, Hyeon Joo; Yoo, Tae-Hyun; Kang, Shin-Wook

    2015-01-01

    There are several reports to demonstrate that rifampicin, a major anti-tuberculosis agent, is associated with some adverse renal effects, with a few cases of rifampicin-induced minimal change disease (MCD). In the present case, a 68-year-old female presented with nausea, vomiting, foamy urine, general weakness and edema. She had been taking rifampicin for 4 weeks due to pleural tuberculosis. The patient had no proteinuria before the anti-tuberculosis agents were started, but urine tests upon admission showed heavy proteinuria with a 24-h urinary protein of 9.2 g/day, and serum creatinine, albumin, and total cholesterol levels were 1.36 mg/dL, 2.40 g/dL, and 283 mg/dL, respectively. MCD was diagnosed, and the patient achieved complete remission after cessation of rifampicin without undergoing steroid therapy. PMID:25684013

  6. Minimal residual disease detection in lymphoma and multiple myeloma: impact on therapeutic paradigms.

    PubMed

    Ferrero, Simone; Drandi, Daniela; Mantoan, Barbara; Ghione, Paola; Omedè, Paola; Ladetto, Marco

    2011-12-01

    Early identification of patients at high risk of relapse is a major goal of current translational research in oncohematology. Minimal residual disease (MRD) detection by polymerase chain reaction-based methods is currently part of the routine clinical management of patients with acute lymphoblastic leukemia. However, the current knowledge indicates that it is also a useful prognostic tool in several mature lymphoproliferative disorders. Its utility is currently well established in follicular lymphoma, mantle cell lymphoma, and multiple myeloma. In some of these entities, clinical trials employing MRD as a decision-making tool are currently ongoing. In the present review, we will discuss the 'state of the art' of MRD evaluation in these three neoplasms with the ultimate aim of providing critical take-home messages for clinicians working in the field. Moreover, we will outline the role of MRD detection in the design of future clinical trials. Copyright © 2011 John Wiley & Sons, Ltd.

  7. Minimal residual disease detection in mantle cell lymphoma: technical aspects and clinical relevance.

    PubMed

    Pott, Christiane

    2011-07-01

    The prognostic impact of minimal residual disease (MRD) has been demonstrated for several hematologic malignancies. While in acute lymphoblastic leukemias MRD assessment by polymerase chain reaction (PCR)-based methods has been established as an important tool for clinical risk assessment and is part of clinical management, data demonstrating a prognostic value of MRD in mantle cell lymphoma (MCL) were sparse and results from randomized trials have been published only recently. In the present review technical aspects of different MRD detection methods are discussed, as well as the prognostic relevance of MRD in the context of clinical trials in patients with MCL. Furthermore, recommendations are given for workflow and useful implication of MRD in future clinical trials design.

  8. Bilinear Factor Matrix Norm Minimization for Robust PCA: Algorithms and Applications.

    PubMed

    Shang, Fanhua; Cheng, James; Liu, Yuanyuan; Luo, Zhi-Quan; Lin, Zhouchen

    2017-09-04

    The heavy-tailed distributions of corrupted outliers and singular values of all channels in low-level vision have proven effective priors for many applications such as background modeling, photometric stereo and image alignment. And they can be well modeled by a hyper-Laplacian. However, the use of such distributions generally leads to challenging non-convex, non-smooth and non-Lipschitz problems, and makes existing algorithms very slow for large-scale applications. Together with the analytic solutions to Lp-norm minimization with two specific values of p, i.e., p=1/2 and p=2/3, we propose two novel bilinear factor matrix norm minimization models for robust principal component analysis. We first define the double nuclear norm and Frobenius/nuclear hybrid norm penalties, and then prove that they are in essence the Schatten-1/2 and 2/3 quasi-norms, respectively, which lead to much more tractable and scalable Lipschitz optimization problems. Our experimental analysis shows that both our methods yield more accurate solutions than original Schatten quasi-norm minimization, even when the number of observations is very limited. Finally, we apply our penalties to various low-level vision problems, e.g. moving object detection, image alignment and inpainting, and show that our methods usually outperform the state-of-the-art methods.

  9. Minimal residual disease in cancer therapy--Small things make all the difference.

    PubMed

    Blatter, Sohvi; Rottenberg, Sven

    2015-01-01

    Minimal residual disease (MRD) is a major hurdle in the eradication of malignant tumors. Despite the high sensitivity of various cancers to treatment, some residual cancer cells persist and lead to tumor recurrence and treatment failure. Obvious reasons for residual disease include mechanisms of secondary therapy resistance, such as the presence of mutant cells that are insensitive to the drugs, or the presence of cells that become drug resistant due to activation of survival pathways. In addition to such unambiguous resistance modalities, several patients with relapsing tumors do not show refractory disease and respond again when the initial therapy is repeated. These cases cannot be explained by the selection of mutant tumor cells, and the precise mechanisms underlying this clinical drug resistance are ill-defined. In the current review, we put special emphasis on cell-intrinsic and -extrinsic mechanisms that may explain mechanisms of MRD that are independent of secondary therapy resistance. In particular, we show that studying genetically engineered mouse models (GEMMs), which highly resemble the disease in humans, provides a complementary approach to understand MRD. In these animal models, specific mechanisms of secondary resistance can be excluded by targeted genetic modifications. This allows a clear distinction between the selection of cells with stable secondary resistance and mechanisms that result in the survival of residual cells but do not provoke secondary drug resistance. Mechanisms that may explain the latter feature include special biochemical defense properties of cancer stem cells, metabolic peculiarities such as the dependence on autophagy, drug-tolerant persisting cells, intratumoral heterogeneity, secreted factors from the microenvironment, tumor vascularization patterns and immunosurveillance-related factors. We propose in the current review that a common feature of these various mechanisms is cancer cell dormancy. Therefore, dormant cancer

  10. The role of multiparametric flow cytometry in the detection of minimal residual disease in acute leukaemia.

    PubMed

    Lee, Denise; Grigoriadis, George; Westerman, David

    2015-12-01

    Flow cytometry is the most accessible method for minimal residual disease (MRD) detection due to its availability in most haematological centres. Using a precise combination of different antibodies, immunophenotypic detection of MRD in acute leukaemia can be performed by identifying abnormal combinations or expressions of antigens on malignant cells at diagnosis, during and post treatment. These abnormal phenotypes, referred to as leukaemia-associated immunophenotypes (LAIPs) are either absent or expressed at low frequency in normal bone marrow (BM) cells and are used to monitor the behaviour and quantitate the amount of residual disease following treatment. In paediatric acute lymphoblastic leukaemia (ALL), the level of MRD by multiparametric flow cytometry (MPFC) during therapy is recognised as an important predictor of outcome. Although less extensively studied, adult ALL and adult and paediatric acute myeloid leukaemia (AML) have also demonstrated similar findings. The challenge now is incorporating this information for risk-stratification so that therapy can be tailored individually and ultimately improve outcome while also limiting treatment-related toxicity. In this review we will elaborate on the current and future role of MPFC in MRD in acute leukaemia while also addressing its limitations.

  11. Is this the time to introduce minimal residual disease in multiple myeloma clinical practice?

    PubMed

    Paiva, Bruno; Puig, Noemi; García-Sanz, Ramón; San Miguel, Jesús F

    2015-05-01

    Increasing therapeutic options and prolonged survival in multiple myeloma have raised interest in the concept of depth of response and its importance to predict patients' outcomes. Although the efficacy of current treatment approaches has greatly improved in the past decade, the definition of complete response (CR) remains unaltered and continues to use conventional serological and morphologic techniques. That notwithstanding, there is growing interest in minimal residual disease (MRD) monitoring, which has emerged in recent years as one of the most relevant prognostic factors in multiple myeloma. MRD can be assessed both inside (e.g., immunophenotypic and molecular techniques) and outside the bone marrow (e.g., PET/CT). Here, we focus on flow- and molecular-based assays by which different cooperative groups have demonstrated the efficacy of MRD assessment to predict outcomes even among patients in CR, and irrespectively of disease risk. Although further standardization is still required, the time has come to implement MRD monitoring in prospective clinical trials as a sensitive tool to evaluate treatment efficacy and for risk-adapted treatment, particularly in the consolidation and maintenance settings. Here, we present a comprehensive and critical review on the methodologic aspects, specific characteristics, and clinical significance of MRD monitoring by flow cytometry, PCR, and next-generation sequencing.

  12. Seasonal relapsing minimal change disease: a novel strategy for avoiding long-term immunosuppression.

    PubMed

    Lawrence, Christopher; Cook, H Terry; Lightstone, Liz

    2012-07-01

    We describe the case of a young woman with seasonal allergic rhinitis who presented with signs of a lower respiratory tract infection, acute renal impairment and the nephrotic syndrome, demonstrated on biopsy to be due to minimal change disease (MCD) with acute tubular injury. Following initiation of high-dose corticosteroids, her respiratory symptoms and renal impairment improved, and the nephrotic syndrome went rapidly into remission, but relapsed, off treatment, in a seasonal fashion. In view of significant side effects related to corticosteroids, relapses were treated with the calcineurin inhibitor tacrolimus with excellent effect, but the patient was keen to avoid the complications of medium-term immunosuppression and so the drug was weaned early. She relapsed for the second time, whilst off tacrolimus, at the same time of year as at her initial presentation. In subsequent years we have successfully managed this patient with seasonal relapsing MCD with seasonal prophylactic tacrolimus therapy. We discuss the natural history of MCD and treatment options and demonstrate the utility of a clear understanding of the natural history of the condition in order to predict disease relapse and tailor therapy to the individual patient.

  13. Usability factors of mobile health application for chronic diseases

    NASA Astrophysics Data System (ADS)

    Zahra, Fatima; Hussain, Azham; Mohd, Haslina

    2016-08-01

    M-health has changed the conventional delivery system of health-care, permitting continuous, pervasive Health-care anywhere, anytime. Chronic disease apps are increasing, as many health workers, patients and clinicians already embracing smartphones in their comprehensive and diverse practices. There are lots of challenges and requirements that need to be addressed for mobile health applications to prevent or eliminate design problems and minimize potential threats for users, the proposed factors for chronic disease mobile applications can be used as a guide for app developers While, the usability testing, and evaluations of chronic disease apps have not yet touched the accuracy level of other web based applications. This study is being conducted to learn about challenges of m-health apps and to identify the factors that affect the usability of such applications.

  14. Ecological applications for flood hazard minimization in the Siwaliks region of Nepal

    NASA Astrophysics Data System (ADS)

    Dhital, Y. P.; Tang, Q.

    2015-12-01

    Water-induced disaster problems including soil erosion, debris flow, landslides and flooding are common due to the unstable landscape of Siwaliks region of Nepal. Ecological applications especially focused on soil bioengineering techniques have been used in Nepal for nearly four decades to deal with erosion problems on slopes, in high way construction and riverbank stabilization. In this study, both vegetative check dams and wire net check dams along with vegetation were used for flood hazard minimization. After three growing seasons, the banks of the ephemeral stream were almost fully stabilized. Vegetation based solutions are found to be more effective than the mechanical methods of stream bank stabilization. Bamboo combinations for check dam construction and planting of bamboo behind check dam are both very useful for stream bank stabilization. Vegetation application on flood damaged bare ground was also found to be very successful. Furthermore, some plants species showed almost equal growth performances on both flood-affected and unaffected bare ground. However, more scientific implementation of ecological applications for flood hazard minimization in those affected areas is essential in future.

  15. Effective treatment with rituximab for the maintenance of remission in frequently relapsing minimal change disease

    PubMed Central

    Shendi, Ali M.; Salama, Alan D.; Khosravi, Maryam; Connolly, John O.; Trompeter, Richard

    2016-01-01

    Abstract Aim Treatment of frequently relapsing or steroid‐dependent minimal change disease (MCD) in children and adults remains challenging. Glucocorticoids and/or other immunosuppressive agents are the mainstay of treatment, but patients often experience toxicity from prolonged exposure and may either become treatment dependent and/or resistant. Increasing evidence suggests that rituximab (RTX) can be a useful alternative to standard immunosuppression and allow withdrawal of maintenance immunosuppressants; however, data on optimal treatment regimens, long‐term efficacy and safety are still limited. Methods We undertook a prospective study of RTX to allow immunosuppression minimization in 15 young adults with frequently relapsing or steroid‐dependent, biopsy‐proven MCD. All patients were in remission at the start of treatment and on a calcineurin inhibitor. Two doses of RTX (1 gr) were given 6 months apart. A subset of patients also received an additional dose 12 months later, in order to examine the benefit of re‐treatment. Biochemical and clinical parameters were monitored over an extended follow‐up period of up to 43 months. Results Median steroid‐free survival after RTX was 25 months (range 4–34). Mean relapse frequency decreased from 2.60 ± 0.28 to 0.4 ± 0.19 (P < 0.001) after RTX. Seven relapses occurred, five of which (71%) when CD19 counts were greater than 100 µ. Immunoglobulin levels remained unchanged, and no major side effects were observed throughout the follow‐up period. Conclusions Rituximab therapy is effective at maintaining prolonged steroid‐free remission and reducing relapse frequency in this group of patients. Our study lends further support for the role of RTX in the treatment of patients with frequently relapsing or steroid‐dependent MCD. PMID:26860320

  16. Minimally Invasive Management of Complicated Diverticular Disease: Current Status and Review of Literature.

    PubMed

    Kaushik, Manu; Bhullar, Jasneet Singh; Bindroo, Sandiya; Singh, Hemindermeet; Mittal, Vijay K

    2016-03-01

    Diverticulitis is a common condition which carries significant morbidity and socioeconomic burden (McGillicuddy et al in Arch Surg 144:1157-1162, 2009). The surgical management of diverticulitis has undergone significant changes in recent years. This article reviews the role of minimally invasive approach in management of complicated diverticulitis, with a focus on recent concepts and advances. A literature review of past 10 years (January 2004 to September 2014) was performed using the electronic database MEDLINE from PubMed which included articles only in English. We identified total of 139 articles, out of which 50 were excluded resulting in 89 full-text articles for review 16 retrospective studies, 7 prospective cohorts, 1 case-control series and 1 systematic review were included. These suggest that urgent surgery is performed for those with sepsis and diffuse peritonitis or those who fail to improve despite medical therapy and/or percutaneous drainage. In addition, 3 randomized control trials: DILALA, LapLAND and the Scandinavian Diverticulitis trial are working towards evaluating whether laparoscopic lavage is safe in management of complicated diverticular diseases. Growing trend toward conservative or minimally invasive treatment modality even in severe acute diverticulitis was noticed. Laparoscopic peritoneal lavage has evolved as a good alternative to invasive surgery, yet clear indications for its role in the management of complicated diverticulitis need to be established. Recent evidence suggests that existing guidelines for optimal management of complicated diverticulitis should be updated. Non-resectional radiographic techniques are likely to play a prominent role in the initial treatment of complicated diverticulitis in the near future.

  17. Application of Sequential Quadratic Programming to Minimize Smart Active Flap Rotor Hub Loads

    NASA Technical Reports Server (NTRS)

    Kottapalli, Sesi; Leyland, Jane

    2014-01-01

    In an analytical study, SMART active flap rotor hub loads have been minimized using nonlinear programming constrained optimization methodology. The recently developed NLPQLP system (Schittkowski, 2010) that employs Sequential Quadratic Programming (SQP) as its core algorithm was embedded into a driver code (NLP10x10) specifically designed to minimize active flap rotor hub loads (Leyland, 2014). Three types of practical constraints on the flap deflections have been considered. To validate the current application, two other optimization methods have been used: i) the standard, linear unconstrained method, and ii) the nonlinear Generalized Reduced Gradient (GRG) method with constraints. The new software code NLP10x10 has been systematically checked out. It has been verified that NLP10x10 is functioning as desired. The following are briefly covered in this paper: relevant optimization theory; implementation of the capability of minimizing a metric of all, or a subset, of the hub loads as well as the capability of using all, or a subset, of the flap harmonics; and finally, solutions for the SMART rotor. The eventual goal is to implement NLP10x10 in a real-time wind tunnel environment.

  18. Whole-genome amplification for the detection of molecular targets and minimal residual disease monitoring in acute lymphoblastic leukaemia.

    PubMed

    Della Starza, Irene; De Novi, Lucia Anna; Nunes, Vittorio; Del Giudice, Ilaria; Ilari, Caterina; Marinelli, Marilisa; Negulici, Alina Delia; Vitale, Antonella; Chiaretti, Sabina; Foà, Robin; Guarini, Anna

    2014-05-01

    Accurate genomic characterization requires sufficient amounts of optimal quality DNA. An approach for increasing the DNA amount is the whole-genome amplification (WGA) method. We applied WGA to the molecular quantification and minimal residual disease (MRD) evaluation of acute lymphoblastic leukaemia (ALL), aiming to compare the results obtained from genomic DNA and amplified DNA with WGA, and to evaluate the applicability and the reliability of WGA-DNA. Twenty paired samples from adult ALL patients were sequenced to identify the functional germline V-D-J segment at diagnosis; real-time quantitative polymerase chain reaction (RQ-PCR) quantitative analysis was performed both at diagnosis and follow-up. Genomic DNA and WGA-DNA screening identified equivalent 87 rearrangements. At diagnosis, the quantitative evaluation of genomic DNA samples showed 1 logarithm difference to WGA-DNA samples; these levels are comparable, being within the degree of acceptability and confidence. In the follow-up samples, RQ-PCR analysis on genomic DNA and WGA showed concordant MRD results in 16/18 samples, while 2/18 were MRD-positive outside the quantitative range by RQ-PCR (i.e. <5 × 10(-5)) on genomic DNA and MRD-negative on WGA-DNA. WGA-DNA enables: (i) the design of accurate targets for MRD evaluation in ALL patients, (ii) accurate disease quantification at diagnosis, (iii) MRD quantification comparable to genomic DNA.

  19. Minimal Residual Disease Detection and Evolved IGH Clones Analysis in Acute B Lymphoblastic Leukemia Using IGH Deep Sequencing

    PubMed Central

    Wu, Jinghua; Jia, Shan; Wang, Changxi; Zhang, Wei; Liu, Sixi; Zeng, Xiaojing; Mai, Huirong; Yuan, Xiuli; Du, Yuanping; Wang, Xiaodong; Hong, Xueyu; Li, Xuemei; Wen, Feiqiu; Xu, Xun; Pan, Jianhua; Li, Changgang; Liu, Xiao

    2016-01-01

    Acute B lymphoblastic leukemia (B-ALL) is one of the most common types of childhood cancer worldwide and chemotherapy is the main treatment approach. Despite good response rates to chemotherapy regiments, many patients eventually relapse and minimal residual disease (MRD) is the leading risk factor for relapse. The evolution of leukemic clones during disease development and treatment may have clinical significance. In this study, we performed immunoglobulin heavy chain (IGH) repertoire high throughput sequencing (HTS) on the diagnostic and post-treatment samples of 51 pediatric B-ALL patients. We identified leukemic IGH clones in 92.2% of the diagnostic samples and nearly half of the patients were polyclonal. About one-third of the leukemic clones have correct open reading frame in the complementarity determining region 3 (CDR3) of IGH, which demonstrates that the leukemic B cells were in the early developmental stage. We also demonstrated the higher sensitivity of HTS in MRD detection and investigated the clinical value of using peripheral blood in MRD detection and monitoring the clonal IGH evolution. In addition, we found leukemic clones were extensively undergoing continuous clonal IGH evolution by variable gene replacement. Dynamic frequency change and newly emerged evolved IGH clones were identified upon the pressure of chemotherapy. In summary, we confirmed the high sensitivity and universal applicability of HTS in MRD detection. We also reported the ubiquitous evolved IGH clones in B-ALL samples and their response to chemotherapy during treatment. PMID:27757113

  20. Minimally Invasive Transforaminal Lumbar Interbody Fusion and Unilateral Fixation for Degenerative Lumbar Disease.

    PubMed

    Wang, Hui-Wang; Hu, Yong-Cheng; Wu, Zhan-Yong; Wu, Hua-Rong; Wu, Chun-Fu; Zhang, Lian-Suo; Xu, Wei-Kun; Fan, Hui-Long; Cai, Jin-Sheng; Ma, Jian-Qing

    2017-08-01

    To evaluate the clinical effect of the minimally invasive transforaminal lumbar interbody fusion combined with posterolateral fusion and unilateral fixation using a tubular retractor in the management of degenerative lumbar disease. A retrospective analysis was conducted to analyze the clinical outcome of 58 degenerative lumbar disease patients who were treated with minimally invasive transforaminal lumbar interbody fusion combined with posterolateral fusion and unilateral fixation during December 2012 to January 2015. The spine was unilaterally approached through a 3.0-cm skin incision centered on the disc space, located 2.5 cm lateral to the midline, and the multifidus muscles and longissimus dorsi were stripped off. After transforaminal lumbar interbody fusion and posterolateral fusion the unilateral pedicle screw fixation was performed. The visual analogue scale (VAS) for back and leg pain, the Oswestry disability index (ODI), and the MacNab score were applied to evaluate clinical effects. The operation time, peri-operative bleeding, postoperative time in bed, hospitalization costs, and the change in the intervertebral height were analyzed. Radiological fusion based on the Bridwell grading system was also assessed at the last follow-up. The quality of life of the patients before and after the operation was assessed using the short form-36 scale (SF-36). Fifty-eight operations were successfully performed, and no nerve root injury or dural tear occurred. The average operation time was 138 ± 33 min, intraoperative blood loss was 126 ± 50 mL, the duration from surgery to getting out of bed was 46 ± 8 h, and hospitalization cost was 1.6 ± 0.2 ten thousand yuan. All of the 58 patients were followed up for 7-31 months, with an average of 14.6 months. The postoperative VAS scores and ODI score were significantly improved compared with preoperative data (P < 0.05). The evaluation of the MacNab score was excellent in 41 patients, good

  1. Real processing (RP) I: The principle of minimal entropy production (PME) of irreversible thermodynamics and the principle of minimal deformation (PMD) of hydrodynamics, their dependence and applications

    NASA Astrophysics Data System (ADS)

    Reiser, Bernhard

    1996-02-01

    The principle of minimal entropy production (PME) of irreversible thermodynamics is generalized to determine process parameters in process engineering with well-known mathematical methods. This useful instrument applied to industrial processes is called real processing (RP). A special form of the PME is the principle of minimal deformation (PMD) which allows for applications in hydrodynamics (HD). A second and independent derivation of the PMD takes a similar way as the derivation of the statement of Helmholtz and Rayleigh (SHR). The generalization of SHR then leads to the PMD derived within HD. Next in a similar way. starting directly from the Navier-Stokes equation (NSE) can lead in a third way to the PMD. Several applications of the PMD are given: An analytical and numerical application of PMD is given for the entrance flow of tubes. Physical and analytical applications are the Crocco-Vazsonyi-type equations opening new possibilities of analytical treatment of process engineering problems. Process engineering models may be replaced by applications of PMD. In particular, turbulence may be treated as the answer of nature on PMD. A basic mathematical treatment of these subjects is possible by the gradient field theory (GFT), a particular method of vector analysis stemming from the Clebsch Ansatz for vector fields, which can be ordered from the author together with an advanced detailed mathematical treatment of these subjects.

  2. Minimal Residual Disease Evaluation in Childhood Acute Lymphoblastic Leukemia: A Clinical Evidence Review

    PubMed Central

    Schaink, Alexis; Higgins, Caroline

    2016-01-01

    Background Leukemia accounts for nearly a third of childhood cancers in Canada, with acute lymphoblastic leukemia (ALL) comprising nearly 80% of cases. Identification of prognostic factors that allow risk stratification and tailored treatment have improved overall survival. However, nearly a quarter of patients considered standard risk on the basis of conventional prognostic factors still relapse, and relapse is associated with increased morbidity and mortality. Relapse is thought to result from extremely low levels of leukemic cells left over once complete remission is reached, termed minimal residual disease (MRD). Poor event-free survival (EFS) as well as overall survival for those who are classified as MRD-positive have been substantiated in seminal studies demonstrating the prognostic value of MRD for EFS in the past few decades. This review sought to further elucidate the relationship between MRD and EFS by looking at relapse, the primary determinant of EFS and the biological mechanism through which MRD is thought to act. This evidence review aimed to ascertain whether MRD is an independent prognostic factor for relapse and to assess the effect of MRD-directed treatment on patient-important outcomes in childhood ALL. Methods Large prospective cohort studies with a priori multivariable analysis that includes potential confounders are required to draw confirmatory conclusions about the independence of a prognostic factor. Data on the prognostic value of MRD for relapse measured by molecular methods (polymerase chain reaction [PCR] of immunoglobulin or T-cell receptor rearrangements) or flow cytometry for leukemia-associated immunophenotypes or difference-from-normal approach were abstracted from included studies. Relevant data on relapse, EFS, and overall survival were abstracted from randomized controlled trials (RCTs) evaluating the effect of MRD-directed treatment. Results A total of 2,832 citations were reviewed, of which 12 studies were included in this

  3. Minimizing losses in bio-electrochemical systems: the road to applications.

    PubMed

    Clauwaert, Peter; Aelterman, Peter; Pham, The Hai; De Schamphelaire, Liesje; Carballa, Marta; Rabaey, Korneel; Verstraete, Willy

    2008-07-01

    Bio-electrochemical systems (BESs) enable microbial catalysis of electrochemical reactions. Plain electrical power production combined with wastewater treatment by microbial fuel cells (MFCs) has been the primary application purpose for BESs. However, large-scale power production and a high chemical oxygen demand conversion rates must be achieved at a benchmark cost to make MFCs economical competitive in this context. Recently, a number of valuable oxidation or reduction reactions demonstrating the versatility of BESs have been described. Indeed, BESs can produce hydrogen, bring about denitrification, or reductive dehalogenation. Moreover, BESs also appear to be promising in the field of online biosensors. To effectively apply BESs in practice, both biological and electrochemical losses need to be further minimized. At present, the costs of reactor materials have to be decreased, and the volumetric biocatalyst activity in the systems has to be increased substantially. Furthermore, both the ohmic cell resistance and the pH gradients need to be minimized. In this review, these losses and constraints are discussed from an electrochemical viewpoint. Finally, an overview of potential applications and innovative research lines is given for BESs.

  4. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.

    PubMed

    Beldjord, Kheira; Chevret, Sylvie; Asnafi, Vahid; Huguet, Françoise; Boulland, Marie-Laure; Leguay, Thibaut; Thomas, Xavier; Cayuela, Jean-Michel; Grardel, Nathalie; Chalandon, Yves; Boissel, Nicolas; Schaefer, Beat; Delabesse, Eric; Cavé, Hélène; Chevallier, Patrice; Buzyn, Agnès; Fest, Thierry; Reman, Oumedaly; Vernant, Jean-Paul; Lhéritier, Véronique; Béné, Marie C; Lafage, Marina; Macintyre, Elizabeth; Ifrah, Norbert; Dombret, Hervé

    2014-06-12

    With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.

  5. Collagenase Clostridium Histolyticum in the Treatment of Peyronie's Disease: Review of a Minimally Invasive Treatment Option.

    PubMed

    Gabrielson, Andrew T; Alzweri, Laith M; Hellstrom, Wayne Jg

    2017-09-06

    Peyronie's disease (PD) is an inflammatory disorder characterized by an abnormal collagen deposition in the tunica albuginea of the penis, leading to fibrous and non-compliant plaques that can impede normal erection. Although pharmacological treatments are available, only intralesional injection therapy and surgical reconstruction have demonstrated tangible clinical efficacy in the management of this condition. Intralesional injection of collagenase clostridium histolyticum (CCH) has come to the forefront of minimally invasive treatment of PD. In this review, the authors provide an update on the safety, efficacy, and indications for CCH. The efficacy of CCH will be assessed on the basis of improvement in the severity of penile fibrosis, curvature, and pain. Numerous well-designed clinical trials and post-approval studies involving more than 1,500 patients have consistently demonstrated the efficacy and tolerability of CCH in the treatment of PD. CCH significantly decreases penile curvature and plaque consistency, as well as improves quality of life. Post-approval studies continue to demonstrate the efficacy of CCH despite broader inclusion criteria for treatment, such as the case with acute phase disease and atypical plaque deformities (i.e., ventral plaques, hourglass narrowing). CCH continues to be the gold standard for non-surgical management of stable phase PD, in the absence of strong evidence supporting oral therapy agents and ongoing evaluation of extracorporeal shockwave therapy. However, recent studies are beginning to provide precedent for the use of CCH in the management of acute phase and atypical PD. Copyright © 2017 Korean Society for Sexual Medicine and Andrology.

  6. Minimal residual disease after transplantation or lenalidomide-based consolidation in myeloma patients: a prospective analysis

    PubMed Central

    Oliva, Stefania; Gambella, Manuela; Gilestro, Milena; Muccio, Vittorio Emanuele; Gay, Francesca; Drandi, Daniela; Ferrero, Simone; Passera, Roberto; Pautasso, Chiara; Bernardini, Annalisa; Genuardi, Mariella; Patriarca, Francesca; Saraci, Elona; Petrucci, Maria Teresa; Pescosta, Norbert; Liberati, Anna Marina; Caravita, Tommaso; Conticello, Concetta; Rocci, Alberto; Musto, Pellegrino; Boccadoro, Mario; Palumbo, Antonio; Omedè, Paola

    2017-01-01

    We analyzed 50 patients who achieved at least a very good partial response in the RV-MM-EMN-441 study. Patients received consolidation with autologous stem-cell transplantation (ASCT) or cyclophosphamide-lenalidomide-dexamethasone (CRD), followed by Lenalidomide-based maintenance. We assessed minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) after consolidation, after 3 and 6 courses of maintenance, and thereafter every 6 months until progression. By MFC analysis, 19/50 patients achieved complete response (CR) after consolidation, and 7 additional patients during maintenance. A molecular marker was identified in 25/50 patients, 4/25 achieved molecular-CR after consolidation, and 3 additional patients during maintenance. A lower MRD value by MFC was found in ASCT patients compared with CRD patients (p=0.0134). Tumor burden reduction was different in patients with high-risk vs standard-risk cytogenetics (3.4 vs 5.2, ln-MFC; 3 vs 6 ln-PCR, respectively) and in patients who relapsed vs those who did not (4 vs 5, ln-MFC; 4.4 vs 7.8 ln-PCR). MRD progression anticipated clinical relapse by a median of 9 months while biochemical relapse by a median of 4 months. MRD allows the identification of a low-risk group, independently of response, and a better characterization of the activity of treatments. PMID:27779105

  7. TFDP3 confers chemoresistance in minimal residual disease within childhood T-cell acute lymphoblastic leukemia

    PubMed Central

    Chu, Ming; Yin, Kailin; Dong, Yujun; Wang, Pingzhang; Xue, Yun; Zhou, Peng; Wang, Yuqi; Wang, Yuedan

    2017-01-01

    Acquired drug resistance in childhood T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem. In this study, a novel gene therapy target for childhood T-ALL to overcome chemoresistance was discovered: TFDP3 increased in the minimal residual disease (MRD) positive childhood T-ALL patients. Then, we established a preclinical model of resistance to induction therapy to examine the functional relevance of TFDP3 to chemoresistance in MRD derived from Jurkat/E6-1. Jurkat xenografts in NOD/SCID mice were exposed to a four drug combination (VXLD) of vincristine (VCR), dexamethasone (DEX), L-asparaginase (L-asp) and daunorubicin (DNR). During the 4-week VXLD treatment, the level of TFDP3 increased 4-fold. High expression of TFDP3 was identified in the re-emerging lines (Jurkat/MRD) with increased chemoresistance, which is correlated with partially promoter demethylation of TFDP3. Downregulation of TFDP3 by RNA interference reversed chemoresistance in Jurkat/MRD accompanied by reinstated E2F1 activity that coincided with increased levels of p53, p73, and associated proapoptotic target genes. Importantly, TFDP3 silencing in vivo induced apparent benefit to overcome chemoresistance in combination with VXLD treatment. Collectively, TFDP3 confers chemoresistance in MRD within childhood T-ALL, indicating that TFDP3 is a potential gene therapy target for residual cancer. PMID:27902457

  8. A Unique Cause of Proteinuria in Pregnancy: Class II Lupus Nephritis with Concomitant Minimal Change Disease

    PubMed Central

    Kunjal, Ryan; Adam-Eldien, Rabie; Makary, Raafat; Jo-Hoy, Francois; Heilig, Charles W.

    2016-01-01

    We report the case of a 22-year-old African American female who presented to another facility for routine follow-up in the 34th week of pregnancy with lower extremity swelling and nephrotic-range proteinuria. Although she was normotensive, it was initially thought that she had preeclampsia. She was monitored carefully and delivery was induced at 37 weeks of gestation. She was transferred to our hospital, where she was diagnosed with systemic lupus erythematosus (SLE) based on clinical and laboratory criteria. Renal biopsy revealed a surprising finding of minimal change disease (MCD) concomitant with class II lupus nephritis (LN). She was managed with pulses and then tapering doses of steroid therapy with dramatic resolution of the nephrotic syndrome. This case demonstrates not only the rare de novo occurrence of SLE in pregnancy, but the unique finding of MCD coexisting with class II LN. We propose that altered T cell activity may be the link between these seemingly distinct entities. PMID:27781205

  9. Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy

    SciTech Connect

    Lockwood, A.H.; Yap, E.W.; Rhoades, H.M.; Wong, W.H. )

    1991-03-01

    We measured CBF and the CMRglc in normal controls and in patients with severe liver disease and evidence for minimal hepatic encephalopathy using positron emission tomography. Regions were defined in frontal, temporal, parietal, and visual cortex; the thalamus; the caudate; the cerebellum; and the white matter along with a whole-slice value obtained at the level of the thalamus. There was no difference in whole-slice CBF and CMRglc values. Individual regional values were normalized to the whole-slice value and subjected to a two-way repeated measures analysis of variance. When normalized CBF and CMRglc values for regions were compared between groups, significant differences were demonstrated (F = 5.650, p = 0.00014 and F = 4.58, p = 0.0073, respectively). These pattern differences were due to higher CBF and CMRglc in the cerebellum, thalamus, and caudate in patients and lower values in the cortex. Standardized coefficients extracted from a discriminant function analysis permitted correct group assignment for 95.5% of the CBF studies and for 92.9% of the CMRglc studies. The similarity of the altered pattern of cerebral metabolism and flow in our patients to that seen in rats subjected to portacaval shunts or ammonia infusions suggests that this toxin may alter flow and metabolism and that this, in turn, causes the clinical expression of encephalopathy.

  10. Limited responsiveness related to the minimal important difference of patient-reported outcomes in rare diseases.

    PubMed

    Johnston, Bradley C; Miller, Patricia A; Agarwal, Arnav; Mulla, Sohail; Khokhar, Rabia; De Oliveira, Kyle; Hitchcock, Christine L; Sadeghirad, Behnam; Mohiuddin, Mukarram; Sekercioglu, Nigar; Seweryn, Michal; Koperny, Magdalena; Bala, Malgorzata M; Adams-Webber, Thomasin; Granados, Alicia; Hamed, Alaa; Crawford, Mark W; van der Ploeg, Ans T; Guyatt, Gordon H

    2016-11-01

    To explore the responsiveness of patient-reported outcomes (PROs) in interventional studies involving patients with rare lysosomal storage diseases (LSDs). We searched eight databases for experimental and nonexperimental studies. Pairs of trained reviewers independently screened articles and subsequently extracted data from the eligible studies. Among studies with 10 or more patients using a valid PRO, we assessed the responsiveness of PROs based on a reanalysis of the data using minimal important difference estimates. Our analyses focused on statistically significant within-group differences in PROs for observational studies or the statistically significant between-group differences in PRO scores for controlled studies. Of 2,679 unique records, 62 interventional studies addressing patients with Fabry (55%), Gaucher (19%), Pompe (16%), and mucopolysaccharidoses (11%) proved eligible. The most frequently used PROs were the Short-Form-36 (25 studies), Brief Pain Inventory (20 studies), EuroQoL-5D (9 studies), and the Fatigue Severity Scale (6 studies). Observational studies suggest that PROs sometimes detect significant within-group changes when present. Randomized trials raise questions regarding the responsiveness of PROs to small differences between groups. Most studies have relied on generic PROs to evaluate quality of life and symptoms in patients with rare LSDs. PROs appear more responsive in observational studies than randomized trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Current Strategies for the Detection of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Rocha, Juliana Maria Camargos; Xavier, Sandra Guerra; de Lima Souza, Marcelo Eduardo; Assumpção, Juliana Godoy; Murao, Mitiko; de Oliveira, Benigna Maria

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Current treatment strategies for childhood ALL result in long-term remission for approximately 90% of patients. However, the therapeutic response is worse among those who relapse. Several risk stratification approaches based on clinical and biological aspects have been proposed to intensify treatment in patients with high risk of relapse and reduce toxicity on those with a greater probability of cure. The detection of residual leukemic cells (minimal residual disease, MRD) is the most important prognostic factor to identify high-risk patients, allowing redefinition of chemotherapy. In the last decades, several standardized research protocols evaluated MRD using immunophenotyping by flow cytometry and/or real-time quantitative polymerase chain reaction at different time points during treatment. Both methods are highly sensitive (10−3 a 10−5), but expensive, complex, and, because of that, require qualified staff and frequently are restricted to reference centers. The aim of this article was to review technical aspects of immunophenotyping by flow cytometry and real-time quantitative polymerase chain reaction to evaluate MRD in ALL. PMID:27158437

  12. New markers for minimal residual disease detection in acute lymphoblastic leukemia

    PubMed Central

    Coustan-Smith, Elaine; Song, Guangchun; Clark, Christopher; Key, Laura; Liu, Peixin; Mehrpooya, Mohammad; Stow, Patricia; Su, Xiaoping; Shurtleff, Sheila; Pui, Ching-Hon; Downing, James R.

    2011-01-01

    To identify new markers for minimal residual disease (MRD) detection in acute lymphoblastic leukemia (ALL), we compared genome-wide gene expression of lymphoblasts from 270 patients with newly diagnosed childhood ALL to that of normal CD19+CD10+ B-cell progenitors (n = 4). Expression of 30 genes differentially expressed by ≥ 3-fold in at least 25% of cases of ALL (or 40% of ALL subtypes) was tested by flow cytometry in 200 B-lineage ALL and 61 nonleukemic BM samples, including samples containing hematogones. Of the 30 markers, 22 (CD44, BCL2, HSPB1, CD73, CD24, CD123, CD72, CD86, CD200, CD79b, CD164, CD304, CD97, CD102, CD99, CD300a, CD130, PBX1, CTNNA1, ITGB7, CD69, CD49f) were differentially expressed in up to 81.4% of ALL cases; expression of some markers was associated with the presence of genetic abnormalities. Results of MRD detection by flow cytometry with these markers correlated well with those of molecular testing (52 follow-up samples from 18 patients); sequential studies during treatment and diagnosis-relapse comparisons documented their stability. When incorporated in 6-marker combinations, the new markers afforded the detection of 1 leukemic cell among 105 BM cells. These new markers should allow MRD studies in all B-lineage ALL patients, and substantially improve their sensitivity. PMID:21487112

  13. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL.

    PubMed

    Strati, Paolo; Keating, Michael J; O'Brien, Susan M; Burger, Jan; Ferrajoli, Alessandra; Jain, Nitin; Tambaro, Francesco Paolo; Estrov, Zeev; Jorgensen, Jeffrey; Challagundla, Pramoda; Faderl, Stefan H; Wierda, William G

    2014-06-12

    The high complete remission rate with first-line combined fludarabine, cyclophosphamide, and rituximab (FCR) begs the question of the value of minimal residual disease (MRD)-negative status as a treatment end point. We report on 237 patients with chronic lymphocytic leukemia who received first-line FCR. MRD was prospectively assessed by 4-color flow cytometry in bone marrow after course 3 and at final response assessment. After course 3 and at final response assessment, 17% and 43% of patients were MRD negative in bone marrow, respectively. A mutated immunoglobulin heavy chain variable gene and trisomy 12 were independently associated with MRD-negative status both after 3 courses of FCR and at final response assessment in multivariable analyses (MVAs). MRD-negative status was independently associated with significantly longer progression-free survival (PFS) and overall survival (OS) in MVA (P = .03 and .02, respectively). This association was confirmed also on landmark MVA at the time of MRD assessment (P = .04 and .05, respectively). MRD-negative patients had comparable PFS and OS, independent of the number of courses received or interim staging. Early MRD eradication may be a desirable goal, prompting consideration of early discontinuation of treatment. This trial was registered at www.clinicaltrials.gov as #NCT00759798.

  14. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL

    PubMed Central

    Strati, Paolo; Keating, Michael J.; O'Brien, Susan M.; Burger, Jan; Ferrajoli, Alessandra; Jain, Nitin; Tambaro, Francesco Paolo; Estrov, Zeev; Jorgensen, Jeffrey; Challagundla, Pramoda; Faderl, Stefan H.

    2014-01-01

    The high complete remission rate with first-line combined fludarabine, cyclophosphamide, and rituximab (FCR) begs the question of the value of minimal residual disease (MRD)–negative status as a treatment end point. We report on 237 patients with chronic lymphocytic leukemia who received first-line FCR. MRD was prospectively assessed by 4-color flow cytometry in bone marrow after course 3 and at final response assessment. After course 3 and at final response assessment, 17% and 43% of patients were MRD negative in bone marrow, respectively. A mutated immunoglobulin heavy chain variable gene and trisomy 12 were independently associated with MRD-negative status both after 3 courses of FCR and at final response assessment in multivariable analyses (MVAs). MRD-negative status was independently associated with significantly longer progression-free survival (PFS) and overall survival (OS) in MVA (P = .03 and .02, respectively). This association was confirmed also on landmark MVA at the time of MRD assessment (P = .04 and .05, respectively). MRD-negative patients had comparable PFS and OS, independent of the number of courses received or interim staging. Early MRD eradication may be a desirable goal, prompting consideration of early discontinuation of treatment. This trial was registered at www.clinicaltrials.gov as #NCT00759798. PMID:24705492

  15. Results of minimal residual disease (MRD) evaluation and MRD-based treatment stratification in childhood ALL.

    PubMed

    Cazzaniga, Giovanni; d'Aniello, Elisabetta; Corral, Lilia; Biondi, Andrea

    2002-12-01

    The study of minimal residual disease (MRD) as a 'surrogate' marker of molecular response to treatment has drawn great interest because of the potential of tailoring treatment and the possibility of gaining insight into the nature of a cure. Polymerase chain reaction-based (PCR-based) detection of MRD by immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements can be applied in more than 90-95% of cases of childhood acute lymphoblastic leukaemia (ALL). Accordingly, several retrospective studies of MRD in childhood ALL have used one of the different PCR approaches for the detection of antigen-receptor gene rearrangements. The promising results on the predictivity of MRD evaluation at the end of induction treatment has raised the need of a new definition of remission. Until now, most PCR-based MRD studies have used semiquantitative methods for the detection of Ig and TCR gene rearrangements. The introduction of real-time quantitative PCR (RQ-PCR) has resulted in the improvement of sensitivity and specificity and has given better quality control of the MRD data. There is an urgent need to incorporate MRD data in clinical studies, properly designed to address treatment questions. In this context several ongoing co-operative study groups have adopted an MRD-based risk group classification to explore whether a better tailored treatment would result in further improvement in cure rates for children with ALL.

  16. Flow cytometry quality requirements for monitoring of minimal disease in plasma cell myeloma.

    PubMed

    Oldaker, Teri A; Wallace, Paul K; Barnett, David

    2016-01-01

    Current therapeutic approaches for plasma cell myeloma (PCM) attain an overall survival of more than 6 years for the majority of newly diagnosed patients. However, PFS and OS are the only accepted FDA clinical endpoints for demonstrating drug efficacy before they can be become frontline therapeutic options. There is, however, recognition that the increasing gap between drug development and approval for mainstream therapeutic use needs to be shortened. As such regulatory bodies such as the FDA are now considering whether biomarker response evaluation, as in measurement of minimal residual disease (MRD) as assessed by flow cytometry (FC), can provide an early, robust prediction of survival and therefore improve the drug approval process. Recently, FC MRD using a standardized eight-color antibody methodology has been shown to have a minimum sensitivity of 0.01% and an upper sensitivity of 0.001%. To ensure that all laboratories using this approach achieve the same levels of sensitivity it is crucially important to have standardized quality management procedures in place. This manuscript accompanies those published in this special issue and describes the minimum that is required for validating and quality monitoring of this highly specific test to ensure any laboratory, irrespective of location, will achieve the expected quality standards required. © 2015 International Clinical Cytometry Society.

  17. Applications of Computer-Assisted Navigation for the Minimally Invasive Reduction of Isolated Zygomatic Arch Fractures.

    PubMed

    Li, Zhi; Yang, Rong-Tao; Li, Zu-Bing

    2015-09-01

    Computer-assisted navigation has been widely used in oral and maxillofacial surgery. The purpose of this study was to describe the applications of computer-assisted navigation for the minimally invasive reduction of isolated zygomatic arch fractures. All patients identified as having isolated zygomatic arch fractures presenting to the authors' department from April 2013 through November 2014 were included in this prospective study. Minimally invasive reductions of isolated zygomatic arch fractures were performed on these patients under the guidance of computer-assisted navigation. The reduction status was evaluated by postoperative computed tomography (CT) 1 week after the operation. Postoperative complications and facial contours were evaluated during follow-up. Functional recovery was evaluated by the difference between the preoperative maximum interincisal mouth opening and that at the final follow-up. Twenty-three patients were included in this case series. The operation proceeded well in all patients. Postoperatively, all patients displayed uneventful healing without postoperative complication. Postoperative CT showed exact reduction in all cases. Satisfactory facial contour and functional recovery were observed in all patients. The preoperative maximal mouth opening ranged from 8 to 25 mm, and the maximal mouth opening at the final follow-up ranged from 36 to 42 mm. Computer-assisted navigation can be used not only for guiding zygomatic arch fracture reduction, but also for assessing reduction. Computer-assisted navigation is an effective and minimally invasive technique that can be applied in the reduction of isolated zygomatic arch fractures. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  18. Application of Design of Experiment Method for Thrust Force Minimization in Step-feed Micro Drilling

    PubMed Central

    Kim, Dong-Woo; Cho, Myeong-Woo; Seo, Tae-Il; Lee, Eung-Sug

    2008-01-01

    Micro drilled holes are utilized in many of today's fabrication processes. Precision production processes in industries are trending toward the use of smaller holes with higher aspect ratios, and higher speed operation for micro deep hole drilling. However, undesirable characteristics related to micro drilling such as small signal-to-noise ratios, wandering drill motion, high aspect ratio, and excessive cutting forces can be observed when cutting depth increases. In this study, the authors attempt to minimize the thrust forces in the step-feed micro drilling process by application of the DOE (Design of Experiment) method. Taking into account the drilling thrust, three cutting parameters, feedrate, step-feed, and cutting speed, are optimized based on the DOE method. For experimental studies, an orthogonal array L27(313) is generated and ANOVA (Analysis of Variance) is carried out. Based on the results it is determined that the sequence of factors affecting drilling thrusts corresponds to feedrate, step-feed, and spindle rpm. A combination of optimal drilling conditions is also identified. In particular, it is found in this study that the feedrate is the most important factor for micro drilling thrust minimization. PMID:27879704

  19. Safety margin of minimized contrast volume during percutaneous coronary intervention in patients with chronic kidney disease.

    PubMed

    Ogata, Nobuhiko; Ikari, Yuji; Nanasato, Mamoru; Okutsu, Masaaki; Kametani, Ryosuke; Abe, Mitsuru; Uehara, Yoshiki; Sumitsuji, Satoru

    2014-07-01

    Maximum allowable contrast dose (MACD) calculated as body weight × 5/serum creatinine has been a standard contrast dye volume (CV) used to decrease contrast-induced acute kidney injury. Recent advances in intravascular ultrasound-guided percutaneous coronary intervention (PCI) can dramatically minimize CV. The safe threshold when using an extremely low-dose CV is unknown. This study was designed as a multicenter, retrospective study of chronic kidney disease (CKD) patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m(2) undergoing elective PCI. We divided the patients into three groups according to following criteria: (1) low dose, CV/eGFR ratio <1.0; (2) medium dose, CV/eGFR ratio ≥1 and

  20. Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma.

    PubMed

    Flores-Montero, J; Sanoja-Flores, L; Paiva, B; Puig, N; García-Sánchez, O; Böttcher, S; van der Velden, V H J; Pérez-Morán, J-J; Vidriales, M-B; García-Sanz, R; Jimenez, C; González, M; Martínez-López, J; Corral-Mateos, A; Grigore, G-E; Fluxá, R; Pontes, R; Caetano, J; Sedek, L; Del Cañizo, M-C; Bladé, J; Lahuerta, J-J; Aguilar, C; Bárez, A; García-Mateo, A; Labrador, J; Leoz, P; Aguilera-Sanz, C; San-Miguel, J; Mateos, M-V; Durie, B; van Dongen, J J M; Orfao, A

    2017-03-10

    Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of multiple myeloma (MM) after therapy. However, current flow-MRD has lower sensitivity than molecular methods and lacks standardization. Here we report on a novel next generation flow (NGF) approach for highly sensitive and standardized MRD detection in MM. An optimized 2-tube 8-color antibody panel was constructed in five cycles of design-evaluation-redesign. In addition, a bulk-lysis procedure was established for acquisition of ⩾10(7) cells/sample, and novel software tools were constructed for automatic plasma cell gating. Multicenter evaluation of 110 follow-up BM from MM patients in very good partial response (VGPR) or CR showed a higher sensitivity for NGF-MRD vs conventional 8-color flow-MRD -MRD-positive rate of 47 vs 34% (P=0.003)-. Thus, 25% of patients classified as MRD-negative by conventional 8-color flow were MRD-positive by NGF, translating into a significantly longer progression-free survival for MRD-negative vs MRD-positive CR patients by NGF (75% progression-free survival not reached vs 7 months; P=0.02). This study establishes EuroFlow-based NGF as a highly sensitive, fully standardized approach for MRD detection in MM which overcomes the major limitations of conventional flow-MRD methods and is ready for implementation in routine diagnostics.Leukemia advance online publication, 10 March 2017; doi:10.1038/leu.2017.29.

  1. Detection of minimal residual disease in B lymphoblastic leukemia by high-throughput sequencing of IGH

    PubMed Central

    Wu, David; Emerson, Ryan O.; Sherwood, Anna; Loh, Mignon L.; Angiolillo, Anne; Howie, Bryan; Vogt, Jennifer; Rieder, Mark; Kirsch, Ilan; Carlson, Christopher; Williamson, David; Wood, Brent L.; Robins, Harlan

    2014-01-01

    Structured Abstract Purpose High-throughput sequencing (HTS) of immunoglobulin heavy chain genes (IGH) in unselected clinical samples for minimal residual disease (MRD) in B lymphoblastic leukemia (B-ALL) has not been tested. As current methods for MRD detection, such as flow cytometry or patient-specific qPCR are complex or difficult to standardize in the clinical laboratory, sequencing may enhance clinical prognostication. Experimental design We sequenced IGH in paired pre- and day 29 post-treatment samples using residual material from consecutive, unselected samples from Children's Oncology Group AALL0932 trial to measure MRD as compared to flow cytometry. We assessed the impact of on-going recombination at IGH on MRD detection in post-treatment samples. Lastly, we evaluated a subset of cases with discordant MRD results between flow cytometry and sequencing. Results We find clonal IGH rearrangements in 92 of 98 pre-treatment patient samples. Further, while on-going recombination of IGH was evident, index clones typically prevailed in MRD-positive post-treatment samples, suggesting that clonal evolution at IGH does not contribute substantively to tumor fitness. MRD was detected by sequencing in all flow cytometry positive cases with no false negative results. Additionally, in a subset of patients, MRD was detected by sequencing, but not by flow cytometry, including a fraction with MRD levels within the sensitivity of flow cytometry. We provide data that suggest that this discordance in some patients may be due to the phenotypic maturation of the transformed cell. Conclusion Our results provide strong support for high-throughput sequencing of IGH to enhance clinical prognostication in B-ALL. PMID:24970842

  2. Tacrolimus improves proteinuria remission in adults with cyclosporine A-resistant or -dependent minimal change disease.

    PubMed

    Xu, Dechao; Gao, Xiang; Bian, Rongrong; Mei, Changlin; Xu, Chenggang

    2017-03-01

    Cyclosporin A (CsA) is considered as an effective treatment option for steroid-resistant or-dependent patients with adult-onset minimal change disease (MCD). However, CsA resistance or dependence is also observed in these patients. Tacrolimus (TAC) is a calcineurin inhibitor that is potent in cytokine suppression. The authors aim to evaluate the efficacy and safety of TAC therapy in CsA-resistant and-dependent adult-onset MCD patients. Patients with adult-onset MCD were enrolled in our department from 2008 to 2012. All patients were demonstrated to be resistant to or dependent on CsA therapy. Prednisone (0.5 mg/kg per day) combined with TAC (0.05-0.1 mg/kg per day) were prescribed to these patients for at least 6 months. The primary outcome was complete or partial remission of proteinuria. Secondary outcomes included time required for complete or partial remission, adverse events, number of relapses, and TAC dosages. A total of 11 MCD patients were enrolled in this observational study. The numbers of patients who presented with resistance to or dependence on CsA were 7 and 4, respectively. The total remission rate was 90.9% (10/11) with the complete remission rate 72.7% (8/11). Most remission patients achieved remission during the first 2 months of TAC therapy. Patients who presented with dependence on CsA had achieved complete remission with TAC therapy, while outcomes for CsA-resistant patients were four complete remissions, two partial remissions and one resistance. The adverse events were observed in this study included infection, diarrhoea, and worsened hypertension. Five patients who had remission experienced relapse. Tacrolimus improves proteinuria remission in adults with CsA-resistant or -dependent MCD. © 2016 Asian Pacific Society of Nephrology.

  3. [Multiple myeloma: Maintenance therapy after autologous hematopoietic stem cell transplantation, depending on minimal residual disease].

    PubMed

    Solovyev, M V; Mendeleeva, L P; Pokrovskaya, O S; Nareyko, M V; Firsova, M V; Galtseva, I V; Davydova, Yu O; Kapranov, N M; Kuzmina, L A; Gemdzhian, E G; Savchenko, V G

    2017-01-01

    To determine the efficiency of maintenance therapy with bortezomib in patients with multiple myeloma (MM) who have achieved complete remission (CR) after autologous hematopoietic stem cell (auto-HSCT), depending on the presence of minimal residual disease (MRD). In January 2014 to February 2016, fifty-two MM patients (19 men and 33 women) aged 24 to 66 years (median 54 years), who had achieved CR after auto-HSCT, were randomized to perform maintenance therapy with bortezomib during a year. On day 100 after auto-HSCT, all the patients underwent immunophenotyping of bone marrow plasma cells by 6-color flow cytometry to detect MRD. Relapse-free survival (RFS) was chosen as a criterion for evaluating the efficiency of maintenance therapy. After auto-HSCT, MRD-negative patients had a statistically significantly higher 2-year RFS rate than MRD-positive patients: 52.9% (95% confidence interval (CI), 35.5 to 70.5%) versus 37.2% (95% CI, 25.4 to 49.3%) (p=0.05). The presence of MRD statistically significantly increased the risk of relapse (odds ratio 1.7; 95% CI, 1.2 to 3.4; p=0.05). Two-year cumulative risk of relapse (using the Kaplan-Meier) after auto-HSCT did not statistically significantly differ in MRD-negative patients receiving (n=15) and not receiving (n=10) maintenance therapy with bortezomib (p=0.58). After completion of maintenance treatment, 42% of the MRD-positive patients achieved a negative status. In the MRD-positive patients who had received maintenance therapy, the average time to recurrence was 5 months longer than that in the naïve patients: 17.3 versus 12.3 months. The MRD status determined in MM patients who have achieved CR after auto-HSCT is an important factor for deciding on the use of maintenance therapy.

  4. WT1 as a universal marker for minimal residual disease detection and quantification in myeloid leukemias and in myelodysplastic syndrome.

    PubMed

    Cilloni, Daniela; Saglio, Giuseppe

    2004-01-01

    Monitoring of acute leukemia patients during and after treatment for the presence of remaining leukemic cells (minimal residual disease, MRD) has been shown to give major insight into the effectiveness of treatment. However, so far the applicability of this strategy has been limited to those leukemia subsets characterized by genetic markers amenable to sensitive detection by PCR. Although PCR for immunoglobulin and T cell receptor gene rearrangement represents the gold standard for MRD detection in most cases of ALL without any fusion gene transcripts as molecular markers available, the situation in AML is more complicated because, at present, more than 50% of them lack any sort of clonality markers suitable for MRD monitoring. Thus, a number of studies have been performed in an attempt to identify cytogenetic and molecular abnormalities associated with leukemic transformation. In this paper we describe the effectiveness of the quantitative assessment of the Wilms tumor gene (WT1) transcript as a molecular marker for the detection of the leukemic clone useful for monitoring the presence of MRD in all the patients affected by acute and chronic leukemias as well as myelodysplastic syndromes. Copyright 2004 S. Karger AG, Basel

  5. Implementation of a simplified flow cytometric assays for minimal residual disease monitoring in childhood acute lymphoblastic leukemia.

    PubMed

    Vinhas, Ester; Lucena-Silva, Norma; Pedrosa, Francisco

    2016-06-25

    Monitoring minimal residual disease (MRD) in B-lineage acute lymphoblastic leukemia (ALL) to assess treatment response is crucial for risk assignment. Flow cytometry can be used to monitor MRD in ALL but the implementation of this approach requires extensive expertise. If resources are limited, the costs of full flow cytometric MRD testing might be prohibitive. We evaluated the applicability of a previously reported simplified MRD assay, designed to distinguish leukemic from normal lymphoblastic during remission induction therapy. Fifty-nine samples from children with ALL, enrolled in the RE-LLA study at a pediatric oncology center in Recife (Brazil), were evaluated for MRD on day 19 and on day 26 of remission induction therapy. We compared results obtained by a trainee in Recife and an expert. The method was implemented successfully and the concordance between results obtained by the trainee and the expert was practically absolute at the end of the study. It is possible to implement reliable measurements of MRD during remission induction therapy in childhood ALL despite limited resources. The simplicity of the MRD method used in this study does not require extensive prior training in leukemia immunophenotyping. © 2016 International Clinical Cytometry Society. © 2016 International Clinical Cytometry Society.

  6. Is There a Role for Minimal Residual Disease Monitoring in Follicular Lymphoma in the Chemo-Immunotherapy Era?

    PubMed Central

    Gritti, Giuseppe; Pavoni, Chiara; Rambaldi, Alessandro

    2017-01-01

    After 25 years, evaluation of minimal residual disease (MRD) in follicular lymphoma (FL) has become a standardized technique frequently integrated into clinical trials for its consistent and independent prognostic significance. Achievement of a sustained MRD negativity is a marker of treatment sensibility that has been associated with excellent clinical outcome in terms of clinical response and progression-free survival, independently from the employed therapy. However, no survival advantages has been reported for MRD negative patients and despite the compelling results of clinical trials, MRD evaluation has currently no role in clinical practice. Ongoing clinical trials will help in clarifying the potential setting in which MRD monitoring may have a routine clinical application i.e. allowing de-escalation of standard maintenance therapy in very low risk patients. In this review the clinical implications of MRD monitoring in Rituximab-era are discussed in light of the current treatment paradigms most aimed at reducing toxicities, and the response definition that now routinely integrates PET scan. PMID:28101314

  7. IMRT for Sinonasal Tumors Minimizes Severe Late Ocular Toxicity and Preserves Disease Control and Survival

    SciTech Connect

    Duprez, Frederic; Madani, Indira; Morbee, Lieve; Bonte, Katrien; Deron, Philippe; Domjan, Vilmos; Boterberg, Tom; De Gersem, Werner; De Neve, Wilfried

    2012-05-01

    Purpose: To report late ocular (primary endpoint) and other toxicity, disease control, and survival (secondary endpoints) after intensity-modulated radiotherapy (IMRT) for sinonasal tumors. Methods and Materials: Between 1998 and 2009, 130 patients with nonmetastatic sinonasal tumors were treated with IMRT at Ghent University Hospital. Prescription doses were 70 Gy (n = 117) and 60-66 Gy (n = 13) at 2 Gy per fraction over 6-7 weeks. Most patients had adenocarcinoma (n = 82) and squamous cell carcinoma (n = 23). One hundred and one (101) patients were treated postoperatively. Of 17 patients with recurrent tumors, 9 were reirradiated. T-stages were T1-2 (n = 39), T3 (n = 21), T4a (n = 38), and T4b (n = 22). Esthesioneuroblastoma was staged as Kadish A, B, and C in 1, 3, and 6 cases, respectively. Results: Median follow-up was 52, range 15-121 months. There was no radiation-induced blindness in 86 patients available for late toxicity assessment ({>=}6 month follow-up). We observed late Grade 3 tearing in 10 patients, which reduced to Grade 1-2 in 5 patients and Grade 3 visual impairment because of radiation-induced ipsilateral retinopathy and neovascular glaucoma in 1 patient. There was no severe dry eye syndrome. The worst grade of late ocular toxicity was Grade 3 (n = 11), Grade 2 (n = 31), Grade 1 (n = 33), and Grade 0 (n = 11). Brain necrosis and osteoradionecrosis occurred in 6 and 1 patients, respectively. Actuarial 5-year local control and overall survival were 59% and 52%, respectively. On multivariate analysis local control was negatively affected by cribriform plate and brain invasion (p = 0.044 and 0.029, respectively) and absence of surgery (p = 0.009); overall survival was negatively affected by cribriform plate and orbit invasion (p = 0.04 and <0.001, respectively) and absence of surgery (p = 0.001). Conclusions: IMRT for sinonasal tumors allowed delivering high doses to targets at minimized ocular toxicity, while maintaining disease control and survival

  8. Use of Minimal Residual Disease Assessment to Redefine Induction Failure in Pediatric Acute Lymphoblastic Leukemia.

    PubMed

    O'Connor, David; Moorman, Anthony V; Wade, Rachel; Hancock, Jeremy; Tan, Ronald M R; Bartram, Jack; Moppett, John; Schwab, Claire; Patrick, Katharine; Harrison, Christine J; Hough, Rachael; Goulden, Nick; Vora, Ajay; Samarasinghe, Sujith

    2017-02-20

    Purpose Our aim was to determine the role of end-of-induction (EOI) minimal residual disease (MRD) assessment in the identification and stratification of induction failure in patients with pediatric acute lymphoblastic leukemia (ALL) and to identify genetic abnormalities that drive disease in these patients. Patients and Methods Analysis included 3,113 patients who were treated in the Medical Research Council UKALL2003 multicenter randomized trial (NCT00222612) between 2003 and 2011. MRD was measured by using standardized real-time quantitative PCR. Median follow-up was 5 years 9 months. Results Fifty-nine patients (1.9%) had morphologic induction failure with 5-year event-free survival (EFS) of 50.7% (95% CI, 37.4 to 64.0) and 5-year overall survival of 57.7% (95% CI, 44.2 to 71.2). Of these, a small proportion of patients with M2 marrow (6 of 44) and a low EOI MRD level (< 0.01%) had 5-year EFS of 100%. Conversely, among patients with morphologic remission 2.3% (61 of 2,633) had high MRD (≥ 5%) and 5-year EFS of 47.0% (95% CI, 32.9 to 61.1), which was similar to those with morphologic induction failure. Redefining induction failure to include morphologic induction failure and/or MRD ≥ 5% identified 3.9% (120 of 3,133 patients) of the trial cohort with 5-year EFS of 48.0% (95% CI, 39.3 to 58.6). Induction failure (morphologic or MRD ≥ 5%) occurred most frequently in T-ALL (10.1%; 39 of 386 T-ALL cases) and B-other ALL, that is, lacking established chromosomal abnormalities (5.6%; 43 of 772 B-other cases). Genetic testing within the B-other group revealed the presence of PDGFRB gene fusions, particularly EBF1-PDGFRB, in almost one third of B-other ALL cases. Conclusion Integration of EOI MRD level with morphology identifies induction failure more precisely than morphology alone. Prevalence of EBF1-PDGFRB fusions in this group highlights the importance of genetic screening to identify abnormalities that may be targets for novel agents.

  9. Patient-tailored analysis of minimal residual disease in acute myeloid leukemia using next-generation sequencing.

    PubMed

    Malmberg, Erik B R; Ståhlman, Sara; Rehammar, Anna; Samuelsson, Tore; Alm, Sofie J; Kristiansson, Erik; Abrahamsson, Jonas; Garelius, Hege; Pettersson, Louise; Ehinger, Mats; Palmqvist, Lars; Fogelstrand, Linda

    2017-01-01

    Next-generation sequencing techniques have revealed that leukemic cells in acute myeloid leukemia often are characterized by a limited number of somatic mutations. These mutations can be the basis for the detection of leukemic cells in follow-up samples. The aim of this study was to identify leukemia-specific mutations in cells from patients with acute myeloid leukemia and to use these mutations as markers for minimal residual disease. Leukemic cells and normal lymphocytes were simultaneously isolated at diagnosis from 17 patients with acute myeloid leukemia using fluorescence-activated cell sorting. Exome sequencing of these cells identified 240 leukemia-specific single nucleotide variations and 22 small insertions and deletions. Based on estimated allele frequencies and their accuracies, 191 of these mutations qualified as candidates for minimal residual disease analysis. Targeted deep sequencing with a significance threshold of 0.027% for single nucleotide variations and 0.006% for NPM1 type A mutation was developed for quantification of minimal residual disease. When tested on follow-up samples from a patient with acute myeloid leukemia, targeted deep sequencing of single nucleotide variations as well as NPM1 was more sensitive than minimal residual disease quantification with multiparameter flow cytometry. In conclusion, we here describe how exome sequencing can be used for identification of leukemia-specific mutations in samples already at diagnosis of acute myeloid leukemia. We also show that targeted deep sequencing of such mutations, including single nucleotide variations, can be used for high-sensitivity quantification of minimal residual disease in a patient-tailored manner.

  10. Detection of minimal residual disease in NPM1-mutated acute myeloid leukemia by next-generation sequencing

    PubMed Central

    Salipante, Stephen J.; Fromm, Jonathan R.; Shendure, Jay; Wood, Brent L.; Wu, David

    2014-01-01

    Detection of minimal residual disease predicts adverse outcome in patients with acute myeloid leukemia. Currently, minimal residual disease may be detected by RQ-PCR or flow cytometry, both of which have practical and diagnostic limitations. Here, we describe a next-generation sequencing assay for minimal residual disease detection in NPM1-mutated acute myeloid leukemia, which encompasses ∼60% of patients with normal karyotype acute myeloid leukemia. Exon 12 of NPM1 was PCR amplified using sequencing adaptor-linked primers and deep sequenced to enable detection of low-prevalence, acute myeloid leukemia-specific activating mutations. We benchmarked our results against flow cytometry, the standard-of-care for acute myeloid leukemia minimal residual disease diagnosis at our institution. The performance of both approaches was evaluated using defined dilutions of an NPM1-mutation positive cell line and longitudinal clinical samples from acute myeloid leukemia patients. Using defined control material, we found this assay sensitive to approximately 0.001% mutant cells, outperforming flow cytometry by an order-of-magnitude. Next-generation sequencing was precise and semi-quantitative over 4 orders-of-magnitude. In 22 longitudinal samples from 6 acute myeloid leukemia patients, next-generation sequencing detected minimal residual disease in all samples deemed negative by flow cytometry. Further, in one-third of patients, sequencing detected alternate NPM1-mutations in addition to the patient's index mutation, consistent with tumor heterogeneity. Next-generation sequencing provides information without prior knowledge of NPM1 mutation subtype or validation of allele-specific probes as required for RQ-PCR assays, and without generation and interpretation of complex multi-dimensional flow cytometry data. This approach may complement current technologies to enhance patient-specific clinical decision-making. PMID:24743218

  11. Therapeutic variability in adult minimal change disease and focal segmental glomerulosclerosis

    PubMed Central

    Fernandez-Juarez, Gema; Villacorta, Javier; Ruiz-Roso, Gloria; Panizo, Nayara; Martinez-Marín, Isabel; Marco, Helena; Arrizabalaga, Pilar; Díaz, Montserrat; Perez-Gómez, Vanessa; Vaca, Marco; Rodríguez, Eva; Cobelo, Carmen; Fernandez, Loreto; Avila, Ana; Praga, Manuel; Quereda, Carlos; Ortiz, Alberto

    2016-01-01

    Background Variability in the management of glomerulonephritis may negatively impact efficacy and safety. However, there are little/no data on actual variability in the treatment of minimal change disease (MCD)/focal segmental glomerulosclerosis (FSGS) in adults. We assessed Spanish practice patterns for the management of adult nephrotic syndrome due to MCD or FSGS. The absence of reasonably good evidence on treatment for a disease often increases the variability substantially. Identification of evidence–practice gaps is the first necessary step in the knowledge-to-action cyclical process. We aim to analyse the real clinical practice in adults in hospitals in Spain and compare this with the recently released Kidney Disease: Improving Global Outcomes clinical practice guideline for glomerulonephritis. Methods Participating centres were required to include all adult patients (age >18 years) with a biopsy-proven diagnosis of MCD or FSGS from 2007 to 2011. Exclusion criteria included the diagnosis of secondary nephropathy. Results We studied 119 Caucasian patients with biopsy-proven MCD (n = 71) or FSGS (n = 48) from 13 Spanish hospitals. Of these patients, 102 received immunosuppressive treatment and 17 conservative treatment. The initial treatment was steroids, except in one patient in which mycophenolate mofetil was used. In all patients, the steroids were given as a single daily dose. The mean duration of steroid treatment at initial high doses was 8.7 ± 13.2 weeks and the mean global duration was 38 ± 32 weeks. The duration of initial high-dose steroids was <4 weeks in 41% of patients and >16 weeks in 10.5% of patients. We did find a weak and negative correlation between the duration of whole steroid treatment in the first episode and the number of the later relapses (r = −0.24, P = 0.023). There were 98 relapses and they were more frequent in MCD than in FSGs patients (2.10 ± 1.6 versus 1.56 ± 1.2; P = 0.09). The chosen treatment was mainly steroids (95

  12. Evaluation of minimal disseminated disease in cryopreserved ovarian tissue from bone and soft tissue sarcoma patients.

    PubMed

    Dolmans, M M; Iwahara, Y; Donnez, J; Soares, M; Vaerman, J L; Amorim, C A; Poirel, H

    2016-10-01

    What is the risk of finding malignant cells in cryopreserved ovarian tissue from sarcoma patients? Minimal disseminated disease (MDD) was not detected in frozen-thawed ovarian tissue from 26 patients by any of the sensitive methods applied. In case of leukemia, the risk of malignant cell transmission through the graft is well known and widely documented. However, for bone cancer, like Ewing sarcoma or osteosarcoma, only a small number of case reports, have been published. These cancers often affect prepubertal girls, in whom ovarian tissue cryopreservation and transplantation is the only option to preserve fertility. The presence of malignant cells in cryopreserved ovarian tissue from patients with bone/soft tissue sarcoma was investigated with disease-specific markers for each patient, using immunohistochemistry (IHC), FISH and real-time quantitative RT-PCR (qPCR), with the original tumor serving as a positive control. Forty-eight sarcoma patients were enrolled in the study, 12 of whom subsequently died. In each case, tissue from the primary tumor was investigated in order to identify markers (immunohistochemical and/or molecular) to analyze the ovarian tissue case by case. Ovarian tissue from osteosarcoma (n = 15), liposarcoma (n = 1) and undifferentiated sarcoma (n = 5) patients could not be evaluated, as no specific markers were detected by FISH or sensitive IHC in any of their primary tumoral tissue. One patient with Li-Fraumeni syndrome was also excluded from the study. IHC analyses were therefore performed on ovarian tissue from 26 patients and qPCR on 19. The primary tumors involved were Ewing sarcoma family of tumors (n = 14), rhabdomyosarcoma (n = 7), synovial sarcoma (n = 2), clear cell sarcoma (n = 2) and a malignant peripheral nerve sheath tumor (n = 1). MDD was not detected in any of the 26 analyzed samples using sensitive techniques in this largest reported series, even from patients who subsequently died and/or those who presented

  13. A 4-DOF haptic master using ER fluid for minimally invasive surgery system application

    NASA Astrophysics Data System (ADS)

    Oh, Jong-Seok; Han, Young-Min; Lee, Sang-Rock; Choi, Seung-Bok

    2013-04-01

    This paper presents a novel 4-degrees-of-freedom (4-DOF) haptic master using a electrorheological (ER) fluid which is applicable to minimally invasive surgery (MIS) systems. By adopting a controllable ER fluid, the master can easily generate 4-DOF repulsive forces with the advantages of a simple mechanism and continuous force control capability. The proposed master consists of two actuators: an ER spherical joint for 3-DOF rotational motion and an ER piston device for 1-DOF translational motion. The generated torque/force models are mathematically derived by analyzing the mechanism geometry and using the Bingham characteristics of an ER Fluid. The haptic master is optimally designed and manufactured based on the mathematical torque/force models. The repulsive torque/force responses are experimentally evaluated and expressed by the first-order and second-order dynamic equations for each motion. A sliding mode controller (SMC), which is known to be robust to uncertainties, is then designed and empirically implemented to achieve the desired torque/force trajectories. It is demonstrated by presenting torque/force tracking results of both rotational and translational motions that the proposed 4-DOF ER haptic master integrated with the SMC can provide an effective haptic control performance for MIS applications.

  14. Global error minimization in image mosaicing using graph connectivity and its applications in microscopy

    PubMed Central

    Khurd, Parmeshwar; Grady, Leo; Oketokoun, Rafiou; Sundar, Hari; Gajera, Tejas; Gibbs-Strauss, Summer; Frangioni, John V.; Kamen, Ali

    2011-01-01

    Several applications such as multiprojector displays and microscopy require the mosaicing of images (tiles) acquired by a camera as it traverses an unknown trajectory in 3D space. A homography relates the image coordinates of a point in each tile to those of a reference tile provided the 3D scene is planar. Our approach in such applications is to first perform pairwise alignment of the tiles that have imaged common regions in order to recover a homography relating the tile pair. We then find the global set of homographies relating each individual tile to a reference tile such that the homographies relating all tile pairs are kept as consistent as possible. Using these global homographies, one can generate a mosaic of the entire scene. We derive a general analytical solution for the global homographies by representing the pair-wise homographies on a connectivity graph. Our solution can accommodate imprecise prior information regarding the global homographies whenever such information is available. We also derive equations for the special case of translation estimation of an X-Y microscopy stage used in histology imaging and present examples of stitched microscopy slices of specimens obtained after radical prostatectomy or prostate biopsy. In addition, we demonstrate the superiority of our approach over tree-structured approaches for global error minimization. PMID:22811964

  15. Design and fabrication of an IPMC-embedded tube for minimally invasive surgery applications

    NASA Astrophysics Data System (ADS)

    Liu, Jiayu; Wang, Yanjie; Zhao, Dongxu; Zhang, Chi; Chen, Hualing; Li, Dichen

    2014-03-01

    Minimally Invasive Surgery (MIS) is receiving much attention for a number of reasons, including less trauma, faster recovery and enhanced precision. The traditional robotic actuators do not have the capabilities required to fulfill the demand for new applications in MIS. Ionic Polymer-Metal Composite (IPMC), one of the most promising smart materials, has extensive desirable characteristics such as low actuation voltage, large bending deformation and high functionality. Compared with traditional actuators, IPMCs can mimic biological muscle and are highly promising for actuation in robotic surgery. In this paper, a new approach which involves molding and integrating IPMC actuators into a soft silicone tube to create an active actuating tube capable of multi-degree-of-freedom motion is presented. First, according to the structure and performance requirements of the actuating tube, the biaxial bending IPMC actuators fabricated by using solution casting method have been implemented. The silicone was cured at a suitable temperature to form a flexible tube using molds fabricated by 3D Printing technology. Then an assembly based fabrication process was used to mold or integrate biaxial bending IPMC actuators into the soft silicone material to create an active control tube. The IPMC-embedded tube can generate multi-degree-of-freedom motions by controlling each IPMC actuator. Furthermore, the basic performance of the actuators was analyzed, including the displacement and the response speed. Experimental results indicate that IPMC-embedded tubes are promising for applications in MIS.

  16. Minimally invasive unilateral pedicle screw fixation and lumbar interbody fusion for the treatment of lumbar degenerative disease.

    PubMed

    Lin, Bin; Xu, Yang; He, Yong; Zhang, Bi; Lin, Qiuyan; He, Mingchang

    2013-08-01

    Minimally invasive unilateral pedicle screw fixation for the treatment of degenerative lumbar diseases has won the support of many surgeons. However, few data are available regarding clinical research on unilateral pedicle screw fixation associated with minimally invasive techniques for the treatment of lumbar spinal diseases. The purpose of this study was to evaluate clinical outcomes in a selected series of patients with lumbar degenerative diseases treated with minimally invasive unilateral vs classic bilateral pedicle screw fixation and lumbar interbody fusion. Patients in the unilateral group (n=43) underwent minimally invasive unilateral pedicle screw fixation with the Quadrant system (Medtronic, Memphis, Tennessee). The bilateral group (n=42) underwent bilateral instrumentation via the classic approach. Visual analog scale pain scores, Oswestry Disability Index scores, fusion rate, operative time, blood loss, and complications were analyzed. Mean operative time was 75 minutes in the unilateral group and 95 minutes in the bilateral group. Mean blood loss was 220 mL in the unilateral group and 450 mL in the bilateral group. Mean postoperative visual analog scale pain score was 3.10±0.16 in the unilateral group and 3.30±1.10 in the bilateral group. Mean postoperative Oswestry Disability Index score was 15.67±2.3 in the unilateral group and 14.93±2.6 in the bilateral group. Successful fusion was achieved in 92.34% of patients in the unilateral group and 93.56% of patients in the bilateral group. Minimally invasive unilateral pedicle screw fixation is an effective and reliable option for the surgical treatment of lumbar degenerative disease. It causes less blood loss, requires less operative time, and has a fusion rate comparable with that of conventional bilateral fixation. Copyright 2013, SLACK Incorporated.

  17. Minimal Residual Disease Evaluation in Childhood Acute Lymphoblastic Leukemia: An Economic Analysis

    PubMed Central

    Gajic-Veljanoski, O.; Pham, B.; Pechlivanoglou, P.; Krahn, M.; Higgins, Caroline; Bielecki, Joanna

    2016-01-01

    Background Minimal residual disease (MRD) testing by higher performance techniques such as flow cytometry and polymerase chain reaction (PCR) can be used to detect the proportion of remaining leukemic cells in bone marrow or peripheral blood during and after the first phases of chemotherapy in children with acute lymphoblastic leukemia (ALL). The results of MRD testing are used to reclassify these patients and guide changes in treatment according to their future risk of relapse. We conducted a systematic review of the economic literature, cost-effectiveness analysis, and budget-impact analysis to ascertain the cost-effectiveness and economic impact of MRD testing by flow cytometry for management of childhood precursor B-cell ALL in Ontario. Methods A systematic literature search (1998–2014) identified studies that examined the incremental cost-effectiveness of MRD testing by either flow cytometry or PCR. We developed a lifetime state-transition (Markov) microsimulation model to quantify the cost-effectiveness of MRD testing followed by risk-directed therapy to no MRD testing and to estimate its marginal effect on health outcomes and on costs. Model input parameters were based on the literature, expert opinion, and data from the Pediatric Oncology Group of Ontario Networked Information System. Using predictions from our Markov model, we estimated the 1-year cost burden of MRD testing versus no testing and forecasted its economic impact over 3 and 5 years. Results In a base-case cost-effectiveness analysis, compared with no testing, MRD testing by flow cytometry at the end of induction and consolidation was associated with an increased discounted survival of 0.0958 quality-adjusted life-years (QALYs) and increased discounted costs of $4,180, yielding an incremental cost-effectiveness ratio (ICER) of $43,613/QALY gained. After accounting for parameter uncertainty, incremental cost-effectiveness of MRD testing was associated with an ICER of $50,249/QALY gained. In

  18. Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients.

    PubMed

    Paiva, Bruno; Cedena, Maria-Teresa; Puig, Noemi; Arana, Paula; Vidriales, Maria-Belen; Cordon, Lourdes; Flores-Montero, Juan; Gutierrez, Norma C; Martín-Ramos, María-Luisa; Martinez-Lopez, Joaquin; Ocio, Enrique M; Hernandez, Miguel T; Teruel, Ana-Isabel; Rosiñol, Laura; Echeveste, María-Asunción; Martinez, Rafael; Gironella, Mercedes; Oriol, Albert; Cabrera, Carmen; Martin, Jesus; Bargay, Joan; Encinas, Cristina; Gonzalez, Yolanda; Van Dongen, Jacques J M; Orfao, Alberto; Bladé, Joan; Mateos, Maria-Victoria; Lahuerta, Juan José; San Miguel, Jesús F

    2016-06-23

    The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second-generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first- to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10(-5); n = 54, 34%), MRD positive (between <10(-4) and ≥10(-5); n = 20, 12%), and MRD positive (≥10(-4); n = 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P = .007) and overall survival (OS) (HR, 3.1; P = .04), with significant benefit for MRD-negative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10(-4) and ≥10(-5) vs ≥10(-4) (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P = .01). Using second-generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P = .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249.

  19. A primal-dual fixed point algorithm for convex separable minimization with applications to image restoration

    NASA Astrophysics Data System (ADS)

    Chen, Peijun; Huang, Jianguo; Zhang, Xiaoqun

    2013-02-01

    Recently, the minimization of a sum of two convex functions has received considerable interest in a variational image restoration model. In this paper, we propose a general algorithmic framework for solving a separable convex minimization problem from the point of view of fixed point algorithms based on proximity operators (Moreau 1962 C. R. Acad. Sci., Paris I 255 2897-99). Motivated by proximal forward-backward splitting proposed in Combettes and Wajs (2005 Multiscale Model. Simul. 4 1168-200) and fixed point algorithms based on the proximity operator (FP2O) for image denoising (Micchelli et al 2011 Inverse Problems 27 45009-38), we design a primal-dual fixed point algorithm based on the proximity operator (PDFP2Oκ for κ ∈ [0, 1)) and obtain a scheme with a closed-form solution for each iteration. Using the firmly nonexpansive properties of the proximity operator and with the help of a special norm over a product space, we achieve the convergence of the proposed PDFP2Oκ algorithm. Moreover, under some stronger assumptions, we can prove the global linear convergence of the proposed algorithm. We also give the connection of the proposed algorithm with other existing first-order methods. Finally, we illustrate the efficiency of PDFP2Oκ through some numerical examples on image supper-resolution, computerized tomographic reconstruction and parallel magnetic resonance imaging. Generally speaking, our method PDFP2O (κ = 0) is comparable with other state-of-the-art methods in numerical performance, while it has some advantages on parameter selection in real applications.

  20. SU-E-J-167: Dosimetric Consequences From Minimal Displacements in APBI with SAVI Applicators

    SciTech Connect

    Chandrasekara, S; Dumitru, N; Hyvarinen, M; Pella, S

    2015-06-15

    Purpose: To determine the importance of providing proper solid immobilization in every fraction of treatment in APBI with brachytherapy. Methods: 125 patients treated with APBI brachytherapy with SAVI applicators at SFRO Boca Raton, from 2013–2015 were considered for this retrospective study. The CT scans of each patient, which were taken before each treatment, were imported in to the Oncentra treatment planning system. Then they were compared with the initial CT scan which was used for the initial plan. Deviation in displacements in reference to ribs and skin surface was measured and dosimetric evaluations respective to the initial image were performed. Results: Small deviations in displacements were observed from the SAVI applicator to the ribs and the skin surface. Dosimetric evaluations revealed, very small changes in the inter-fractionation position make significant differences in the maximum dose to critical organs. Additionally, the volume of the cavity also changed between fractions. As a Result, the maximum dose manifested variance between 10% and 32% in ribs and skin surface respectively. Conclusion: It appears that taking a CT scan before each treatment is necessary to minimize the risk of delivering undesired high doses to the critical organs. This study indicates, in 30% of the cases re-planning was necessary between treatments. We conclude that, treatment planning teams should evaluate the placement of the device by analyzing the CT images before each treatment and they must be prepared for re-planning if needed. This study also reveals the urgent need of improving the immobilization methods with APBI when treating with the SAVI applicator.

  1. Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909.

    PubMed

    Liu, Hongtao; Johnson, Jeffrey L; Koval, Greg; Malnassy, Greg; Sher, Dorie; Damon, Lloyd E; Hsi, Eric D; Bucci, Donna Marie; Linker, Charles A; Cheson, Bruce D; Stock, Wendy

    2012-04-01

    In the present study, the prognostic impact of minimal residual disease during treatment on time to progression and overall survival was analyzed prospectively in patients with mantle cell lymphoma treated on the Cancer and Leukemia Group B 59909 clinical trial. Peripheral blood and bone marrow samples were collected during different phases of the Cancer and Leukemia Group B 59909 study for minimal residual disease analysis. Minimal residual disease status was determined by quantitative polymerase chain reaction of IgH and/or BCL-1/JH gene rearrangement. Correlation of minimal residual disease status with time to progression and overall survival was determined. In multivariable analysis, minimal residual disease, and other risk factors were correlated with time to progression. Thirty-nine patients had evaluable, sequential peripheral blood and bone marrow samples for minimal residual disease analysis. Using peripheral blood monitoring, 18 of 39 (46%) achieved molecular remission following induction therapy. The molecular remission rate increased from 46 to 74% after one course of intensification therapy. Twelve of 21 minimal residual disease positive patients (57%) progressed within three years of follow up compared to 4 of 18 (22%) molecular remission patients (P=0.049). Detection of minimal residual disease following induction therapy predicted disease progression with a hazard ratio of 3.7 (P=0.016). The 3-year probability of time to progression among those who were in molecular remission after induction chemotherapy was 82% compared to 48% in patients with detectable minimal residual disease. The prediction of time to progression by post-induction minimal residual disease was independent of other prognostic factors in multivariable analysis. Detection of minimal residual disease following induction immunochemotherapy was an independent predictor of time to progression following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma.

  2. Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909

    PubMed Central

    Liu, Hongtao; Johnson, Jeffrey L.; Koval, Greg; Malnassy, Greg; Sher, Dorie; Damon, Lloyd E.; Hsi, Eric D.; Bucci, Donna Marie; Linker, Charles A.; Cheson, Bruce D.; Stock, Wendy

    2012-01-01

    Background In the present study, the prognostic impact of minimal residual disease during treatment on time to progression and overall survival was analyzed prospectively in patients with mantle cell lymphoma treated on the Cancer and Leukemia Group B 59909 clinical trial. Design and Methods Peripheral blood and bone marrow samples were collected during different phases of the Cancer and Leukemia Group B 59909 study for minimal residual disease analysis. Minimal residual disease status was determined by quantitative polymerase chain reaction of IgH and/or BCL-1/JH gene rearrangement. Correlation of minimal residual disease status with time to progression and overall survival was determined. In multivariable analysis, minimal residual disease, and other risk factors were correlated with time to progression. Results Thirty-nine patients had evaluable, sequential peripheral blood and bone marrow samples for minimal residual disease analysis. Using peripheral blood monitoring, 18 of 39 (46%) achieved molecular remission following induction therapy. The molecular remission rate increased from 46 to 74% after one course of intensification therapy. Twelve of 21 minimal residual disease positive patients (57%) progressed within three years of follow up compared to 4 of 18 (22%) molecular remission patients (P=0.049). Detection of minimal residual disease following induction therapy predicted disease progression with a hazard ratio of 3.7 (P=0.016). The 3-year probability of time to progression among those who were in molecular remission after induction chemotherapy was 82% compared to 48% in patients with detectable minimal residual disease. The prediction of time to progression by post-induction minimal residual disease was independent of other prognostic factors in multivariable analysis. Conclusions Detection of minimal residual disease following induction immunochemotherapy was an independent predictor of time to progression following immunochemotherapy and autologous

  3. Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting.

    PubMed

    Irving, Julie; Jesson, Jenny; Virgo, Paul; Case, Marian; Minto, Lynne; Eyre, Lisa; Noel, Nigel; Johansson, Ulrika; Macey, Marion; Knotts, Linda; Helliwell, Margaret; Davies, Paul; Whitby, Liam; Barnett, David; Hancock, Jeremy; Goulden, Nick; Lawson, Sarah

    2009-06-01

    Minimal residual disease detection, used for clinical management of children with acute lymphoblastic leukemia, can be performed by molecular analysis of antigen-receptor gene rearrangements or by flow cytometric analysis of aberrant immunophenotypes. For flow minimal residual disease to be incorporated into larger national and international trials, a quality assured, standardized method is needed which can be performed in a multi-center setting. We report a four color, flow cytometric protocol established and validated by the UK acute lymphoblastic leukemia Flow minimal residual disease group. Quality assurance testing gave high inter-laboratory agreement with no values differing from a median consensus value by more than one point on a logarithmic scale. Prospective screening of B-ALL patients (n=206) showed the method was applicable to 88.3% of patients. The minimal residual disease in bone marrow aspirates was quantified and compared to molecular data. The combined risk category concordance (minimal residual disease levels above or below 0.01%) was 86% (n=134). Thus, this standardized protocol is highly reproducible between laboratories, sensitive, applicable, and shows good concordance with molecular-based analysis.

  4. Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting;

    PubMed Central

    Irving, Julie; Jesson, Jenny; Virgo, Paul; Case, Marian; Minto, Lynne; Eyre, Lisa; Noel, Nigel; Johansson, Ulrika; Macey, Marion; Knotts, Linda; Helliwell, Margaret; Davies, Paul; Whitby, Liam; Barnett, David; Hancock, Jeremy; Goulden, Nick; Lawson, Sarah

    2009-01-01

    Minimal residual disease detection, used for clinical management of children with acute lymphoblastic leukemia, can be performed by molecular analysis of antigen-receptor gene rearrangements or by flow cytometric analysis of aberrant immunophenotypes. For flow minimal residual disease to be incorporated into larger national and international trials, a quality assured, standardized method is needed which can be performed in a multi-center setting. We report a four color, flow cytometric protocol established and validated by the UK acute lymphoblastic leukemia Flow minimal residual disease group. Quality assurance testing gave high inter-laboratory agreement with no values differing from a median consensus value by more than one point on a logarithmic scale. Prospective screening of B-ALL patients (n=206) showed the method was applicable to 88.3% of patients. The minimal residual disease in bone marrow aspirates was quantified and compared to molecular data. The combined risk category concordance (minimal residual disease levels above or below 0.01%) was 86% (n=134). Thus, this standardized protocol is highly reproducible between laboratories, sensitive, applicable, and shows good concordance with molecular-based analysis. PMID:19377076

  5. Application of geographic information systems to waste minimization efforts at Los Alamos National Laboratory

    SciTech Connect

    Lyttle, T.W.; Smith, D.M.; Burns, M.; Weinrach, J.B.

    1993-01-01

    At Los Alamos National Laboratory (LANL), facility waste streams tend to be small but highly diverse. Initial characterization of such waste streams is often difficult in part due to a lack of tools to assist the generators themselves in completing such assessments. A methodology has been developed at LANL to allow process knowledgeable field personnel to develop baseline waste generation assessments and to evaluate potential waste minimization technology. This Process Waste Assessment (PWA) system is an application constructed within the Process Modeling System and currently being integrated with the InFoCAD Geographic Information System (GIS) . The Process Modeling System (PMS) is an object-oriented, mass balance-based, discrete-event simulation framework written using the Common Lisp Object System (CLOS) . Analytical capabilities supported within the PWA system include: complete mass balance specifications, historical characterization of selected waste streams and generation of facility profiles for materials consumption, resource utilization and worker exposure. Development activities include integration with the LANL facilities management Geographic Information System (GIS) and provisions for a Best Available Technologies (BAT) database. The environments used to develop these assessment tools will be discussed in addition to a review of initial implementation results.

  6. Ultrasound-based navigation for minimally invasive surgical atrial fibrillation treatment: workflow and application prototype

    NASA Astrophysics Data System (ADS)

    Hastenteufel, Mark; Yang, Siwei; Christoph, Carsten; Vetter, Marcus; Meinzer, Hans-Peter; Wolf, Ivo

    2005-04-01

    Atrial fibrillation (AF) is the most common arrhythmia and results in an increased risk of ischemic stroke. Recently, a european consortium has developed a new minimally invasive device for surgical AF treatment. It consists of a micro-robot holding an end-effector called "umbrella" containing 22 radiofrequency powered electrodes. Surgery using this new device can only be performed having an appropriate navigation technique. Therefore, we have developed an image-based navigation workflow and a prototypic navigation application. First, a navigation workflow including an appropriate intra-operative image-modality was defined. Intraoperative ultrasound became the imaging modality of choice. Once the umbrella is unfolded inside the left atrium, data is acquired and segmented. Using a reliable communication protocol, mobility values are transferred from the control software to the navigation system. A deformation model predicts the behavior of the umbrella during repositioning. Prior to surgery, desired ablation lines can be interactively planned and actually made ablation lines are visualized during surgery. Several in-vitro tests were performed. The navigation prototype has been integrated and tested within the overall system successfully. Image acquisitions of the umbrella showed the feasibility of the navigation procedure. More in-vitro and in-vivo tests are currently performed to make the new device and the described navigation procedure ready for clinical use.

  7. Minimal interference beam size/profile measurement techniques applicable to the Collider

    SciTech Connect

    Nexsen, W.; Dutt, S.; Kauffmann, S.; Lebedev, V.; Maschke, A.; Mokhov, N.; Richardson, R.; Tsyganov, E.; Zinchenko, A.

    1993-05-01

    The imaging of synchrotron radiation (SR) has been suggested as a technique for providing a continuous, non-interfering monitor of the beam profile in the Collider rings at the Superconducting Super Collider. A closer examination has raised questions concerning the applicability of SR imaging in this case because of the diffraction broadening of the image, the requirements for axial space and location in the lattice, and the complexity of the system. We have surveyed the known, alternative, minimal interference techniques for measuring beam size and have evaluated them for possible Collider usage. We conclude that of the approaches that appear feasible, all require at least some development for our usage and that the development of an electron beam probe offers the best promise. We recommend that flying wires be used for cross-checking and calibrating the electron beam probe diagnostic and for luminosity measurements when the highest accuracy is required, but flying wires should not be used as the primary diagnostic because of their limited lifetime.

  8. Standardizing minimal residual disease by flow cytometry for precursor B lineage acute lymphoblastic leukemia in a developing country.

    PubMed

    Patkar, Nikhil; Alex, Ansu Abu; B, Bargavi; Ahmed, Rayaz; Abraham, Aby; George, Biju; Vishwabandya, Auro; Srivastava, Alok; Mathews, Vikram

    2012-07-01

    In addition to standard risk criteria at diagnosis, minimal residual disease (MRD) following initiation of therapy is a well-recognized risk factor to predict relapse. Literature from developing countries addressing therapeutic or laboratory practices related to MRD, is largely lacking. In a first paper from India, we describe our experience in establishing a flow cytometry-based MRD assay for precursor B lineage ALL (BCP-ALL) with emphasis on the assay standardization and cost. Normal templates for B cell development were established in 10 control patients using CD45, CD11a, CD38, CD20, CD10, CD19, CD58, CD34, CD123, and CD22. BCP-ALL samples (n = 42) were characterized at diagnosis to identify a suitable marker for follow-up during mid (D+21) and end of induction (D+33). Both, multiparametric immunophenotyping and single marker detection of LAIP were used for data analysis. In 95.2% of BCP-ALL at least two informative markers could be obtained when a minimum of four cocktail combinations were used. The combination CD20, CD10, CD45, and CD19 was the most useful (71.4%) followed by combinations containing CD38 (66.7%), CD22 (57.1%), CD11a (52.4%), and CD58 (33.3%). Using our approach, 60 and 47% of patients had detectable MRD at mid and end induction time points, respectively. We have described a relatively cost effective MRD panel which is applicable to over 90% of patients. We hope that this data would encourage more centers in India and other resource constrained health delivery systems to develop MRD assays. Copyright © 2012 International Clinical Cytometry Society.

  9. Determining the Minimally Important Difference in the Clinical Disease Activity Index For Improvement and Worsening in Early Rheumatoid Arthritis

    PubMed Central

    Curtis, JR; Yang, S; Chen, L; Pope, JE; Keystone, EC; Haraoui, B; Boire, G; Thorne, JC; Tin, D; Hitchon, CA; Bingham, CO; Bykerk, VP

    2015-01-01

    Background Simplified measures to quantify rheumatoid arthritis (RA) disease activity are increasingly used. The minimally clinically important differences (MCID) for some measures, such as the clinical disease activity index (CDAI), have not been well-defined in real-world clinic settings, especially for early RA patients with low/moderate disease activity. Methods Data from Canadian Early Arthritis Cohort patients were used to examine absolute change in CDAI in the first year after enrollment, stratified by disease activity. MCID cutpoints were derived to optimize the sum of sensitivity and specificity versus the gold standard of patient self-reported improvement or worsening. Specificity, positive predictive value and negative predictive values were calculated against patient self-reported improvement (gold standard) and for change in pain, HAQ and DAS28 improvement. Discrimination was examined using area under receiver operator curves (ROC). Similar methods were used to evaluate MCIDs for worsening for patients who achieved low disease activity. Results A total of 578 patients (mean (SD) age 54.1 (15.3) years; 75% women, median (IQR) disease duration 5.3 (3.3, 8.0) months) contributed 1169 visit pairs to the improvement analysis. The MCID cutpoints for improvement were 12 (patients starting in high disease activity, CDAI>22), 6 (moderate, CDAI 10–22), and 1 (low disease activity, CDAI <10). Performance characteristics were acceptable using these cutpoints for pain, HAQ, and DAS28. The MCID for CDAI worsening among patients who achieved low disease activity was 2 units. Conclusions These minimally important absolute differences in CDAI can be used to evaluate improvement and worsening and increase the utility of CDAI in clinical practice. PMID:25988705

  10. Hematopoietic stem cell recipients do not develop post-transplantation immune tolerance to antigens present on minimal residual disease.

    PubMed

    Natzke, Amanda Martinelli; Shaw, Joanne L; McKeller, Morgan R; Emo, Kris Lambert; Mullen, Craig A

    2007-01-01

    The immune environment present after allogeneic hematopoietic stem cell transplantation (HSCT) contributes to the control of leukemia. Our laboratory has demonstrated in a murine model that vaccination of recipients after transplantation with recipient tumor vaccines does not exacerbate graft-versus-host disease but does induce meaningful graft-versus-tumor effects. We previously demonstrated that part of the reason for the lack of graft-versus-host disease from post-transplantation vaccination is due to gradual acquisition of tolerance or unresponsiveness to recipient immunodominant minor histocompatibility antigens that are ubiquitously expressed in the recipient. However, our prior studies have not critically addressed the question of whether a similar process of acquisition of unresponsiveness to or tolerance of antigens present on minimal residual disease also occurs. The present study tested the hypothesis that unresponsiveness to antigens present on minimal residual disease present at the time of HSCT would also occur. The answer to this question would have a significant effect on the potential efficacy of post-transplantation tumor vaccines. In a murine model of major histocompatibility complex matched, minor histocompatibility antigen mismatched HSCT (C3.SW female donors and C57BL/6 female recipients), we tested whether transplant recipients would acquire unresponsiveness to antigens present on small numbers of residual leukemia/lymphoma cells. We employed a male C57BL/6 lymphoid malignancy with an immunoglobulin/c-myc oncogene in these studies using as a model of tumor-restricted antigen the well-characterized male (HY) antigen system present only on the tumor but not present as ubiquitous minor antigens in the recipient. After HSCT, recipients did not mount immune responses to the ubiquitously distributed immunodominant recipient strain H7 minor histocompatibility antigen, but did retain the capacity to mount significant T cell responses to HY antigens

  11. Partial Sum Minimization of Singular Values in Robust PCA: Algorithm and Applications.

    PubMed

    Oh, Tae-Hyun; Tai, Yu-Wing; Bazin, Jean-Charles; Kim, Hyeongwoo; Kweon, In So

    2016-04-01

    Robust Principal Component Analysis (RPCA) via rank minimization is a powerful tool for recovering underlying low-rank structure of clean data corrupted with sparse noise/outliers. In many low-level vision problems, not only it is known that the underlying structure of clean data is low-rank, but the exact rank of clean data is also known. Yet, when applying conventional rank minimization for those problems, the objective function is formulated in a way that does not fully utilize a priori target rank information about the problems. This observation motivates us to investigate whether there is a better alternative solution when using rank minimization. In this paper, instead of minimizing the nuclear norm, we propose to minimize the partial sum of singular values, which implicitly encourages the target rank constraint. Our experimental analyses show that, when the number of samples is deficient, our approach leads to a higher success rate than conventional rank minimization, while the solutions obtained by the two approaches are almost identical when the number of samples is more than sufficient. We apply our approach to various low-level vision problems, e.g., high dynamic range imaging, motion edge detection, photometric stereo, image alignment and recovery, and show that our results outperform those obtained by the conventional nuclear norm rank minimization method.

  12. Insights into Spared Memory Capacity in Amnestic MCI and Alzheimer's Disease via Minimal Interference

    ERIC Educational Resources Information Center

    Dewar, Michaela; Pesallaccia, Martina; Cowan, Nelson; Provinciali, Leandro; Della Sala, Sergio

    2012-01-01

    Impairment on standard tests of delayed recall is often already maximal in the aMCI stage of Alzheimer's Disease. Neuropathological work shows that the neural substrates of memory function continue to deteriorate throughout the progression of the disease, hinting that further changes in memory performance could be tracked by a more sensitive test…

  13. Minimizing crop damage through understanding relationships between pyrethrum phenology and ray blight disease severity

    USDA-ARS?s Scientific Manuscript database

    The most damaging foliar disease of pyrethrum in Australia is ray blight caused by Stagonosporopsis tanaceti. The probability of growers incurring economic losses caused by this disease has been substantially reduced by the implementation of a prophylactically-applied spring fungicide program. Th...

  14. Insights into Spared Memory Capacity in Amnestic MCI and Alzheimer's Disease via Minimal Interference

    ERIC Educational Resources Information Center

    Dewar, Michaela; Pesallaccia, Martina; Cowan, Nelson; Provinciali, Leandro; Della Sala, Sergio

    2012-01-01

    Impairment on standard tests of delayed recall is often already maximal in the aMCI stage of Alzheimer's Disease. Neuropathological work shows that the neural substrates of memory function continue to deteriorate throughout the progression of the disease, hinting that further changes in memory performance could be tracked by a more sensitive test…

  15. POLLUTION BALANCE METHOD AND THE DEMONSTRATION OF ITS APPLICATION TO MINIMIZING WASTE IN A BIOCHEMICAL PROCESS

    EPA Science Inventory

    In this study, we introduced several modifications to the WAR (waste reduction) algorithm developed earlier. These modifications were made for systematically handling sensitivity analysis and various tasks of waste minimization. A design hierarchy was formulated to promote appro...

  16. POLLUTION BALANCE METHOD AND THE DEMONSTRATION OF ITS APPLICATION TO MINIMIZING WASTE IN A BIOCHEMICAL PROCESS

    EPA Science Inventory

    In this study, we introduced several modifications to the WAR (waste reduction) algorithm developed earlier. These modifications were made for systematically handling sensitivity analysis and various tasks of waste minimization. A design hierarchy was formulated to promote appro...

  17. [Minimally invasive technologies in the treatment of severe forms of acute pancreatitis at various periods of the disease].

    PubMed

    Bagnenko, S F; Tolstoĭ, A D; Rukhliada, N V; Goltsov, V R; Skorodumov, A V; Bondarev, M R; Sheianov, D S; Zakharova, E V

    2002-01-01

    The choice of the optimum technique of the sanitation procedure in treatment of acute necrotizing pancreatitis (ANP) is now one of the most disputable problems. Clinical estimation of the efficiency of various operative techniques of treatment of ANP at various stages of disease has been made. In the aseptic phase laparoscopic decompression of the pancreas is indicated when the patient has evident hemorrhagic parapancreatitis. In the phase of septic sequestration of ANP the optimum method of minimally invasive surgical intervention is considered to be minilaparotomy which is expedient for abscesses of small volume, lipid abscesses of any volume with the minimal content of necrotizing tissues as the first step of sanitation in critical patient. High quantity of the necrotizing tissues in the zone of the destructive focus requires traditional laparotomy of the abscess under conditions of preventive maintenance of the endotoxic shock.

  18. [Economic impact of Alzheimer's Disease in Brazil: is it possible to improve care and minimize costs?].

    PubMed

    Gutierrez, Beatriz Aparecida Ozello; Silva, Henrique Salmazo da; Guimarães, Cristina; Campino, Antonio Carlos

    2014-11-01

    The scope of this study is to discuss data relating to the costs involved with Alzheimer's Disease and the initiatives in terms of care in order to reduce costs and help family members and caregivers to cope with the disease. The biggest cost for people with mild Alzheimer's Disease is the cost of time spent by the unremunerated caregiver, and for those at the advanced stages of the disease it is the cost of institutional care. In this respect, the literature proposes the adoption of models of care that maximize the functional independence of the elderly and maintain their skills, such as Day Care Centers for the Elderly and rehabilitation programs and support offered to the elderly and their family members. These models of care need to be discussed, structured and deployed in the context of the Brazilian reality.

  19. Using population viability criteria to assess strategies to minimize disease threats for an endangered carnivore.

    PubMed

    Doak, Daniel F; Bakker, Victoria J; Vickers, Winston

    2013-04-01

    Outbreaks of infectious disease represent serious threats to the viability of many vertebrate populations, but few studies have included quantitative evaluations of alternative approaches to the management of disease. The most prevalent management approach is monitoring for and rapid response to an epizootic. An alternative is vaccination of a subset of the free-living population (i.e., a "vaccinated core") such that some individuals are partially or fully immune in the event of an epizootic. We developed a simulation model describing epizootic dynamics, which we then embedded in a demographic simulation to assess these alternative approaches to managing rabies epizootics in the island fox (Urocyon littoralis), a species composed of only 6 small populations on the California Channel Islands. Although the monitor and respond approach was superior to the vaccinated-core approach for some transmission models and parameter values, this type of reactive management did not protect the population from rabies under many disease-transmission assumptions. In contrast, a logistically feasible program of prophylactic vaccination for part of the wild population yielded low extinction probabilities across all likely disease-transmission scenarios, even with recurrent disease introductions. Our use of a single metric of successful management-probability of extreme endangerment (i.e., quasi extinction)-to compare very different management approaches allowed an objective assessment of alternative strategies for controlling the threats posed by infectious disease outbreaks.

  20. Minimal Pairs: Minimal Importance?

    ERIC Educational Resources Information Center

    Brown, Adam

    1995-01-01

    This article argues that minimal pairs do not merit as much attention as they receive in pronunciation instruction. There are other aspects of pronunciation that are of greater importance, and there are other ways of teaching vowel and consonant pronunciation. (13 references) (VWL)

  1. Nanobiomaterials' applications in neurodegenerative diseases.

    PubMed

    Silva Adaya, Daniela; Aguirre-Cruz, Lucinda; Guevara, Jorge; Ortiz-Islas, Emma

    2017-02-01

    The blood-brain barrier is the interface between the blood and brain, impeding the passage of most circulating cells and molecules, protecting the latter from foreign substances, and maintaining central nervous system homeostasis. However, its restrictive nature constitutes an obstacle, preventing therapeutic drugs from entering the brain. Usually, a large systemic dose is required to achieve pharmacological therapeutic levels in the brain, leading to adverse effects in the body. As a consequence, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. One such tool is nanotechnology, in which nanostructures that are 1-100 nm are designed to deliver drugs to the brain. In this review, we examine many nanotechnology-based approaches to the treatment of neurodegenerative diseases. The review begins with a brief history of nanotechnology, followed by a discussion of its definition, the properties of most reported nanomaterials, their biocompatibility, the mechanisms of cell-material interactions, and the current status of nanotechnology in treating Alzheimer's, Parkinson's diseases, and amyotrophic lateral sclerosis. Of all strategies to deliver drug to the brain that are used in nanotechnology, drug release systems are the most frequently reported.

  2. Minimally Invasive Early Operative Treatment of Progressive Foot and Ankle Deformity Associated With Charcot-Marie-Tooth Disease.

    PubMed

    Boffeli, Troy J; Tabatt, Jessica A

    2015-01-01

    Charcot-Marie-Tooth disease is a neuromuscular disorder that commonly results in a predictable pattern of progressive bilateral lower extremity weakness, numbness, contracture, and deformity, including drop foot, loss of ankle eversion strength, dislocated hammertoes, and severe cavus foot deformity. Late stage reconstructive surgery will be often necessary if the deformity becomes unbraceable or when neuropathic ulcers have developed. Reconstructive surgery for Charcot-Marie-Tooth deformity is generally extensive and sometimes staged. Traditional reconstructive surgery involves a combination of procedures, including tendon lengthening or transfer, osteotomy, and arthrodesis. The described technique highlights our early surgical approach, which involves limited intervention before the deformity becomes rigid, severe, or disabling. We present 2 cases to contrast our early minimally invasive technique with traditional late stage reconstruction. Charcot-Marie-Tooth disease affects different muscles at various stages of disease progression. As 1 muscle becomes weak, the antagonist will overpower it and cause progressive deformity. The focus of the early minimally invasive approach is to decrease the forces that cause progressive deformity yet maintain function, where possible. Our goal has been to maintain a functional and braceable foot and ankle, with the hope of avoiding or limiting the extent of future major reconstructive surgery. The presented cases highlight the patient selection criteria, the ideal timing of early surgical intervention, the procedure selection criteria, and operative pearls. The early minimally invasive approach includes plantar fasciotomy, Achilles tendon lengthening, transfer of the peroneus longus to the fifth metatarsal, Hibbs and Jones tendon transfer, and hammertoe repair of digits 1 to 5.

  3. Stochastic quasi-Newton method: Application to minimal model for proteins

    NASA Astrophysics Data System (ADS)

    Chau, C. D.; Sevink, G. J. A.; Fraaije, J. G. E. M.

    2011-01-01

    Knowledge of protein folding pathways and inherent structures is of utmost importance for our understanding of biological function, including the rational design of drugs and future treatments against protein misfolds. Computational approaches have now reached the stage where they can assess folding properties and provide data that is complementary to or even inaccessible by experimental imaging techniques. Minimal models of proteins, which make possible the simulation of protein folding dynamics by (systematic) coarse graining, have provided understanding in terms of descriptors for folding, folding kinetics, and folded states. Here we focus on the efficiency of equilibration on the coarse-grained level. In particular, we applied a new regularized stochastic quasi-Newton (S-QN) method, developed for accelerated configurational space sampling while maintaining thermodynamic consistency, to analyze the folding pathway and inherent structures of a selected protein, where regularization was introduced to improve stability. The adaptive compound mobility matrix B in S-QN, determined by a factorized secant update, gives rise to an automated scaling of all modes in the protein, in particular an acceleration of protein domain dynamics or principal modes and a slowing down of fast modes or “soft” bond constraints, similar to lincs/shake algorithms, when compared to conventional Langevin dynamics. We used and analyzed a two-step strategy. Owing to the enhanced sampling properties of S-QN and increased barrier crossing at high temperatures (in reduced units), a hierarchy of inherent protein structures is first efficiently determined by applying S-QN for a single initial structure and T=1>Tθ, where Tθ is the collapse temperature. Second, S-QN simulations for several initial structures at very low temperature (T=0.01

  4. MINIMIZING THE RISK OF PREGNANCY, SEXUALLY TRANSMITTED DISEASES, AND HIV AMONG INCARCERATED ADOLESCENT GIRLS

    PubMed Central

    ST LAWRENCE, JANET S.; SNODGRASS, C. EDWARD; ROBERTSON, ANGELA; BAIRD-THOMAS, CONNIE

    2010-01-01

    Delinquent girls are at elevated risk for unplanned pregnancy and sexually transmitted diseases when compared with non-delinquent peers. Participants—234 incarcerated female juveniles—completed demographic, individual, partner, peer, and family measures and were tested for sexually transmitted diseases. Disease rates were as follows: chlamydia (20%), gonorrhea (4%), and syphilis (1%). Stepwise multiple linear regression analysis assessed the relationship of the predictor variable sets with sexual risk. Demographic and individual variables had the strongest associations with risk. Peer, partner, or family variables did not account for significant additional variance. The results suggest that an intervention could be delivered during the window of opportunity during the girls’ incarceration, changing their knowledge, attitudes, and skills that are implicated in risky sexual behavior before they are released back into the community. PMID:20585415

  5. Minimal Residual Disease and Childhood Leukemia: Standard of Care Recommendations From the Pediatric Oncology Group of Ontario MRD Working Group.

    PubMed

    Athale, Uma H; Gibson, Paul J; Bradley, Nicole M; Malkin, David M; Hitzler, Johann

    2016-06-01

    Minimal residual disease (MRD) is an independent predictor of relapse risk in children with leukemia and is widely used for risk-adapted treatment. This article summarizes current evidence supporting the use of MRD, including clinical significance, current international clinical practice, impact statement, and recommended indications. The proposed MRD recommendations have been endorsed by the MRD Working Group of the Pediatric Oncology Group of Ontario and provide the foundation for a strategy that aims at equitable access to MRD evaluation for children with leukemia.

  6. Should the presence of minimal residual disease (MRD) in morphologic complete remission alter post-remission strategy in AML?

    PubMed

    Stone, Richard M

    2011-12-01

    Minimal residual disease (MRD) monitoring, particularly via multiparameter flow (MPF) cytometry assessed after chemotherapy, has been very useful in the prognostic and therapeutic approach for children with acute lymphoblastic leukemia. While many studies suggest that MRD monitoring (using MPF or other techniques that are more sensitive than morphologic examination) might be able to accurately predict patient outcome, there is very little data suggesting that treatment decisions should be altered based on such measurements. Proving that MPF-defined MRD should prompt a change in treatment plan optimally requires a contemporaneous control group or at least a historical control treated in standard fashion.

  7. Borrelia burgdorferi has minimal impact on the Lyme disease reservoir host Peromyscus leucopus.

    PubMed

    Schwanz, Lisa E; Voordouw, Maarten J; Brisson, Dustin; Ostfeld, Richard S

    2011-02-01

    The epidemiology of vector-borne zoonotic diseases is determined by encounter rates between vectors and hosts. Alterations to the behavior of reservoir hosts caused by the infectious agent have the potential to dramatically alter disease transmission and human risk. We examined the effect of Borrelia burgdorferi, the etiological agent of Lyme disease, on one of its most important reservoir hosts, the white-footed mouse, Peromyscus leucopus. We mimic natural infections in mice using the vector (Black-legged ticks, Ixodes scapularis) and examine the immunological and behavioral responses of mouse hosts. Despite producing antibodies against B. burgdorferi, infected mice did not have elevated white blood cells compared with uninfected mice. In addition, infected and uninfected mice did not differ in their wheel-running activity. Our results suggest that infection with the spirochete B. burgdorferi has little impact on the field activity of white-footed mice. Lyme disease transmission appears to be uncomplicated by pathogen-altered behavior of this reservoir host.

  8. A differential equations approach to l1-minimization with applications to array imaging

    NASA Astrophysics Data System (ADS)

    Moscoso, Miguel; Novikov, Alexei; Papanicolaou, George; Ryzhik, Lenya

    2012-10-01

    We present an ordinary differential equation approach to the analysis of algorithms for constructing l1 minimizing solutions to underdetermined linear systems of full rank. It involves a relaxed minimization problem whose minimum is independent of the relaxation parameter. An advantage of using the ordinary differential equations is that energy methods can be used to prove convergence. The connection to the discrete algorithms is provided by the Crandall-Liggett theory of monotone nonlinear semigroups. We illustrate the effectiveness of the discrete optimization algorithm in some sparse array imaging problems.

  9. Application of optimization techniques to spacecaft fuel usage minimization in deep space navigation

    NASA Technical Reports Server (NTRS)

    Wang, Tseng-Chan; Sunseri, Richard F.; Stanford, Richard H.; Gray, Donald L.; Breckheimer, Peter J.

    1987-01-01

    Mathematical analysis of the minimization of spacecraft fuel usage for both impulsive and finite motor burns is presented. A high precision integrated trajectory search program (SEPV) and several optimization software libraries are used to solve minimum fuel usage problems. The SEPV program has the capacity to vary either the initial spacecraft state or the finite burn parameters to acquire a specified set of target values. Several test examples for the Voyager 2 Uranus Encounter and the Galileo Jupiter Orbiter are presented to show that spacecraft fuel consumption can be minimized in targeting maneuver strategies. The fuel savings achieved by the optimum solution can be significant.

  10. Clonotypic Light Chain Peptides Identified for Monitoring Minimal Residual Disease in Multiple Myeloma without Bone Marrow Aspiration.

    PubMed

    Bergen, H Robert; Dasari, Surendra; Dispenzieri, Angela; Mills, John R; Ramirez-Alvarado, Marina; Tschumper, Renee C; Jelinek, Diane F; Barnidge, David R; Murray, David L

    2016-01-01

    Analytically sensitive techniques for measuring minimal residual disease (MRD) in multiple myeloma (MM) currently require invasive and costly bone marrow aspiration. These methods include immunohistochemistry (IHC), flow cytometry, quantitative PCR, and next-generation sequencing. An ideal MM MRD test would be a serum-based test sensitive enough to detect low concentrations of Ig secreted from multifocal lesions. Patient serum with abundant M-protein before treatment was separated on a 1-dimensional SDS-PAGE gel, and the Ig light-chain (LC) band was excised, trypsin digested, and analyzed on a Q Exactive mass spectrometer by LC-MS/MS. We used the peptide's abundance and sequence to identify tryptic peptides that mapped to complementary determining regions of Ig LCs. The clonotypic target tryptic peptides were used to monitor MRD in subsequent serum samples with prior affinity enrichment. Sixty-two patients were tested, 20 with no detectable disease by IHC and 42 with no detectable disease by 6-color flow cytometry. A target peptide that could be monitored was identified in 57 patients (91%). Of these 57, detectable disease by LC-MS/MS was found in 52 (91%). The ability to use LC-MS/MS to measure disease in patients who are negative by bone marrow-based methodologies indicates that a serum-based approach has more analytical sensitivity and may be useful for measuring deeper responses to MM treatment. The method requires no bone marrow aspiration. © 2015 American Association for Clinical Chemistry.

  11. Is minimally invasive thoracoscopic surgery the new benchmark for treating mitral valve disease?

    PubMed Central

    Goldstone, Andrew B.

    2016-01-01

    The treatment of mitral valve disease remains dynamic; surgeons and patients must now choose between many different surgical options when addressing mitral regurgitation and mitral stenosis. Notably, advances in imaging and surgical instrumentation allow surgeons to perform less invasive mitral valve surgery that spares the sternum. With favorable long-term data now emerging, we compare the benefits and risks of thoracoscopic mitral valve surgery with that through conventional sternotomy or surgery that is robot-assisted. PMID:27942489

  12. Application of the Flexible CO2 Laser in Minimally Invasive Laminectomies: Technical Note

    PubMed Central

    Perez-Cruet, Mick

    2016-01-01

    Background Minimally invasive laminectomy is a very effective surgical method for treating lumbar stenosis. However, this technique can be technically difficult, especially in patients suffering from severe stenosis. The contralateral decompression from a unilateral approach can result in durotomy during removal of the hypertrophied ligamentum flavum. This complication can be difficult to treat through a small working channel. Objective To detail our group’s operative experience with the CO2 laser and discuss our results and previous studies in the literature reporting results.  Methods The CO2 laser (Omniguide, Boston, MA) was investigated in the surgical ablation of the contralateral ligamentum flavum during minimally invasive laminectomies. Forty levels have been investigated thus far. The amount of voltage needed to adequately desiccate and remove the ligamentum flavum safely as well as the effectiveness of this technique were investigated. Results The contralateral ligamentum flavum could be removed effectively using the 9 to 11 watt continuous wavelength (10,600 nanometer) power setting on the CO2 laser. Shrinkage of the contralateral ligamentum flavum facilitated its removal using a number 2 Kerrison Punch. No durotomies occurred, and the use of the laser did not significantly lengthen operative times.  Conclusions The CO2 laser appears to be a useful tool in the armamentarium of instruments available to the minimally invasive spine surgeon and may help to reduce the incidence of durotomies when performing minimally invasive laminectomies. PMID:27433407

  13. Multimodal function optimization using minimal representation size clustering and its application to planning multipaths.

    PubMed

    Hocaoğlu, C; Sanderson, A C

    1997-01-01

    A novel genetic algorithm (GA) using minimal representation size cluster (MRSC) analysis is designed and implemented for solving multimodal function optimization problems. The problem of multimodal function optimization is framed within a hypothesize-and-test paradigm using minimal representation size (minimal complexity) for species formation and a GA. A multiple-population GA is developed to identify different species. The number of populations, thus the number of different species, is determined by the minimal representation size criterion. Therefore, the proposed algorithm reveals the unknown structure of the multimodal function when a priori knowledge about the function is unknown. The effectiveness of the algorithm is demonstrated on a number of multimodal test functions. The proposed scheme results in a highly parallel algorithm for finding multiple local minima. In this paper, a path-planning algorithm is also developed based on the MRSC_GA algorithm. The algorithm utilizes MRSC_GA for planning paths for mobile robots, piano-mover problems, and N-link manipulators. The MRSC_GA is used for generating multipaths to provide alternative solutions to the path-planning problem. The generation of alternative solutions is especially important for planning paths in dynamic environments. A novel iterative multiresolution path representation is used as a basis for the GA coding. The effectiveness of the algorithm is demonstrated on a number of two-dimensional path-planning problems.

  14. A review: the application of minimally invasive surgery to pediatric urology: upper urinary tract procedures.

    PubMed

    Traxel, Erica J; Minevich, Eugene A; Noh, Paul H

    2010-07-01

    This paper is one-half of a 2 part review on minimally-invasive procedures in pediatric urology. This article focuses on upper tract procedures, including complete nephrectomy, partial nephrectomy, pyeloplasty, and ureterocalicostomy. We note important articles on pure laparoscopic as well as robotic-assisted laparoscopic upper urinary tract surgeries, concentrating on their techniques and outcomes.

  15. A review: the application of minimally invasive surgery to pediatric urology: lower urinary tract reconstructive procedures.

    PubMed

    Traxel, Erica J; Minevich, Eugene A; Noh, Paul H

    2010-07-01

    This paper is one-half of a 2 part review on minimally-invasive procedures in pediatric urology. This article focuses on lower tract procedures, including ureteroureterostomy, anti-reflux surgeries, creation of continent catheterizable channels, and augmentation cystoplasty. We note important articles on pure laparoscopic as well as robotic-assisted laparoscopic lower urinary tract surgeries, concentrating on their techniques and outcomes.

  16. Minimally invasive cell-seeded biomaterial systems for injectable/epicardial implantation in ischemic heart disease

    PubMed Central

    Ravichandran, Rajeswari; Venugopal, Jayarama Reddy; Sundarrajan, Subramanian; Mukherjee, Shayanti; Ramakrishna, Seeram

    2012-01-01

    Myocardial infarction (MI) is characterized by heart-wall thinning, myocyte slippage, and ventricular dilation. The injury to the heart-wall muscle after MI is permanent, as after an abundant cell loss the myocardial tissue lacks the intrinsic capability to regenerate. New therapeutics are required for functional improvement and regeneration of the infarcted myocardium, to overcome harmful diagnosis of patients with heart failure, and to overcome the shortage of heart donors. In the past few years, myocardial tissue engineering has emerged as a new and ambitious approach for treating MI. Several left ventricular assist devices and epicardial patches have been developed for MI. These devices and acellular/cellular cardiac patches are employed surgically and sutured to the epicardial surface of the heart, limiting the region of therapeutic benefit. An injectable system offers the potential benefit of minimally invasive release into the myocardium either to restore the injured extracellular matrix or to act as a scaffold for cell delivery. Furthermore, intramyocardial injection of biomaterials and cells has opened new opportunities to explore and also to augment the potentials of this technique to ease morbidity and mortality rates owing to heart failure. This review summarizes the growing body of literature in the field of myocardial tissue engineering, where biomaterial injection, with or without simultaneous cellular delivery, has been pursued to enhance functional and structural outcomes following MI. Additionally, this review also provides a complete outlook on the tissue-engineering therapies presently being used for myocardial regeneration, as well as some perceptivity into the possible issues that may hinder its progress in the future. PMID:23271906

  17. Aptamer and its applications in neurodegenerative diseases.

    PubMed

    Qu, Jing; Yu, Shuqing; Zheng, Yuan; Zheng, Yan; Yang, Hui; Zhang, Jianliang

    2017-02-01

    Aptamers are small single-stranded DNA or RNA oligonucleotide fragments or small peptides, which can bind to targets by high affinity and specificity. Because aptamers are specific, non-immunogenic and non-toxic, they are ideal materials for clinical applications. Neurodegenerative disorders are ravaging the lives of patients. Even though the mechanism of these diseases is still elusive, they are mainly characterized by the accumulation of misfolded proteins in the central nervous system. So it is essential to develop potential measures to slow down or prevent the onset of these diseases. With the advancements of the technologies, aptamers have opened up new areas in this research field. Aptamers could bind with these related target proteins to interrupt their accumulation, subsequently blocking or preventing the process of neurodegenerative diseases. This review presents recent advances in the aptamer generation and its merits and limitations, with emphasis on its applications in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, transmissible spongiform encephalopathy, Huntington's disease and multiple sclerosis.

  18. Differences in the subgingival microbiota of Swedish and USA subjects who were periodontally healthy or exhibited minimal periodontal disease.

    PubMed

    Haffajee, A D; Japlit, M; Bogren, A; Kent, R L; Goodson, J M; Socransky, S S

    2005-01-01

    Previous studies have shown differences in the mean proportions of subgingival species in samples from periodontitis subjects in different countries, which may relate to differences in diet, genetics, disease susceptibility and manifestation. The purpose of the present investigation was to determine whether there were differences in the subgingival microbiotas of Swedish and American subjects who exhibited periodontal health or minimal periodontal disease. One hundred and fifty eight periodontally healthy or minimally diseased subjects (N Sweden=79; USA=79) were recruited. Subjects were measured at baseline for plaque, gingivitis, BOP, suppuration, pocket depth and attachment level at 6 sites per tooth. Subgingival plaque samples taken from the mesial aspect of each tooth at baseline were individually analyzed, in one laboratory, for their content of 40 bacterial species using checkerboard DNA-DNA hybridization (total samples=4345). % DNA probe counts comprised by each species was determined for each site and averaged across sites in each subject. Significance of differences in proportions of each species between countries was determined using ancova adjusting for age, mean pocket depth, gender and smoking status. p values were adjusted for multiple comparisons. Cluster analysis was performed to group subjects based on their subgingival microbial profiles using a chord coefficient and an average unweighted linkage sort. On average, all species were detected in samples from subjects in both countries. After adjusting for multiple comparisons, 5 species were in significantly higher adjusted mean percentages in Swedish than American subjects: Actinomyces naeslundii genospecies 1 (9.7, 3.3); Streptococcus sanguis (2.5, 1.2); Eikenella corrodens (1.7, 1.0); Tannerella forsythensis (3.5, 2.3) and Prevotella melaninogenica (6.3, 1.8). Leptotrichia buccalis was in significantly higher adjusted mean percentages in American (5.5) than Swedish subjects (3.0). Cluster analysis

  19. Comparison between qualitative and real-time polymerase chain reaction to evaluate minimal residual disease in children with acute lymphoblastic leukemia

    PubMed Central

    Paula, Francisco Danilo Ferreira; Elói-Santos, Silvana Maria; Xavier, Sandra Guerra; Ganazza, Mônica Aparecida; Jotta, Patricia Yoshioka; Yunes, José Andrés; Viana, Marcos Borato; Assumpção, Juliana Godoy

    2015-01-01

    Introduction Minimal residual disease is an important independent prognostic factor that can identify poor responders among patients with acute lymphoblastic leukemia. Objective The aim of this study was to analyze minimal residual disease using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements by conventional polymerase chain reaction followed by homo-heteroduplex analysis and to compare this with real-time polymerase chain reaction at the end of the induction period in children with acute lymphoblastic leukemia. Methods Seventy-four patients diagnosed with acute lymphoblastic leukemia were enrolled. Minimal residual disease was evaluated by qualitative polymerase chain reaction in 57 and by both tests in 44. The Kaplan–Meier and multivariate Cox methods and the log-rank test were used for statistical analysis. Results Nine patients (15.8%) were positive for minimal residual disease by qualitative polymerase chain reaction and 11 (25%) by real-time polymerase chain reaction considering a cut-off point of 1 × 10−3 for precursor B-cell acute lymphoblastic leukemia and 1 × 10−2 for T-cell acute lymphoblastic leukemia. Using the qualitative method, the 3.5-year leukemia-free survival was significantly higher in children negative for minimal residual disease compared to those with positive results (84.1% ± 5.6% versus 41.7% ± 17.3%, respectively; p-value = 0.004). There was no significant association between leukemia-free survival and minimal residual disease by real-time polymerase chain reaction. Minimal residual disease by qualitative polymerase chain reaction was the only variable significantly correlated to leukemia-free survival. Conclusion Given the difficulties in the implementation of minimal residual disease monitoring by real-time polymerase chain reaction in most treatment centers in Brazil, the qualitative polymerase chain reaction strategy may be a cost-effective alternative. PMID:26670399

  20. Adult intake of minimally processed fruits and vegetables: Associations with cardiometabolic disease risk factors

    PubMed Central

    Horino, Masako; McCarthy, William J.

    2016-01-01

    Background The U.S. Department of Agriculture launchedChooseMyPlate.gov nutrition recommendations designed to encourage increased fruit and vegetable intake in part as a strategy for improving weight control through the consumption of high satiation foods. Objective The purpose of this cross-sectional study was to assess the relationship between adults’ reported daily intake of fruits and non-starchy vegetables (i.e., those thought to have the lowest energy density) expressed as a proportion of their total daily food intake and objectively measured cardiovascular and metabolic disease risk factors using data from the 2009–2010 National Health and Examination Survey (NHANES). Physical activity was included as a moderator variable. Design This study employed a cross-sectional examination of 2009–2010 NHANES data to assess how daily fruit and non-starchy vegetable intake were associated with anthropometric measures and cardiometabolic blood chemistry markers. Participants/setting Adults free of cardiac or metabolic disease (N=1,197) participated in 24-hour dietary recalls; a variety of cardiometabolic biomarkers and anthropometric measures were also collected from participants. Main outcome measures Among participants with complete data on all variables, the ratio of the combined cup equivalents of fruit and non-starchy vegetable intake to the total gram weight of all foods consumed daily (FV ratio) served as the primary independent variable. Main dependent measures included: fasting glucose, insulin, glycosylated hemoglobin, HDL cholesterol, LDL cholesterol, triglycerides, total cholesterol, waist circumference, and body mass index. Statistical analyses performed Demographic and behavioral predictors of the FV ratio and the association between the FV ratio and cardiometabolic disease risk factors were examined using multivariate regression. Results BMI (β = −2.58, 95% CI [−3.88, −1.28]), waist circumference (β = −6.33, 95% CI [−9.81, −2.84]), and

  1. Adult Intake of Minimally Processed Fruits and Vegetables: Associations with Cardiometabolic Disease Risk Factors.

    PubMed

    Cavallo, David N; Horino, Masako; McCarthy, William J

    2016-09-01

    The US Department of Agriculture launched ChooseMyPlate.gov nutrition recommendations designed to encourage increased fruit and vegetable intake, in part, as a strategy for improving weight control through the consumption of high-satiation foods. The purpose of this cross-sectional study was to assess the relationship between adults' reported daily intake of fruits and nonstarchy vegetables (ie, those thought to have the lowest energy density) expressed as a proportion of their total daily food intake and objectively measured cardiovascular and metabolic disease risk factors using data from the 2009-2010 National Health and Nutrition Examination Survey (NHANES). Physical activity was included as a moderator variable. This study employed a cross-sectional examination of 2009-2010 NHANES data to assess how daily fruit and nonstarchy vegetable intake was associated with anthropometric measures and cardiometabolic blood chemistry markers. Adults free of cardiac or metabolic disease (n=1,197) participated in 24-hour dietary recalls; a variety of cardiometabolic biomarkers and anthropometric measures were also collected from participants. Among participants with complete data on all variables, the ratio of the combined cup-equivalents of fruit and nonstarchy vegetable intake to the total gram weight of all foods consumed daily (F/V ratio) served as the primary independent variable. Main dependent measures included fasting glucose, insulin, glycosylated hemoglobin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol, waist circumference, and body mass index. Demographic and behavioral predictors of the F/V ratio and the association between the F/V ratio and cardiometabolic disease risk factors were examined using multivariate regression. Body mass index (β=-2.58; 95% CI -3.88 to -1.28), waist circumference (β=-6.33; 95% CI -9.81 to -2.84), and insulin (β=-0.21; 95% CI -0.37 to -0.05) were inversely

  2. Robotic applications in the treatment of diseases of the esophagus.

    PubMed

    Kastenmeier, Andrew; Gonzales, Hiram; Gould, Jon C

    2012-08-01

    Minimally invasive treatment of esophageal diseases such as gastroesophageal reflux disease, achalasia, and esophageal cancer is associated with many of the benefits observed after the minimally invasive surgery for other diseases (such as symptomatic cholelithiasis) when compared with the open approach. Laparoscopic treatment of these esophageal conditions is technically complex and subject to several inherent limitations. Robotic surgical systems may allow surgeons to overcome many of these obstacles, enabling more widespread adaptation of these techniques.

  3. Iterative methods for obtaining energy-minimizing parametric snakes with applications to medical imaging.

    PubMed

    Mitrea, Alexandru Ioan; Badea, Radu; Mitrea, Delia; Nedevschi, Sergiu; Mitrea, Paulina; Ivan, Dumitru Mircea; Gurzău, Octavian Mircia

    2012-01-01

    After a brief survey on the parametric deformable models, we develop an iterative method based on the finite difference schemes in order to obtain energy-minimizing snakes. We estimate the approximation error, the residue, and the truncature error related to the corresponding algorithm, then we discuss its convergence, consistency, and stability. Some aspects regarding the prosthetic sugical methods that implement the above numerical methods are also pointed out.

  4. Pollution balance method and the demonstration of its application to minimizing waste in a biochemical process

    SciTech Connect

    Hilaly, A.K.; Sikdar, S.K.

    1995-06-01

    In this study, the authors introduced several modifications to the WAR (waste reduction) algorithm developed earlier. These modifications were made for systematically handling sensitivity analysis and various tasks of waste minimization. A design hierarchy was formulated to promote appropriate waste reduction tasks at designated levels of the hierarchy. A sensitivity coefficient was used to measure the relative impacts of process variables on the pollution index of a process. The use of the WAR algorithm was demonstrated by a fermentation process for making penicillin.

  5. Iterative Methods for Obtaining Energy-Minimizing Parametric Snakes with Applications to Medical Imaging

    PubMed Central

    Mitrea, Alexandru Ioan; Badea, Radu; Mitrea, Delia; Nedevschi, Sergiu; Mitrea, Paulina; Ivan, Dumitru Mircea; Gurzău, Octavian Mircia

    2012-01-01

    After a brief survey on the parametric deformable models, we develop an iterative method based on the finite difference schemes in order to obtain energy-minimizing snakes. We estimate the approximation error, the residue, and the truncature error related to the corresponding algorithm, then we discuss its convergence, consistency, and stability. Some aspects regarding the prosthetic sugical methods that implement the above numerical methods are also pointed out. PMID:22474542

  6. Effectiveness of minimally supervised home aerobic training in patients with systemic rheumatic disease.

    PubMed

    Daltroy, L H; Robb-Nicholson, C; Iversen, M D; Wright, E A; Liang, M H

    1995-11-01

    The effectiveness of an exercise prescription and unsupervised home exercise programme was tested on 37 subjects with rheumatoid arthritis and 34 with systemic lupus erythematosus. Subjects were randomly assigned to control or stationary bicycling at home, using loaned bicycles. Exercise subjects (with bicycles) did better than controls, but not significantly, on all outcomed measures (exercise tolerance test, fatigue, depression and helplessness) at 3 months. Bicycles were reclaimed at 3 months and all subjects in both groups given instructions for home exercise. Exercise in the second 3 months was predicted primarily by baseline exercise habits and fatigue. It is concluded that although safe, unsupervised home exercise programmes may benefit few patients. Future research should address methods of stimulating and maintaining unsupervised exercise programmes in patients with systemic rheumatic disease.

  7. Minimally invasive biopsy of parasellar lesions: safety and clinical applications of the endoscopic, transnasal approach.

    PubMed

    Samandouras, George; Kerr, Richard S C; Milford, Chris A

    2005-08-01

    The base of the skull can be affected by a variety of tumours requiring a wide range of treatment modalities. In formulating a management plan, histological diagnosis can play an essential role. Existing methods of skull base biopsy, especially in the anatomically critical parasellar region, include either prolonged open skull base approaches or image-guided needle biopsies. The latter methods can be time-consuming and cannot reliably avoid surrounding critical neurovascular structures. The experience with an endoscopic, transnasal biopsy of parasellar tumours in selected patients is presented. A preliminary series of 11 patients harbouring parasellar lesions with some degree of extension to the sphenoid or maxillary sinus underwent endoscopic, transnasal biopsy. The procedure was diagnostic in all cases. There was no operative mortality and minimal morbidity only recorded. The biopsy results affected the patients' management and, based on these results, major skull base surgery was avoided in four cases. Direct endoscopic visualization prompted avoidance of a vascular catastrophe of an atypical vascular lesion. The endoscopic, transnasal biopsy appears to offer a number of advantages over existing methods in selected patients. It is minimally invasive as it employs the use of natural osseous corridors. Tissue sampling under direct visualization minimizes the risks of negative biopsies or damage to critical neurovascular structures. The use of additional imaging employed by image-guided needle biopsies in not necessary. When planning treatment of parasellar tumours, the endoscopic, transnasal route should be considered.

  8. Minimally invasive coronary artery bypass grafting versus stenting for patients with proximal left anterior descending coronary artery disease.

    PubMed

    Shirai, Kazuyuki; Lansky, Alexandra J; Mehran, Roxana; Dangas, George D; Costantini, Costantino O; Fahy, Martin; Slack, Steven; Mintz, Gary S; Stone, Gregg W; Leon, Martin B

    2004-04-15

    The purpose of this study was to compare the clinical outcomes of stenting and minimally invasive coronary artery bypass grafting (MIDCAB) in patients with proximal left anterior descending (LAD) coronary artery disease. The Patency, Outcome, Economics of Minimally invasive direct coronary bypass (POEM) study demonstrated that MIDCAB had similar safety and long-term efficacy for LAD revascularization compared with conventional coronary artery bypass grafting. Although LAD stenting is superior to conventional balloon angioplasty, whether it is comparable to MIDCAB is not known. We identified a matched population of 429 consecutive patients with 1-vessel disease who underwent elective proximal LAD stenting and compared their clinical outcomes with those of the 152 patients in the MIDCAB group of the POEM study. The in-hospital event rate was similar in both groups, except for a shorter length of hospital stay with LAD stenting compared with MIDCAB (2.68 vs 4.07 days, p <0.0001). At 6-month follow-up, the incidence of death and Q-wave myocardial infarction or that of cerebrovascular accident was not significantly different between these 2 groups. However, target vessel revascularization was significantly higher with LAD stenting than MIDCAB (13.3% vs 6.6%, p = 0.045). In the subgroup of patients without diabetes, all clinical events were similar in both groups, and the benefit of a shorter hospital stay associated with stenting was maintained. Compared with MIDCAB, LAD stenting is associated with higher repeat revascularization rates but offers the advantage of shorter hospitalization. For nondiabetics with proximal LAD disease, stenting may be the revascularization strategy of choice.

  9. Serum permeability activity in steroid-resistant minimal change nephrotic syndrome is abolished by treatment of Hodgkin disease.

    PubMed

    Aggarwal, Nidhi; Batwara, Ruchika; McCarthy, Ellen T; Sharma, Ram; Sharma, Mukut; Savin, Virginia J

    2007-11-01

    A circulating permeability factor is present in some patients with minimal change nephrotic syndrome (MCNS) or focal segmental glomerulosclerosis. Nephrotic syndrome occurs in less than 1% of patients with Hodgkin disease. A substance derived from T lymphocytes may be responsible for proteinuria in these patients, but a circulating permeability factor was not shown. Serum permeability activity (P(alb)) of a young man who presented with MCNS was tested over 11 years. He first was treated with oral prednisone, then cyclosporine (CsA; 4 mg/kg/d). Two years after the initial diagnosis, during CsA-induced remission of nephrotic syndrome, Hodgkin disease was diagnosed and he underwent systemic chemotherapy with doxorubicin hydrochloride, bleomycin, vinblastine, and dacarbazine and radiation therapy. P(alb) was 0.67 before CsA therapy. Although CsA treatment decreased proteinuria to protein less than 100 mg/d, P(alb) did not change. P(alb) decreased to 0.19 within 2 weeks of initiation of chemotherapy for Hodgkin disease and has remained at less than 0.17 for the last 9 years. The patient, in remission from Hodgkin disease, has normal renal function and no detectable proteinuria. This is the first demonstration of the presence of P(alb) in a patient with MCNS and subsequent Hodgkin disease. It also is the first report that aggressive chemotherapy abolishes P(alb). Although the potential causal relationship between nephrotic syndrome and Hodgkin disease in this patient is not clear, the immediate decrease in P(alb) during treatment suggests that aggressive chemotherapy may be an effective treatment for patients with high P(alb) in steroid-resistant MCNS or focal segmental glomerulosclerosis.

  10. [The application of minimally invasive surgery for different type of thoracolumbar fractures].

    PubMed

    Shui, Xiao-long; Xu, Hua-zi; Chi, Yong-long; Ni, Wen-fei; Lin, Yan; Huang, Qi-shan; Mao, Fang-min; Wang, Xiang-yang; Wang, Sheng; Xu, Hui

    2011-12-01

    To study the therapeutic method and effect of minimally invasive surgery for the thoracolumbar fractures. A retrospective review of the minimally invasive surgically treatment thoracolumbar fractures from February 2005 to June 2010 was performed. There were 183 cases, 126 males and 57 females, aged 18 to 68 years, average 38.9 years. The involved levels of fractures were T(11) in 22, T(12) in 61, L(1) in 71, L(2) in 29. According to Gertzbein classification, 145 cases were type A fractures, 34 cases were type B fractures, 4 cases were type C fractures; According to Load-sharing score, 51 cases were 4 scores, 56 cases were 5 scores, 17 cases were 6 scores, 12 cases were 7 scores, 24 cases were 8 scores, 23 cases were 9 scores. Different surgical methods were selected according to the minimally invasive surgical strategy, 22 patients were treated with the minimally invasive percutaneous pedicle screws osteosynthesis (MIPPSO group), 102 patients were treated with the small-incision pedicle screws osteosynthesis (SISPSO group), 31 patients were treated with the small incision anterior thoracolumbar surgery (SIATS group) assisted by thoracoscope or headlight, and 28 patients were treated with the 270° decompression and reconstruction surgery (270° DRS group) via a posterior small incision. Preoperative and postoperative neurological status, the correction and loss of Cobb's angle, the decompression scope of spinal canal, the location and union of bone graft were followed up and reviewed. All of 183 cases had successful surgery and were followed up. In the MIPPSO group, operative time was 52 - 100 min, blood loss was 35 - 55 ml. In the the SISPSO group, operative time was 48-68 min, the blood loss was 45 - 65 ml the correction of Cobb's angle in the two groups was 8° - 19°. In the SIATS group, operative time was 140 - 220 min, the blood loss was 160 - 1500 ml the correction of Cobb's angle was 15° - 25°, 1 case had pleural effusion, 1 had lateral femoral cutaneous

  11. Management of diabetes across the course of disease: minimizing obesity-associated complications

    PubMed Central

    Apovian, Caroline M

    2011-01-01

    Obesity increases the risk for developing type 2 diabetes mellitus (T2DM) and this in turn correlates with an elevated probability of long-term diabetes complications once diabetes is established. Interventions aimed at lowering weight via changes in diet and lifestyle have repeatedly been shown to improve glycemic control in patients with T2DM and even to reverse early disease. Weight gain, a potential side effect of treatment for patients with T2DM, is also an important concern, and it has been noted that weight increases associated with antidiabetes therapy may blunt cardiovascular risk reductions achieved by decreasing blood glucose. Among older agents, metformin and acarbose have the lowest risk for weight gain, while sulfonylureas, meglitinides, and thiazolidinediones are all associated with weight increases. Clinical trial results have also consistently demonstrated that treatment with glucagon-like peptide-1 receptor agonists and amylin lowers weight, and that dipeptidyl peptidase-4 inhibitors are weight neutral in patients with T2DM. Conventional human insulin formulations are known to increase weight in patients with T2DM. However, some insulin analogs, particularly insulin detemir, have lower liability for this adverse event. The use of both pharmacologic and surgical therapies aimed at treating obesity rather than lowering blood glucose have the potential to improve glycemic control and even resolve T2DM in some patients. PMID:22135499

  12. Minimization of Radiation Exposure due to Computed Tomography in Inflammatory Bowel Disease

    PubMed Central

    Mc Laughlin, Patrick D.; O'Connor, Owen J.; O'Neill, Siobhán B.; Shanahan, Fergus; Maher, Michael M.

    2012-01-01

    Patient awareness and concern regarding the potential health risks from ionizing radiation have peaked recently (Coakley et al., 2011) following widespread press and media coverage of the projected cancer risks from the increasing use of computed tomography (CT) (Berrington et al., 2007). The typical young and educated patient with inflammatory bowel disease (IBD) may in particular be conscious of his/her exposure to ionising radiation as a result of diagnostic imaging. Cumulative effective doses (CEDs) in patients with IBD have been reported as being high and are rising, primarily due to the more widespread and repeated use of CT (Desmond et al., 2008). Radiologists, technologists, and referring physicians have a responsibility to firstly counsel their patients accurately regarding the actual risks of ionizing radiation exposure; secondly to limit the use of those imaging modalities which involve ionising radiation to clinical situations where they are likely to change management; thirdly to ensure that a diagnostic quality imaging examination is acquired with lowest possible radiation exposure. In this paper, we synopsize available evidence related to radiation exposure and risk and we report advances in low-dose CT technology and examine the role for alternative imaging modalities such as ultrasonography or magnetic resonance imaging which avoid radiation exposure. PMID:22577571

  13. [Application of saliva in disease diagnosis].

    PubMed

    Xingqun, Cheng; Xuedong, Zhou; Xin, Xu

    2016-12-01

    Saliva is secreted by salivary glands and performs a variety of functions, including mouth cleaning and protection, antibacterial activity, and digestion. With the rapid progress in salivaomics, saliva became recognized as a potential pool of biological markers. Being a non-invasive and safe source, saliva is a potential substitute for blood in diagnosis and prognosis of diseases. This review summarizes the latest advancement in saliva-related studies and presents the potential value of saliva in early diagnosis of oral diseases, such as dental caries, periodontal disease, cancer, diabetes, and other systemic disorders. Saliva biomarkers can reveal changes ranging from changes in biochemical index, DNA, RNA, and proteins to the diversification of microbiota structure. By integrating recent data, this paper discusses the clinical significance and application prospect of saliva in early diagnosis of diseases and in translational and precision medicine.

  14. Superiority of traditional village diet and lifestyle in minimizing cardiovascular disease risk in Papua New Guineans.

    PubMed

    Kende, M

    2001-01-01

    In the traditional society of Papua New Guinea (PNG) atherosclerotic cardiovascular diseases (CVD) are rare. However, among the urban population reports of cases of atheroma-related CVD are increasing. The purpose of this study was therefore to compare the CVD risk factors in a homogeneous population of the Southern Highlands Province living in both rural and urban areas differing only in their diet and lifestyle. A total of 221 Samberigi people over the age of 25 years were selected for the survey. These included 123 individuals from remote villages of Samberigi and 98 of their relatives who had lived in Port Moresby city continuously for a minimum of 5 years. The anthropometric measurements, blood lipid, blood glucose and glycosylated haemoglobin (HbA1c) levels were measured and compared. The rural diets were mainly of vegetarian type, limited in variety and low in fat and protein content. In the urban subjects, the typical meal comprised refined foods with high fat and protein content. The urban men and women had significantly (p < 0.05) greater body weight, body mass index (BMI), and waist and hip circumferences than their rural counterparts. In Port Moresby, 57% of the men and 67% of the women were overweight or obese compared to 28% of their rural counterparts. Similarly, the mean plasma total cholesterol, low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), fasting blood glucose and HbA1c were significantly higher in the urban group. However, no significant differences were demonstrated for waist to hip ratio, LDLC/HDLC ratio and lipoprotein (a) levels between the two groups. The total cholesterol, LDLC and HbA1c were positively associated with age and BMI in both rural and urban locations. In conclusion, there were significant increases in CVD risk factors in the urban population compared to the rural residents. This was predominantly due to the adoption of a western lifestyle and diet as people moved from rural villages

  15. Features and Role of Minimally Invasive Palliative Procedures for Pain Management in Malignant Pelvic Diseases: A Review.

    PubMed

    Cascella, Marco; Muzio, Maria Rosaria; Viscardi, Daniela; Cuomo, Arturo

    2017-07-01

    Pain is a common and debilitating symptom in pelvic cancer diseases. Failure in controlling this pain through pharmacological approaches calls for employing multimodal management and invasive techniques. Various strategies are commonly used for this purpose, including palliative radiotherapy, epidural medications and intrathecal administration of analgesic and local anesthetic drugs with pumps, and neural or plexus blockade. This review focuses on the features of minimally invasive palliative procedures (MIPPs), such as radiofrequency ablation, laser-induced thermotherapy, cryoablation, irreversible electroporation, electrochemotherapy, microwave ablation, and cementoplasty as well as their role in palliation of cancer pelvic pain. Despite the evidence of effectiveness and safety of these interventions, there are still many barriers to accessing MIPPs, including the availability of trained staff, the lack of precise criteria of indication, and the high costs.

  16. A clofarabine-based bridging regimen in patients with relapsed ALL and persistent minimal residual disease (MRD).

    PubMed

    Gossai, N; Verneris, M R; Karras, N A; Gorman, M F; Patel, N J; Burke, M J

    2014-03-01

    In patients with relapsed ALL, minimal residual disease (MRD) identified prior to allogeneic hematopoietic cell transplantation (HCT) is a strong predictor of relapse. We report our experience using a combination of reduced-dosing clofarabine, CY and etoposide as a 'bridge' to HCT in eight patients with high risk or relapsed ALL and pre-HCT MRD. All patients had detectable MRD (>0.01%, flow cytometry) at the start of therapy with all eight achieving MRD reduction following one cycle. The regimen was well tolerated with seven grade 3/4 toxicities occurring among four of the eight patients. Five patients (62.5%) are alive, one died from relapse (12.5%) and two from transplant-related mortality (25%). The combination of reduced-dose clofarabine, CY and etoposide as bridging therapy appears to be well tolerated in patients with relapsed ALL and is effective in reducing pre-HCT MRD.

  17. Davidon-Broyden rank-one minimization methods in Hilbert space with application to optimal control problems

    NASA Technical Reports Server (NTRS)

    Straeter, T. A.

    1972-01-01

    The Davidon-Broyden class of rank one, quasi-Newton minimization methods is extended from Euclidean spaces to infinite-dimensional, real Hilbert spaces. For several techniques of choosing the step size, conditions are found which assure convergence of the associated iterates to the location of the minimum of a positive definite quadratic functional. For those techniques, convergence is achieved without the problem of the computation of a one-dimensional minimum at each iteration. The application of this class of minimization methods for the direct computation of the solution of an optimal control problem is outlined. The performance of various members of the class are compared by solving a sample optimal control problem. Finally, the sample problem is solved by other known gradient methods, and the results are compared with those obtained with the rank one quasi-Newton methods.

  18. System pharmacogenomics application in infectious diseases.

    PubMed

    Mandlik, Vineetha; Kabra, Ritika; Singh, Shailza

    2017-03-21

    The new era in systems pharmacology has revolutionized the human biology. Its applicability, precise treatment, adequate response and safety measures fit into all the paradigm of medical/clinical practice. The importance of mathematical models in understanding the disease pathology and epideomology is now being realized. The advent of high-throughput technologies and the emergence of systems biology have resulted in the creation of systems pharmacogenomics and the focus is now on personalized medicine. However, there are some regulatory issues that need to be addresssed; are we ready for this universal adoption? This article details some of the infectious disease pharmacogenomics to the developments in this area.

  19. Minimal energy packings of weakly semiflexible polymers: Application to targeted self-assembly of nanostructures

    NASA Astrophysics Data System (ADS)

    Harwayne-Gidansky, Jared; Hoy, Robert S.; O'Hern, Corey S.

    2012-02-01

    Using exact enumeration, we characterize how structure, mechanical and thermodynamic stability of minimal energy packings of short ``sticky tangent sphere'' (SHS) polymer chains vary with angular interaction strength kb and equilibrium bond angle θ0. While flexible SHS polymers possess highly degenerate ground states (i. e. many differently ordered ``macrostates'' [1]), angular interactions dramatically break this degeneracy. The macrostate associated with the ground state semiflexible packing changes as kb and θ0 are varied. Further degeneracy breaking arises from angular interactions' influence on packing size, asymmetry, and vibrational entropy. The strength of these effects increases with chain length N. Our exact analysis provides design principles for self-assembly of polymers into a variety of structures that can be tuned by varying N, kb and θ0. [4pt] [1] R. S. Hoy and C. S. O'Hern, Phys. Rev. Lett. 105, 068001 (2010).

  20. Application of edible coating with starch and carvacrol in minimally processed pumpkin.

    PubMed

    Santos, Adriele R; da Silva, Alex F; Amaral, Viviane C S; Ribeiro, Alessandra B; de Abreu Filho, Benicio A; Mikcha, Jane M G

    2016-04-01

    The present study evaluated the effect of an edible coating of cassava starch and carvacrol in minimally processed pumpkin (MPP). The minimal inhibitory concentration (MIC) of carvacrol against Escherichia coli, Salmonella enterica serotype Typhimurium, Aeromonas hydrophila, and Staphylococcus aureus was determined. The edible coating that contained carvacrol at the MIC and 2 × MIC was applied to MPP, and effects were evaluated with regard to the survival of experimentally inoculated bacteria and autochthonous microflora in MPP. Total titratable acidity, pH, weight loss, and soluble solids over 7 days of storage under refrigeration was also analyzed. MIC of carvacrol was 312 μg/ml. Carvacrol at the MIC reduced the counts of E. coli and S. Typhimurium by approximately 5 log CFU/g. A. hydrophila was reduced by approximately 8 log CFU/g, and S. aureus was reduced by approximately 2 log CFU/g on the seventh day of storage. Carvacrol at the 2 × MIC completely inhibited all isolates on the first day of Storage. coliforms at 35 °C and 45 °C were not detected (< 3 MPN/g) with either treatment on all days of shelf life. The treatment groups exhibited a reduction of approximately 2 log CFU/g in psychrotrophic counts compared with controls on the last day of storage. Yeast and mold were not detected with either treatment over the same period. The addition of carvacrol did not affect total titratable acidity, pH, or soluble solids and improved weight loss. The edible coating of cassava starch with carvacrol may be an interesting approach to improve the safety and microbiological quality of MPP.

  1. Periodic Application of Stochastic Cost Optimization Methodology to Achieve Remediation Objectives with Minimized Life Cycle Cost

    NASA Astrophysics Data System (ADS)

    Kim, U.; Parker, J.

    2016-12-01

    Many dense non-aqueous phase liquid (DNAPL) contaminated sites in the U.S. are reported as "remediation in progress" (RIP). However, the cost to complete (CTC) remediation at these sites is highly uncertain and in many cases, the current remediation plan may need to be modified or replaced to achieve remediation objectives. This study evaluates the effectiveness of iterative stochastic cost optimization that incorporates new field data for periodic parameter recalibration to incrementally reduce prediction uncertainty and implement remediation design modifications as needed to minimize the life cycle cost (i.e., CTC). This systematic approach, using the Stochastic Cost Optimization Toolkit (SCOToolkit), enables early identification and correction of problems to stay on track for completion while minimizing the expected (i.e., probability-weighted average) CTC. This study considers a hypothetical site involving multiple DNAPL sources in an unconfined aquifer using thermal treatment for source reduction and electron donor injection for dissolved plume control. The initial design is based on stochastic optimization using model parameters and their joint uncertainty based on calibration to site characterization data. The model is periodically recalibrated using new monitoring data and performance data for the operating remediation systems. Projected future performance using the current remediation plan is assessed and reoptimization of operational variables for the current system or consideration of alternative designs are considered depending on the assessment results. We compare remediation duration and cost for the stepwise re-optimization approach with single stage optimization as well as with a non-optimized design based on typical engineering practice.

  2. Development of optical fiber Bragg grating force-reflection sensor system of medical application for safe minimally invasive robotic surgery

    NASA Astrophysics Data System (ADS)

    Song, Hoseok; Kim, Kiyoung; Lee, Jungju

    2011-07-01

    Force feedback plays a very important role in medical surgery. In minimally invasive surgery (MIS), however, the very long and stiff bars of surgical instruments greatly diminish force feedback for the surgeon. In the case of minimally invasive robotic surgery (MIRS), force feedback is totally eliminated. Previous researchers have reported that the absence of force feedback increased the average force magnitude applied to the tissue by at least 50%, and increased the peak force magnitude by at least a factor of two. Therefore, it is very important to provide force information in MIRS. Recently, many sensors are being developed for MIS and MIRS, but some obstacles to their application in actual medical surgery must be surmounted. The most critical problems are size limit and sterilizability. Optical fiber sensors are among the most suitable sensors for the surgical environment. The optical fiber Bragg grating (FBG) sensor, in particular, offers an important additional advantage over other optical fiber sensors in that it is not influenced by the intensity of the light source. In this paper, we present the initial results of a study on the application of a FBG sensor to measure reflected forces in MIRS environments and suggest the possibility of successful application to MIRS systems.

  3. Application of augmented-Lagrangian methods in meteorology: Comparison of different conjugate-gradient codes for large-scale minimization

    NASA Technical Reports Server (NTRS)

    Navon, I. M.

    1984-01-01

    A Lagrange multiplier method using techniques developed by Bertsekas (1982) was applied to solving the problem of enforcing simultaneous conservation of the nonlinear integral invariants of the shallow water equations on a limited area domain. This application of nonlinear constrained optimization is of the large dimensional type and the conjugate gradient method was found to be the only computationally viable method for the unconstrained minimization. Several conjugate-gradient codes were tested and compared for increasing accuracy requirements. Robustness and computational efficiency were the principal criteria.

  4. Application of augmented-Lagrangian methods in meteorology: Comparison of different conjugate-gradient codes for large-scale minimization

    NASA Technical Reports Server (NTRS)

    Navon, I. M.

    1984-01-01

    A Lagrange multiplier method using techniques developed by Bertsekas (1982) was applied to solving the problem of enforcing simultaneous conservation of the nonlinear integral invariants of the shallow water equations on a limited area domain. This application of nonlinear constrained optimization is of the large dimensional type and the conjugate gradient method was found to be the only computationally viable method for the unconstrained minimization. Several conjugate-gradient codes were tested and compared for increasing accuracy requirements. Robustness and computational efficiency were the principal criteria.

  5. Detection of Minimal Residual Disease by Flow Cytometry for Patients with Multiple Myeloma Submitted to Autologous Hematopoietic Stem Cell Transplantation

    PubMed Central

    Dal Bó, Suzane; Pezzi, Annelise; Amorin, Bruna; Valim, Vanessa; Isabel Bittencourt, Rosane; Silla, Lucia

    2013-01-01

    The treatment strategy in multiple myeloma (MM) is to get complete remission followed by high-dose chemotherapy and autologous Hematopoietic Stem Cell Transplantation (HSCT). Neoplastic Plasma Cells (NPCs) are CD45−/dim, CD38+high, CD138+, CD19−, and  CD56+high in most cases. The description of this immunophenotype is of major importance as it leads to the correct identification of minimal residual disease (MRD). Samples from 44 Patients were analyzed prospectively in this study. We analyzed if the presence of MRD at three months after HSCT was predictive of relapse or death. There were 40 evaluable patients of whom 16/40 patients had MRD at three moths after HSCT and there were none in cytological relapse. The mean overall survival (OS) was 34 months and disease-free survival (RFS) was 28 months after HSCT. There was no significant difference in the log rank analysis comparing OS and the presence of MRD (P = 0,611) and RFS (P = 0,3106). Here, we demonstrate that three color flow cytometry (FCM) is more sensitive for MDR evaluation than cytological analyzes. However, based in our data we can not affirm that MRD is a good predictor of MM relapse or death. In conclusion, our results could be attributed to a short followup, small sample size, and over most to the inability of a three-color FCM to detect the NPC population. PMID:23864957

  6. Targeted gene correction minimally impacts whole-genome mutational load in human-disease-specific induced pluripotent stem cell clones.

    PubMed

    Suzuki, Keiichiro; Yu, Chang; Qu, Jing; Li, Mo; Yao, Xiaotian; Yuan, Tingting; Goebl, April; Tang, Senwei; Ren, Ruotong; Aizawa, Emi; Zhang, Fan; Xu, Xiuling; Soligalla, Rupa Devi; Chen, Feng; Kim, Jessica; Kim, Na Young; Liao, Hsin-Kai; Benner, Chris; Esteban, Concepcion Rodriguez; Jin, Yabin; Liu, Guang-Hui; Li, Yingrui; Izpisua Belmonte, Juan Carlos

    2014-07-03

    The utility of genome editing technologies for disease modeling and developing cellular therapies has been extensively documented, but the impact of these technologies on mutational load at the whole-genome level remains unclear. We performed whole-genome sequencing to evaluate the mutational load at single-base resolution in individual gene-corrected human induced pluripotent stem cell (hiPSC) clones in three different disease models. In single-cell clones, gene correction by helper-dependent adenoviral vector (HDAdV) or Transcription Activator-Like Effector Nuclease (TALEN) exhibited few off-target effects and a low level of sequence variation, comparable to that accumulated in routine hiPSC culture. The sequence variants were randomly distributed and unique to individual clones. We also combined both technologies and developed a TALEN-HDAdV hybrid vector, which significantly increased gene-correction efficiency in hiPSCs. Therefore, with careful monitoring via whole-genome sequencing it is possible to apply genome editing to human pluripotent cells with minimal impact on genomic mutational load.

  7. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

    PubMed Central

    Tie, Jeanne; Wang, Yuxuan; Tomasetti, Cristian; Li, Lu; Springer, Simeon; Kinde, Isaac; Silliman, Natalie; Tacey, Mark; Wong, Hui-Li; Christie, Michael; Kosmider, Suzanne; Skinner, Iain; Wong, Rachel; Steel, Malcolm; Tran, Ben; Desai, Jayesh; Jones, Ian; Haydon, Andrew; Hayes, Theresa; Price, Tim J.; Strausberg, Robert L.; Diaz, Luis A.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Gibbs, Peter

    2017-01-01

    Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence. PMID:27384348

  8. Early detection of tumor relapse/regrowth by consecutive minimal residual disease monitoring in high-risk neuroblastoma patients

    PubMed Central

    Hirase, Satoshi; Saitoh, Atsuro; Hartomo, Tri Budi; Kozaki, Aiko; Yanai, Tomoko; Hasegawa, Daiichiro; Kawasaki, Keiichiro; Kosaka, Yoshiyuki; Matsuo, Masafumi; Yamamoto, Nobuyuki; Mori, Takeshi; Hayakawa, Akira; Iijima, Kazumoto; Nishio, Hisahide; Nishimura, Noriyuki

    2016-01-01

    Neuroblastoma is an aggressive pediatric tumor accounting for ~15% of cancer-associated mortalities in children. Despite the current intensive therapy, >50% of high-risk patients experience tumor relapse or regrowth caused by the activation of minimal residual disease (MRD). Although several MRD detection protocols using various reverse transcription-quantitative polymerase chain reaction (RT-qPCR) markers have been reported to evaluate the therapeutic response and disease status of neuroblastoma patients, their clinical significance remains elusive. The present study reports two high-risk neuroblastoma patients, whose MRD was consecutively monitored using 11 RT-qPCR markers (CHRNA3, CRMP1, DBH, DCX, DDC, GABRB3, GAP43, ISL1, KIF1A, PHOX2B and TH) during their course of treatment. The two patients initially responded to the induction therapy and reached MRD-negative status. The patients' MRD subsequently became positive with no elevation of their urinary homovanillic acid, urinary vanillylmandelic acid and serum neuron-specific enolase levels at 13 or 19 weeks prior to the clinical diagnosis of tumor relapse or regrowth. The present cases highlight the possibility of consecutive MRD monitoring using 11 markers to enable an early detection of tumor relapse or regrowth in high-risk neuroblastoma patients. PMID:27446404

  9. Application of the microbiological method DEFT/APC to detect minimally processed vegetables treated with gamma radiation

    NASA Astrophysics Data System (ADS)

    Araújo, M. M.; Duarte, R. C.; Silva, P. V.; Marchioni, E.; Villavicencio, A. L. C. H.

    2009-07-01

    Marketing of minimally processed vegetables (MPV) are gaining impetus due to its convenience, freshness and apparent health effect. However, minimal processing does not reduce pathogenic microorganisms to safe levels. Food irradiation is used to extend the shelf life and to inactivate food-borne pathogens. In combination with minimal processing it could improve safety and quality of MPV. A microbiological screening method based on the use of direct epifluorescent filter technique (DEFT) and aerobic plate count (APC) has been established for the detection of irradiated foodstuffs. The aim of this study was to evaluate the applicability of this technique in detecting MPV irradiation. Samples from retail markets were irradiated with 0.5 and 1.0 kGy using a 60Co facility. In general, with a dose increment, DEFT counts remained similar independent of the irradiation while APC counts decreased gradually. The difference of the two counts gradually increased with dose increment in all samples. It could be suggested that a DEFT/APC difference over 2.0 log would be a criteria to judge if a MPV was treated by irradiation. The DEFT/APC method could be used satisfactorily as a screening method for indicating irradiation processing.

  10. Surface water seal application to minimize volatilization loss of methyl isothiocyanate from soil columns.

    PubMed

    Simpson, Catherine R; Nelson, Shad D; Stratmann, Jerry E; Ajwa, Husein A

    2010-06-01

    Metam-sodium (MS, sodium methyldithiocarbamate) has been identified as a promising alternative chemical to replace methyl bromide (MeBr) in soil preplant fumigation. One degradation product of MS in soil is the volatile gas methyl isothiocyanate (MITC) which controls soilborne pests. Inconsistent results associated with MS usage indicate that there is a need to determine cultural practices that increase pest control efficacy. Sealing the soil surface with water after MS application may be a sound method to reduce volatilization loss of MITC from soils and increase the contact time necessary for MITC to control pests. The objective of this research was to develop a preliminary soil surface water application amount that would potentially inhibit the off-gassing rate of MITC. Off-gassing rate was consistently reduced with increasing water seal application. The application of a 2.5-3.8 cm water seal provided significantly lower (71-74% reduction in MITC volatilization) total fumigant loss compared with no water seal. The most favorable reduction in MITC off-gassing was observed in the 2.5 cm water seal. This suggests that volatilization of MITC-generating compounds can be highly suppressed using adequate surface irrigation following chemical application in this soil type (sandy clay loam), based on preliminary bench-scale soil column studies. .

  11. Barlow's Mitral Valve Disease: A Comparison of Neochordal (Loop) and Edge-To-Edge (Alfieri) Minimally Invasive Repair Techniques.

    PubMed

    da Rocha E Silva, Jaqueline G; Spampinato, Ricardo; Misfeld, Martin; Seeburger, Joerg; Pfanmüller, Bettina; Eifert, Sandra; Mohr, Friedrich W; Borger, Michael A

    2015-12-01

    Barlow's mitral valve (MV) disease remains a surgical challenge. We compared short- and medium-term outcomes of neochordal ("loop") versus edge-to-edge ("Alfieri") minimally invasive MV repair in patients with Barlow's disease. From January 2009 to April 2014, 123 consecutive patients with Barlow's disease (defined as bileaflet billowing or prolapse [or both], excessive leaflet tissue, and annular dilatation with or without calcification) underwent minimally invasive MV operations for severe mitral regurgitation (MR) at our institution. Three patients (2.4%) underwent MV replacement during the study period and were excluded from subsequent analysis. The loop MV repair technique was used in 68 patients (55.3%) and an edge-to-edge repair was performed in 44 patients (35.8%). Patients who underwent a combination of these 2 techniques (n = 8 [6.5%]) were excluded. The median age was 48 years, and 62.5% of patients were men. Concomitant procedures included closure of a patent foramen ovale or atrial septal defect (n = 19), tricuspid valve repair (n = 5), and atrial fibrillation ablation (n = 15). Follow-up was performed 24.7 ± 17 months postoperatively and was 98% complete. No deaths occurred perioperatively or during follow-up. Aortic cross-clamp time (64.1 ± 17.6 minutes versus 95.9 ± 29.5 minutes) and cardiopulmonary bypass (CPB) time (110.0 ± 24.2 minutes versus 146.4 ± 39.1 minutes) were significantly shorter (p < 0.001) in patients who received edge-to-edge repair. Although patients who underwent edge-to-edge repair received a larger annuloplasty ring (38.6 ± 1.5 mm versus 35.8 ± 2.7 mm; p < 0.001), the early postoperative resting mean gradients were higher (3.3 ± 1.2 mm Hg versus 2.6 ± 1.2 mm Hg; p = 0.007) and the mitral orifice area tended to be smaller in this group (2.8 ± 0.7 cm(2) versus 3.0 ± 0.7 cm(2); p = 0.06). The amount of residual MR was similar between groups (0.3 ± 0.6 versus 0.6 ± 1.0 for edge-to-edge versus loop procedures

  12. Minimizing errors from linear and nonlinear weights of WENO scheme for broadband applications with shock waves

    NASA Astrophysics Data System (ADS)

    Arshed, Ghulam M.; Hoffmann, Klaus A.

    2013-08-01

    Improvements in the numerical algorithm for the dynamics of flows that involve discontinuities and broadband fluctuations simultaneously are proposed. These two flow features suggest numerical strategies of a paradoxical nature because the discontinuities demand dissipation, and the small-scale smooth features require the opposite. There may be several ways to approach such a complicated issue, but the natural choice is a numerical technique that can adjust adaptively with flow regimes. The weighted essentially non-oscillatory (WENO) scheme may be this choice. However, there are two sources of dissipation associated with the WENO procedure: the upwind optimal stencil and the nonlinear adaption mechanism. The current work suggests a robust and comprehensive treatment for the minimization of dissipation error from these two sources. The optimization technique, which is guided by restriction on the linear optimal weights derived from stability and consistency requirement, is used to delay the dissipation of the upwind optimal stencil to those wavenumbers for which the dispersion error is large. The parallel advantage of this technique is the improvement of the dispersion property. Nevertheless, optimization decreases the formal order of accuracy of the optimal stencil from fifth order to third order. This loss of accuracy is derived by Taylor series expansion. Using Taylor-series expansion and WENO procedure, the third-order accuracy is verified in the smooth region, except at the critical point of order two, where the order of accuracy reduces to at least second order. This possible loss of accuracy at the second-order critical point is restored in an attempt to reduce the dissipation induced by the nonlinear adaptive weights. Modification of the nonlinear weights to reduce the dissipation is introduced by redefining them with an additional smoothness indicator. Other suggestions to minimize the dissipation of the nonlinear weights are also reviewed. The numerical

  13. Minimal change disease

    MedlinePlus

    ... blood vessels inside the nephron where blood is filtered to make urine and waste is removed. The ... with: ACE inhibitor medicines Blood pressure control Diuretics (water pills) You may also be told to reduce ...

  14. Teaching the Concept of Gibbs Energy Minimization through Its Application to Phase-Equilibrium Calculation

    ERIC Educational Resources Information Center

    Privat, Romain; Jaubert, Jean-Noe¨l; Berger, Etienne; Coniglio, Lucie; Lemaitre, Ce´cile; Meimaroglou, Dimitrios; Warth, Vale´rie

    2016-01-01

    Robust and fast methods for chemical or multiphase equilibrium calculation are routinely needed by chemical-process engineers working on sizing or simulation aspects. Yet, while industrial applications essentially require calculation tools capable of discriminating between stable and nonstable states and converging to nontrivial solutions,…

  15. Teaching the Concept of Gibbs Energy Minimization through Its Application to Phase-Equilibrium Calculation

    ERIC Educational Resources Information Center

    Privat, Romain; Jaubert, Jean-Noe¨l; Berger, Etienne; Coniglio, Lucie; Lemaitre, Ce´cile; Meimaroglou, Dimitrios; Warth, Vale´rie

    2016-01-01

    Robust and fast methods for chemical or multiphase equilibrium calculation are routinely needed by chemical-process engineers working on sizing or simulation aspects. Yet, while industrial applications essentially require calculation tools capable of discriminating between stable and nonstable states and converging to nontrivial solutions,…

  16. Novel/non-conventional manure application practices to minimize environmental impacts

    USDA-ARS?s Scientific Manuscript database

    Livestock manure can supply essential crop nutrients and contribute to improved soil quality. However, conventional surface broadcast application can result in adverse environmental effects from NH3 volatilization, odor, and runoff losses of nutrients and pathogens. Incorporation of manure by tillag...

  17. Noninvasive electrocardiographic imaging (ECGI): application of the generalized minimal residual (GMRes) method.

    PubMed

    Ramanathan, Charulatha; Jia, Ping; Ghanem, Raja; Calvetti, Daniela; Rudy, Yoram

    2003-09-01

    Electrocardiographic imaging (ECGI) is a developing imaging modality for cardiac electrophysiology and arrhythmias. It reconstructs epicardial potentials, electrograms, and isochrones from electrocardiographic body-surface potentials noninvasively. Current ECGI methodology employs Tikhonov regularization, which imposes constraints on the reconstructed potentials or their derivatives. This approach can sometimes reduce spatial resolution by smoothing the solution. Accuracy depends on a priori knowledge of solution characteristics and determination of an optimal regularization parameter. These properties led us to implement an independent, iterative approach for ECGI--the generalized minimal residual (GMRes) method--which does not apply constraints. GMRes was applied to experimental data during activation/repolarization of normal and infarcted hearts. GMRes reconstructions were compared to Tikhonov reconstructions and to measured "gold standards" in isolated hearts. Overall, the accuracy of GMRes solutions was similar to Tikhonov regularization. However, in certain cases GMRes recovered localized potential features (e.g., multiple potential minima), which were lost in the Tikhonov solution. Simultaneous use of these two complementary methods in clinical ECGI will ensure reliability and maximal extraction of diagnostic information in the absence of a priori information about a patient's condition.

  18. Application of free energy minimization to the design of adaptive multi-agent teams

    NASA Astrophysics Data System (ADS)

    Levchuk, Georgiy; Pattipati, Krishna; Fouse, Adam; Serfaty, Daniel

    2017-05-01

    Many novel DoD missions, from disaster relief to cyber reconnaissance, require teams of humans and machines with diverse capabilities. Current solutions do not account for heterogeneity of agent capabilities, uncertainty of team knowledge, and dynamics of and dependencies between tasks and agent roles, resulting in brittle teams. Most importantly, the state-of-the-art team design solutions are either centralized, imposing role and relation assignment onto agents, or completely distributed, suitable for only homogeneous organizations such as swarms. Centralized design models can't provide insights for team's self-organization, i.e. adapting team structure over time in distributed collaborative manner by team members with diverse expertise and responsibilities. In this paper we present an information-theoretic formalization of team composition and structure adaptation using a minimization of variational free energy. The structure adaptation is obtained in an iterative distributed and collaborative manner without the need for centralized control. We show that our model is lightweight, predictive, and produces team structures that theoretically approximate an optimal policy for team adaptation. Our model also provides a unique coupling between the structure and action policy, and captures three essential processes of learning, perception, and control.

  19. Applicability of PM3 to transphosphorylation reaction path: Toward designing a minimal ribozyme

    NASA Technical Reports Server (NTRS)

    Manchester, John I.; Shibata, Masayuki; Setlik, Robert F.; Ornstein, Rick L.; Rein, Robert

    1993-01-01

    A growing body of evidence shows that RNA can catalyze many of the reactions necessary both for replication of genetic material and the possible transition into the modern protein-based world. However, contemporary ribozymes are too large to have self-assembled from a prebiotic oligonucleotide pool. Still, it is likely that the major features of the earliest ribozymes have been preserved as molecular fossils in the catalytic RNA of today. Therefore, the search for a minimal ribozyme has been aimed at finding the necessary structural features of a modern ribozyme (Beaudry and Joyce, 1990). Both a three-dimensional model and quantum chemical calculations are required to quantitatively determine the effects of structural features of the ribozyme on the reaction it catalyzes. Using this model, quantum chemical calculations must be performed to determine quantitatively the effects of structural features on catalysis. Previous studies of the reaction path have been conducted at the ab initio level, but these methods are limited to small models due to enormous computational requirements. Semiempirical methods have been applied to large systems in the past; however, the accuracy of these methods depends largely on a simple model of the ribozyme-catalyzed reaction, or hydrolysis of phosphoric acid. We find that the results are qualitatively similar to ab initio results using large basis sets. Therefore, PM3 is suitable for studying the reaction path of the ribozyme-catalyzed reaction.

  20. Applicability of PM3 to transphosphorylation reaction path: Toward designing a minimal ribozyme

    NASA Technical Reports Server (NTRS)

    Manchester, John I.; Shibata, Masayuki; Setlik, Robert F.; Ornstein, Rick L.; Rein, Robert

    1993-01-01

    A growing body of evidence shows that RNA can catalyze many of the reactions necessary both for replication of genetic material and the possible transition into the modern protein-based world. However, contemporary ribozymes are too large to have self-assembled from a prebiotic oligonucleotide pool. Still, it is likely that the major features of the earliest ribozymes have been preserved as molecular fossils in the catalytic RNA of today. Therefore, the search for a minimal ribozyme has been aimed at finding the necessary structural features of a modern ribozyme (Beaudry and Joyce, 1990). Both a three-dimensional model and quantum chemical calculations are required to quantitatively determine the effects of structural features of the ribozyme on the reaction it catalyzes. Using this model, quantum chemical calculations must be performed to determine quantitatively the effects of structural features on catalysis. Previous studies of the reaction path have been conducted at the ab initio level, but these methods are limited to small models due to enormous computational requirements. Semiempirical methods have been applied to large systems in the past; however, the accuracy of these methods depends largely on a simple model of the ribozyme-catalyzed reaction, or hydrolysis of phosphoric acid. We find that the results are qualitatively similar to ab initio results using large basis sets. Therefore, PM3 is suitable for studying the reaction path of the ribozyme-catalyzed reaction.

  1. Ex vivo expanded mesenchymal stromal cell minimal quality requirements for clinical application.

    PubMed

    Torre, Maria Luisa; Lucarelli, Enrico; Guidi, Simona; Ferrari, Maura; Alessandri, Giulio; De Girolamo, Laura; Pessina, Augusto; Ferrero, Ivana

    2015-03-15

    Mesenchymal stromal cells (MSCs), as advanced therapy products, must satisfy all the requirements for human use of medicinal products, aiming to maintain the quality and safety of the cells. The MSC manufacturing process for clinical use should comply with the principles of Good Manufacturing Practice (GMP). This ensures that cell preparations are produced and controlled, from the collection and manipulation of raw materials, through the processing of intermediate products, to the quality controls, storage, labeling and packaging, and release. The objective of this document is to provide the minimal quality requirements for the MSC production and its delivery for clinical use, so that the safety of the final cell therapy product will not be compromised. For this purpose, the document evaluates the most important steps of GMP-compliant MSC production: the isolation and expansion process; the validation phase of the process, including all quality controls for the characterization, functionality, potency, and safety of MSCs; and the quality control at the batch release to guarantee the safety of patient infusion.

  2. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol.

    PubMed

    Van der Velden, V H J; Corral, L; Valsecchi, M G; Jansen, M W J C; De Lorenzo, P; Cazzaniga, G; Panzer-Grümayer, E R; Schrappe, M; Schrauder, A; Meyer, C; Marschalek, R; Nigro, L L; Metzler, M; Basso, G; Mann, G; Den Boer, M L; Biondi, A; Pieters, R; Van Dongen, J J M

    2009-06-01

    Acute lymphoblastic leukemia (ALL) in infants younger than 1 year is a rare but relatively homogeneous disease ( approximately 80% MLL gene rearranged, approximately 70% CD10-negative) when compared with childhood and adult ALL. Several studies in children and adults with ALL have shown that minimal residual disease (MRD) status is a strong and independent prognostic factor. We therefore evaluated the prognostic significance of MRD in infant ALL. Ninety-nine infant patients treated according to the Interfant-99 protocol were included in this study. MRD was analyzed by real-time quantitative PCR analysis of rearranged immunoglobulin genes, T-cell receptor genes and MLL genes at various time points (TP) during therapy. Higher MRD levels at the end of induction (TP2) and consolidation (TP3) were significantly associated with lower disease-free survival. Combined MRD information at TP2 and TP3 allowed recognition of three patients groups that significantly differed in outcome. All MRD-high-risk patients (MRD levels > or =10(-4) at TP3; 26% of patients) relapsed. MRD-low-risk patients (MRD level <10(-4) at both TP2 and TP3) constituted 44% of patients and showed a relapse-rate of only 13%, whereas remaining patients (MRD-medium-risk patients; 30% of patients) had a relapse rate of 31%. Comparison between the current Interfant-06 stratification at diagnosis and the here presented MRD-based stratification showed that both stratifications recognized different subgroups of patients. These data indicate that MRD diagnostics has added value for recognition of risk groups in infant ALL and that MRD diagnostics can be used for treatment intervention in infant ALL as well.

  3. [Comparative analysis of insulin glargine vs. insulin detemir: A cost-minimization study applicable to Colombia].

    PubMed

    Fragozo, Argemiro; Puerta, María Fernanda; Misas, Juan Diego

    2015-01-01

    More than 90% of subjects diagnosed with diabetes mellitus present with type 2, which is recognized for peripheral insulin resistance. To determine the costs of achieving glycemic target with the use of basal insulin analogs, insulin glargine (IG) once a day vs. insulin detemir (ID) once or twice a day, with a cost minimization model built from a third-party payer perspective in Colombia. A systematic review of comparative clinical trials between IG and ID in patients with insulin-resistant type 2 diabetes was performed to determine data of use, effectiveness and frequency of and adverse events. The goal of glycemic control (effectiveness measure) was defined as HbA1c=7%. The costs of insulin were extracted from the Integrated System of Medication Prices 2012 (Ministerio de Salud y Protección Social de Colombia) and the IMS Consulting Group mobile average cost for the past year as of December, 2012. Sensitivity analyses were performed via Montecarlo simulations for dose and medication costs (insulin). Five publications met inclusion criteria. The range of the difference between insulin doses was 3.2 IU to 33 IU. The percentage of patients requiring two ID doses was 12.6-100%. There were no significant differences in hypoglycemic events. For both retail and institutional channels, there was a higher differential cost between IG vs. ID favoring IG in 4 and 5 studies, respectively. For the retail channel only one study showed the opposite results. As only medication costs are considered, differences in insulin units between IG and ID result in a differential cost in favor of IG that makes it a cost/effective alternative.

  4. Application of volcanic ash particles for protein affinity purification with a minimized silica-binding tag.

    PubMed

    Abdelhamid, Mohamed A A; Ikeda, Takeshi; Motomura, Kei; Tanaka, Tatsuya; Ishida, Takenori; Hirota, Ryuichi; Kuroda, Akio

    2016-11-01

    We recently reported that the spore coat protein, CotB1 (171 amino acids), from Bacillus cereus mediates silica biomineralization and that the polycationic C-terminal sequence of CotB1 (14 amino acids), designated CotB1p, serves as a silica-binding tag when fused to other proteins. Here, we reduced the length of this silica-binding tag to only seven amino acids (SB7 tag: RQSSRGR) while retaining its affinity for silica. Alanine scanning mutagenesis indicated that the three arginine residues in the SB7 tag play important roles in binding to a silica surface. Monomeric l-arginine, at concentrations of 0.3-0.5 M, was found to serve as a competitive eluent to release bound SB7-tagged proteins from silica surfaces. To develop a low-cost, silica-based affinity purification procedure, we used natural volcanic ash particles with a silica content of ∼70%, rather than pure synthetic silica particles, as an adsorbent for SB7-tagged proteins. Using green fluorescent protein, mCherry, and mKate2 as model proteins, our purification method achieved 75-90% recovery with ∼90% purity. These values are comparable to or even higher than that of the commonly used His-tag affinity purification. In addition to low cost, another advantage of our method is the use of l-arginine as the eluent because its protein-stabilizing effect would help minimize alteration of the intrinsic properties of the purified proteins. Our approach paves the way for the use of naturally occurring materials as adsorbents for simple, low-cost affinity purification.

  5. [The detection of minimal residual disease in patients with chronic B-cell lymphatic leukemia using patient-specified polymerase chain reaction].

    PubMed

    Sidorova, Iu V; Sorokina, T V; Biderman, B V; Nikulina, E E; Kisilichina, D G; Naumova, E V; Pochtar', M E; Lugovskaia, S A; Ivanova, V L; Kovaleva, L G; Ptushkin, V V; Nikitin, E A; Sudarikov, A B

    2011-12-01

    The new effective protocols of treatment of chronic B-cell lymphatic leukemia, including purine analogs and monoclonal antibodies, provide robust remissions under this disease. Accordingly, the requirements to remission quality assessment are changed too. In particular the assessment of minimal residual disease is obligatory. To assess minimal residual disease in terms of quantity in case of chronic B-cell lymphatic leukemia the technique of polymerase chain reaction was applied in real time with patient-specific primers from the area of V-D-J combinations of genes of heavy chain of immunoglobulin. The study included samples from 60 patients suffering of chronic B-cell lymphatic leukemia. In 15 of them (25%), it was impossible to apply neither the sequence analysis of genes of heavy chain of immunoglobulin nor the fitting of patient-specific primer. The results of quantitative determination of minimal residual disease were obtained in 45 patients (55 tests). The minimal residual disease was detected in 30 of 55 samples (54.5%) and was not detected in 25 of 55 samples (45.5%). At the same time, the quantitative determination of minimal residual disease was implemented in regard to the initial level of neoplastic cells. The method sensitivity qualified by serial dilutions, consisted 10(-5) or 1 neoplastic cell to 100 000 normal cells. The comparative analysis was applied to the results of determination of minimal residual disease using two methods -polymerase chain reaction in real time using patient-specified primers and four-color flow cytofluometry. The determination of minimal residual disease with both methods was implemented in 37 patients (45 tests). The results of both methods matched in 93.3% (42 tests out of 45) with maximal disparity of one degree. Then Spearman factor consisted 0.87 (p < 0.0001). In 3 out of 45 tests (6.7%) neoplastic cells were detected with only one method. In the first case, it was the method of four-color flow cytofluometry and in

  6. Widespread and efficient marker gene expression in the airway epithelia of fetal sheep after minimally invasive tracheal application of recombinant adenovirus in utero.

    PubMed

    Peebles, D; Gregory, L G; David, A; Themis, M; Waddington, S N; Knapton, H J; Miah, M; Cook, T; Lawrence, L; Nivsarkar, M; Rodeck, C; Coutelle, C

    2004-01-01

    Cystic fibrosis is a common lethal genetic disease caused by functional absence of the cystic fibrosis transmembrane conductance regulator (CFTR). Although a candidate disease for in utero gene therapy, demonstration of potentially therapeutic levels of transgene expression in the fetal airways after minimally invasive gene delivery is a mandatory prerequisite before application of this approach in humans can be considered. We report here on the delivery of a beta-galactosidase expressing adenovirus directly to the airways of fetal sheep in utero using ultrasound-guided percutaneous injection of the trachea in the fetal chest. Injection of adenoviral particles to the fetal airways was not associated with mortality and resulted in low-level expression in the peripheral airways. However, complexation of the virus with DEAE dextran, which confers a positive charge to the virus, and pretreatment of the airways with Na-caprate, which opens tight junctions, increased transgene expression, and a combination of these two enhancers resulted in widespread and efficient gene transfer of the fetal trachea and bronchial tree. Using a percutaneous ultrasound-guided injection technique, we have clearly demonstrated proof of principle for substantial transgene delivery to the fetal airways providing levels of gene expression that could be relevant for a therapeutic application of CFTR expressing vectors.

  7. Applications of supercritical fluid technology to pollution prevention and waste minimization

    SciTech Connect

    Turner, R.J.

    1995-10-01

    One approach to the prevention of pollution and the reduction of worker exposure from conventional solvents is the use of less hazardous substitutes. One of the more novel substitutes is carbon dioxide. Although carbon dioxide is a gas at ordinary conditions, it can be liquified by application of pressure. In its supercritical state, it exhibits good solvent properties. Separation of the carbon dioxide from the extracted materials can be accomplished by pressure reduction, adsorption onto activated carbon, or with a membrane process, e.g., decaffeination of coffee. This paper presents a brief overview of the university and federal laboratory collaborative efforts focusing on processes using supercritical carbon dioxide as a substitute for hazardous solvents. The SCCO2 technology applications under this program include extraction of natural pharmaceutical materials, phase-transfer catalysis, solvent replacement in chemical synthesis, temperature-solubility relationships, and separation of organic materials from soils and slurries. A paper on the extraction of heavy metals with SCCO2 was presented by Ataai et.al. at the 87th National Meeting, A&WMA. This work is also supported by the EPA.

  8. Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia

    PubMed Central

    Ravandi, Farhad; Jorgensen, Jeffrey L.; O'Brien, Susan M.; Jabbour, Elias; Thomas, Deborah A.; Borthakur, Gautam; Garris, Rebecca; Huang, Xuelin; Garcia-Manero, Guillermo; Burger, Jan A.; Ferrajoli, Alessandra; Wierda, William; Kadia, Tapan; Jain, Nitin; Wang, Sa A.; Konoplev, Sergei; Kebriaei, Partow; Champlin, Richard E.; McCue, Deborah; Estrov, Zeev; Cortes, Jorge E; Kantarjian, Hagop M.

    2016-01-01

    SUMMARY The prognostic value of minimal residual disease (MRD) assessed by multi-parameter flow cytometry (MFC) was investigated among 340 adult patients with B-cell acute lymphoblastic leukaemia (B-ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15-84). Median white blood cell count (WBC) was 9.35 × 109/l (range, 0.4-658.1 ×109/l). MRD by MFC was initially assessed with a sensitivity of 0.01%, using a 15-marker, 4-colour panel and subsequently a 6-colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease-free survival (DFS) and overall survival (OS)(P=0.004 and P=0.04, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P=0.002 and P<0.0001, respectively) and OS (P=0.003 and P<0.0001, respectively). Multivariate analysis including age, WBC at presentation, cytogenetics (standard vs. high risk) and MRD status at CR, 3 months and 6 months, indicated that MRD negative status at CR was an independent predictor of DFS (P<0.05). Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in adult patients with ALL PMID:26492205

  9. Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia.

    PubMed

    Ravandi, Farhad; Jorgensen, Jeffrey L; O'Brien, Susan M; Jabbour, Elias; Thomas, Deborah A; Borthakur, Gautam; Garris, Rebecca; Huang, Xuelin; Garcia-Manero, Guillermo; Burger, Jan A; Ferrajoli, Alessandra; Wierda, William; Kadia, Tapan; Jain, Nitin; Wang, Sa A; Konoplev, Sergei; Kebriaei, Partow; Champlin, Richard E; McCue, Deborah; Estrov, Zeev; Cortes, Jorge E; Kantarjian, Hagop M

    2016-02-01

    The prognostic value of minimal residual disease (MRD) assessed by multi-parameter flow cytometry (MFC) was investigated among 340 adult patients with B-cell acute lymphoblastic leukaemia (B-ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15-84). Median white blood cell count (WBC) was 9·35 × 10(9) /l (range, 0·4-658·1 ×1 0(9) /l). MRD by MFC was initially assessed with a sensitivity of 0·01%, using a 15-marker, 4-colour panel and subsequently a 6-colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease-free survival (DFS) and overall survival (OS) (P = 0·004 and P = 0·03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0·004 and P < 0·0001, respectively) and OS (P = 0·004 and P < 0·0001, respectively). Multivariate analysis including age, WBC at presentation, cytogenetics (standard versus high risk) and MRD status at CR, 3 and 6 months, indicated that MRD negative status at CR was an independent predictor of DFS (P < 0·05). Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in adult patients with ALL. © 2015 John Wiley & Sons Ltd.

  10. Blastoid variant of mantle cell lymphoma: late progression from classical mantle cell lymphoma and quantitation of minimal residual disease.

    PubMed

    Pott, Christiane; Schrader, Carsten; Brüggemann, Monika; Ritgen, Matthias; Harder, Lana; Raff, Thorsten; Tiemann, Markus; Dreger, Peter; Kneba, Michael

    2005-04-01

    Classical mantle cell lymphoma (MCL) and its blastoid variant (MCL-BV) are characterized by an extremely poor prognosis. Long-time survivors are rare, only very few patients with an overall survival over 10 years have been reported. We present a case of a 41-year-old male with a 12 yr history of MCL stage I to show, that very late relapses in MCL are possible and may present as a transformation into an aggressive blastoid variant and to illustrate the value of quantitative minimal residual disease (MRD) monitoring for treatment guidance. Diagnostic lymph node and bone marrow samples were investigated by immunohistochemistry. Clonality analysis was performed by immunoglobulin heavy chain gene (IGVH) and t(11;14) PCR. The MRD assessment was done by real-time quantitative PCR (RQ-PCR) on available follow-up samples. By histologic review and sequencing of the clonal IGVH and t(11;14) PCR products we demonstrated a common clonal origin of the leucemic MCL-BV and the classical MCL diagnosed 12 yr earlier. Quantitative MRD assessment revealed significant MRD levels after intensive conventional chemotherapy including Rituximab. Therefore, treatment was early intensified by myeloablative radio-chemotherapy and allogeneic peripheral stem cell transplantation from an unrelated HLA-identical donor. This did not translate into a sustained remission as reflected by persisting MRD levels after transplantation and the patient died from rapid progressive disease 3.5 months after transplant. This report presents a rare case of long-term survivor of MCL with a progression of the original MCL cell clone to MCL-BV and demonstrates the clinical value of quantitative MRD assessment for optimized therapeutic management. Copyright 2005 Blackwell Munksgaard.

  11. Retrospective monitoring of minimal residual disease using hairpin-shaped clone specific primers in B-cell lymphoma affected dogs.

    PubMed

    Gentilini, Fabio; Turba, Maria E; Forni, Monica

    2013-06-15

    Lymphoma is one of the most common forms of cancer in dogs as it is in humans but, unlike humans, the cure rates in canines are still very low. Despite the fact that high grade B-cell lymphomas are considered to be chemotherapy responsive, almost all treated dogs ultimately relapse and die due to the residual malignant lymphocytes, namely minimal residual disease (MRD). It would be extremely valuable for clinicians to detect, monitor and quantify MRD for risk group stratification, effective treatment intervention and outcome prediction. The PCRs targeting the Ig gene rearrangements constitute one of the most reliable tools to this end. We have recently validated a method which exploits hairpin-shaped primers for quantifying MRD. In the present study, that method is conveniently used for retrospectively monitoring MRD in the peripheral blood of 8 dogs diagnosed with B-cell lymphoma who underwent chemotherapy. All dogs attained complete remission. The median disease-free interval was 254.5 days (range 63-774) while the median survival time was 313.5 days (range 143-817 days). At admission, all dogs, except one which had already been treated with prednisone, had circulating neoplastic cells. All dogs attained complete remission (CR) which was almost always matched with a complete MRD response. The persistence of MRD despite apparent CR indicated a worse prognosis and a short duration of CR. Finally, the relapse is consistently anticipated by the reappearance of MRD in the peripheral blood. The study confirmed the suitability of an MRD monitoring assay as a clinical decision-making tool.

  12. Comparison between qualitative and real-time polymerase chain reaction to evaluate minimal residual disease in children with acute lymphoblastic leukemia.

    PubMed

    Paula, Francisco Danilo Ferreira; Elói-Santos, Silvana Maria; Xavier, Sandra Guerra; Ganazza, Mônica Aparecida; Jotta, Patricia Yoshioka; Yunes, José Andrés; Viana, Marcos Borato; Assumpção, Juliana Godoy

    2015-01-01

    Minimal residual disease is an important independent prognostic factor that can identify poor responders among patients with acute lymphoblastic leukemia. The aim of this study was to analyze minimal residual disease using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements by conventional polymerase chain reaction followed by homo-heteroduplex analysis and to compare this with real-time polymerase chain reaction at the end of the induction period in children with acute lymphoblastic leukemia. Seventy-four patients diagnosed with acute lymphoblastic leukemia were enrolled. Minimal residual disease was evaluated by qualitative polymerase chain reaction in 57 and by both tests in 44. The Kaplan-Meier and multivariate Cox methods and the log-rank test were used for statistical analysis. Nine patients (15.8%) were positive for minimal residual disease by qualitative polymerase chain reaction and 11 (25%) by real-time polymerase chain reaction considering a cut-off point of 1×10(-3) for precursor B-cell acute lymphoblastic leukemia and 1×10(-2) for T-cell acute lymphoblastic leukemia. Using the qualitative method, the 3.5-year leukemia-free survival was significantly higher in children negative for minimal residual disease compared to those with positive results (84.1%±5.6% versus 41.7%±17.3%, respectively; p-value=0.004). There was no significant association between leukemia-free survival and minimal residual disease by real-time polymerase chain reaction. Minimal residual disease by qualitative polymerase chain reaction was the only variable significantly correlated to leukemia-free survival. Given the difficulties in the implementation of minimal residual disease monitoring by real-time polymerase chain reaction in most treatment centers in Brazil, the qualitative polymerase chain reaction strategy may be a cost-effective alternative. Copyright © 2015 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier

  13. Minimal residual disease monitoring after allogeneic transplantation may help to individualize post-transplant therapeutic strategies in acute myeloid malignancies.

    PubMed

    Díez-Campelo, María; Pérez-Simón, José Antonio; Pérez, Jose; Alcoceba, Miguel; Richtmon, Juan; Vidriales, Belén; San Miguel, Jesús

    2009-03-01

    This study evaluates the prognostic value of minimal residual disease (MRD) monitoring by multiparametric flow cytometry in 41 patients with acute myeloid leukemia or myelodysplastic syndrome undergoing allogeneic transplantation. MRD assessment after transplant (day +100) allowed to discriminate different risk populations, being the most significant cut-off value for outcome level of MRD < or > or = 10(-3). Outcome was significantly better among patients with low (<10(-3)) versus high (> or = 10(-3)) MRD at day +100 after transplant. Thus, overall survival was 73% versus 25% at 4 years among patients with low versus high MRD at day +100 after transplant (P = 0.002); 74% of patients with low MRD were event free at 4 years as compared to 17% among patients with high MRD (P = 0.01). In multivariate analysis, MRD value as well as chronic GVHD significantly influenced outcome. In conclusion, MRD monitoring early post-transplant is an important tool for outcome prediction and should be considered in decision making after allogeneic transplantation.

  14. Immaturity associated antigens are lost during induction for T cell lymphoblastic leukemia: implications for minimal residual disease detection

    PubMed Central

    Roshal, Mikhail; Fromm, Jonathan R; Winter, Stuart; Dunsmore, Kimberly; Wood, Brent

    2011-01-01

    Background Induction chemotherapy for acute leukemia often leads to antigenic shifts in residual abnormal blast populations. Studies in precursor B cell ALL (B-ALL) and AML have demonstrated that chemotherapy commonly results in the loss of antigens associated with immaturity, limiting their utility for minimal residual disease (MRD) detection. Little information is available about the stability of these antigens in precursor T cell ALL (T-ALL) though it is presumed that CD99 and TdT are highly informative based on limited studies. Methods In a longitudinal investigation, we explored patterns of lineage specific and immaturity associated antigens in T-ALL in a large cohort of patients treated under the multicenter Children's Oncology Group (COG) protocol. All samples were analyzed using multicolor flow cytometry in a standardized fashion at a single institution. Results We report that markers of immaturity particularly, TdT and CD99 dramatically decline on leukemic blasts during therapy. CD34 and CD10 expression is confined to a minority of pre-treatment samples and is also not stable. In contrast, lineage associated markers including CD2, CD3, CD4, CD5, CD7 and CD8 failed to show significant trends. Conclusions Our study strongly argues for expansion of immunophenotyping panels for T-ALL MRD to decrease reliance on immature antigens. This study represents the first demonstration of consistent immunophenotypic shifts in T-ALL. PMID:20155852

  15. Increase in myeloid-derived suppressor cells (MDSCs) associated with minimal residual disease (MRD) detection in adult acute myeloid leukemia.

    PubMed

    Sun, Hui; Li, Yi; Zhang, Zhi-fen; Ju, Ying; Li, Li; Zhang, Bing-chang; Liu, Bin

    2015-11-01

    Myeloid-derived suppressor cells (MDSCs) are thought to help provide a cellular microenvironments in many solid tumors, in which transformed cells proliferate, acquire new mutations, and evade host immunosurveillance. In the present study, we found that MDSCs (CD33 + CD11b + HLA-DR(low/neg)) in bone marrow were significantly increased in adult acute myeloid leukemia (AML) patients. MDSCs levels in newly diagnosed AML patients correlated well with extramedullary infiltration and plasma D-dimer levels. Remission rates in the MDSCs > 1500 group and MDSCs < 1500 group were 72.73 and 81.25 %, respectively. No significant differences were found between the two groups. MDSC levels in the complete remission group were significantly decreased after chemotherapy, while in the partial remission and non-remission groups, there were no significant differences. The level of MDSCs in the high minimal residual disease (MRD) group was significantly higher than that in the middle and low MRD groups. High levels of Wilms' Tumor-1 (WT-1) protein were strongly correlated with higher bone marrow MDSC levels. In conclusion, we report here a population of immunosuppressive monocytes in the bone marrow of patients with AML characterized by the CD33(high)CD11b + HLA-DR(low/neg) phenotype. These cells appear to impact the clinical course and prognosis of AML. This data may provide potentially important targets for novel therapies.

  16. Pretransplantation Minimal Residual Disease Predicts Survival in Patients with Mantle Cell Lymphoma Undergoing Autologous Stem Cell Transplantation in Complete Remission.

    PubMed

    Cowan, Andrew J; Stevenson, Philip A; Cassaday, Ryan D; Graf, Solomon A; Fromm, Jonathan R; Wu, David; Holmberg, Leona A; Till, Brian G; Chauncey, Thomas R; Smith, Stephen D; Philip, Mary; Orozco, Johnnie J; Shustov, Andrei R; Green, Damian J; Libby, Edward N; Bensinger, William I; Shadman, Mazyar; Maloney, David G; Press, Oliver W; Gopal, Ajay K

    2016-02-01

    Autologous stem cell transplantation (ASCT) is standard therapy for mantle cell lymphoma (MCL) in remission after induction chemotherapy, with the best results for patients in complete remission (CR). We hypothesized that evaluation of minimal residual disease (MRD) before ASCT could further stratify outcomes for these patients. Patients with MCL who underwent ASCT in clinical CR between 1996 and 2011 with pretransplantation MRD testing were eligible. Presence of a clonal IgH rearrangement, t(11; 14) by PCR or positive flow cytometry from blood or bone marrow, was considered positive. An adjusted proportional hazards model for associations with progression-free (PFS) and overall survival (OS) was performed. Of 75 MCL patients in CR, 8 (11%) were MRD positive. MRD positivity was associated with shorter OS and PFS. The median OS for MRD-negative patients was not reached, with 82% survival at 5 years, whereas for the MRD-positive patients, median OS was 3.01 years (hazard ratio [HR], 4.04; P = .009), with a median follow-up of 5.1 years. The median PFS for MRD-negative patients was not reached with 75% PFS at 5 years, whereas for MRD-positive patients, it was 2.38 years (HR, 3.69; P = .002). MRD positivity is independently associated with poor outcomes after ASCT for MCL patients in CR. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  17. Absolute lymphocyte count is associated with minimal residual disease level in childhood B-cell precursor acute lymphoblastic leukemia.

    PubMed

    Shen, Hong-Qiang; Feng, Jian-Hua; Tang, Yong-Min; Song, Hua; Yang, Shi-Long; Shi, Shu-Wen; Xu, Wei-Qun

    2013-06-01

    The prognostic value of absolute lymphocyte count (ALC) has been a recent matter of debate in childhood acute lymphoblastic leukemia (ALL). In the current study, ALCs at the time of diagnosis (ALC-0), after 7 days of initial therapy (ALC-8) and at interim of the induction therapy (ALC-22) were examined in Chinese children with B-cell precursor (BCP) ALL and correlated with the level of minimal residual disease (MRD) at day 22 of induction therapy. Medical and laboratory records of 140 patients diagnosed with childhood BCP ALL were retrieved and analyzed. ALC-22 is significantly correlated with MRD level at day 22 of therapy and can be a good prognostic factor for childhood BCP-ALL. Furthermore, lymphocyte count at initial diagnosis is correlated with MRD level at day 22 in childhood BCP-ALL with the immnunophenotype of CD19(pos)/CD10(pos)/CD34(pos)/CD45(neg) and role as a new prognostic factor was determined.

  18. Follow-up of post-transplant minimal residual disease and chimerism in childhood lymphoblastic leukaemia: 90 d to react.

    PubMed

    Pochon, Cécile; Oger, Emmanuel; Michel, Gérard; Dalle, Jean-Hugues; Salmon, Alexandra; Nelken, Brigitte; Bertrand, Yves; Cavé, Hélène; Cayuela, Jean-Michel; Grardel, Nathalie; Macintyre, Elizabeth; Margueritte, Geneviève; Méchinaud, Françoise; Rohrlich, Pierre; Paillard, Catherine; Demeocq, François; Schneider, Pascale; Plantaz, Dominique; Poirée, Marilyne; Eliaou, Jean-François; Semana, Gilbert; Drunat, Séverine; Jonveaux, Philippe; Bordigoni, Pierre; Gandemer, Virginie

    2015-04-01

    Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention. © 2014 John Wiley & Sons Ltd.

  19. Concurrent detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia by flow cytometry and real-time PCR.

    PubMed

    Kerst, Gunter; Kreyenberg, Hermann; Roth, Carmen; Well, Catrin; Dietz, Klaus; Coustan-Smith, Elaine; Campana, Dario; Koscielniak, Ewa; Niemeyer, Charlotte; Schlegel, Paul G; Müller, Ingo; Niethammer, Dietrich; Bader, Peter

    2005-03-01

    Minimal (i.e. submicroscopic) residual disease (MRD) predicts outcome in childhood acute lymphoblastic leukaemia (ALL). To be used clinically, MRD assays must be reliable and accurate. Two well-established techniques, flow cytometry (FC) and polymerase chain reaction (PCR), can detect leukaemic cells with a sensitivity of 0.01% (10(-4)). We analysed diagnostic samples of 45 ALL-patients (37 B-lineage ALL, eight T-lineage ALL) by four-colour FC and real-time PCR. Leukaemia-associated immunophenotypes, at a sensitivity of MRD detection by FC at the 0.01% level, were identified in 41 cases (91%); antigen-receptor gene rearrangements suitable for MRD detection with a sensitivity of 0.01% or better by PCR were identified in 38 cases (84%). The combined use of FC and PCR allowed MRD monitoring in all 45 patients. In 105 follow-up samples, MRD estimates by both methods were highly concordant, with a deviation factor of <5 by Bland-Altman analysis. Importantly, the concordance between FC and PCR was also observed in regenerating bone marrow samples containing high proportions of CD19(+) cells, and in samples studied 24 h after collection. We conclude that both MRD assays yield generally concordant results. Their combined use should enable MRD monitoring in virtually all patients and prevent false-negative results due to clonal evolution or phenotypic shifts.

  20. Tubular B7-1 expression parallels proteinuria levels, but not clinical outcomes in adult minimal change disease patients

    PubMed Central

    Lee, Sung Woo; Baek, Seon Ha; Paik, Jin Ho; Kim, Sejoong; Na, Ki Young; Chae, Dong-Wan; Chin, Ho Jun

    2017-01-01

    B7-1 is thought to play a pathogenic role in minimal-change disease (MCD). Recently, however, doubts have arisen regarding the role of B7-1 expression in MCD. Therefore, we aimed to identify the presence and clinical significance of B7-1 expression in MCD patients. The study participants included 28 adult MCD patients for whom kidney specimens were available. The intensity of B7-1 expression was assessed by two independent specialists. We analysed the association between the intensity of B7-1 expression and clinicopathological variables. No B7-1 expression in the glomeruli was observed in any of the 28 patients. Unexpectedly, however, 75.0% of the patients exhibited tubular B7-1 expression, with 35.7% demonstrating weak positive expressions and 39.3% demonstrating strong positive expressions. The level of proteinuria significantly increased as the intensity of tubular B7-1 expression increased. We also found trends of increasing blood urea nitrogen and serum creatinine levels with increased intensity of tubular B7-1 expression. However, we could not observe definite differences in long- and short-term clinical outcomes depending on the intensity of tubular B7-1 expression. In conclusion, B7-1 was expressed in renal tubular cells but not in glomeruli in adult MCD patients. The intensity of tubular B7-1 expression paralleled proteinuria levels, but not clinical outcomes. PMID:28150736

  1. Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia.

    PubMed

    Vidriales, María-Belén; Pérez-López, Estefanía; Pegenaute, Carlota; Castellanos, Marta; Pérez, José-Juan; Chandía, Mauricio; Díaz-Mediavilla, Joaquín; Rayón, Consuelo; de Las Heras, Natalia; Fernández-Abellán, Pascual; Cabezudo, Miguel; de Coca, Alfonso García; Alonso, Jose M; Olivier, Carmen; Hernández-Rivas, Jesús M; Montesinos, Pau; Fernández, Rosa; García-Suárez, Julio; García, Magdalena; Sayas, María-José; Paiva, Bruno; González, Marcos; Orfao, Alberto; San Miguel, Jesús F

    2016-01-01

    The clinical utility of minimal residual disease (MRD) analysis in acute myeloid leukaemia (AML) is not yet defined. We analysed the prognostic impact of MRD level at complete remision after induction therapy using multiparameter flow cytometry in 306 non-APL AML patients. First, we validated the prognostic value of MRD-thresholds we have previously proposed (≥ 0.1%; ≥ 0.01-0.1%; and <0.01), with a 5-year RFS of 38%, 50% and 71%, respectively (p=0.002). Cytogenetics is the most relevant prognosis factor in AML, however intermediate risk cytogenetics represent a grey zone that require other biomarkers for risk stratification, and we show that MRD evaluation discriminate three prognostic subgroups (p=0.03). Also, MRD assessments yielded relevant information on favourable and adverse cytogenetics, since patients with favourable cytogenetics and high MRD levels have poor prognosis and patients with adverse cytogenetics but undetectable MRD overcomes the adverse prognosis. Interestingly, in patients with intermediate or high MRD levels, intensification with transplant improved the outcome as compared with chemotherapy, while the type of intensification therapy did not influenced the outcome of patients with low MRD levels. Multivariate analysis revealed age, MRD and cytogenetics as independent variables. Moreover, a scoring system, easy in clinical practice, was generated based on MRD level and cytogenetics.

  2. Assessing the effectiveness of manure application timing options to minimize P loss from fields

    NASA Astrophysics Data System (ADS)

    Archibald, J. A.; Fuka, D. R.; Schneider, R.; Easton, Z. M.; Walter, M. T.

    2015-12-01

    It is widely understood that spreading manure before a large runoff event causes water quality problems downstream. Phosphorus (P) is a pollutant that is particularly susceptible to these types of events, as P is often disproportionately transported in overland runoff. While the benefit of avoiding the intersection of manure and runoff is unmistakable, it is less clear what length of time is needed between manure application and runoff, and also, what types of predictions can be most effective (i.e. what is the benefit of runoff predictions over simple rain predictions?). In this study, we model the effect of prediction type and avoidance window size on resultant P export. This research aims to help land managers optimize the needs of their crops with water protection goals in the age of increasing online decision support tool options.

  3. Optimizing convergence rates of alternating minimization reconstruction algorithms for real-time explosive detection applications

    NASA Astrophysics Data System (ADS)

    Bosch, Carl; Degirmenci, Soysal; Barlow, Jason; Mesika, Assaf; Politte, David G.; O'Sullivan, Joseph A.

    2016-05-01

    X-ray computed tomography reconstruction for medical, security and industrial applications has evolved through 40 years of experience with rotating gantry scanners using analytic reconstruction techniques such as filtered back projection (FBP). In parallel, research into statistical iterative reconstruction algorithms has evolved to apply to sparse view scanners in nuclear medicine, low data rate scanners in Positron Emission Tomography (PET) [5, 7, 10] and more recently to reduce exposure to ionizing radiation in conventional X-ray CT scanners. Multiple approaches to statistical iterative reconstruction have been developed based primarily on variations of expectation maximization (EM) algorithms. The primary benefit of EM algorithms is the guarantee of convergence that is maintained when iterative corrections are made within the limits of convergent algorithms. The primary disadvantage, however is that strict adherence to correction limits of convergent algorithms extends the number of iterations and ultimate timeline to complete a 3D volumetric reconstruction. Researchers have studied methods to accelerate convergence through more aggressive corrections [1], ordered subsets [1, 3, 4, 9] and spatially variant image updates. In this paper we describe the development of an AM reconstruction algorithm with accelerated convergence for use in a real-time explosive detection application for aviation security. By judiciously applying multiple acceleration techniques and advanced GPU processing architectures, we are able to perform 3D reconstruction of scanned passenger baggage at a rate of 75 slices per second. Analysis of the results on stream of commerce passenger bags demonstrates accelerated convergence by factors of 8 to 15, when comparing images from accelerated and strictly convergent algorithms.

  4. Identification of integrated airframe: Propulsion effects on an F-15 aircraft for application to drag minimization

    NASA Technical Reports Server (NTRS)

    Schkolnik, Gerard S.

    1993-01-01

    The application of an adaptive real-time measurement-based performance optimization technique is being explored for a future flight research program. The key technical challenge of the approach is parameter identification, which uses a perturbation-search technique to identify changes in performance caused by forced oscillations of the controls. The controls on the NASA F-15 highly integrated digital electronic control (HIDEC) aircraft were perturbed using inlet cowl rotation steps at various subsonic and supersonic flight conditions to determine the effect on aircraft performance. The feasibility of the perturbation-search technique for identifying integrated airframe-propulsion system performance effects was successfully shown through flight experiments and postflight data analysis. Aircraft response and control data were analyzed postflight to identify gradients and to determine the minimum drag point. Changes in longitudinal acceleration as small as 0.004 g were measured, and absolute resolution was estimated to be 0.002 g or approximately 50 lbf of drag. Two techniques for identifying performance gradients were compared: a least-squares estimation algorithm and a modified maximum likelihood estimator algorithm. A complementary filter algorithm was used with the least squares estimator.

  5. Minimizing health risks during secondary effluent application via subsurface drip irrigation.

    PubMed

    Oron, Gideon; Gillerman, Lieonid; Lael, Avraham; Manor, Yossi; Braude, Erez; Bick, Amos

    2010-01-01

    Health risks posed on consumers due to the use of agricultural products irrigated with reclaimed wastewater were assessed by numerical simulation. The analysis is based on defining of an Exposure Model (EM) which takes into account several parameters: (i) the quality of the applied wastewater, (ii) the irrigation method, (iii) the elapsed times between irrigation, harvest, and product consumption, and; (iv) the consumers' habits. The exposure model is used for numerical simulation of human consumers' risks by running the Monte Carlo simulation method. Although some deviations in the numerical simulation which are probably due to uncertainty (impreciseness in quality of input data) and variability due to diversity among populations reasonable results were accepted. Accordingly, there is a several orders of magnitude difference in the risk of infection between the different exposure scenarios with the same water quality. The variability indicates the need for setting risk-based criteria for wastewater reclamation, including the application method and environmental conditions, rather than single water quality guidelines. Extra data is required to decrease uncertainty in the risk assessment. Future research needs to include definite acceptable risk criteria, more accurate dose-response modeling, information regarding pathogen survival in treated wastewater, additional data related to the passage of pathogens into and in the plants during irrigation, and information referring to the consuming habits of the human community.

  6. Analysis of the application of decontamination technologies to radioactive metal waste minimization using expert systems

    SciTech Connect

    Bayrakal, S.

    1993-09-30

    Radioactive metal waste makes up a significant portion of the waste currently being sent for disposal. Recovery of this metal as a valuable resource is possible through the use of decontamination technologies. Through the development and use of expert systems a comparison can be made of laser decontamination, a technology currently under development at Ames Laboratory, with currently available decontamination technologies for applicability to the types of metal waste being generated and the effectiveness of these versus simply disposing of the waste. These technologies can be technically and economically evaluated by the use of expert systems techniques to provide a waste management decision making tool that generates, given an identified metal waste, waste management recommendations. The user enters waste characteristic information as input and the system then recommends decontamination technologies, determines residual contamination levels and possible waste management strategies, carries out a cost analysis and then ranks, according to cost, the possibilities for management of the waste. The expert system was developed using information from literature and personnel experienced in the use of decontamination technologies and requires validation by human experts and assignment of confidence factors to the knowledge represented within.

  7. Approach toward minimizing chemical interference in FAB mass spectra: the development and application of thermally - assisted FAB

    SciTech Connect

    Ackermann, B.L.

    1987-01-01

    Interferences with fast atom bombardment (FAB) mass spectrometry can be classified into two major categories. The first includes impurities which remain after analyte isolation/purification, and is especially problematic in samples of biological origin. The second type of chemical interference originates from the matrix used for FAB. An example of the first type, also known as sample-related interference, is presented in the context of the analysis of the urinary metabolites of the analgesic acetaminophen by means of the off-line combination of reverse phase HPLC and FAB. Recommendations are made for efficient use of these two methods with specific regard to minimizing chemical interferences. In addition, a method for calculating analyte signal to background (S/B) values is introduced as a means of evaluating the quality of the FAB mass spectrum. A method known as thermally-assisted FAB (TA-FAB) is introduced as a means of minimizing matrix-related background. Success to date has been achieved using aqueous saccharide solutions as TA-FAB matrices. Several important improvements to FAB result from thermal control of the matrix including a selection against matrix background, and the possibility of valid background subtraction. The development of TA-FAB is described in the context of applications of the technique to the analysis of several representative nonvolatile biomolecules including a series of cyclic tetrapeptide mycotoxins. In the final section, the hypothesis of ternary perculation (TP) is submitted to account for behavior observed during TA-FAB.

  8. Stress echo applications beyond coronary artery disease.

    PubMed

    Picano, Eugenio; Pellikka, Patricia A

    2014-04-01

    heart disease, and whenever there is a mismatch between symptoms during stress and findings at rest. Increasing societal concern regarding cost, environment and radiation risks of medical imaging will lead to a preferential application of ultrasound over competing techniques, due to its unsurpassed versatility, portability, absence of radiation, and low cost.

  9. Erratum: Psychoneuroimmunology: application to ocular diseases.

    PubMed

    Ventura, Lori M

    2009-09-01

    Psychoneuroimmunology (PNI) is a relatively new discipline within the field of neuroscience which researches the relationship between emotional states, the central and peripheral nervous systems, and the endocrine and immune systems. Negative psychological states, such as stress, anxiety, and depression, may alter immune system regulation and modulation of peripheral cytokines. A plethora of PNI studies have shown that increased psychological stress and depression are associated with an alteration of immune functioning and worsened health outcomes for many conditions. To date, application of PNI methodology has not been reported for ocular diseases. This article provides an historical perspective on the origins of the rift between the emotional and spiritual from physical aspects of disease. A review of how stress is mediated through sympathetic adrenomedullary and hypothalamic pituitary axis activation with shifts in immunity is provided. The literature which supports spirituality in healing is presented. Finally, ocular diseases which would be most amenable to a PNI approach are discussed.[This corrects the article on p. in vol. .].

  10. Application of Nanomedicine to the CNS Diseases.

    PubMed

    Carradori, D; Gaudin, A; Brambilla, D; Andrieux, K

    2016-01-01

    Drug delivery to the brain is a challenge because of the many mechanisms that protect the brain from the entry of foreign substances. Numerous molecules which could be active against brain disorders are not clinically useful due to the presence of the blood-brain barrier. Nanoparticles can be used to deliver these drugs to the brain. Encapsulation within colloidal systems can allow the passage of nontransportable drugs across this barrier by masking their physicochemical properties. It should be noted that the status of the blood-brain barrier is different depending on the brain disease. In fact, in some pathological situations such as tumors or inflammatory disorders, its permeability is increased allowing very easy translocation of carriers. This chapter gathers the promising results obtained by using nanoparticles as drug delivery systems with the aim to improve the therapy of some CNS diseases such as brain tumor, Alzheimer's disease, and stroke. The data show that several approaches can be investigated: (1) carrying drug through a permeabilized barrier, (2) crossing the barrier thanks to receptor-mediated transcytosis pathway in order to deliver drug into the brain parenchyma, and also (3) targeting and treating the endothelial cells themselves to preserve locally the brain tissue. The examples given in this chapter contribute to demonstrate that delivering drugs into the brain is one of the most promising applications of nanotechnology in clinical neuroscience. © 2016 Elsevier Inc. All rights reserved.

  11. Minimization of thermal impact by application of electrode cooling in a co-linear PEF treatment chamber.

    PubMed

    Meneses, Nicolas; Jaeger, Henry; Knorr, Dietrich

    2011-10-01

    A co-linear pulsed electric field (PEF) treatment chamber was analyzed and optimized considering electrical process conditions, temperature, and retention of heat-sensitive compounds during a continuous PEF treatment of peach juice. The applicability of a jacket heat-exchanger device surrounding the ground electrode was studied in order to provide active cooling and to avoid temperature peaks within the treatment chamber thus reducing the total thermal load to which the product is exposed. Simulation of the PEF process was performed using a finite element method prior to experimental verification. Inactivation of polyphenoloxydase (PPO) and peroxidase (POD) as well as the degradation of ascorbic acid (AA) in peach juice was quantified and used as indirect indicators for the temperature distribution. Peaks of product temperature within the treatment chamber were reduced, that is, from 98 to 75 °C and retention of the indicators PPO, POD, and AA increased by more than 10% after application of the active electrode cooling device. Practical Application:  The co-linear PEF treatment chamber is widely used for continuous PEF treatment of liquid products and also suitable for industrial scale application; however, Joule heating in combination with nonuniform electric field distribution may lead to unwanted thermal effects. The proposed design showed potential to reduce the thermal load, to which the food is exposed, allowing the retention of heat-sensitive components. The design is applicable at laboratory or industrial scale to perform PEF trials avoiding temperature peaks, which is also the basis for obtaining inactivation kinetic models with minimized thermal impact on the kinetic variables.

  12. Minimally invasive mitral valve replacement is a safe and effective surgery for patients with rheumatic valve disease: A retrospective study.

    PubMed

    Zhai, Junyu; Wei, Lai; Huang, Ben; Wang, Chunsheng; Zhang, Hongqiang; Yin, Kanhua

    2017-06-01

    The aim of the study was to evaluate the treatment of minimally invasive mitral valve replacement (MIMVR) through a right minithoracotomy for patients with rheumatic mitral valve disease.From February 2009 to December 2016, 360 patients with rheumatic mitral valve disease underwent mitral valve replacement by the same surgeon. Among them, 150 patients accepted MIMVR through a right minithoracotomy, whereas the other 210 accepted a traditional median sternotomy. After matching by patients by age, sex, EuroSCORE, New York Heart Association (NYHA) classification, renal and liver function, and degree of mitral valve disease, we selected 224 patients for analysis in our retrospective study.In the MIMVR group (112 patients), the aortic cross-clamp time (ACC time) (55.25 ± 2.18 minutes) was significantly longer than that in the control group (112 patients; 36.05 ± 1.40 minutes) (P < .0001). In contrast, the cardiopulmonary bypass time (CPB time) was shorter in the MIMVR group than in the control group (61.13 ± 2.57 vs 78.65 ± 4.05 minutes, respectively, P < .0001). Patients who accepted MIMVR surgery had less drainage 24 hours postoperation (324.10 ± 34.55 vs 492.90 ± 34.05 mL, P < .0001) and had less total drainage (713.46 ± 65.35 vs 990.49 ± 67.88 mL, P < .0001) than those who underwent median sternotomy. Thirty-two percent of patients in the MIMVR group needed a blood transfusion (1.35 ± .28 units of red blood cells, 155.36 ± 33.43 mL plasma), whereas 67.0% of the control group needed a blood transfusion (2.15 ± .24 units of red blood cells, 287.50 ± 33.54 mL plasma) (Ptransfusion < .001, Pcell = .029, Pplasma = .006). In total, 5 deaths occurred during the perioperative period; 3 occurred in the MIMVR group. The average hospital stay was significantly shorter in the MIMVR group than that in the control group (6.56 ± .23 vs 8.53 ± .59 days, P = .003

  13. Minimal covering problem and PLA minimization

    SciTech Connect

    Young, M.H.; Muroga, S.

    1985-12-01

    Solving the minimal covering problem by an implicit enumeration method is discussed. The implicit enumeration method in this paper is a modification of the Quine-McCluskey method tailored to computer processing and also its extension, utilizing some new properties of the minimal covering problem for speedup. A heuristic algorithm is also presented to solve large-scale problems. Its application to the minimization of programmable logic arrays (i.e., PLAs) is shown as an example. Computational experiences are presented to confirm the improvements by the implicit enumeration method discussed.

  14. How and why minimal residual disease studies are necessary in leukemia: a review from WP10 and WP12 of the European LeukaemiaNet

    PubMed Central

    Béné, Marie C.; Kaeda, Jaspal S.

    2009-01-01

    Resistance to therapeutic agents is a major factor in the failure of cancer treatments. In leukemia, the resistant cells remaining in the bone marrow and/or peripheral blood constitute minimal residual disease and are detectable by highly sensitive assays when the patient appears to be in complete remission. Early detection of the expansion of residual cells permits clinical intervention with the aim of reversing the proliferation of resistant leukemic cells. Therefore, accurate and precise measurement of minimal residual disease can greatly enhance optimization of oncology patients' clinical management. This notion is supported by a large body of data among chronic myeloid leukemia patients, but minimal residual disease detection and monitoring is increasingly applied to other types of leukemia, and is starting to be a factor in decision-making for some therapeutic trials in childhood acute lymphoblastic leukemia. Here, from the solid ground of minimal residual disease detection in chronic myeloid leukemia, the current state of the art and development of molecular techniques in other leukemias and the growing field of multiparameter flow cytometry are reviewed in two separate parts reporting on the respective advances, advantages and pitfalls of these emerging methods. PMID:19586938

  15. Cost-minimization analysis favors outpatient quick diagnosis unit over hospitalization for the diagnosis of potentially serious diseases.

    PubMed

    Sanclemente-Ansó, Carmen; Bosch, Xavier; Salazar, Albert; Moreno, Ramón; Capdevila, Cristina; Rosón, Beatriz; Corbella, Xavier

    2016-05-01

    Quick diagnosis units (QDUs) are a promising alternative to conventional hospitalization for the diagnosis of suspected serious diseases, most commonly cancer and severe anemia. Although QDUs are as effective as hospitalization in reaching a timely diagnosis, a full economic evaluation comparing both approaches has not been reported. To evaluate the costs of QDU vs. conventional hospitalization for the diagnosis of cancer and anemia using a cost-minimization analysis on the proven assumption that health outcomes of both approaches were equivalent. Patients referred to the QDU of Bellvitge University Hospital of Barcelona over 51 months with a final diagnosis of severe anemia (unrelated to malignancy), lymphoma, and lung cancer were compared with patients hospitalized for workup with the same diagnoses. The total cost per patient until diagnosis was analyzed. Direct and non-direct costs of QDU and hospitalization were compared. Time to diagnosis in QDU patients (n=195) and length-of-stay in hospitalized patients (n=237) were equivalent. There were considerable costs savings from hospitalization. Highest savings for the three groups were related to fixed direct costs of hospital stays (66% of total savings). Savings related to fixed non-direct costs of structural and general functioning were 33% of total savings. Savings related to variable direct costs of investigations were 1% of total savings. Overall savings from hospitalization of all patients were €867,719.31. QDUs appear to be a cost-effective resource for avoiding unnecessary hospitalization in patients with anemia and cancer. Internists, hospital executives, and healthcare authorities should consider establishing this model elsewhere. Copyright © 2015. Published by Elsevier B.V.

  16. Clinical utility of next-generation sequencing-based minimal residual disease in paediatric B-cell acute lymphoblastic leukaemia.

    PubMed

    Sekiya, Yuko; Xu, Yinyan; Muramatsu, Hideki; Okuno, Yusuke; Narita, Atsushi; Suzuki, Kyogo; Wang, Xinan; Kawashima, Nozomu; Sakaguchi, Hirotoshi; Yoshida, Nao; Hama, Asahito; Takahashi, Yoshiyuki; Kato, Koji; Kojima, Seiji

    2017-01-01

    We assessed the clinical utility of next-generation sequencing (NGS)-based monitoring of minimal residual disease (MRD) in a uniformly treated cohort of 79 patients with paediatric B-cell acute lymphoblastic leukaemia. Bone marrow samples were collected at the time of diagnosis, days 33 and 80, pre- (4-5 months) and post- (24 months) maintenance therapy time points, and at relapse. We identified leukaemia-specific CDR3 sequences in 72 of 79 patients (91%) and detected MRD in 59 of 232 samples. Although MRD was detected in 28 of 55 samples (51%) on day 33, the frequencies of MRD detection decreased to 25% (16/65) at day 80, 19% (11/58) at 4-5 months and 7·4% (4/54) at 24 months. In a univariate analysis, positive MRD results on day 80 [relative risk (RR) 95% confidence interval (CI) = 7·438 (2·561-21·6), P < 0·001], at 4-5 months [RR (95% CI) = 10·24 (3·374-31·06), P < 0·001], and at 24 months [RR (95% CI) = 19·26 (4·974-74·59), P < 0·001] exhibited statistically significant associations with inferior leukaemia-free survival; this was confirmed using a Cox proportional hazard model. Our study suggests the promising potential of NGS-MRD for patients with B-cell ALL. © 2016 John Wiley & Sons Ltd.

  17. Serum peptidomic profiling identifies a minimal residual disease detection and prognostic biomarker for patients with acute leukemia

    PubMed Central

    SONG, WEI; WANG, NA; LI, WEI; WANG, GUANJUN; HU, JIFAN; HE, KUN; LI, YAN; MENG, YING; CHEN, NAIFEI; WANG, SHAOXIN; HU, LINGYUN; XU, BIN; WANG, JIE; LI, AILING; CUI, JIUWEI

    2013-01-01

    The evaluation of minimal residual disease (MRD) in acute leukemia (AL) is currently recognized as a potential critical tool to assess the response and relapse rate of treatments. The present study investigated serum peptides from patients with AL to identify biomarkers that would be useful in providing clinical evaluations and independent prognostic information. The patterns of serum peptides from 123 patients with AL and 49 healthy controls were analyzed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Furthermore, diagnostic models of differential peptides were established using the support vector machine (SVM) algorithm to discriminate between the AL patients and healthy controls or between the AL patients with various degrees of remission. Finally, the peptides were applied to evaluate the prognosis of the affected patients. The area under the receiver operating characteristic (ROC) curve (AUC), analyzed using the SVM algorithm to distinguish between the AL patients and healthy controls, was 0.921. The AUC of the models for distinguishing between the newly-diagnosed AL patients and those in AL-hematological complete remission (HCR) and between the AL-HCR patients from those in AL-molecular remission (MR), was 0.824 and 0.919, respectively. A short serum peptide of m/z 4625 was identified to decrease in density in parallel with an increase in the degree of remission, which was used to monitor the MRD level. The intensity of the m/z 4625 peptide was significantly correlated with a poor overall survival (OS). The m/z 4625 peptide was identified to be a partial fragment of SERPINA3. The serum peptide pattern is high in sensitivity and specificity and may be used to discriminate between AL patients with various degrees of remission. The m/z 4625 peptide may be used to monitor the MRD levels and provide independent prognostic information in patients with AL. PMID:24179540

  18. Quantitative detection of the human cervical cancer oncogene for monitoring the minimal residual disease in acute leukemia

    PubMed Central

    Guo, Xiao-Nan; Ren, Jin-Hai; Zhang, Jing-Nan; Wang, Ying

    2015-01-01

    The human cervical cancer oncogene (HCCR) has been shown to be over-expressed in some solid tumors, and its function is involved in negative regulation of p53 tumor suppressor gene. However, the roles of HCCR in leukemia remain unclear. The present study is to investigate whether the expression levels of HCCR mRNA are associated with clinical prognosis in patients with acute leukemia (AL) and to explore the potential use as a biomarker for monitoring minimal residual disease (MRD) in AL. The mRNA levels of HCCR1 and HCCR2 were quantified by real-time reverse transcription polymerase chain reaction in bone marrow samples from 80 adult de novo AL patients and 20 normal healthy donors. The expressions of HCCR1 and HCCR2 were significantly higher in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) than those in healthy donors (P < 0.01), but there was no significant difference between AML and ALL (P > 0.05). Besides white blood cell count, we did not find any significant correlation between HCCR expression and clinical characteristics, such as age, sex, CD34 antigen expression, and response to chemotherapy. HCCR was monitored in 12 cases during remission and/or relapse. Significant reductions of both HCCR1 and HCCR2 mRNA levels were observed in patients who had achieved complete remission after chemotherapy but not in patients with non-responsive. However, an increased HCCR expression was detected in these patients who relapsed. Our findings suggest that HCCR gene is over-expressed in AL patients and may be as a useful biomarker for monitoring MRD in AL. PMID:25034723

  19. Wilms tumor gene (WT1) as a new marker for the detection of minimal residual disease in leukemia.

    PubMed

    Sugiyama, H

    1998-06-01

    WT1 (Wilms tumor gene) expression is a new tumor marker of leukemic blast cells of AML, ALL, and CML. Minimal residual disease (MRD) of leukemia can be detected at frequencies as low as 1 in 10(3) to 10(4) normal bone marrow (BM) cells and 1 in 10(5) normal peripheral blood (PB) cells by means of the quantitation of expression levels of the WT1 gene using reverse transcriptase-polymerase chain reaction (RT-PCR). This is regardless of the types of leukemia or the presence or absence of tumor-specific DNA markers. Thus, the WT1 assay makes it possible to rapidly assess the effectiveness of treatment and to evaluate the degree of eradication of leukemic cells in individual leukemia patients. Moreover, molecular relapse using PCR can be diagnosed by the monitoring of WT1 expression levels in BM or PB 1-24 months (means, 7 months for BM and 8 months for PB) before the clinical relapse became apparent. In case of rapid or gradual increase in WT1 expression levels to or over 10(-2) after return to normal BM levels during CR; or retention of the WTI expression at levels near or over 10(-2) in BM without return to normal BM levels even in CR (WT1 expression level in K562 cells was defined as 1.0), it seems that clinical relapse is impending. Since WT1 antisense oligomers inhibit the growth of leukemic cells, it is apparent that the WT1 gene plays an important role in leukemogenesis.

  20. Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance.

    PubMed

    Paiva, Bruno; Corchete, Luis A; Vidriales, Maria-Belen; Puig, Noemi; Maiso, Patricia; Rodriguez, Idoia; Alignani, Diego; Burgos, Leire; Sanchez, Maria-Luz; Barcena, Paloma; Echeveste, Maria-Asuncion; Hernandez, Miguel T; García-Sanz, Ramón; Ocio, Enrique M; Oriol, Albert; Gironella, Mercedes; Palomera, Luis; De Arriba, Felipe; Gonzalez, Yolanda; Johnson, Sarah K; Epstein, Joshua; Barlogie, Bart; Lahuerta, Juan José; Blade, Joan; Orfao, Alberto; Mateos, María-Victoria; San Miguel, Jesús F

    2016-04-14

    Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered atwww.clinicaltrials.gov as #NCT01237249. © 2016 by The American Society of Hematology.

  1. Standardization of WT1 mRNA quantitation for minimal residual disease monitoring in childhood AML and implications of WT1 gene mutations: a European multicenter study.

    PubMed

    Willasch, A M; Gruhn, B; Coliva, T; Kalinova, M; Schneider, G; Kreyenberg, H; Steinbach, D; Weber, G; Hollink, I H I M; Zwaan, C M; Biondi, A; van der Velden, V H J; Reinhardt, D; Cazzaniga, G; Bader, P; Trka, J

    2009-08-01

    A standardized, sensitive and universal method for minimal residual disease (MRD) detection in acute myeloid leukemia (AML) is still pending. Although hyperexpression of Wilms' tumor (WT1) gene transcript has been frequently proposed as an MRD marker in AML, wide comparability of the various methods used for evaluating WT1 expression has not been given. We established and standardized a multicenter approach for quantifying WT1 expression by quantitative reverse transcriptase PCR (qRT-PCR), on the basis of a primer/probe set combination at exons 6 and 7. In a series of quality-control rounds, we analyzed 69 childhood AML samples and 47 normal bone marrow (BM) samples from 4 participating centers. Differences in the individual WT1 expressions levels ranged within <0.5 log of the mean in 82% of the cases. In AML samples, the median WT1/1E+04 Abelson (ABL) expression was 3.5E+03 compared with that of 2.3E+01 in healthy BM samples. As 11.5% of childhood AML samples in this cohort harbored WT1 mutations in exon 7, the effect of mutations on WT1 expression has been investigated, showing that mutated cases expressed significantly higher WT1 levels than wild-type cases. Hence, our approach showed high reproducibility and applicability, even in patients with WT1 mutations; therefore, it can be widely used for the quantitation of WT1 expression in future clinical trials.

  2. Current applications of lasers in heart disease

    NASA Astrophysics Data System (ADS)

    Lee, Garrett; Chan, Ming C.; Mason, Dean T.

    1993-03-01

    Although the laser has been in existence for abut 30 years, its application in heart disease has only been examined in the past decade. Much attention has been given its exciting potential in treating coronary artery disease. Transmitted through a catheter comprised of one or more thin optical fibers which can be threaded nonsurgically into the coronary artery, the laser can ablate atherosclerotic plaque that obstructs the artery and diminishes blood flow to the myocardium. In clinical studies, the laser can treat some obstructive lesions that are not suitable for balloon angioplasty (i.e., long and diffuse lesions, very tight stenoses, ostial lesions, calcified lesions). In patients who failed balloon angioplasty due to severe dissection or abrupt closure, the laser may seal up the dissections and restore antegrade blood flow. In addition, the laser may have other applications and treatment modalities that are still under investigation. It may ablate ectopic ventricular foci, or terminate supraventricular tachyrhythmia by destroying the heart's abnormal conduction pathways. It can cut the hypertrophied septum that is associated with left ventricular outflow tract obstruction, or create a channel in the atrial septum as a palliative procedure in newborns with transposition of the great vessels. It may provide a wider orifice for blood flow within the heart in infants with pulmonary outflow obstruction and in adults with aortic valvular stenosis. It is also capable of fusing small thin-walled blood vessels together. Further, a more intriguing possibility is its use to bore several tiny channels in the myocardium to allow oxygenated blood from within the ventricular chamber to perfuse the ischemic heart tissue.

  3. Experiment design for nonparametric models based on minimizing Bayes Risk: application to voriconazole[Formula: see text].

    PubMed

    Bayard, David S; Neely, Michael

    2017-04-01

    An experimental design approach is presented for individualized therapy in the special case where the prior information is specified by a nonparametric (NP) population model. Here, a NP model refers to a discrete probability model characterized by a finite set of support points and their associated weights. An important question arises as to how to best design experiments for this type of model. Many experimental design methods are based on Fisher information or other approaches originally developed for parametric models. While such approaches have been used with some success across various applications, it is interesting to note that they largely fail to address the fundamentally discrete nature of the NP model. Specifically, the problem of identifying an individual from a NP prior is more naturally treated as a problem of classification, i.e., to find a support point that best matches the patient's behavior. This paper studies the discrete nature of the NP experiment design problem from a classification point of view. Several new insights are provided including the use of Bayes Risk as an information measure, and new alternative methods for experiment design. One particular method, denoted as MMopt (multiple-model optimal), will be examined in detail and shown to require minimal computation while having distinct advantages compared to existing approaches. Several simulated examples, including a case study involving oral voriconazole in children, are given to demonstrate the usefulness of MMopt in pharmacokinetics applications.

  4. Nephrotic syndrome due to minimal change disease secondary to spider bite: clinico-pathological case of a non-described complication of latrodectism

    PubMed Central

    Enos, Daniel; Moreira, José Luis; Alvaredo, Fátima; Oddó, David

    2017-01-01

    Abstract The patient was an 18-year-old man who developed nephrotic syndrome after a ‘wheat spider’ bite (Latrodectus mactans). Due to this atypical manifestation of latrodectism, a renal biopsy was performed showing minimal change disease. The nephrotic syndrome subsided after 1 week without specific treatment. This self-limited evolution suggests that the mechanism of podocyte damage was temporary and potentially mediated by a secondary mechanism of hypersensitivity or direct effect of the α-latrotoxin. The patient did not show signs of relapse in subsequent checkup. This is the first reported case of nephrotic syndrome due to a minimal change lesion secondary to latrodectism. PMID:28396739

  5. Nephrotic syndrome due to minimal change disease secondary to spider bite: clinico-pathological case of a non-described complication of latrodectism.

    PubMed

    Méndez, Gonzalo P; Enos, Daniel; Moreira, José Luis; Alvaredo, Fátima; Oddó, David

    2017-04-01

    The patient was an 18-year-old man who developed nephrotic syndrome after a 'wheat spider' bite (Latrodectus mactans). Due to this atypical manifestation of latrodectism, a renal biopsy was performed showing minimal change disease. The nephrotic syndrome subsided after 1 week without specific treatment. This self-limited evolution suggests that the mechanism of podocyte damage was temporary and potentially mediated by a secondary mechanism of hypersensitivity or direct effect of the α-latrotoxin. The patient did not show signs of relapse in subsequent checkup. This is the first reported case of nephrotic syndrome due to a minimal change lesion secondary to latrodectism.

  6. Minimally invasive procedure reduces adjacent segment degeneration and disease: New benefit-based global meta-analysis

    PubMed Central

    Li, Xiao-Chuan; Huang, Chun-Ming; Zhong, Cheng-Fan; Liang, Rong-Wei; Luo, Shao-Jian

    2017-01-01

    Objective Adjacent segment pathology (ASP) is a common complication presenting in patients with axial pain and dysfunction, requiring treatment or follow-up surgery. However, whether minimally invasive surgery (MIS), including MIS transforaminal / posterior lumbar interbody fusion (MIS-TLIF/PLIF) decreases the incidence rate of ASP remains unknown. The aim of this meta-analysis was to compare the incidence rate of ASP in patients undergoing MIS versus open procedures. Methods This systematic review was undertaken by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. We searched electronic databases, including PubMed, EMBASE, SinoMed, and the Cochrane Library, without language restrictions, to identify clinical trials comparing MIS to open procedures. The results retrieved were last updated on June 15, 2016. Results Overall, 9 trials comprising 770 patients were included in the study; the quality of the studies included 4 moderate and 5 low-quality studies. The pooled data analysis demonstrated low heterogeneity between the trials and a significantly lower ASP incidence rate in patients who underwent MIS procedure, compared with those who underwent open procedure (p = 0.0001). Single-level lumbar interbody fusion was performed in 6 trials of 408 patients and we found a lower ASP incidence rate in MIS group, compared with those who underwent open surgery (p = 0.002). Moreover, the pooled data analysis showed a significant reduction in the incidence rate of adjacent segment disease (ASDis) (p = 0.0003) and adjacent segment degeneration (ASDeg) (p = 0.0002) for both procedures, favoring MIS procedure. Subgroup analyses showed no difference in follow-up durations between the procedures (p = 0.93). Conclusion Therefore, we conclude that MIS-TLIF/PLIF can reduce the incidence rate of ASDis and ASDeg, compared with open surgery. Although the subgroup analysis did not indicate a difference in follow-up duration between the two

  7. Increased myeloid precursors in regenerating bone marrow; implications for detection of minimal residual disease in acute myeloid leukemia.

    PubMed

    Zeleznikova, T; Stevulova, L; Kovarikova, A; Babusikova, O

    2007-01-01

    Presented study is focused on exact immunophenotypic definition of myeloid precursors and their following stages in regenerating bone marrow during treatment of ALL/AML for correct interpretation of the immunophenotype results and proper distinction from minimal residual disease (MRD) by multiparameter flow cytometry. This study includes bone marrow samples from 36 controls, 27 patients with AML, 39 patients with B-ALL undergoing therapy who remained in complete remission after treatment and also 30 B-ALL patients one year after the end of therapy. We observed substantial expansion of immature bone marrow populations in the regenerating bone marrows, which were identified by expression of CD34 and/or CD117 markers by 4-color flow cytometry. Myeloid precursors were significantly increased after cessation of induction therapy cycle of B-ALL (1.27+/-2.04%, p=0.0064) and also AML patients (0.87+/-0.77%, p=0.001), but also during follow-up of B-ALL patients (1.42+/-2.36%, p=0.0001) when compared with non-treated controls (0.38+/-0.29%). Some cases where their frequencies achieved up to 12% reflect the massive regeneration of myeloid lineage in bone marrow after chemotherapy cycles. Especially in these cases accurate interpretation of such a high frequency of immature myeloid cells as myeloid precursors was very important to exclude incoming relapse or secondary leukemia. The myeloid precursors represented by CD34+ in regenerating bone marrow expressed CD45 (94.8+/-5.5%), CD117 (38.3+/-26.2%), CD38 (91.4+/-5.7%), HLA-DR (90.6+/-7.6%), CD13 (73.0+/-20.8%) and CD33 (85.2+/-15.6%), while CD90 (2.7+/-2.5%), CD133 (10.0+/-8.2%) and T or B lymphocyte markers were negative. Comparing immunophenotypes with control bone marrows, only difference in expression of CD33 marker was found (85.2+/-15.6% versus 63.0+/-17.4% p=0.024). In addition, according to expression of these markers three different subsets of myeloid precursor cells were identified in regenerating bone marrow samples

  8. Quantitative assessment of minimal residual disease (MRD) in canine lymphoma by using real-time polymerase chain reaction.

    PubMed

    Yamazaki, Jumpei; Baba, Kenji; Goto-Koshino, Yuko; Setoguchi-Mukai, Asuka; Fujino, Yasuhito; Ohno, Koichi; Tsujimoto, Hajime

    2008-12-15

    Lymphoma is the most common hematopoietic malignancy in dogs. Although a large proportion of dogs with lymphoma can achieve clinical remission by initial chemotherapy, most dogs die as a consequence of tumor relapse. We established a quantitative detection system for minimal residual disease (MRD) in canine lymphoma by using real-time polymerase chain reaction (PCR). A canine T-cell lymphoma-derived cell line, namely, UL-1, was used to examine the specificity and sensitivity of the MRD detecting system. Allele-specific oligonucleotide primers and probes were designed based on the sequence of T-cell receptor gamma chain (TCRgamma) gene fragment of UL-1 cells in conjunction with its downstream sequence, which were obtained from the dog genome database. The real-time PCR system for plasmid DNA containing the TCRgamma gene derived from UL-1 cells and the genomic DNA of UL-1 cells revealed that the system was accurate for 10-100,000 copies per reaction and its sensitivity was 1 cell per 10,000 cells. In order to monitor the kinetics of tumor cell number in canine lymphoma, we quantified the level of MRD in the peripheral blood of 7 dogs with lymphoma under chemotherapy. Since the lymphoma cells from the 7 patients were shown to be B-cell origin from the finding of clonal rearrangement of immunoglobulin heavy chain (IgH) gene, allele-specific oligonucleotide primers and probes were prepared based on the sequence of rearranged IgH gene in each case. The number of peripheral blood tumor cells measured by the real-time PCR was comparable to that estimated by conventional hematological examination in 2 cases of stage V lymphoma. MRD in the peripheral blood was detectable in all 7 cases, even in the complete remission (CR) phase. In the 7 lymphoma dogs, changes in the MRD levels of peripheral blood generally paralleled with the changes in the volumes of lymph nodes. Molecular CR, in which the MRD level was below the detection limit, was not observed in any of these 7 patients

  9. Minimal residual disease before and after transplantation for childhood acute lymphoblastic leukaemia: is there any room for intervention?

    PubMed

    Balduzzi, Adriana; Di Maio, Lucia; Silvestri, Daniela; Songia, Simona; Bonanomi, Sonia; Rovelli, Attilio; Conter, Valentino; Biondi, Andrea; Cazzaniga, Giovanni; Valsecchi, Maria G

    2014-02-01

    Eighty-two children and adolescents who underwent allogeneic transplantation for acute lymphoblastic leukaemia in remission (period 2001-2011, median follow-up 4·9 years) had been assessed for minimal residual disease (MRD) by real-time quantitative polymerase chain reaction before and at 1, 3, 6, 9 and 12 months after transplantation. Five-year event-free survival (EFS) and cumulative incidence of relapse were 77·7% [standard error (SE) 5·7] and 11·4% (SE 4·4), respectively, for patients with pre-transplant MRD <1 × 10(-4) (68%), versus 30·8% (SE 9·1; P < 0·001) and 61·5% (SE 9·5; P < 0·001), respectively, for those with MRD ≥1 × 10(-4) (32%). Pre-transplant MRD ≥1 × 10(-4) was associated with a 9·2-fold risk of relapse [95% confidence interval (CI) 3·54-23·88; P < 0·001] compared with patients with MRD <1 × 10(-4). Patients who received additional chemotherapy pre-transplant to reduce MRD had a fivefold reduction of risk of failure (hazard ratio 0·19, CI 0·05-0·70, P = 0·01). Patients who experienced MRD positivity post-transplant did not necessarily relapse (5-year EFS 40·3%, SE 9·3), but had a 2·5-fold risk of failure (CI 1·05-5·75; P = 0·04) if any MRD was detected in the first 100 d, which increased to 7·8-fold (CI 2·2-27·78; P = 0·002) if detected after 6 months. Anticipated immunosuppression-tapering according to MRD may have improved outcome, nevertheless all patients with post-transplant MRD ≥1 × 10(-3) ultimately relapsed, regardless of immunosuppression discontinuation or donor-lymphocyte-infusion. In conclusion, MRD before transplantation had the strongest impact on relapse and MRD positivity after transplantation, mostly if detected early and at low levels, did not necessarily imply relapse. Additional intensified chemotherapy and modulation of immunosuppression may reduce relapse risk and improve ultimate outcome.

  10. What is minimally invasive dentistry?

    PubMed

    Ericson, Dan

    2004-01-01

    Minimally Invasive Dentistry is the application of "a systematic respect for the original tissue." This implies that the dental profession recognizes that an artifact is of less biological value than the original healthy tissue. Minimally invasive dentistry is a concept that can embrace all aspects of the profession. The common delineator is tissue preservation, preferably by preventing disease from occurring and intercepting its progress, but also removing and replacing with as little tissue loss as possible. It does not suggest that we make small fillings to restore incipient lesions or surgically remove impacted third molars without symptoms as routine procedures. The introduction of predictable adhesive technologies has led to a giant leap in interest in minimally invasive dentistry. The concept bridges the traditional gap between prevention and surgical procedures, which is just what dentistry needs today. The evidence-base for survival of restorations clearly indicates that restoring teeth is a temporary palliative measure that is doomed to fail if the disease that caused the condition is not addressed properly. Today, the means, motives and opportunities for minimally invasive dentistry are at hand, but incentives are definitely lacking. Patients and third parties seem to be convinced that the only things that count are replacements. Namely, they are prepared to pay for a filling but not for a procedure that can help avoid having one.

  11. Shifting Paradigms in Minimally Invasive Surgery: Applications of Transanal Natural Orifice Transluminal Endoscopic Surgery in Colorectal Surgery

    PubMed Central

    Lee, Grace Clara; Sylla, Patricia

    2015-01-01

    Since the advent of laparoscopy, minimally invasive techniques such as single port laparoscopy, robotics, endoscopically assisted laparoscopy, and transanal endoscopic surgery continue to revolutionize the field of colorectal surgery. Transanal natural orifice transluminal endoscopic surgery (NOTES) represents a further paradigm shift by combining the advantages of these earlier techniques to reduce the size and number of abdominal incisions and potentially optimize rectal dissection, especially with respect to performance of an oncologically adequate total mesorectal excision (TME) for rectal cancer. Since the first experimental report of transanal rectosigmoid resection in 2007, the potential impact of transanal NOTES in colorectal surgery has been extensively investigated in experimental models and recently transitioned to clinical application. There have been 14 clinical trials of transanal TME (taTME) for rectal cancer that have demonstrated the feasibility and preliminary oncologic safety of this approach in carefully selected patients, with results comparable to outcomes after laparoscopic and open TME, including cumulative intraoperative and postoperative complication rates of 5.5 and 35.5%, respectively, 97.3% rate of complete or near-complete specimens, and 93.6% rate of negative margins. Transanal NOTES has also been safely applied to proctectomy and colectomy for benign indications. The consensus among published series suggests that taTME is most safely performed with transabdominal assistance by surgeons experienced with laparoscopic TME, transanal endoscopic surgery, and sphincter-preserving techniques including intersphincteric resection. Future applications of transanal NOTES may include evolution to a pure endoscopic transanal approach for TME, colectomy, and sentinel lymph node biopsy for rectal cancer, with a potential role for robotic assistance. PMID:26491411

  12. FMRI activation with an "affective speech" paradigm in vegetative and minimally conscious States: applicability and prognostic value.

    PubMed

    Piperno, R; Battistini, A; Cevolani, D; Maffei, M; Leonardi, M; Agati, R

    2012-07-01

    Vegetative state (VS) and minimally conscious state (MCS) are considered different clinical entities but their differential diagnosis remains challenging. Some VS patients can show an MCS-like activation in functional magnetic resonance imaging (fMRI) studies that seems to predict recovery from VS. We studied fMRI activation with an affective speech paradigm in a cohort of non-communicative brain-injured individuals consecutively admitted to a post-acute neurorehabilitation facility in five years. Among 93 eligible subjects, 65 met the clinical criteria for VS and 28 for MCS. Because of exclusion criteria, activation studies were performed in only 30 cases out of 93 and analysed in only 24 (about ¼ of the eligible cases): 19 VS and five MCS patients. The passive acoustic stimulus consisted in a familiar voice narrating a significant episode in the patient's life, administered by nonmagnetic earphones. All the MCS patients showed an activation spread to secondary associative cortices but also 52.7% of the VS patients displayed an "atypical" large-scale activation pattern. Regarding the clinical outcome, 80% of the patients with large-scale network activation (LSNA) had some recovery of consciousness. Our results confirm that the VS patients with LSNA at fMRI study have potential for further recovery of consciousness, whereas no patient without activation or only typical activation improved. fMRI study with an affective speech paradigm, when applicable, seems to have a valuable prognostic value in VS patients, even if there are major limitations in terms of applicability.

  13. Validity, reliability and minimal detectable change of the balance evaluation systems test (BESTest), mini-BESTest and brief-BESTest in patients with end-stage renal disease.

    PubMed

    Jácome, Cristina; Flores, Inês; Martins, Filipa; Castro, Conceição; McPhee, Charlotte C; Shepherd, Ellen; Demain, Sara; Figueiredo, Daniela; Marques, Alda

    2017-09-08

    This study determined the validity, test-retest reliability and minimal detectable change of the balance evaluation systems test (BESTest), mini-balance evaluation systems test (Mini-BESTest) and brief-balance evaluation systems test (Brief-BESTest) in patients with end-stage renal disease. A cross-sectional study with 74 patients with end-stage renal disease (male 66.2%; 63.9 ± 15.1 years old) was conducted. Participants were asked to report the number of falls during the previous 12 months and to complete the activity-specific balance confidence (ABC) scale. The BESTest was administered, and the Mini-BESTest and Brief-BESTest scores were computed based on the BESTest performance. Validity was assessed by correlating balance tests with each other and with the ABC scale. Test-retest relative reliability and agreement were explored with the intraclass correlation coefficient (ICC) equation (2,1) and the Bland and Altman method. Minimal detectable changes at the 95% confidence level were established. Balance test scores were significantly correlated with each other (spearman's correlation = 0.89-0.92) and with the ABC scale (spearman's correlation = 0.49-0.59). Balance tests presented high test-retest reliability (ICC = 0.84-0.94), with no evidence of bias. Minimal detectable change values were 10.8 (expressed as a percentage 13.5%), 5.3 (23.7%) and 5.6 (34%) points for the BESTest, Mini-BESTest and Brief-BESTest, respectively. All tests are valid and reliable to assess balance in patients with end-stage renal disease. Nevertheless, based on the minimal detectable changes found, BESTest and Mini-BESTest may be the most recommended tests for this specific population. Implications for Rehabilitation Balance evaluation systems test (BESTest), mini-balance evaluation systems test (Mini-BESTest) and brief-balance evaluation systems test (Brief-BESTest) are reliable and valid in patients with end stage renal disease (ESRD). The minimal detectable

  14. Designing patient-centric applications for chronic disease management.

    PubMed

    Tsalatsanis, Athanasios; Gil-Herrera, Eleazar; Yalcin, Ali; Djulbegovic, Benjamin; Barnes, Laura

    2011-01-01

    Chronic diseases such as diabetes and heart disease are the leading causes of disability and death in the developed world. Technological interventions such as mobile applications have the ability to facilitate and motivate patients in chronic disease management, but these types of interventions present considerable design challenges. The primary objective of this paper is to present the challenges arising from the design and implementation of software applications aiming to assist patients in chronic disease management. We also outline preliminary results regarding a self-management application currently under development targeting young adults suffering from type 1 diabetes.

  15. [Application of precision medicine in obesity and metabolic disease surgery].

    PubMed

    Wang, Cunchuan; Gao, Zhiguang

    2016-01-01

    The U. S. A. president Obama called for a new initiative to fund precision medicine during his State of Union Address on January 20th, 2015, which meant that the human medicine enters a new era. The meaning of "precision medicine" is significantly similar to the concept of precision obesity and metabolic disease surgery, which was proposed by the author in early August 2011. Nowadays, obesity and metabolic disease surgery has been transformed from open surgery to laparoscopic surgery, the extensive mode to the precision mode. The key value concept is to minimize postoperative complication, minimize postoperative hospital stay and obtain the best effect of weight loss by accurate preoperative assessment, delicate operation, excellent postoperative management and scientific follow-up. The precision obesity and metabolic disease surgery has more development space in the future.

  16. Multiscale Optimization of a Truncated Newton Minimization Algorithm and Application to Proteins and Protein-Ligand Complexes.

    PubMed

    Zhu, Kai; Shirts, Michael R; Friesner, Richard A; Jacobson, Matthew P

    2007-03-01

    We optimize a truncated Newton (TN) minimization algorithm and computer package, TNPACK, developed for macromolecular minimizations by applying multiscale methods, analogous to those used in molecular dynamics (e.g., r-RESPA). The molecular mechanics forces are divided into short- and long-range components, with the long-range forces updated only intermittently in the iterative evaluations. This algorithm, which we refer to as MSTN, is implemented as a modification to the TNPACK package and is tested on energy minimizations of protein loops, entire proteins, and protein-ligand complexes and compared with the unmodified truncated Newton algorithm, a quasi-Newton algorithm (LBFGS), and a conjugate gradient algorithm (CG+). In vacuum minimizations, the speedup of MSTN relative to the unmodified TN algorithm (TNPACK) depends on system size and the distance cutoffs used for defining the short- and long-range interactions and the long-range force updating frequency, but it is 4 to 5 times greater in the work reported here. This algorithm works best for the minimization of small portions of a protein and shows some degradation (speedup factor of 2-3) for the minimization of entire proteins. The MSTN algorithm is faster than the quasi-Newton and conjugate gradient algorithms by approximately 1 order of magnitude. We also present a modification of the algorithm which permits minimizations with a generalized Born implicit solvent model, using a self-consistent procedure that increases the computational expense, relative to a vacuum, by only a small factor (∼3-4).

  17. Vibration attenuation of rotating machines by application of magnetorheological dampers to minimize energy losses in the rotor support

    NASA Astrophysics Data System (ADS)

    Zapoměl, J.; Ferfecki, P.

    2016-09-01

    A frequently used technological solution for minimization of undesirable effects caused by vibration of rotating machines consists in placing damping devices in the rotor supports. The application of magnetorheological squeeze film dampers enables their optimum performance to be achieved in a wide range of rotating speeds by adapting their damping effect to the current operating conditions. The damping force, which is produced by squeezing the layer of magnetorheological oil, can be controlled by changing magnetic flux passing through the lubricant. The force acting between the rotor and its frame is transmitted through the rolling element bearing, the lubricating layer and the squirrel spring. The loading of the bearing produces a time variable friction moment, energy losses, uneven rotor running, and has an influence on the rotor service life and the current fluctuation in electric circuits. The carried out research consisted in the development of a mathematical model of a magnetorheological squeeze film damper, its implementation into the computational models of rotor systems, and in performing the study on the dependence of the energy losses and variation of the friction moment on the damping force and its control. The new and computationally stable mathematical model of a magnetorheological squeeze film damper, its implementation in the computational models of rigid rotors and learning more on the energy losses generated in the rotor supports in dependence on the damping effect are the principal contributions of this paper. The results of the computational simulations prove that a suitable control of the damping force enables the energy losses to be reduced in a wide velocity range.

  18. Minimal Reduplication

    ERIC Educational Resources Information Center

    Kirchner, Jesse Saba

    2010-01-01

    This dissertation introduces Minimal Reduplication, a new theory and framework within generative grammar for analyzing reduplication in human language. I argue that reduplication is an emergent property in multiple components of the grammar. In particular, reduplication occurs independently in the phonology and syntax components, and in both cases…

  19. Minimal Reduplication

    ERIC Educational Resources Information Center

    Kirchner, Jesse Saba

    2010-01-01

    This dissertation introduces Minimal Reduplication, a new theory and framework within generative grammar for analyzing reduplication in human language. I argue that reduplication is an emergent property in multiple components of the grammar. In particular, reduplication occurs independently in the phonology and syntax components, and in both cases…

  20. Determining the Minimally Important Difference in the Clinical Disease Activity Index for Improvement and Worsening in Early Rheumatoid Arthritis Patients.

    PubMed

    Curtis, J R; Yang, S; Chen, L; Pope, J E; Keystone, E C; Haraoui, B; Boire, G; Thorne, J C; Tin, D; Hitchon, C A; Bingham, C O; Bykerk, V P

    2015-10-01

    Simplified measures to quantify rheumatoid arthritis (RA) disease activity are increasingly used. The minimum clinically important differences (MCID) for some measures, such as the Clinical Disease Activity Index (CDAI), have not been well-defined in real-world clinic settings, especially for early RA patients with low/moderate disease activity. Data from Canadian Early Arthritis Cohort patients were used to examine absolute change in CDAI in the first year after enrollment, stratified by disease activity. MCID cut points were derived to optimize the sum of sensitivity and specificity versus the gold standard of patient self-reported improvement or worsening. Sensitivity, specificity, positive predictive values, and negative predictive values were calculated against patient self-reported improvement (gold standard) and for change in pain, Health Assessment Questionnaire (HAQ), and Disease Activity Score in 28 joints (DAS28) improvement. Discrimination was examined using the area under receiver operator curves. Similar methods were used to evaluate MCIDs for worsening for patients who achieved low disease activity. A total of 578 patients (mean ± SD age 54.1 ± 15.3 years, 75% women, median [interquartile range] disease duration 5.3 [3.3, 8.0] months) contributed 1,169 visit pairs to the improvement analysis. The MCID cut points for improvement were 12 (patients starting in high disease activity: CDAI >22), 6 (moderate: CDAI 10-22), and 1 (low disease activity: CDAI <10). Performance characteristics were acceptable using these cut points for pain, HAQ, and DAS28. The MCID for CDAI worsening among patients who achieved low disease activity was 2 units. These minimum important absolute differences in CDAI can be used to evaluate improvement and worsening and increase the utility of CDAI in clinical practice. © 2015, American College of Rheumatology.

  1. Disease resistance: Molecular mechanisms and biotechnological applications

    USDA-ARS?s Scientific Manuscript database

    This special issue “Disease resistance: molecular mechanisms and biotechnological applications” contains 11 review articles and four original research papers. Research in the area of engineering for disease resistance continues to progress although only 10% of the transgenic plants registered for ...

  2. Impact of persistent minimal residual disease post-consolidation therapy in children and adolescents with advanced Burkitt leukaemia: a Children's Oncology Group Pilot Study Report.

    PubMed

    Shiramizu, Bruce; Goldman, Stanton; Smith, Lynette; Agsalda-Garcia, Melissa; Galardy, Paul; Perkins, Sherrie L; Frazer, J Kimble; Sanger, Warren; Anderson, James R; Gross, Thomas G; Weinstein, Howard; Harrison, Lauren; Barth, Matthew J; Mussolin, Lara; Cairo, Mitchell S

    2015-08-01

    Patient-specific primers from 10 children/adolescents with Burkitt leukaemia (BL) ± central nervous system disease who were treated with French-British-American/Lymphome Malins de Burkitt 96 C1 plus rituximab were developed from diagnostic blood/bone marrow. Minimal residual disease (MRD) was assessed by real-time polymerase chain reaction at the end of induction (EOI) and consolidation (EOC). Seventy per cent (7/10) and 71% (5/7) were MRD-positive at EOI and EOC, respectively, with no disease recurrences. MRD after induction and consolidation did not predict relapse and subsequent therapy appeared to eliminate MRD. Thus, assessing MRD at a later time point is warranted in future trials to determine its clinical significance.

  3. Evolutionary perspectives on wildlife disease: concepts and applications

    PubMed Central

    Vander Wal, Eric; Garant, Dany; Pelletier, Fanie

    2014-01-01

    Wildlife disease has the potential to cause significant ecological, socioeconomic, and health impacts. As a result, all tools available need to be employed when host–pathogen dynamics merit conservation or management interventions. Evolutionary principles, such as evolutionary history, phenotypic and genetic variation, and selection, have the potential to unravel many of the complex ecological realities of infectious disease in the wild. Despite this, their application to wildlife disease ecology and management remains in its infancy. In this article, we outline the impetus behind applying evolutionary principles to disease ecology and management issues in the wild. We then introduce articles from this special issue on Evolutionary Perspectives on Wildlife Disease: Concepts and Applications, outlining how each is exemplar of a practical wildlife disease challenge that can be enlightened by applied evolution. Ultimately, we aim to bring new insights to wildlife disease ecology and its management using tools and techniques commonly employed in evolutionary ecology. PMID:25469154

  4. Evolutionary perspectives on wildlife disease: concepts and applications.

    PubMed

    Vander Wal, Eric; Garant, Dany; Pelletier, Fanie

    2014-08-01

    Wildlife disease has the potential to cause significant ecological, socioeconomic, and health impacts. As a result, all tools available need to be employed when host-pathogen dynamics merit conservation or management interventions. Evolutionary principles, such as evolutionary history, phenotypic and genetic variation, and selection, have the potential to unravel many of the complex ecological realities of infectious disease in the wild. Despite this, their application to wildlife disease ecology and management remains in its infancy. In this article, we outline the impetus behind applying evolutionary principles to disease ecology and management issues in the wild. We then introduce articles from this special issue on Evolutionary Perspectives on Wildlife Disease: Concepts and Applications, outlining how each is exemplar of a practical wildlife disease challenge that can be enlightened by applied evolution. Ultimately, we aim to bring new insights to wildlife disease ecology and its management using tools and techniques commonly employed in evolutionary ecology.

  5. Clinical-scale isolation of 'minimally manipulated' cytomegalovirus-specific donor lymphocytes for the treatment of refractory cytomegalovirus disease.

    PubMed

    Odendahl, Marcus; Grigoleit, G Ulrich; Bönig, Halvard; Neuenhahn, Michael; Albrecht, Julia; Anderl, Florian; Germeroth, Lothar; Schmitz, Marc; Bornhäuser, Martin; Einsele, Hermann; Seifried, Erhard; Busch, Dirk H; Tonn, Torsten

    2014-09-01

    Reactivation of cytomegalovirus (CMV) after hematopoietic stem cell transplantation remains a major cause of morbidity despite improved antiviral drug therapies. Selective restoration of CMV immunity by adoptive transfer of CMV-specific T cells is the only alternative approach that has been shown to be effective and non-toxic. We describe the results of clinical-scale isolations of CMV-specific donor lymphocytes with the use of a major histocompatibility (MHC) class I peptide streptamer-based isolation method that yields minimally manipulated cytotoxic T cells of high purity. Enrichment of CMV-specific cytotoxic T lymphocytes (CTLs) was performed by labeling 1 × 10(10) leukocytes from a non-mobilized mononuclear cell (MNC) apheresis with MHC class I streptamers and magnetic beads. Thereafter, positively labeled CMV-specific CTLs were isolated through the use of CliniMACS (magnetic-activated cell sorting), and MHC streptamers were released through the use of d-biotin. The purity of enriched CMV-specific CTLs was determined on the basis of MHC streptamer staining and fluorescence-activated cell sorting. A total of 22 processes were performed with the use of five different MHC class I streptamers. The median frequency of CMV-specific CTLs in the starting apheresis product was 0.41% among CD3+ T cells. The isolation process yielded a total of 7.77 × 10(6) CMV-specific CTLs, with a median purity of 90.2%. Selection reagents were effectively removed from the final cell product; the CMV-specific CTLs displayed excellent viability and cytotoxicity and were stable for at least 72 h at 4°C after MNC collection. Clinical-scale isolation of "minimally manipulated" CMV-specific donor CTLs through the use of MHC class I streptamers is feasible and yields functional CTLs at clinically relevant dosages. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  6. Evaluation of the performance during hard turning of OHNS steel with minimal cutting fluid application and its comparison with minimum quantity lubrication

    NASA Astrophysics Data System (ADS)

    Raj, Anil; Wins, K. Leo Dev; Varadarajan, A. S.

    2016-09-01

    Cutting fluid application plays a significant role in the manufacturing industries that acts as a coolant as well as a lubricant. The conventional flood cooling application of cutting fluids not only increases the production cost on account of the expenses involved in procurement, storage and disposal but also creates serious environmental and health hazards. In order to overcome these negative effects, techniques like Minimum quantity lubrication (MQL) and Minimal Cutting fluid application (MCFA) have increasingly found their way into the area of metal cutting and have already been established as an alternative to conventional wet machining. This paper investigates the effect of minimal Cutting fluid application (MCFA) which involves application of high velocity pulsing jet of proprietary cutting fluids at the contact zones using a special fluid application system. During hard turning of oil hardened non shrinkable steel (OHNS) on cutting temperature and tool wear and to compare the performance with Minimum quantity lubrication (MQL) assisted hard turning in which cutting fluid is carried in a high velocity stream of air. An attempt was also made to compare the performance during Turning with MCFA and MQL application with conventional wet and dry turning by analysing the tool wear pattern using SEM images.

  7. Role of minimal residual disease and chimerism after reduced-intensity and myeloablative allo-transplantation in acute myeloid leukemia and high-risk myelodysplastic syndrome.

    PubMed

    Bernal, Teresa; Diez-Campelo, María; Godoy, Vicky; Rojas, Silvia; Colado, Enrique; Alcoceba, Miguel; González, Marcos; Vidriales, Belén; Sánchez-Guijo, Fermín M; López-Corral, Lucía; Luño, Elisa; del Cañizo, Consuelo

    2014-05-01

    We evaluated the impact of detection of minimal residual disease by flow cytometry (FCMRD) and CD3 chimerism in relapse in a cohort of 87 patients with acute myeloid leukemia or myelodysplastic syndrome undergoing stem cell transplantation. Patients with a positive FCMRD at day +100 after transplantation showed higher relapse rates and worse overall survival. In multivariate analysis, a positive FCMRD after transplantation was a significant predictor of relapse. Mixed chimerism showed a trend to statistical signification. We conclude that FCMRD at day 100 after SCT is the best predictor of relapse after SCT in patients with aggressive myeloid malignancies.

  8. Comparison of methylprednisolone plus prednisolone with prednisolone alone as initial treatment in adult-onset minimal change disease: a retrospective cohort study.

    PubMed

    Shinzawa, Maki; Yamamoto, Ryohei; Nagasawa, Yasuyuki; Oseto, Susumu; Mori, Daisuke; Tomida, Kodo; Hayashi, Terumasa; Izumi, Masaaki; Fukunaga, Megumu; Yamauchi, Atsushi; Tsubakihara, Yoshiharu; Isaka, Yoshitaka

    2014-06-06

    Previous studies suggested that intravenous methylprednisolone possibly accelerates remission of proteinuria in adult-onset minimal change disease; its impact on relapse of proteinuria is unknown. This multicenter retrospective cohort study included 125 adult-onset minimal change disease patients diagnosed by kidney biopsy between 2000 and 2009 and treated initially with corticosteroid in five nephrology centers in Japan participating in the Study of Outcomes and Practice Patterns of Minimal Change Disease. Times to first remission and first relapse of proteinuria after initiating the first immunosuppressive therapy were compared between 65 patients with initial use of intravenous methylprednisolone followed by prednisolone and 60 patients with initial use of prednisolone alone using multivariate Cox proportional hazards models. After calculating the probability of receiving methylprednisolone and prednisolone using a logistic regression model (propensity score), the results were ascertained using propensity score-matched and -stratified models. During the median 3.6 years of observation (interquartile range=2.0-6.9), all 65 patients in the methylprednisolone and prednisolone group achieved remission within 11 (8-20) days of the corticosteroid initiation, whereas in the prednisolone group, 58 of 60 patients (96.7%) achieved remission within 19 (12-37) days (P<0.001). After achieving first remission, 32 (49.2%) patients in the methylprednisolone and prednisolone group and 43 (74.1%) patients in the prednisolone group developed at least one relapse. Multivariate Cox proportional hazards models revealed that methylprednisolone and prednisolone use was significantly associated with early remission (multivariate-adjusted hazard ratio, 1.56; 95% confidence interval, 1.06 to 2.30) and lower incidence of relapse (0.50; 95% confidence interval, 0.29 to 0.85) compared with prednisolone use alone. These results were ascertained in propensity score-based models. No significant

  9. Comparison of Methylprednisolone Plus Prednisolone with Prednisolone Alone as Initial Treatment in Adult-Onset Minimal Change Disease: A Retrospective Cohort Study

    PubMed Central

    Shinzawa, Maki; Yamamoto, Ryohei; Nagasawa, Yasuyuki; Oseto, Susumu; Mori, Daisuke; Tomida, Kodo; Hayashi, Terumasa; Izumi, Masaaki; Fukunaga, Megumu; Yamauchi, Atsushi; Tsubakihara, Yoshiharu

    2014-01-01

    Background and objectives Previous studies suggested that intravenous methylprednisolone possibly accelerates remission of proteinuria in adult-onset minimal change disease; its impact on relapse of proteinuria is unknown. Design, setting, participants, & measurements This multicenter retrospective cohort study included 125 adult-onset minimal change disease patients diagnosed by kidney biopsy between 2000 and 2009 and treated initially with corticosteroid in five nephrology centers in Japan participating in the Study of Outcomes and Practice Patterns of Minimal Change Disease. Times to first remission and first relapse of proteinuria after initiating the first immunosuppressive therapy were compared between 65 patients with initial use of intravenous methylprednisolone followed by prednisolone and 60 patients with initial use of prednisolone alone using multivariate Cox proportional hazards models. After calculating the probability of receiving methylprednisolone and prednisolone using a logistic regression model (propensity score), the results were ascertained using propensity score-matched and -stratified models. Results During the median 3.6 years of observation (interquartile range=2.0–6.9), all 65 patients in the methylprednisolone and prednisolone group achieved remission within 11 (8–20) days of the corticosteroid initiation, whereas in the prednisolone group, 58 of 60 patients (96.7%) achieved remission within 19 (12–37) days (P<0.001). After achieving first remission, 32 (49.2%) patients in the methylprednisolone and prednisolone group and 43 (74.1%) patients in the prednisolone group developed at least one relapse. Multivariate Cox proportional hazards models revealed that methylprednisolone and prednisolone use was significantly associated with early remission (multivariate-adjusted hazard ratio, 1.56; 95% confidence interval, 1.06 to 2.30) and lower incidence of relapse (0.50; 95% confidence interval, 0.29 to 0.85) compared with prednisolone use

  10. Lipidomics applications for discovering biomarkers of diseases in clinical chemistry.

    PubMed

    Zhao, Ying-Yong; Cheng, Xian-long; Lin, Rui-Chao

    2014-01-01

    Lipids are the fundamental components of biological membranes as well as the metabolites of organisms. Lipids play diverse and important roles in biologicals. The lipid imbalance is closely associated with numerous human lifestyle-related diseases, such as atherosclerosis, obesity, diabetes, and Alzheimer's disease. Lipidomics or lipid profiling is a system-based study of all lipids aiming at comprehensive analysis of lipids in the biological system. Lipidomics has been accepted as a lipid-related research tool in lipid biochemistry, clinical biomarker discovery, disease diagnosis, and in understanding disease pathology. Lipidomics will not only provide insights into the specific functions of lipid species in health and disease, but will also identify potential biomarkers for establishing preventive or therapeutic programs for human diseases. This review presents an overview of lipidomics followed by in-depth discussion of its application to the study of human diseases, including extraction methods of lipids, analytical technologies, data analysis, and clinical research in cancer, neuropsychiatric disease, cardiovascular disease, kidney disease, and respiratory disease. We describe the current status of the identification of metabolic biomarkers in different diseases. We also discuss the lipidomics for the future perspectives and their potential problems. The application of lipidomics in clinical studies may provide new insights into lipid profiling and pathophysiological mechanisms.

  11. Metabolomics: Applications and Promise in Mycobacterial Disease

    PubMed Central

    Banoei, Mohammad Mehdi; Winston, Brent W.; Schraufnagel, Dean E.

    2015-01-01

    Until recently, the study of mycobacterial diseases was trapped in culture-based technology that is more than a century old. The use of nucleic acid amplification is changing this, and powerful new technologies are on the horizon. Metabolomics, which is the study of sets of metabolites of both the bacteria and host, is being used to clarify mechanisms of disease, and can identify changes leading to better diagnosis, treatment, and prognostication of mycobacterial diseases. Metabolomic profiles are arrays of biochemical products of genes in their environment. These complex patterns are biomarkers that can allow a more complete understanding of cell function, dysfunction, and perturbation than genomics or proteomics. Metabolomics could herald sweeping advances in personalized medicine and clinical trial design, but the challenges in metabolomics are also great. Measured metabolite concentrations vary with the timing within a condition, the intrinsic biology, the instruments, and the sample preparation. Metabolism profoundly changes with age, sex, variations in gut microbial flora, and lifestyle. Validation of biomarkers is complicated by measurement accuracy, selectivity, linearity, reproducibility, robustness, and limits of detection. The statistical challenges include analysis, interpretation, and description of the vast amount of data generated. Despite these drawbacks, metabolomics provides great opportunity and the potential to understand and manage mycobacterial diseases. PMID:26196272

  12. Applications of Doppler ultrasound in clinical vascular disease

    NASA Technical Reports Server (NTRS)

    Barnes, R. W.; Hokanson, D. E.; Sumner, D. S.; Strandness, D. E., Jr.

    1975-01-01

    Doppler ultrasound has become the most useful and versatile noninvasive technique for objective evaluation of clinical vascular disease. Commercially available continuous-wave instruments provide qualitative and quantitative assessment of venous and arterial disease. Pulsed Doppler ultrasound was developed to provide longitudinal and transverse cross-sectional images of the arterial lumen with a resolution approaching that of conventional X-ray techniques. Application of Doppler ultrasound in venous, peripheral arterial, and cerebrovascular diseases is reviewed.

  13. Applications of Doppler ultrasound in clinical vascular disease

    NASA Technical Reports Server (NTRS)

    Barnes, R. W.; Hokanson, D. E.; Sumner, D. S.; Strandness, D. E., Jr.

    1975-01-01

    Doppler ultrasound has become the most useful and versatile noninvasive technique for objective evaluation of clinical vascular disease. Commercially available continuous-wave instruments provide qualitative and quantitative assessment of venous and arterial disease. Pulsed Doppler ultrasound was developed to provide longitudinal and transverse cross-sectional images of the arterial lumen with a resolution approaching that of conventional X-ray techniques. Application of Doppler ultrasound in venous, peripheral arterial, and cerebrovascular diseases is reviewed.

  14. Optimized oral cholera vaccine distribution strategies to minimize disease incidence: A mixed integer programming model and analysis of a Bangladesh scenario.

    PubMed

    Smalley, Hannah K; Keskinocak, Pinar; Swann, Julie; Hinman, Alan

    2015-11-17

    In addition to improved sanitation, hygiene, and better access to safe water, oral cholera vaccines can help to control the spread of cholera in the short term. However, there is currently no systematic method for determining the best allocation of oral cholera vaccines to minimize disease incidence in a population where the disease is endemic and resources are limited. We present a mathematical model for optimally allocating vaccines in a region under varying levels of demographic and incidence data availability. The model addresses the questions of where, when, and how many doses of vaccines to send. Considering vaccine efficacies (which may vary based on age and the number of years since vaccination), we analyze distribution strategies which allocate vaccines over multiple years. Results indicate that, given appropriate surveillance data, targeting age groups and regions with the highest disease incidence should be the first priority, followed by other groups primarily in order of disease incidence, as this approach is the most life-saving and cost-effective. A lack of detailed incidence data results in distribution strategies which are not cost-effective and can lead to thousands more deaths from the disease. The mathematical model allows for what-if analysis for various vaccine distribution strategies by providing the ability to easily vary parameters such as numbers and sizes of regions and age groups, risk levels, vaccine price, vaccine efficacy, production capacity and budget.

  15. Multi-center analysis of the effect of T-cell acute lymphoblastic leukemia subtype and minimal residual disease on allogeneic stem cell transplantation outcomes.

    PubMed

    Brammer, J E; Saliba, R M; Jorgensen, J L; Ledesma, C; Gaballa, S; Poon, M; Maziarz, R T; Champlin, R E; Hosing, C; Kebriaei, P

    2017-01-01

    This study aims to provide a detailed analysis of allogeneic stem cell transplantation (allo-SCT) outcomes in a large T-cell acute lymphoblastic leukemia (T-ALL) cohort with a specific emphasis on the effects of pre-transplant minimal residual disease (MRD) and disease subtype, including the aggressive early-thymic precursor (ETP) subtype. Data from 102 allo-SCT patients with a diagnosis of T-ALL from three centers were retrospectively analyzed. Patients were grouped into four T-ALL subtypes: ETP, early, cortical and mature. At 3 years, overall survival (OS), PFS, non-relapse mortality and cumulative incidence (CI) progression were 35, 33, 11 and 55%, respectively. Patients transplanted in first complete remission (CR1) had a 3-year OS of 62% versus those transplanted in CR2 or greater (24%) (hazards ratio 1.6, P=0.2). Patients with MRD positivity at the time of transplant had significantly higher rates of progression compared with those with MRD negativity (76 vs 34%, hazards ratio 2.8, P=0.006). There was no difference in OS, PFS or cumulative incidence (CI) progression between disease subtypes, including ETP (n=16). ETP patients transplanted in CR1 (n=10) had OS of 47%, comparable to other disease subtypes, suggesting that allo-SCT can overcome the poor prognosis associated with ETP. MRD status at transplant was highly predictive of disease relapse, suggesting novel therapies are necessary to improve transplant outcomes.

  16. [Application of proteomics to neurological diseases].

    PubMed

    Brea, D; Cristobo, I; Sobrino, T; Rodríguez-González, R; Mosquera, E; Moldes, O; Castillo, J

    2007-04-01

    Proteomic is a set of tools that allows the separation and identification of proteins expressed by a cell, tissue or organism. Two-dimensional electrophoresis is the central tool that allows qualitative and quantitative comparisons of protein patterns between samples. Differential analysis of protein expression patterns in different neurological diseases (stroke, Alzheimer, Parkinson, amyotrophic lateral sclerosis, Hungtington, epilepsy) allows the identification of diagnostic and/or prognostic biomarkers. Subsequently, validation of these markers may help to identify new diagnostic and therapeutic targets.

  17. Human Pluripotent Stem Cells: Applications and Challenges in Neurological Diseases

    PubMed Central

    Hibaoui, Youssef; Feki, Anis

    2012-01-01

    The ability to generate human pluripotent stem cells (hPSCs) holds great promise for the understanding and the treatment of human neurological diseases in modern medicine. The hPSCs are considered for their in vitro use as research tools to provide relevant cellular model for human diseases, drug discovery, and toxicity assays and for their in vivo use in regenerative medicine applications. In this review, we highlight recent progress, promises, and challenges of hPSC applications in human neurological disease modeling and therapies. PMID:22934023

  18. Minimally invasive valve surgery.

    PubMed

    Woo, Y Joseph

    2009-08-01

    Traditional cardiac valve replacement surgery is being rapidly supplanted by innovative, minimally invasive approaches toward the repair of these valves. Patients are experiencing benefits ranging from less bleeding and pain to faster recovery and greater satisfaction. These operations are proving to be safe, highly effective, and durable, and their use will likely continue to increase and become even more widely applicable.

  19. Minimization of the root of a quadratic functional under a system of affine equality constraints with application to portfolio management

    NASA Astrophysics Data System (ADS)

    Landsman, Zinoviy

    2008-10-01

    We present an explicit closed form solution of the problem of minimizing the root of a quadratic functional subject to a system of affine constraints. The result generalizes Z. Landsman, Minimization of the root of a quadratic functional under an affine equality constraint, J. Comput. Appl. Math. 2007, to appear, see , articles in press, where the optimization problem was solved under only one linear constraint. This is of interest for solving significant problems pertaining to financial economics as well as some classes of feasibility and optimization problems which frequently occur in tomography and other fields. The results are illustrated in the problem of optimal portfolio selection and the particular case when the expected return of finance portfolio is certain is discussed.

  20. Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Time to Move Toward a Minimal Residual Disease-Based Definition of Complete Remission?

    PubMed

    Araki, Daisuke; Wood, Brent L; Othus, Megan; Radich, Jerald P; Halpern, Anna B; Zhou, Yi; Mielcarek, Marco; Estey, Elihu H; Appelbaum, Frederick R; Walter, Roland B

    2016-02-01

    Patients with acute myeloid leukemia (AML) who are in morphologic complete remission are typically considered separately from patients with active disease (ie, ≥ 5% marrow blasts by morphology) in treatment algorithms for allogeneic hematopoietic cell transplantation (HCT), which implies distinct outcomes for these two groups. It is well recognized that the presence of minimal residual disease (MRD) at the time of transplantation is associated with adverse post-HCT outcome for those patients in morphologic remission. This effect of pre-HCT MRD prompted us to compare outcomes in consecutive patients in MRD-positive remission with patients with active AML who underwent myeloablative allogeneic HCT at our institution. We retrospectively studied 359 consecutive adults with AML who underwent myeloablative allogeneic HCT from a peripheral blood or bone marrow donor between 2006 and 2014. Pre-HCT disease staging included 10-color multiparametric flow cytometry on bone marrow aspirates in all patients. Any level of residual disease was considered to be MRD positive. Three-year relapse estimates were 67% in 76 patients in MRD-positive morphologic remission and 65% in 48 patients with active AML compared with 22% in 235 patients in MRD-negative remission. Three-year overall survival estimates were 26%, 23%, and 73% in these three groups, respectively. After multivariable adjustment, MRD-negative remission status remained statistically significantly associated with longer overall and progression-free survival as well as lower risk of relapse compared with MRD-positive morphologic remission status or having active disease, with similar outcomes between the latter two groups. The similarities in outcomes between patients in MRD-positive morphologic remission and those with active disease at the time of HCT support the use of treatment algorithms that use MRD- rather than morphology-based disease assessments. © 2015 by American Society of Clinical Oncology.

  1. Development and application of the near-infrared and white-light thoracoscope system for minimally invasive lung cancer surgery

    NASA Astrophysics Data System (ADS)

    Mao, Yamin; Wang, Kun; He, Kunshan; Ye, Jinzuo; Yang, Fan; Zhou, Jian; Li, Hao; Chen, Xiuyuan; Wang, Jun; Chi, Chongwei; Tian, Jie

    2017-06-01

    In minimally invasive surgery, the white-light thoracoscope as a standard imaging tool is facing challenges of the low contrast between important anatomical or pathological regions and surrounding tissues. Recently, the near-infrared (NIR) fluorescence imaging shows superior advantages over the conventional white-light observation, which inspires researchers to develop imaging systems to improve overall outcomes of endoscopic imaging. We developed an NIR and white-light dual-channel thoracoscope system, which achieved high-fluorescent signal acquisition efficiency and the simultaneously optimal visualization of the NIR and color dual-channel signals. The system was designed to have fast and accurate image registration and high signal-to-background ratio by optimizing both software algorithms and optical hardware components for better performance in the NIR spectrum band. The system evaluation demonstrated that the minimally detectable concentration of indocyanine green (ICG) was 0.01 μM, and the spatial resolution was 35 μm. The in vivo feasibility of our system was verified by the preclinical experiments using six porcine models with the intravenous injection of ICG. Furthermore, the system was successfully applied for guiding the minimally invasive segmentectomy in three lung cancer patients, which revealed that our system held great promise for the clinical translation in lung cancer surgeries.

  2. Development and application of the near-infrared and white-light thoracoscope system for minimally invasive lung cancer surgery.

    PubMed

    Mao, Yamin; Wang, Kun; He, Kunshan; Ye, Jinzuo; Yang, Fan; Zhou, Jian; Li, Hao; Chen, Xiuyuan; Wang, Jun; Chi, Chongwei; Tian, Jie

    2017-06-01

    In minimally invasive surgery, the white-light thoracoscope as a standard imaging tool is facing challenges of the low contrast between important anatomical or pathological regions and surrounding tissues. Recently, the near-infrared (NIR) fluorescence imaging shows superior advantages over the conventional white-light observation, which inspires researchers to develop imaging systems to improve overall outcomes of endoscopic imaging. We developed an NIR and white-light dual-channel thoracoscope system, which achieved high-fluorescent signal acquisition efficiency and the simultaneously optimal visualization of the NIR and color dual-channel signals. The system was designed to have fast and accurate image registration and high signal-to-background ratio by optimizing both software algorithms and optical hardware components for better performance in the NIR spectrum band. The system evaluation demonstrated that the minimally detectable concentration of indocyanine green (ICG) was 0.01 ?? ? M , and the spatial resolution was 35 ?? ? m . The in vivo feasibility of our system was verified by the preclinical experiments using six porcine models with the intravenous injection of ICG. Furthermore, the system was successfully applied for guiding the minimally invasive segmentectomy in three lung cancer patients, which revealed that our system held great promise for the clinical translation in lung cancer surgeries.

  3. How to minimize ischemic complication related to swollen temporalis muscle following indirect revascularization surgery in moyamoya disease: a technical report.

    PubMed

    Joo, Sung Pil; Kim, Tae Sun; Moon, Hyung Sik

    2014-05-01

    There are several reports in the literature of postoperative ischemic events due to swelling of the temporalis muscle after indirect revascularization surgery. Here, we report our surgical technique for preventing ischemic events during the acute postoperative recovery period in moyamoya patients. We used various types of titanium mesh to cover the bony defect area in 8 patients (10 operations) with moyamoya disease. The mesh was cut and manipulated according to the shape of the bony defect. Surgical results were favorable, with no newly developed ischemic event or infarction in the acute recovery period. The mesh formed an outer table of skull, so there was no compressive effect on the temporalis muscle and no cosmetic defects. The titanium mesh appears to be effective and useful for prevention of ischemic insult in the treatment of moyamoya disease. The choice of this procedure depends on both the operative findings of temporalis muscle thickness and the status of ischemic vulnerability of moyamoya brain. Georg Thieme Verlag KG Stuttgart · New York.

  4. Spontaneous remission of therapy-resistant minimal change nephritis in an adult woman 12 years after onset of the disease.

    PubMed

    Raml, Anton; Sedlak, Martin; Schmekal, Bernhard; Stuby, Ulrike; Syre', Georg; Biesenbach, Georg

    2006-07-01

    A 23-year old woman was admitted to our hospital because of severe edema due to steroid resistant minimal change nephritis (MCN). The diagnosis was proven by renal biopsy nine years ago. At that time, steroid therapy led to a complete remission. Seven years later, patient was 22 years old, a relapse with severe nephrotic syndrome occurred. The diagnosis MCN was confirmed by a second renal biopsy. A combined therapy with prednisolone and cyclosporine A (CSA) led only to a partial reduction of protein excretion, the edema did not disappear. After 3 months, patient declined further therapy with CSA. On admission to our hospital, one year later in December 2000, the woman showed a severe nephrotic syndrome with edema and fluid lung, despite high doses of furosemide. Urinary protein excretion was 12.5 g/day, serum creatinine was increased to 1.4 mg/dl, the serum protein was reduced to 47 g/l. A repeated renal biopsy confirmed again the diagnosis MCN. Once again, a steroid bolus monotherapy over 4 weeks and an immunosuppressive therapy with CSA over 6 weeks had no effect on proteinuria. Further therapy regimes with mofetil mycophenolat, azathioprine, chlorambucil and cyclophosphamide over a period of 6-12 weeks of each regime was not well tolerated, proteinuria remained high with > 10 g/day. Moreover the patient suffered from severe edema despite furosemide infusions. Therefore, an additional mechanical ultrafiltration was performed 2-4 times monthly. Three months after the last immunosuppressive therapy the edema disappeared spontaneously, the diuretic therapy could be stopped. Serum creatinine was 0.8 mg/dl, protein in urine was still high with 9.8 g/day but serum protein for the first time was normal with 65 g/l. Three months later, the protein excretion was reduced to 0.48 g/l, and all other laboratory data were normal. Meanwhile, the woman has now enjoyed a complete second spontaneous remission for a period of three years.

  5. Minimal prevalence of authorship misrepresentation among internal medicine residency applicants: do previous estimates of "misrepresentation" represent insufficient case finding?.

    PubMed

    Hebert, Randy S; Smith, Cheri G; Wright, Scott M

    2003-03-04

    High rates of authorship misrepresentation have been documented among medical trainees. To assess misrepresentation among internal medicine residency applicants while comparing searches used by previous authors (searches 1 and 2) to a more comprehensive strategy (search 3). Review of 497 residency applications. Two university-based internal medicine residency programs. Search 1 was limited to MEDLINE. Search 2 added Current Contents, Science Citation Index, and BIOSIS and included searching journals by hand. Search 3 added seven other databases and contacts to librarians, editors, and coauthors. 224 applicants reported 634 articles; 630 (99%) were verified. The number of applicants with misrepresented citations varied depending on the search used (56 applicants [25%] in search 1 vs. 34 applicants [15%] in search 2 vs. 4 applicants [1.8%] in search 3). Using a comprehensive search, we found substantially less misrepresentation than had been reported. Previous studies probably overestimated the magnitude of the problem.

  6. Safely Increase the Minimally Invasive Hysterectomy Rate: A Novel Three-Tiered Preoperative Categorization System Can Predict the Difficulty for Benign Disease

    PubMed Central

    Andryjowicz, Esteban; Wray, Teresa B; Reinaldo Ruiz, V; Rudolf, James; Noroozkhani, Sara; Crowder, Sandra; Slezak, Jeff M

    2015-01-01

    Context: A nonlaparotomic route is recommended for hysterectomy for benign indications. Objective: 1) Predict the difficulty of hysterectomy to treat benign disease as measured by operative time and risk of laparotomy, 2) confirm the safety and quality of increasing our minimally invasive hysterectomy (MIH) rate, and 3) determine whether the assistant’s experience affected the likelihood of an MIH being performed in equally difficult hysterectomies. Design: All hysterectomies for benign disease performed at the Kaiser Permanente Fontana Medical Center in Fontana, CA, in 2012 were reviewed for length of surgery, length of stay, complications, and readmissions. A three-tiered category system was developed from four preoperative parameters (body mass index, number of vaginal deliveries, clinical uterine size, and history of major abdominal surgery) to anticipate length and difficulty of surgery. Main Outcome Measures: Rates of MIH, complications, and readmissions as well as length of surgery and length of stay for similarly difficult hysterectomies. These outcomes were compared with surgeons’ and assistants’ experience. Results: Of 576 hysterectomies performed for benign disease, 89% were MIH with a 3% complication rate and 4% readmission rate. An increase in the hysterectomy category was statistically significantly associated with longer surgery times and a higher percentage of laparotomy. With the most experienced assistants, the MIH rate was 98%. Conclusions: Using 4 preoperative parameters, the average operating time for hysterectomy for benign disease can be predicted. A higher hysterectomy category predicts a more difficult surgery. Our center has increased its MIH rate to 89% while maintaining safety. PMID:26222092

  7. Minimally Invasive Transforaminal Lumbar Interbody Fusion with Percutaneous Bilateral Pedicle Screw Fixation for Lumbosacral Spine Degenerative Diseases. A retrospective database of 40 consecutive treated cases and literature review.

    PubMed

    Millimaggi, Daniele Francesco; DI Norcia, Valerio; Luzzi, Sabino; Alfiero, Tommaso; Galzio, Renato Juan; Ricci, Alessandro

    2017-04-12

    To report our results about minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) with bilateral pedicle screw fixation, in patients with degenerative lumbosacral spine disease. To describe the indications, surgical technique and results of a consecutive series of 40 patients undergone MI-TLIF. Despite the limited number of clinical studies, published data suggest tremendous potential advantages of this technique. Forty patients with radiological findings of degenerative lumbosacral spine disease were undergone MI-TLIF between July 2012 and January 2015. Clinical outcomes were assessed by means of Oswestry Disability Index (ODI) and Health Survey Scoring (SF36) before surgery and at first year follow-up. Furthermore, the following parameters were retrospectively reviewed: age, sex, working activity, body mass index (BMI), type of degenerative disease, number of levels of fusion, operative time, blood loss, length of hospital stay. Average operative time was of 230 minutes, mean estimated blood loss 170 mL, average length of hospital stay 5 days. The ODI improved from a score of 59, preoperatively, to post-operative score of 20 at first year follow-up. Average SF36 score increased from 36 to 54 (Physical Health) and from 29 to 50 (Mental Health) at first year outcome evaluation. MI-TLIF with bilateral pedicle screw fixation is an excellent choice for selected patients suffering from symptomatic degenerative lumbosacral spine disease, especially secondary to recurrent disk herniations.

  8. Application of ozone in the treatment of periodontal disease

    PubMed Central

    Srikanth, Adusumilli; Sathish, Manthena; Sri Harsha, Anumolu Venkatanaga

    2013-01-01

    Gingivitis and periodontitis are most common inflammatory diseases of supporting tissues of teeth. Role of microbial etiology and host response in progression of gingival and periodontal diseases has been well established. Because of the beneficial biological effects of ozone, due to its antimicrobial and immunostimulating effect, it is well indicated in the treatment of gingival and periodontal diseases. The objective of this article is to provide a general review about clinical applications of ozone in treatment of periodontal diseases and to summarize the available in vitro and in vivo studies in Periodontics in which ozone has been used. PMID:23946585

  9. Antimicrobial susceptibility and minimal inhibitory concentration of Pseudomonas aeruginosa isolated from septic ocular surface disease in different animal species

    PubMed Central

    Leigue, L.; Montiani-Ferreira, F.; Moore, B.A.

    2016-01-01

    The purpose of this study was to evaluate the antibiotic susceptibility profile of Pseudomonas aeruginosa isolated from different animal species with septic ocular surface disease. Sixteen strains of P. aeruginosa were isolated from different species of animals (dog, cat, horse, penguin and brown bear) with ocular surface diseases such as conjunctivitis, keratocojnuctivits sicca and ulcerative keratitis. These isolates were tested against 11 different antimicrobials agents using the Kirby-Bauer disk-diffusion method. Minimum inhibitory concentrations (MICs) were determined using E-tests for two antibiotics (tobramycin and ciprofloxacin) commonly used in veterinary ophthalmology practice. Imipenem was the most effective antibiotic, with 100% of the strains being susceptible, followed by amikacin (87.5%), gentamicin, norfloxacin, gatifloxacin and polymyxin (both with 81.5%of susceptibility). MIC90 of ciprofloxacin was 2 µg/ml and the values found ranged from 0.094 µg/ml to 32 µg/ml. For tobramycin, MIC90 was 32 µg/ml and ranged from 0.25 µg/ml to 256 µg/ml. The most effective in vitro antibiotic tested against P. aeruginosa in this study was imipenem, followed by amikacin. The 3 mg/ml eye drops commercially available ciprofloxacin presentations were in vitro effective against all strains tested in this study if applied up to 4 hours after instillation. Whereas for tobramycin the 3 mg/ml eye drops commercial presentations were not in vitro effective against some strains isolated in this study. Thus for ocular infections with P. aeruginosa when using tobramycin the ideal recommendation would be to either use eye drops with higher concentrations or decrease the frequency intervals from four to a minimum of every two hours. PMID:27928519

  10. Minimal cosmography

    NASA Astrophysics Data System (ADS)

    Piazza, Federico; Schücker, Thomas

    2016-04-01

    The minimal requirement for cosmography—a non-dynamical description of the universe—is a prescription for calculating null geodesics, and time-like geodesics as a function of their proper time. In this paper, we consider the most general linear connection compatible with homogeneity and isotropy, but not necessarily with a metric. A light-cone structure is assigned by choosing a set of geodesics representing light rays. This defines a "scale factor" and a local notion of distance, as that travelled by light in a given proper time interval. We find that the velocities and relativistic energies of free-falling bodies decrease in time as a consequence of cosmic expansion, but at a rate that can be different than that dictated by the usual metric framework. By extrapolating this behavior to photons' redshift, we find that the latter is in principle independent of the "scale factor". Interestingly, redshift-distance relations and other standard geometric observables are modified in this extended framework, in a way that could be experimentally tested. An extremely tight constraint on the model, however, is represented by the blackbody-ness of the cosmic microwave background. Finally, as a check, we also consider the effects of a non-metric connection in a different set-up, namely, that of a static, spherically symmetric spacetime.

  11. Twenty-four-month alpha-galactosidase A replacement therapy in Fabry disease has only minimal effects on symptoms and cardiovascular parameters.

    PubMed

    Koskenvuo, J W; Hartiala, J J; Nuutila, P; Kalliokoski, R; Viikari, J S; Engblom, E; Penttinen, M; Knuuti, J; Mononen, I; Kantola, I M

    2008-06-01

    Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipids in different tissues including endothelial cells and smooth-muscle cells and cardiomyocytes, and cardiovascular complications are common in the disease. Since 2001, specific enzyme replacement therapy (ERT) with alpha-galactosidase A has been available. It has been reported to improve clinical symptoms and quality of life. However, limited and controversial data on its efficacy to cardiac involvement have been published. Nine patients (5 male) with Fabry disease were included in an open-label prospective follow-up study of 24-month ERT. Comprehensive cardiovascular evaluation was performed by MRI, stress echocardiography and quality of life assessment. Plasma globotriaosylceramide decreased from 6.2 to 1.4 microg/ml during ERT (p<0.05). The only other measured parameters that changed significantly were resting heart rate that decreased from 79 to 67 bpm (p<0.01) and end-systolic volume that decreased by 12.4 ml (p<0.05). The other parameters consisting of quality of life, self-estimated cardiovascular condition, diastolic function, exercise capacity, ECG parameters, ejection fraction and ventricular mass did not change. ERT has only minimal effect on symptoms and cardiovascular morphology and function in Fabry disease. Therefore, effective conventional medical therapy is still of major importance in Fabry disease. Larger ERT studies are warranted, especially in women, to solve current open questions, such as the age at which ERT should be started, optimal dosage and intervals between infusions. Furthermore, longer follow-up studies are needed to assess the effects of ERT on prognosis.

  12. Development and Feasibility Testing of Image-Guided Minimally Invasive Tissue for Diagnosis Treatment of Benign and Malignant Breast Disease

    NASA Technical Reports Server (NTRS)

    Jeffrey, Stefanie S.

    1999-01-01

    Dr. Robert Mah and Dr. Stefanie Jeffrey worked on the development of the NASA Smart Probe in its application as a device to measure and interpret physiologic and image-based parameters of breast tissue. To date the following has been achieved: 1 . Choice of candidate sensors to be tested in breast tissue. 2. Preliminary designs for probe tip, specifically use of different tip shapes, cutting edges, and sensor configuration. 3. Design of sonographic guidance system. 4. Design of data extraction and analysis tool using scanned information of images of the breast tissue to provide a higher dimension of information for breast tissue characterization and interpretation. 5. Initial ex-vivo (fruit and tofu) and in-vivo (rodent) testing to confirm unique substance and tissue characterization by the Smart Probe software.

  13. Development and Feasibility Testing of Image-Guided Minimally Invasive Tissue for Diagnosis Treatment of Benign and Malignant Breast Disease

    NASA Technical Reports Server (NTRS)

    Jeffrey, Stefanie S.

    1999-01-01

    Dr. Robert Mah and Dr. Stefanie Jeffrey worked on the development of the NASA Smart Probe in its application as a device to measure and interpret physiologic and image-based parameters of breast tissue. To date the following has been achieved: 1 . Choice of candidate sensors to be tested in breast tissue. 2. Preliminary designs for probe tip, specifically use of different tip shapes, cutting edges, and sensor configuration. 3. Design of sonographic guidance system. 4. Design of data extraction and analysis tool using scanned information of images of the breast tissue to provide a higher dimension of information for breast tissue characterization and interpretation. 5. Initial ex-vivo (fruit and tofu) and in-vivo (rodent) testing to confirm unique substance and tissue characterization by the Smart Probe software.

  14. Neurotherapeutic applications of nanoparticles in Alzheimer's disease.

    PubMed

    Sahni, Jasjeet Kaur; Doggui, Sihem; Ali, Javed; Baboota, Sanjula; Dao, Lé; Ramassamy, Charles

    2011-06-10

    A rapid increase in incidence of neurodegenerative disorders has been observed with the aging of the population. Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly. It is characterized by memory dysfunction, loss of lexical access, spatial and temporal disorientation and impairment of judgement clinically. Unfortunately, clinical development of drugs for the symptomatic and disease-modifying treatment of AD has resulted in both promise and disappointment. Indeed, a large number of drugs with differing targets and mechanisms of action were investigated with only a few of them being clinically available. The targeted drug delivery to the central nervous system (CNS), for the diagnosis and treatment of neurodegenerative disorders such as AD, is restricted due to the limitations posed by the blood-brain barrier (BBB) as well as due to opsonization by plasma proteins in the systemic circulation and peripheral side-effects. Over the last decade, nanoparticle-mediated drug delivery represents one promising strategy to successfully increase the CNS penetration of several therapeutic moieties. Different nanocarriers are being investigated to treat and diagnose AD by delivering at a constant rate a host of therapeutics over times extending up to days, weeks or even months. This review provides a concise incursion on the current pharmacotherapies for AD besides reviewing and discussing the literature on the different drug molecules that have been successfully encapsulated in nanoparticles (NPs). Some of them have been shown to cross the BBB and have been tested either for diagnosis or treatment of AD. Finally, the route of NPs administration and the future prospects will be discussed.

  15. Applications of Spectral Gradient Algorithm for Solving Matrix ℓ2,1-Norm Minimization Problems in Machine Learning

    PubMed Central

    Xiao, Yunhai; Wang, Qiuyu; Liu, Lihong

    2016-01-01

    The main purpose of this study is to propose, then analyze, and later test a spectral gradient algorithm for solving a convex minimization problem. The considered problem covers the matrix ℓ2,1-norm regularized least squares which is widely used in multi-task learning for capturing the joint feature among each task. To solve the problem, we firstly minimize a quadratic approximated model of the objective function to derive a search direction at current iteration. We show that this direction descends automatically and reduces to the original spectral gradient direction if the regularized term is removed. Secondly, we incorporate a nonmonotone line search along this direction to improve the algorithm’s numerical performance. Furthermore, we show that the proposed algorithm converges to a critical point under some mild conditions. The attractive feature of the proposed algorithm is that it is easily performable and only requires the gradient of the smooth function and the objective function’s values at each and every step. Finally, we operate some experiments on synthetic data, which verifies that the proposed algorithm works quite well and performs better than the compared ones. PMID:27861526

  16. Percutaneous internal jugular venous cannulation for extracorporeal circulation during minimally invasive technique in children with congenital heart disease: operative technique and results.

    PubMed

    Vida, Vladimiro L; Tiberio, Ivo; Gallo, Michele; Guariento, Alvise; Suti, Emirjeta; Pittarello, Demetrio; Stellin, Giovanni

    2016-10-01

    The aim of this study was to evaluate the safety and efficacy of the percutaneous cannulation of the internal jugular venous (PCIJV) for extracorporeal circulation during minimally invasive cardiac surgery (MICS) in children with simple congenital heart disease. From September 2007, 83 children (<16 years) underwent PCIJV for extracorporeal circulation. Primary outcome of the study was to evaluate the safety and advantages of PCIJV technique. Technical steps and pitfalls of PCIJV technique are described. Median age at surgery was 9 years (range 3.5-16 years) and median body weight was 31 kilograms (range 13-72 kilograms); 32 patients (40%) had a body weight less than 30 kilograms. The PCIJV was achieved with a 14 French cannula in 61 pts (73%), with a 17 Fr cannula in 22 (23%). The PIJVC was judged difficult in 2 patients (2.4%); in both of them cannulation was achieved at a different venous site There were no procedure-related complications and no flow disturbances during the extracorporeal circulation. The PCIJV during MICS is an effective and reproducible technique for achieving peripheral CPB in children with simple CHDs. We progressively expanded the use of this technique in smaller children and this allows us to further minimize surgical trauma without experiencing venous drainage's problems.

  17. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL).

    PubMed

    Bassan, Renato; Spinelli, Orietta; Oldani, Elena; Intermesoli, Tamara; Tosi, Manuela; Peruta, Barbara; Rossi, Giuseppe; Borlenghi, Erika; Pogliani, Enrico M; Terruzzi, Elisabetta; Fabris, Pietro; Cassibba, Vincenzo; Lambertenghi-Deliliers, Giorgio; Cortelezzi, Agostino; Bosi, Alberto; Gianfaldoni, Giacomo; Ciceri, Fabio; Bernardi, Massimo; Gallamini, Andrea; Mattei, Daniele; Di Bona, Eros; Romani, Claudio; Scattolin, Anna Maria; Barbui, Tiziano; Rambaldi, Alessandro

    2009-04-30

    Clinical risk classification is inaccurate in predicting relapse in adult patients with acute lymphoblastic leukemia, sometimes resulting in patients receiving inappropriate chemotherapy or stem cell transplantation (SCT). We studied minimal residual disease (MRD) as a predictive factor for recurrence and as a decisional tool for postconsolidation maintenance (in MRD(neg)) or SCT (in MRD(pos)). MRD was tested at weeks 10, 16, and 22 using real-time quantitative polymerase chain reaction with 1 or more sensitive probes. Only patients with t(9;22) or t(4;11) were immediately eligible for allogeneic SCT. Of 280 registered patients (236 in remission), 34 underwent an early SCT, 60 suffered from relapse or severe toxicity, and 142 were evaluable for MRD at the end of consolidation. Of these, 58 were MRD(neg), 54 MRD(pos), and 30 were not assessable. Five-year overall survival/disease-free survival rates were 0.75/0.72 in the MRD(neg) group compared with 0.33/0.14 in MRD(pos) (P = .001), regardless of the clinical risk class. MRD was the most significant risk factor for relapse (hazard ratio, 5.22). MRD results at weeks 16 to 22 correlated strongly with the earlier time point (P = .001) using a level of 10(-4) or higher to define persistent disease. MRD analysis during early postremission therapy improves risk definitions and bolsters risk-oriented strategies. ClinicalTrials.gov identifier: NCT00358072.

  18. Efficacy and safety of single-trocar technique for minimally invasive surgery of the chest in the treatment of noncomplex pleural disease.

    PubMed

    Migliore, Marcello

    2003-11-01

    To assess the efficacy and the safety of a single-trocar technique for minimally invasive surgery of the chest in the management of multiple noncomplex thoracic diseases, a prospective study was performed and the results are presented. Between October 1998 and December 2001, 100 patients underwent video-assisted thoracic surgery through a single trocar. The patients were divided into 4 groups as follows: (1) benign, (2) malignant, (3) pleural effusion, and (4) empyema. The following data were analyzed: age, sex, forced vital capacity, forced expiratory volume in 1 second, percentage of the predicted forced expiratory volume in 1 second, type of anesthesia, anesthesia time, surgery time, intraoperative complications, morbidity, chest tube removal, hospital stay, and follow-up. The patient population consisted of 64 men and 36 women with a mean age of 62 years (range 31-92 years). General anesthesia was used in 53 patients (25 double-lumen and 28 single-lumen tube) and local anesthesia and sedation in 47 patients. Talc pleurodesis was performed in 55 patients. Mean operative time was 65 +/- 37 minutes, 48 +/- 18 minutes for simple and 67 +/- 37 minutes (P =.004) for complex pleural effusion. Mean anesthesia time was 102 +/- 85 minutes. Chest tubes were removed after 5 +/- 2 days. Mean overall hospital stay was 6 +/- 3 days, 5 +/- 2 days for benign diseases, 7 +/- 3 days for malignant diseases, and 8 +/- 3 for empyema. Morbidity was present in 19 patients. Two patients had intraoperative bleeding; 1 required a mini-thoracotomy to control it. There was no hospital mortality. Three patients had wound infection, and no patient with malignant diseases had port site metastasis. Video-assisted thoracic surgery through a single trocar is simple, effective, and beneficial for all patients in the diagnosis and treatment of noncomplex diseases of the chest. Furthermore, with this newest type of technologically advanced instrumentation it is possible to carry out simple

  19. Application of the Chick Embryo Chorioallantoic Membrane in Neurosurgery Disease

    PubMed Central

    Yuan, Yong-Jie; Xu, Kan; Wu, Wei; Luo, Qi; Yu, Jin-Lu

    2014-01-01

    The chick embryo chorioallantoic membrane (CAM) is a highly vascularized extraembryonic membrane. Because of its ease of accessibility, extensive vascularization and immunodeficient environment, the CAM has been broadly used in the oncology, biology, pharmacy, and tissue regeneration research. The present review summarizes the application of the CAM in neurosurgery disease research. We focused on the use of the CAM as an assay for the research of glioma, vascular anomalies, Moyamoya Disease, and the blood-brain barrier. PMID:25419173

  20. Theory of protein misfolding and applications to misfolding diseases

    NASA Astrophysics Data System (ADS)

    Plotkin, Steven S.

    2009-03-01

    Physics-based algorithms can predict the misfolding mechanisms of proteins involved in aggregation-related diseases, including ALS and the Prion diseases. Predictions based on such an algorithm that we have developed, which employs both atomistic interactions and surface-area based coarse-graining, have been recently verified by immunological assays and point to diagnostic and therapeutic applications. I will describe the results of our misfolding theory, and discuss future directions towards drug research.

  1. Restoration of Thoracolumbar Spine Stability and Alignment in Elderly Patients Using Minimally Invasive Spine Surgery (MISS). A Safe and Feasible Option in Degenerative and Traumatic Spine Diseases.

    PubMed

    Barbagallo, Giuseppe M V; Raudino, Giuseppe; Visocchi, Massimiliano; Alobaid, A Abdulrazzaq; Al-Mutair, A Abdulaziz; Naveen, Thomas; Certo, Francesco

    2017-01-01

    Minimally invasive spine surgery (MISS), including percutaneous pedicle-screw fixation (PPSF), mini-open transforaminal lumbar interbody fusion (m-open TLIF), vertebroplasty, and stentoplasty, allows the preservation of neurological function and the restoration of spine stability, while reducing associated risks and complications. This study aimed to analyze the safety and efficacy of MISS in elderly patients suffering from degenerative or traumatic thoracolumbar diseases. Forty-five patients (28 females), with a mean age of 73 years (range 65-89), suffering from osteoporotic vertebral fractures (24), degenerative spondylolisthesis (15), and lumbar canal stenosis with instability and/or de novo scoliosis (6) were included.Twenty-one patients underwent PPSF and m-open TLIF. The remaining patients received PPSF without interbody fusion, and in six of these fenestrated screws were used for vertebral body cement augmentation.Functional evaluation was obtained with a visual analog scale (VAS) and the Oswestry Disability Index (ODI) pre- and postoperatively. Preoperative imaging included X-rays, computed tomography (CT), and magnetic resonance imaging (MRI). Patients were followed-up with X-rays, and a CT scan was also obtained at the last follow-up. Follow-up ranged from 6 to 59 months (mean 28 months). Follow-up CT scan documented intersomatic fusion in only 14 % of patients treated with m-open TLIF. Despite the high incidence of non-union, mean VAS and ODI scores showed a significant improvement, with a reduction of mean VAS from 9 to 4 and a reduction of mean ODI from 76.33 to 38.15 %. Only three patients developed postoperative complications. No patients showed neurological deficits.Minimally invasive spine surgery for degenerative and traumatic spinal diseases is a safe and effective treatment also in elderly patients.

  2. Cost-minimization analysis of lanthanum carbonate versus sevelamer hydrochloride in US patients with end-stage renal disease.

    PubMed

    Keith, Michael S; Wilson, Rosamund J; Preston, Peter; Copley, J Brian

    2014-09-01

    Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used in the clinical management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to assess the cost-effectiveness of LC monotherapy compared with SH monotherapy in US patients with ESRD in a clinical practice setting. This was a post hoc assessment of phosphate binder costs among US patients with ESRD who converted from SH to LC monotherapy in a previously published, 16-week, Phase IV, real-world study. Calculations of drug costs used both average wholesale price (AWP) and wholesale acquisition cost (WAC). There were 953 patients with available baseline SH dose data; 950 also had a recorded LC dose >0 mg at baseline, and 691 had dose data available for both SH at baseline and LC at week 16 (post hoc analysis population). Baseline demographic characteristics were similar in excluded patients and the post hoc analysis population. Mean (SD) serum phosphate levels were 5.91 (1.66) mg/dL at baseline and 5.93 (1.85) mg/dL after conversion to LC monotherapy for 16 weeks. Mean AWP costs were US$35.72 (16.89) per day at baseline and US$24.69 (8.28) per day at week 16, yielding an overall mean cost change (defined as LC cost - SH cost) of -US$11.03 (16.37) per day in favor of LC. The overall mean WAC cost change was -US$9.17 (13.64) per day. Within baseline SH dose subgroups 2400 to 4800, >4800 to 7200, >7200 to 9600, and >9600 mg/d, the mean AWP cost change ranged from US$2.78 (9.26) per day in favor of SH for the 2400- to 4800-mg/d subgroup to -US$33.15 (12.58) per day in favor of LC for the >9600-mg/d subgroup. Mean WAC cost changes showed a similar trend, ranging from US$2.33 (7.72) per day to -US$27.59 (10.48) per day. Linear regression analyses revealed that the inflection SH doses corresponding to a mean cost change of zero were 4905 mg/d (AWP) and 4908 mg/d (WAC). For the 455 (66%) patients in the post hoc analysis

  3. Discovering rare behaviours in stochastic differential equations using decision procedures: applications to a minimal cell cycle model.

    PubMed

    Ghosh, Arup Kumar; Hussain, Faraz; Jha, Susmit; Langmead, Christopher J; Jha, Sumit Kumar

    2014-01-01

    Stochastic Differential Equation (SDE) models are used to describe the dynamics of complex systems with inherent randomness. The primary purpose of these models is to study rare but interesting or important behaviours, such as the formation of a tumour. Stochastic simulations are the most common means for estimating (or bounding) the probability of rare behaviours, but the cost of simulations increases with the rarity of events. To address this problem, we introduce a new algorithm specifically designed to quantify the likelihood of rare behaviours in SDE models. Our approach relies on temporal logics for specifying rare behaviours of interest, and on the ability of bit-vector decision procedures to reason exhaustively about fixed-precision arithmetic. We apply our algorithm to a minimal parameterised model of the cell cycle, and take Brownian noise into account while investigating the likelihood of irregularities in cell size and time between cell divisions.

  4. Influenza SIRS with Minimal Pneumonitis.

    PubMed

    Erramilli, Shruti; Mannam, Praveen; Manthous, Constantine A

    2016-01-01

    Although systemic inflammatory response syndrome (SIRS) is a known complication of severe influenza pneumonia, it has been reported very rarely in patients with minimal parenchymal lung disease. We here report a case of severe SIRS, anasarca, and marked vascular phenomena with minimal or no pneumonitis. This case highlights that viruses, including influenza, may cause vascular dysregulation causing SIRS, even without substantial visceral organ involvement.

  5. Application of Intraoperative CT-Guided Navigation in Simultaneous Minimally Invasive Anterior and Posterior Surgery for Infectious Spondylitis

    PubMed Central

    Dubey, Navneet Kumar; Lee, Ching-Yu; Li, Yen-Yao; Cheng, Chin-Chang; Shi, Chung-Sheng

    2017-01-01

    This study was aimed at evaluating the safety and efficacy of using intraoperative computed tomography- (iCT-) guided navigation in simultaneous minimally invasive anterior and posterior surgery for infectious spondylitis. Nine patients with infectious spondylitis were enrolled in this study. The average operative time was 327.6 min (range, 210–490) and intraoperative blood loss was 407 cc (range, 50–1,200). The average duration of hospital stay was 48.9 days (range, 11–76). Out of a total of 54 pedicle screws employed, 53 screws (98.1%) were placed accurately. A reduced visual analog scale on back pain (from 8.2 to 2.2) and Oswestry disability index (from 67.1% to 25.6%) were found at the 2-year follow-up. All patients had achieved resolution of spinal infection with reduced average erythrocyte sedimentation rate (from 83.9 to 14.1 mm/hr) and average C-reactive protein (from 54.4 to 4.8 mg/dL). Average kyphotic angle correction was 10.5° (range, 8.4°–12.6°) postoperatively and 8.5° (range, 6.9°–10.1°) after 2 years. In conclusion, the current iCT-guided navigation approach has been demonstrated to be an alternative method during simultaneous minimally invasive anterior and posterior surgery for infectious spondylitis. It can provide a good intraoperative orientation and visualization of anatomic structures and also a high pedicle screw placement accuracy in patient's lateral decubitus position. PMID:28299317

  6. Application of Intraoperative CT-Guided Navigation in Simultaneous Minimally Invasive Anterior and Posterior Surgery for Infectious Spondylitis.

    PubMed

    Wu, Meng-Huang; Dubey, Navneet Kumar; Lee, Ching-Yu; Li, Yen-Yao; Cheng, Chin-Chang; Shi, Chung-Sheng; Huang, Tsung-Jen

    2017-01-01

    This study was aimed at evaluating the safety and efficacy of using intraoperative computed tomography- (iCT-) guided navigation in simultaneous minimally invasive anterior and posterior surgery for infectious spondylitis. Nine patients with infectious spondylitis were enrolled in this study. The average operative time was 327.6 min (range, 210-490) and intraoperative blood loss was 407 cc (range, 50-1,200). The average duration of hospital stay was 48.9 days (range, 11-76). Out of a total of 54 pedicle screws employed, 53 screws (98.1%) were placed accurately. A reduced visual analog scale on back pain (from 8.2 to 2.2) and Oswestry disability index (from 67.1% to 25.6%) were found at the 2-year follow-up. All patients had achieved resolution of spinal infection with reduced average erythrocyte sedimentation rate (from 83.9 to 14.1 mm/hr) and average C-reactive protein (from 54.4 to 4.8 mg/dL). Average kyphotic angle correction was 10.5° (range, 8.4°-12.6°) postoperatively and 8.5° (range, 6.9°-10.1°) after 2 years. In conclusion, the current iCT-guided navigation approach has been demonstrated to be an alternative method during simultaneous minimally invasive anterior and posterior surgery for infectious spondylitis. It can provide a good intraoperative orientation and visualization of anatomic structures and also a high pedicle screw placement accuracy in patient's lateral decubitus position.

  7. A Selective Role for Dopamine in Learning to Maximize Reward But Not to Minimize Effort: Evidence from Patients with Parkinson's Disease.

    PubMed

    Skvortsova, Vasilisa; Degos, Bertrand; Welter, Marie-Laure; Vidailhet, Marie; Pessiglione, Mathias

    2017-06-21

    Instrumental learning is a fundamental process through which agents optimize their choices, taking into account various dimensions of available options such as the possible reward or punishment outcomes and the costs associated with potential actions. Although the implication of dopamine in learning from choice outcomes is well established, less is known about its role in learning the action costs such as effort. Here, we tested the ability of patients with Parkinson's disease (PD) to maximize monetary rewards and minimize physical efforts in a probabilistic instrumental learning task. The implication of dopamine was assessed by comparing performance ON and OFF prodopaminergic medication. In a first sample of PD patients (n = 15), we observed that reward learning, but not effort learning, was selectively impaired in the absence of treatment, with a significant interaction between learning condition (reward vs effort) and medication status (OFF vs ON). These results were replicated in a second, independent sample of PD patients (n = 20) using a simplified version of the task. According to Bayesian model selection, the best account for medication effects in both studies was a specific amplification of reward magnitude in a Q-learning algorithm. These results suggest that learning to avoid physical effort is independent from dopaminergic circuits and strengthen the general idea that dopaminergic signaling amplifies the effects of reward expectation or obtainment on instrumental behavior.SIGNIFICANCE STATEMENT Theoretically, maximizing reward and minimizing effort could involve the same computations and therefore rely on the same brain circuits. Here, we tested whether dopamine, a key component of reward-related circuitry, is also implicated in effort learning. We found that patients suffering from dopamine depletion due to Parkinson's disease were selectively impaired in reward learning, but not effort learning. Moreover, anti-parkinsonian medication restored the

  8. [Clinical applications of arterial spin labeling technique in brain diseases].

    PubMed

    Wang, Li; Zheng, Gang; Zhao, Tiezhu; Guo, Chao; Li, Lin; Lu, Guangming

    2013-02-01

    Arterial spin labeling (ASL) technique is a kind of perfusion functional magnetic resonance imaging method that is based on endogenous contrast, and it can measure cerebral blood flow (CBF) noninvasively. The ASL technique has advantages of noninvasiveness, simplicity and relatively lower costs so that it is more suitable for longitudinal studies compared with previous perfusion methods, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), CT and the contrast agent based magnetic resonance perfusion imaging. This paper mainly discusses the current clinical applications of ASL in brain diseases as cerebrovascular diseases, brain tumors, Alzheimer's disease and epilepsy, etc.

  9. Novel Applications of Radionuclide Imaging in Peripheral Vascular Disease

    PubMed Central

    Stacy, Mitchel R.; Sinusas, Albert J.

    2015-01-01

    Peripheral vascular disease (PVD) is a progressive atherosclerotic disease that leads to stenosis or occlusion of blood vessels supplying the lower extremities. Current diagnostic imaging techniques commonly focus on evaluation of anatomy or blood flow at the macrovascular level and do not permit assessment of the underlying pathophysiology associated with disease progression or treatment response. Molecular imaging with radionuclide-based approaches, such as PET and SPECT, can offer novel insight into PVD by providing non-invasive assessment of biological processes such as angiogenesis and atherosclerosis. This review discusses emerging radionuclide-based imaging approaches that have potential clinical applications in the evaluation of PVD progression and treatment. PMID:26590787

  10. Novel Applications of Radionuclide Imaging in Peripheral Vascular Disease.

    PubMed

    Stacy, Mitchel R; Sinusas, Albert J

    2016-02-01

    Peripheral vascular disease (PVD) is a progressive atherosclerotic disease that leads to stenosis or occlusion of blood vessels supplying the lower extremities. Current diagnostic imaging techniques commonly focus on evaluation of anatomy or blood flow at the macrovascular level and do not permit assessment of the underlying pathophysiology associated with disease progression or treatment response. Molecular imaging with radionuclide-based approaches can offer novel insight into PVD by providing noninvasive assessment of biological processes such as angiogenesis and atherosclerosis. This article discusses emerging radionuclide-based imaging approaches that have potential clinical applications in the evaluation of PVD progression and treatment.

  11. An image-intensive ePR for image-guided minimally invasive spine surgery applications including real-time intra-operative image acquisition, archival, and display

    NASA Astrophysics Data System (ADS)

    Documet, Jorge R.; Le, Anh; Liu, Brent; Huang, H. K.; Chiu, John

    2009-02-01

    Recent developments in medical imaging informatics have improved clinical workflow in Radiology enterprise but gaps remain in the clinical workflow from diagnosis to surgical treatment through post-operative follow-up. One solution to bridge this gap is the development of an electronic patient record (ePR) that integrates key imaging and informatics data during the pre, intra, and post-operative phases of clinical workflow. We present an ePR system based on standards and tailored to the clinical application for image-guided minimally invasive spinal surgery (MISS). The ePR system has been implemented in a clinical environment for a half-year.

  12. Nanomedicines for renal disease: current status and future applications

    PubMed Central

    Kamaly, Nazila; He, John C.; Ausiello, Dennis A.; Farokhzad, Omid C.

    2017-01-01

    Treatment and management of kidney disease currently presents an enormous global burden, and the application of nanotechnology principles to renal disease therapy, although still at an early stage, has profound transformative potential. The increasing translation of nanomedicines to the clinic, alongside research efforts in tissue regeneration and organ-on-a-chip investigations, are likely to provide novel solutions to treat kidney diseases. Our understanding of renal anatomy and of how the biological and physicochemical properties of nanomedicines (the combination of a nanocarrier and a drug) influence their interactions with renal tissues has improved dramatically. Tailoring of nanomedicines in terms of kidney retention and binding to key membranes and cell populations associated with renal diseases is now possible and greatly enhances their localization, tolerability, and efficacy. This Review outlines nanomedicine characteristics central to improved targeting of renal cells and highlights the prospects, challenges, and opportunities of nanotechnology-mediated therapies for renal diseases. PMID:27795549

  13. New three-dimensional head-mounted display system, TMDU-S-3D system, for minimally invasive surgery application: procedures for gasless single-port radical nephrectomy.

    PubMed

    Kihara, Kazunori; Fujii, Yasuhisa; Masuda, Hitoshi; Saito, Kazutaka; Koga, Fumitaka; Matsuoka, Yoh; Numao, Noboru; Kojima, Kazuyuki

    2012-09-01

    We present an application of a new three-dimensional head-mounted display system that combines a high-definition three-dimensional organic electroluminescent head-mounted display with a high-definition three-dimensional endoscope to minimally invasive surgery, using gasless single-port radical nephrectomy procedures as a model. This system presents the surgeon with a higher quality of magnified three-dimensional imagery in front of the eyes regardless of head position, and simultaneously allows direct vision by moving the angle of sight downward. It is also significantly less expensive than the current robotic surgery system. While carrying out gasless single-port radical nephrectomy, the system provided the surgeon with excellent three-dimensional imagery of the operative field, direct vision of the outside and inside of the patient, and depth perception and tactile feedback through the devices. All four nephrectomies were safely completed within the operative time, blood loss was within usual limits and there were no complications. The display was light enough to comfortably be worn for a long operative time. Our experiences show that the three-dimensional head-mounted display system might facilitate maneuverability and safety in minimally invasive procedures, without prohibitive cost, and thus might mitigate the drawbacks of other three-dimensional vision systems. Because of the potential benefits that this system offers, it deserves further refinements of its role in various minimally invasive surgeries.

  14. Comparison of outcomes after donor lymphocyte infusion with or without prior chemotherapy for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Mo, Xiao-Dong; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2017-03-11

    The efficacy of donor lymphocyte infusion (DLI) without chemotherapy was investigated and compared with that of chemotherapy prior to DLI (Chemo-DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). We enrolled 115 consecutive patients who received either DLI (n = 20) or Chemo-DLI (n = 95) during the same period. For each DLI recipient, three recipients matched for age at the HSCT, underlying diseases, and the year of the HSCT were randomly selected from the Chemo-DLI cohort (n = 60). The 2-year cumulative incidence of severe acute graft-versus-host disease (GVHD) and chronic GVHD was comparable between the groups. Fifteen (75.0%) and 47 (78.3%) patients in the DLI and Chemo-DLI groups turned MRD-negative, respectively. The 2-year cumulative incidences of relapse and non-relapse mortality after intervention were 30.7 versus 39.6% (P = 0.582) and 10.3 versus 6.0% (P = 0.508) in the DLI and Chemo-DLI groups, respectively. The 2-year probabilities of disease-free, overall, and GVHD-free/relapse-free survival after preemptive intervention were 58.9 versus 54.3% (P = 0.862), 69.3 versus 78.1% (P = 0.361), and 44.4 versus 35.1% (P = 0.489) in the DLI and Chemo-DLI groups, respectively. In multivariate analysis, the intervention method did not significantly influence the clinical outcomes. In summary, preemptive DLI alone may be effective for patients who are MRD-positive and may be a potential alternative for patients who refuse or are unable to receive Chemo-DLI after HSCT.

  15. The reliability, minimal detectable change and concurrent validity of a gravity-based bubble inclinometer and iphone application for measuring standing lumbar lordosis.

    PubMed

    Salamh, Paul A; Kolber, Morey

    2014-01-01

    To investigate the reliability, minimal detectable change (MDC90) and concurrent validity of a gravity-based bubble inclinometer (inclinometer) and iPhone® application for measuring standing lumbar lordosis. Two investigators used both an inclinometer and an iPhone® with an inclinometer application to measure lumbar lordosis of 30 asymptomatic participants. ICC models 3,k and 2,k were used for the intrarater and interrater analysis, respectively. Good interrater and intrarater reliability was present for the inclinometer with Intraclass Correlation Coefficients (ICC) of 0.90 and 0.85, respectively and the iPhone® application with ICC values of 0.96 and 0.81. The minimal detectable change (MDC90) indicates that a change greater than or equal to 7° and 6° is needed to exceed the threshold of error using the iPhone® and inclinometer, respectively. The concurrent validity between the two instruments was good with a Pearson product-moment coefficient of correlation (r) of 0.86 for both raters. Ninety-five percent limits of agreement identified differences ranging from 9° greater in regards to the iPhone® to 8° less regarding the inclinometer. Both the inclinometer and iPhone® application possess good interrater reliability, intrarater reliability and concurrent validity for measuring standing lumbar lordosis. This investigation provides preliminary evidence to suggest that smart phone applications may offer clinical utility comparable to inclinometry for quantifying standing lumbar lordosis. Clinicians should recognize potential individual differences when using these devices interchangeably.

  16. Is demography destiny? Application of machine learning techniques to accurately predict population health outcomes from a minimal demographic dataset.

    PubMed

    Luo, Wei; Nguyen, Thin; Nichols, Melanie; Tran, Truyen; Rana, Santu; Gupta, Sunil; Phung, Dinh; Venkatesh, Svetha; Allender, Steve

    2015-01-01

    For years, we have relied on population surveys to keep track of regional public health statistics, including the prevalence of non-communicable diseases. Because of the cost and limitations of such surveys, we often do not have the up-to-date data on health outcomes of a region. In this paper, we examined the feasibility of inferring regional health outcomes from socio-demographic data that are widely available and timely updated through national censuses and community surveys. Using data for 50 American states (excluding Washington DC) from 2007 to 2012, we constructed a machine-learning model to predict the prevalence of six non-communicable disease (NCD) outcomes (four NCDs and two major clinical risk factors), based on population socio-demographic characteristics from the American Community Survey. We found that regional prevalence estimates for non-communicable diseases can be reasonably predicted. The predictions were highly correlated with the observed data, in both the states included in the derivation model (median correlation 0.88) and those excluded from the development for use as a completely separated validation sample (median correlation 0.85), demonstrating that the model had sufficient external validity to make good predictions, based on demographics alone, for areas not included in the model development. This highlights both the utility of this sophisticated approach to model development, and the vital importance of simple socio-demographic characteristics as both indicators and determinants of chronic disease.

  17. [Application of artificial neural networks in infectious diseases].

    PubMed

    Xu, Jun-fang; Zhou, Xiao-nong

    2011-02-28

    With the development of information technology, artificial neural networks has been applied to many research fields. Due to the special features such as nonlinearity, self-adaptation, and parallel processing, artificial neural networks are applied in medicine and biology. This review summarizes the application of artificial neural networks in the relative factors, prediction and diagnosis of infectious diseases in recent years.

  18. Minimal residual disease after bone marrow transplantation for chronic myelogenous leukemia and implications for graft-versus-leukemia effect: a review of recent results.

    PubMed

    Miyamura, K; Barrett, A J; Kodera, Y; Saito, H

    1994-08-01

    Cure of leukemia by allogeneic BMT is achieved by the combined effect of the myeloablative preparative regimen and an allo-immune response of donor cells to residual leukemia termed the graft-versus-leukemia (GVL) effect. In the first year following BMT for CML, PCR used to detect the leukemia-specific BCR/ABL message frequently reveals subclinical levels of persisting leukemia. In a meta-analysis of reports on qualitative PCR findings after BMT for CML in 12 recently published series, we found that for unmanipulated BMT in chronic phase, PCR detection was not associated with a higher relapse risk and that most patients became PCR negative within 2 years post-BMT. In contrast, PCR detection of BCR/ABL transcripts was a more reliable predictor in recipients of T cell-depleted BMT and in those transplanted in accelerated or blastic phase of their disease. For accurate prediction of relapse, serial quantitative PCR is necessary. It could also be used to monitor efficacy of experimental treatments of relapse with interferon or donor lymphocyte transfusions. Furthermore, studies of the association of GVHD with PCR detection of BCR/ABL message may shed light on the relationship of GVL with minimal residual disease in CML.

  19. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study

    PubMed Central

    Rawstron, A C; Fazi, C; Agathangelidis, A; Villamor, N; Letestu, R; Nomdedeu, J; Palacio, C; Stehlikova, O; Kreuzer, K-A; Liptrot, S; O'Brien, D; de Tute, R M; Marinov, I; Hauwel, M; Spacek, M; Dobber, J; Kater, A P; Gambell, P; Soosapilla, A; Lozanski, G; Brachtl, G; Lin, K; Boysen, J; Hanson, C; Jorgensen, J L; Stetler-Stevenson, M; Yuan, C; Broome, H E; Rassenti, L; Craig, F; Delgado, J; Moreno, C; Bosch, F; Egle, A; Doubek, M; Pospisilova, S; Mulligan, S; Westerman, D; Sanders, C M; Emerson, R; Robins, H S; Kirsch, I; Shanafelt, T; Pettitt, A; Kipps, T J; Wierda, W G; Cymbalista, F; Hallek, M; Hillmen, P; Montserrat, E; Ghia, P

    2016-01-01

    In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10−5). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10−4) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10−6). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL. PMID:26639181

  20. Minimal residual disease (MRD) monitoring using rearrangement of T-cell receptor and immunoglobulin H gene in the treatment of adult acute lymphoblastic leukemia patients.

    PubMed

    Toubai, Tomomi; Tanaka, Junji; Ota, Shuichi; Fukuhara, Takashi; Hashino, Satoshi; Kondo, Takeshi; Kasai, Masaharu; Kakinoki, Yasutaka; Masauzi, Nobuo; Morioka, Masanobu; Kawamura, Tsugumichi; Iwasaki, Hiroshi; Asaka, Masahiro; Imamura, Masahiro

    2005-11-01

    We evaluate whether molecular monitoring of minimal residual disease (MRD) using TCR delta (TCRD), TCR gamma (TCRG), and immunoglobulin H (IgH) gene rearrangements in the bone marrow (BM) is correlated with clinical events in ALL patients. The 14 patients enrolled in this study included 6 males and 8 females with a median age of 53 years (range, 25-79 years), and the median duration of follow-up was 417 days (range, 57-617 days). The median WBC count was 11.3 x 10(9)/L at diagnosis. All patients had L2 type ALL. Eleven patients had a monoclonal pattern of IgH (7), TCRD (3) and TCRG (1), and 3 patients had two clonal patterns. Eleven of the 14 patients achieved the first complete remission (CR) after the first induction chemotherapy. We analyzed 9 of 11 CR patients who could be examined immediately after induction chemotherapy (including re-induction therapy). Event-free survival (EFS, 0%) and disease-free survival (DFS, 0%) at 1 year in CR patients with MRD level >or=10(-3) (n = 3) were significantly lower than those in CR patients with MRD level <10(-3) (n = 6) (log-rank test, P = 0.013, 0.013). A lower MRD in BM value after induction chemotherapy was associated significantly with longer survival in the log-rank test. Our data provide evidence that molecular MRD status of BM is a strong predictor of outcome in adult ALL.

  1. Predictive role of minimal residual disease and log clearance in acute myeloid leukemia: a comparison between multiparameter flow cytometry and Wilm's tumor 1 levels.

    PubMed

    Rossi, Giovanni; Minervini, Maria Marta; Melillo, Lorella; di Nardo, Francesco; de Waure, Chiara; Scalzulli, Potito Rosario; Perla, Gianni; Valente, Daniela; Sinisi, Nicola; Cascavilla, Nicola

    2014-07-01

    In acute myeloid leukemia (AML), the detection of minimal residual disease (MRD) as well as the degree of log clearance similarly identifies patients with poor prognosis. No comparison was provided between the two approaches in order to identify the best one to monitor follow-up patients. In this study, MRD and clearance were assessed by both multiparameter flow cytometry (MFC) and WT1 expression at different time points on 45 AML patients achieving complete remission. Our results by WT1 expression showed that log clearance lower than 1.96 after induction predicted the recurrence better than MRD higher than 77.0 copies WT1/10(4) ABL. Conversely, on MFC, MRD higher than 0.2 % after consolidation was more predictive than log clearance below 2.64. At univariate and multivariate analysis, positive MRD values and log clearance below the optimal cutoffs were associated with a shorter disease-free survival (DFS). At the univariate analysis, positive MRD values were also associated with overall survival (OS). Therefore, post-induction log clearance by WT1 and post-consolidation MRD by MFC represented the most informative approaches to identify the relapse. At the optimal timing of assessment, positive MRD and log-clearance values lower than calculated thresholds similarly predicted an adverse prognosis in AML.

  2. Minimization of the Vibration Energy of Thin-Plate Structures and the Application to the Reduction of Gearbox Vibration

    NASA Technical Reports Server (NTRS)

    Inoue, Katsumi; Krantz, Timothy L.

    1995-01-01

    While the vibration analysis of gear systems has been developed, a systematic approach to the reduction of gearbox vibration has been lacking. The technique of reducing vibration by shifting natural frequencies is proposed here for gearboxes and other thin-plate structures using the theories of finite elements, modal analysis, and optimization. A triangular shell element with 18 degrees of freedom is developed for structural and dynamic analysis. To optimize, the overall vibration energy is adopted as the objective function to be minimized at the excitation frequency by varying the design variable (element thickness) under the constraint of overall constant weight. Modal analysis is used to determine the sensitivity of the vibration energy as a function of the eigenvalues and eigenvectors. The optimum design is found by the gradient projection method and a unidimensional search procedure. By applying the computer code to design problems for beams and plates, it was verified that the proposed method is effective in reducing vibration energy. The computer code is also applied to redesign the NASA Lewis gear noise rig test gearbox housing. As one example, only the shape of the top plate is varied, and the vibration energy levels of all the surfaces are reduced, yielding an overall reduction of 1/5 compared to the initial design. As a second example, the shapes of the top and two side plates are varied to yield an overall reduction in vibration energy of 1/30.

  3. Meta-analysis on continuous outcomes in minimal important difference units: an application with appropriate variance calculations.

    PubMed

    Shrier, Ian; Christensen, Robin; Juhl, Carsten; Beyene, Joseph

    2016-12-01

    To compare results from meta-analyses for mean differences in minimal important difference (MID) units (MDMID), when MID is treated as a random variable vs. a constant. Meta-analyses of published data. We calculated the variance of MDMID as a random variable using the delta method and as a constant. We assessed performance under different assumptions. We compare meta-analysis results from data originally used to present the MDMID and data from osteoarthritis studies using different domain instruments. Depending on the data set and depending on the values of rho and coefficient of variation of the MID (CoVMID), estimates of treatment effect and P-values between an approach considering the MID as a constant vs. as a random variable may differ appreciably. Using our data sets, we provide examples of the potential magnitude. When rho = 0.5 and CoVMID = 0.8, considering MID as a constant overestimated the treatment effect by 33-110% and decreased the P-value for heterogeneity from above 0.95 to below 0.08. When rho = 0.8 and CoVMID = 0.5, the magnitude of the effects was similar. Considering MID as a random variable avoids unrealistic assumptions and provides more appropriate treatment effect estimates. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Experimental approach to controllably vary protein oxidation while minimizing electrode adsorption for boron-doped diamond electrochemical surface mapping applications.

    PubMed

    McClintock, Carlee S; Hettich, Robert L

    2013-01-02

    Oxidative protein surface mapping has become a powerful approach for measuring the solvent accessibility of folded protein structures. A variety of techniques exist for generating the key reagent (i.e., hydroxyl radicals) for these measurements; however, these approaches range significantly in their complexity and expense of operation. This research expands upon earlier work to enhance the controllability of boron-doped diamond (BDD) electrochemistry as an easily accessible tool for producing hydroxyl radicals in order to oxidize a range of intact proteins. Efforts to modulate the oxidation level while minimizing the adsorption of protein to the electrode involved the use of relatively high flow rates to reduce protein residence time inside the electrochemical flow chamber. Additionally, a different cell activation approach using variable voltage to supply a controlled current allowed us to precisely tune the extent of oxidation in a protein-dependent manner. In order to gain perspective on the level of protein adsorption onto the electrode surface, studies were conducted to monitor protein concentration during electrolysis and gauge changes in the electrode surface between cell activation events. This report demonstrates the successful use of BDD electrochemistry for greater precision in generating a target number of oxidation events upon intact proteins.

  5. Emerging diagnostic and therapeutic molecular imaging applications in vascular disease

    PubMed Central

    Eraso, Luis H; Reilly, Muredach P; Sehgal, Chandra; Mohler, Emile R

    2013-01-01

    Assessment of vascular disease has evolved from mere indirect and direct measurements of luminal stenosis to sophisticated imaging methods to depict millimeter structural changes of the vasculature. In the near future, the emergence of multimodal molecular imaging strategies may enable robust therapeutic and diagnostic (‘theragnostic’) approaches to vascular diseases that comprehensively consider structural, functional, biological and genomic characteristics of the disease in individualized risk assessment, early diagnosis and delivery of targeted interventions. This review presents a summary of recent preclinical and clinical developments in molecular imaging and theragnostic applications covering diverse atherosclerosis events such as endothelial activation, macrophage infammatory activity, plaque neovascularization and arterial thrombosis. The main focus is on molecular targets designed for imaging platforms commonly used in clinical medicine including magnetic resonance, computed tomography and positron emission tomography. A special emphasis is given to vascular ultrasound applications, considering the important role this imaging platform plays in the clinical and research practice of the vascular medicine specialty. PMID:21310769

  6. Principles and application of antibody libraries for infectious diseases.

    PubMed

    Lim, Bee Nar; Tye, Gee Jun; Choong, Yee Siew; Ong, Eugene Boon Beng; Ismail, Asma; Lim, Theam Soon

    2014-12-01

    Antibodies have been used efficiently for the treatment and diagnosis of many diseases. Recombinant antibody technology allows the generation of fully human antibodies. Phage display is the gold standard for the production of human antibodies in vitro. To generate monoclonal antibodies by phage display, the generation of antibody libraries is crucial. Antibody libraries are classified according to the source where the antibody gene sequences were obtained. The most useful library for infectious diseases is the immunized library. Immunized libraries would allow better and selective enrichment of antibodies against disease antigens. The antibodies generated from these libraries can be translated for both diagnostic and therapeutic applications. This review focuses on the generation of immunized antibody libraries and the potential applications of the antibodies derived from these libraries.

  7. Stem Cells Applications in Regenerative Medicine and Disease Therapeutics

    PubMed Central

    2016-01-01

    Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation. PMID:27516776

  8. Stem Cells Applications in Regenerative Medicine and Disease Therapeutics.

    PubMed

    Mahla, Ranjeet Singh

    2016-01-01

    Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation.

  9. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy.

    PubMed

    Rawstron, A C; Kennedy, B; Evans, P A; Davies, F E; Richards, S J; Haynes, A P; Russell, N H; Hale, G; Morgan, G J; Jack, A S; Hillmen, P

    2001-07-01

    Previous studies have suggested that the level of residual disease at the end of therapy predicts outcome in chronic lymphocytic leukemia (CLL). However, available methods for detecting CLL cells are either insensitive or not routinely applicable. A flow cytometric assay was developed that can differentiate CLL cells from normal B cells on the basis of their CD19/CD5/CD20/CD79b expression. The assay is rapid and can detect one CLL cell in 10(4) to 10(5) leukocytes in all patients. We have compared this assay to conventional assessment in 104 patients treated with CAMPATH-1H and/or autologous transplant. During CAMPATH-1H therapy, circulating CLL cells were rapidly depleted in responding patients, but remained detectable in nonresponders. Patients with more than 0.01 x 10(9)/L circulating CLL cells always had significant (> 5%) marrow disease, and blood monitoring could be used to time marrow assessments. In 25 out of 104 patients achieving complete remission by National Cancer Institute (NCI) criteria, the detection of residual bone marrow disease at more than 0.05% of leukocytes in 6 out of 25 patients predicted significantly poorer event-free (P =.0001) and overall survival (P =.007). CLL cells are detectable at a median of 15.8 months (range, 5.5-41.8) posttreatment in 9 out of 18 evaluable patients with less than 0.05% CLL cells at end of treatment. All patients with detectable disease have progressively increasing disease levels on follow-up. The use of sensitive techniques, such as the flow assay described here, allow accurate quantitation of disease levels and provide an accurate method for guiding therapy and predicting outcome. These results suggest that the eradication of detectable disease may lead to improved survival and should be tested in future studies.

  10. Assessment of Uncertainty in Ambient NO2 Concentration Determination and its Minimization through Application of Lab Scale Findings

    NASA Astrophysics Data System (ADS)

    Goyal, S. K.; Chavhan, C. D.

    2015-06-01

    Uncertainty/variability in measurement of NO2 in ambient air using Sodium Arsenite (SA) manual monitoring method (also known as modified Jacob & Hochheiser method) has been assessed through co-located sampling. Three sampling systems have been deployed and operated simultaneously for five days to find out variations in actual concentration determination. Significant variation in NO2 concentrations has been observed during sampling for 16 h (representing daytime activities) and 8 h (representing nighttime activities). Monitoring during co-located sampling showed considerable variation in flow rate, which can greatly influence the measured NO2 concentration, as in calculation a factor (82 %) for absorption efficiency of NO2 gas in absorption medium is used. At 0.5 l/min flow rate, the absorption efficiency for 8 h sampling is found to be about 69 %, which reduces to about 45 % at 1 l/min for the same sampling duration. Therefore, determination of actual NO2 concentration using this method at different conditions of flow rate and sampling duration may lead to under/over estimation of NO2 concentration, depending upon the specific sampling conditions, and may also affect decision making process involving this parameter. Further, efforts are made to minimize the variations in concentration determination through use of empirical relationships developed in laboratory studies carried out earlier by the present author. The variations are found to be reduced considerably after applying certain correction factors for absorption efficiency of NO2 due to sampling condition variations. This demonstrates the usefulness of lab scale experiments to the actual field monitoring scenario for appropriate decision making.

  11. Three-dimensional elastic image registration based on strain energy minimization: application to prostate magnetic resonance imaging.

    PubMed

    Zhang, Bao; Arola, Dwayne D; Roys, Steve; Gullapalli, Rao P

    2011-08-01

    The use of magnetic resonance (MR) imaging in conjunction with an endorectal coil is currently the clinical standard for the diagnosis of prostate cancer because of the increased sensitivity and specificity of this approach. However, imaging in this manner provides images and spectra of the prostate in the deformed state because of the insertion of the endorectal coil. Such deformation may lead to uncertainties in the localization of prostate cancer during therapy. We propose a novel 3-D elastic registration procedure that is based on the minimization of a physically motivated strain energy function that requires the identification of similar features (points, curves, or surfaces) in the source and target images. The Gauss-Seidel method was used in the numerical implementation of the registration algorithm. The registration procedure was validated on synthetic digital images, MR images from prostate phantom, and MR images obtained on patients. The registration error, assessed by averaging the displacement of a fiducial landmark in the target to its corresponding point in the registered image, was 0.2 ± 0.1 pixels on synthetic images. On the prostate phantom and patient data, the registration errors were 1.0 ± 0.6 pixels (0.6 ± 0.4 mm) and 1.8 ± 0.7 pixels (1.1 ± 0.4 mm), respectively. Registration also improved image similarity (normalized cross-correlation) from 0.72 ± 0.10 to 0.96 ± 0.03 on patient data. Registration results on digital images, phantom, and prostate data in vivo demonstrate that the registration procedure can be used to significantly improve both the accuracy of localized therapies such as brachytherapy or external beam therapy and can be valuable in the longitudinal follow-up of patients after therapy.

  12. Interferon-α: A Potentially Effective Treatment for Minimal Residual Disease in Acute Leukemia/Myelodysplastic Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mo, Xiao-Dong; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2015-11-01

    In this prospective clinical study, the safety and efficacy of preemptive interferon-α (IFN-α) treatment were investigated and compared with preemptive donor lymphocyte infusion (DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). Patients undergoing allogeneic HSCT were eligible if they had acute leukemia or myelodysplastic syndrome and were MRD-positive after HSCT. Patients who were able to receive DLI were assigned to a preemptive DLI group (n = 45); patients who could not or did not agree to receive DLI after HSCT received preemptive IFN-α. A total of 22 patients received preemptive IFN-α; the median treatment duration was 35 days (range, 4 to 180 days). Seven patients relapsed, and 1 patient died from severe pneumonia. The 1-year cumulative incidence of chronic graft-versus-host disease (cGVHD) after intervention was 90.9% for the IFN-α group and 62.9% for the DLI group (P < .001). MRD status after preemptive intervention was comparable in the 2 groups, and the 1-year cumulative incidence of relapse after intervention was 27.3% for the IFN-α group and 35.6% for the DLI group (P = .514). The 1-year cumulative incidence of nonrelapse mortality after intervention was 4.5% for the IFN-α group and 4.4% for the DLI group (P = .985). The 1-year probability of disease-free survival after intervention was 68.2% for the IFN-α group and 60.0% for the DLI group (P = .517). In multivariate analysis, early-onset MRD, persistent MRD after intervention, and absence of cGVHD after intervention were significantly associated with poorer clinical outcomes. Thus, preemptive IFN-α may be a potential alternative for MRD-positive patients who cannot receive preemptive DLI after HSCT.

  13. Bone Marrow Minimal Residual Disease Was an Early Response Marker and a Consistent Independent Predictor of Survival After Anti-GD2 Immunotherapy

    PubMed Central

    Cheung, Nai-Kong V.; Ostrovnaya, Irina; Kuk, Deborah; Cheung, Irene Y.

    2015-01-01

    Purpose Immunotherapy is a standard of care for children with high-risk neuroblastoma, where bone marrow (BM) is the predominant metastatic site. Early response markers of minimal residual disease (MRD) in the BM that are also predictive of survival could help individualize patient therapies. Patients and Methods After achieving first remission (n = 163), primary refractory disease (n = 102), or second remission (n = 95), children with stage 4 neuroblastoma received anti-GD2 3F8 antibody immunotherapy. BM MRD before 3F8 treatment and after cycle 2 (postMRD) was measured using a four-marker panel (B4GALNT1, PHOX2B, CCND1, and ISL1) by quantitative reverse transcription polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic variables were tested in both univariable and multivariable analyses, and MRD markers were further assessed individually and in combination as binary composite (postMRD: 0 and 1) and as equal sum (postMRDSum: 0 to 4) using the Cox regression models, and their predictive accuracy was determined by the concordance index. Results When BM was evaluated after cycle 2, individual markers were highly predictive of PFS and OS. The prediction accuracy improved when they were combined in postMRDSum. A multivariable model taking into account all the variables significant in the univariable analyses identified postMRDSum to be independently predictive of PFS and OS. When the model for OS also included missing killer immunoglobulin-like receptor ligand, human antimouse antibody response, and the enrollment disease status, the concordance index was 0.704. Conclusion BM MRD after two cycles of immunotherapy was confirmed as an early response marker and a consistent independent predictor of survival. PMID:25559819

  14. The evaluation of minimal residual disease in multiple myeloma by fluorescent molecular beacons in real time PCR of IgH gene rearrangements and correlation with flow cytometry.

    PubMed

    Kara, I O; Duman, B B; Afsar, C U

    2013-01-01

    Multiple myeloma (MM) patients relapse after a period of time despite longer disease-free survival due to novel treatment options. In this study we aimed to assess the value of real-time polymerase chain reaction (RT-PCR) for detecting the immunoglobulin heavy chain (IgH) gene rearrangement using allele-specific molecular beacons as fluorescence probes to quantify minimal residual disease (MRD) and also to correlate post-treatment flow cytometric detection of plasma cells' (PCs) expression of CD19, CD38, CD45, CD56 and CD138 in MM. After diagnosis of 17 MM patients, the CDR1, CDR2 and CDR3 regions of the IgH gene were analysed and sequenced to identify IgH's clonal nature. Unique sequences of the clonal IgH rearrangement were used to design specific molecular beacon probes for each MM patient. Examined were also the co-expression of CD19, CD38, CD45, CD56, and CD138 molecules in bone marrow aspirates of patients with MM by flow cytometry. Detection of MRD was positive in 13 (76%) of 17 patients by RT-PCR. The infiltration ratio was significantly correlated with CD138 expression (p=0.009). Significant correlation was also found between RT-PCR detection of MRD and CD138 expression (p=0.006). Nevertheless, no correlation was observed among other surface antigens (CD38, CD45, CD56). Our results indicated that RT-PCR with specific molecular beacons provide a feasible, accurate and reproducible method for the determination of MRD in MM. Flow cytometry detection of CD138 expression may be used as a disease marker in addition to RT-PCR.

  15. CONMIN- CONSTRAINED FUNCTION MINIMIZATION

    NASA Technical Reports Server (NTRS)

    Vanderplaats, G. N.

    1994-01-01

    In many mathematical problems, it is necessary to determine the minimum and maximum of a function of several variables, limited by various linear and nonlinear inequality constraints. It is seldom possible, in practical applications, to solve these problems directly. In most cases, an iterative method must be used to numerically obtain a solution. The CONMIN program was developed to numerically perform the minimization of a multi-variable function subject to a set of inequality constraints. The function need not be a simple analytical equation; it may be any function which can be numerically evaluated. The basic analytic technique used by CONMIN is to minimize the function until one or more of the constraints become active. The minimization process then continues by following the constraint boundaries in a direction such that the value of the function continues to decrease. When a point is reached where no further decrease in the function can be obtained, the process is terminated. Function maximization may be achieved by minimizing the negative of the function. This program is written in FORTRAN IV for batch execution and has been implemented on a CDC 6000 series computer with a central memory requirement of approximately 43K (octal) of 60 bit words. The CONMIN program was originally developed in 1973 and last updated in 1978.

  16. Validation of minimally invasive measurement of myocardial perfusion using electron beam computed tomography and application in human volunteers

    PubMed Central

    Bell, M; Lerman, L; Rumberger, J

    1999-01-01

    minimally invasive technique has also been demonstrated.


Keywords: electron beam computed tomography; cardiac imaging; myocardial blood flow; indicator dilution PMID:10336923

  17. Comparison between Three Promising ß-emitting Radionuclides, 67Cu, 47Sc and 161Tb, with Emphasis on Doses Delivered to Minimal Residual Disease

    PubMed Central

    Champion, Christophe; Quinto, Michele A.; Morgat, Clément; Zanotti-Fregonara, Paolo; Hindié, Elif

    2016-01-01

    PURPOSE: Radionuclide therapy is increasingly seen as a promising option to target minimal residual disease. Copper-67, scandium-47 and terbium-161 have a medium-energy β- emission which is similar to that of lutetium-177, but offer the advantage of having diagnostic partner isotopes suitable for pretreatment imaging. The aim of this study was to compare the efficacy of 67Cu, 47Sc and 161Tb to irradiate small tumors. METHODS: The absorbed dose deriving from a homogeneous distribution of 67Cu, 47Sc or 161Tb in water-density spheres was calculated with the Monte Carlo code CELLDOSE. The diameters of the spheres ranged from 5 mm to 10 µm, thus simulating micrometastases or single tumor cells. All electron emissions, including β- spectra, Auger and conversion electrons were taken into account. Because these radionuclides differ in electron energy per decay, the simulations were run assuming that 1 MeV was released per µm3, which would result in a dose of 160 Gy if totally absorbed. RESULTS: The absorbed dose was similar for the three radionuclides in the 5-mm sphere (146-149 Gy), but decreased differently in smaller spheres. In particular, 161Tb delivered higher doses compared to the other radionuclides. For instance, in the 100-µm sphere, the absorbed dose was 24.1 Gy with 67Cu, 14.8 Gy with 47Sc and 44.5 Gy with 161Tb. Auger and conversion electrons accounted for 71% of 161Tb dose. The largest dose differences were found in cell-sized spheres. In the 10-µm sphere, the dose delivered by 161Tb was 4.1 times higher than that from 67Cu and 8.1 times that from 47Sc. CONCLUSION: 161Tb can effectively irradiate small tumors thanks to its decay spectrum that combines medium-energy β- emission and low-energy conversion and Auger electrons. Therefore 161Tb might be a better candidate than 67Cu and 47Sc for treating minimal residual disease in a clinical setting. PMID:27446495

  18. Metabolomics and Its Application to Acute Lung Diseases

    PubMed Central

    Stringer, Kathleen A.; McKay, Ryan T.; Karnovsky, Alla; Quémerais, Bernadette; Lacy, Paige

    2016-01-01

    Metabolomics is a rapidly expanding field of systems biology that is gaining significant attention in many areas of biomedical research. Also known as metabonomics, it comprises the analysis of all small molecules or metabolites that are present within an organism or a specific compartment of the body. Metabolite detection and quantification provide a valuable addition to genomics and proteomics and give unique insights into metabolic changes that occur in tangent to alterations in gene and protein activity that are associated with disease. As a novel approach to understanding disease, metabolomics provides a “snapshot” in time of all metabolites present in a biological sample such as whole blood, plasma, serum, urine, and many other specimens that may be obtained from either patients or experimental models. In this article, we review the burgeoning field of metabolomics in its application to acute lung diseases, specifically pneumonia and acute respiratory disease syndrome (ARDS). We also discuss the potential applications of metabolomics for monitoring exposure to aerosolized environmental toxins. Recent reports have suggested that metabolomics analysis using nuclear magnetic resonance (NMR) and mass spectrometry (MS) approaches may provide clinicians with the opportunity to identify new biomarkers that may predict progression to more severe disease, such as sepsis, which kills many patients each year. In addition, metabolomics may provide more detailed phenotyping of patient heterogeneity, which is needed to achieve the goal of precision medicine. However, although several experimental and clinical metabolomics studies have been conducted assessing the application of the science to acute lung diseases, only incremental progress has been made. Specifically, little is known about the metabolic phenotypes of these illnesses. These data are needed to substantiate metabolomics biomarker credentials so that clinicians can employ them for clinical decision

  19. Heat shock proteins: applications in health and disease.

    PubMed

    Jindal, S

    1996-01-01

    Heat shock proteins (hsps) assist the assembly, folding and translocation of other proteins, and apparently have a role in protecting cells against injuries and other types of stress. In addition, hsps are frequently recognized by the immune system as predominant antigens during infections and during the progression of certain autoimmune diseases and, thus, might provide a novel route for the development of immunotherapeutics. This review focuses on applications for hsps in health and disease, and discusses the pros and cons of considering them as targets for the development of therapeutics/pharmaceuticals.

  20. Marine bioactives: pharmacological properties and potential applications against inflammatory diseases.

    PubMed

    D'Orazio, Nicolantonio; Gammone, Maria Alessandra; Gemello, Eugenio; De Girolamo, Massimo; Cusenza, Salvatore; Riccioni, Graziano

    2012-04-01

    application of many marine bioactives against inflammatory diseases.

  1. Marine Bioactives: Pharmacological Properties and Potential Applications against Inflammatory Diseases

    PubMed Central

    D’Orazio, Nicolantonio; Gammone, Maria Alessandra; Gemello, Eugenio; De Girolamo, Massimo; Cusenza, Salvatore; Riccioni, Graziano

    2012-01-01

    application of many marine bioactives against inflammatory diseases. PMID:22690145

  2. Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission

    PubMed Central

    Grubovikj, Rada M.; Alavi, Asif; Koppel, Ahrin; Territo, Mary; Schiller, Gary J.

    2012-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45–7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0–14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS. PMID:24213327

  3. High prognostic value of minimal residual disease detected by flow-cytometry-enhanced fluorescence in situ hybridization in core-binding factor acute myeloid leukemia (CBF-AML).

    PubMed

    Wang, Libing; Gao, Lei; Xu, Sheng; Gong, Shenglan; Liu, Min; Qiu, Huiying; Xu, Xiaoqian; Ni, Xiong; Chen, Li; Lu, Shuqing; Chen, Jie; Song, Xianmin; Zhang, Weiping; Yang, Jianmin; Hu, Xiaoxia; Wang, Jianmin

    2014-10-01

    Acute myeloid leukemia (AML) is generally regarded as a disorder of stem cells, known as leukemic initiating cells (LICs), which initiate the disease and contribute to relapses. Although the phenotype of these cells remains unclear in most patients, they are enriched within the CD34(+)CD38(-) population. In core-binding factor (CBF) AML, the cytogenetic abnormalities also exist in LIC. The aim of this study was to determine the prognostic power of minimal residual disease (MRD) measured by fluorescence in situ hybridization (FISH) in CD34(+)CD38(-) cells sorted by flow cytometry at different periods during therapy. Thirty-six patients under 65 years of age with de novo CBF-AML treated with intensive chemotherapy were retrospectively included in this study. Correlations with relapse-free survival (RFS) and overall survival were evaluated with univariate and multivariate analyses. FISH efficiently identified LICs in the CD34(+)CD38(-) population. The presence of FISH(+)CD34(+)CD38(-) cells before consolidation was negatively associated with cumulative incidence of relapse (64 vs 18 %, P = .012), which showed prognostic value for RFS (12 vs 68 %, P = .008) and OS (11 vs 75 %, P = .0005), and retained prognostic significance for RFS in multivariate analysis. The detection of FISH(+)CD34(+)CD38(-) cells before consolidation therapy significantly correlated with long-term survival. Fluorescence-activated cell sorting (FACS)-FISH could be potentially adopted as a MRD monitor approach in clinical practice to identify CBF-AML patients at risk of treatment failure during therapy.

  4. Upper abdominal procedures in advanced stage ovarian or primary peritoneal carcinoma patients with minimal or no gross residual disease: an analysis of Gynecologic Oncology Group (GOG) 182.

    PubMed

    Rodriguez, Noah; Miller, Austin; Richard, Scott D; Rungruang, Bunja; Hamilton, Chad A; Bookman, Michael A; Maxwell, G Larry; Horowitz, Neil S; Krivak, Thomas C

    2013-09-01

    To examine the utility of upper abdominal procedures (UAPs) performed in a cohort of optimally cytoreduced patients with advanced stage epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) and identify potential areas where aggressive surgery may impact survival. We reviewed 2655 patients enrolled in Gynecologic Oncology Group (GOG) 182 who had complete resection (CR) or minimal residual (MR) disease <1cm. Demographic, pathologic, surgical, and outcome data were collected. UAPs included diaphragm stripping or resection, liver resection, splenectomy, pancreatectomy, and porta hepatis surgery. Effect of UAP and CR on PFS/OS was assessed by Kaplan-Meier and proportional hazards methods. Four-hundred eighty-two patients (18.1%) underwent a total of 590 UAPs. There were 351 (13.1%) diaphragm surgeries, 112 (4.2%) liver surgeries, 108 (4%) splenectomies, 12 (0.5%) pancreatectomies, and 7 (0.2%) porta hepatis surgeries. Comparing patients who did not have UAPs to patients who had UAPs, the PFS was 18.2 months (mos) and 14.8 mos (p < 0.01) and OS was 49.8 mos v. 43.7 mos (p = 0.01), respectively. However, in the multivariable analysis this survival benefit did not remain (PFS HR = 1.03, 95% CI 0.91-1.15; OS HR=0.92, 95%CI 0.81-1.04). The OS of the 141 patients who had an UAP and achieved CR compared to the 341 patients who had an UAP with MR was 54.6 compared to 40.4 mos (p=0.0005). UAP procedures should only be performed when CR is attainable. A significant proportion of patients with MR were left with diaphragmatic disease that could potentially be completely resected. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Microarray-based classification of a consecutive series of 121 childhood acute leukemias: prediction of leukemic and genetic subtype as well as of minimal residual disease status.

    PubMed

    Andersson, A; Ritz, C; Lindgren, D; Edén, P; Lassen, C; Heldrup, J; Olofsson, T; Råde, J; Fontes, M; Porwit-Macdonald, A; Behrendtz, M; Höglund, M; Johansson, B; Fioretos, T

    2007-06-01

    Gene expression analyses were performed on 121 consecutive childhood leukemias (87 B-lineage acute lymphoblastic leukemias (ALLs), 11 T-cell ALLs and 23 acute myeloid leukemias (AMLs)), investigated during an 8-year period at a single center. The supervised learning algorithm k-nearest neighbor was utilized to build gene expression predictors that could classify the ALLs/AMLs according to clinically important subtypes with high accuracy. Validation experiments in an independent data set verified the high prediction accuracies of our classifiers. B-lineage ALLs with uncharacteristic cytogenetic aberrations or with a normal karyotype displayed heterogeneous gene expression profiles, resulting in low prediction accuracies. Minimal residual disease status (MRD) in T-cell ALLs with a high (>0.1%) MRD at day 29 could be classified with 100% accuracy already at the time of diagnosis. In pediatric leukemias with uncharacteristic cytogenetic aberrations or with a normal karyotype, unsupervised analysis identified two novel subgroups: one consisting mainly of cases remaining in complete remission (CR) and one containing a few patients in CR and all but one of the patients who relapsed. This study of a consecutive series of childhood leukemias confirms and extends further previous reports demonstrating that global gene expression profiling provides a valuable tool for genetic and clinical classification of childhood leukemias.

  6. Clinicopathological features, diagnosis, and treatment of IgA nephropathy with minimal change disease related to exposure to mercury-containing cosmetics: a case report
.

    PubMed

    Niu, Hong-Xin; Li, Shen-Heng; Li, Hong-Ying; Chen, Yi-Hua; Liu, Wei-Wei; Li, Pei-Lin; Long, Hai-Bo

    2017-04-01

    Membranous nephropathy and minimal change disease (MCD) have been involved in mercury-induced nephrotic syndrome. IgA nephropathy is not known to be a common pathological type. In the present article, we report a case of IgA nephropathy with MCD following exposure to mercury-containing skin lightening cream. The patient was a 39-year-old woman who presented with nephrotic syndrome. She had a 6-month history of using as many as 8 kinds of skin-lightening creams, and urinary mercury excretion was high. Renal biopsy revealed IgA nephropathy with MCD. The use of cosmetics was stopped and chelation therapy was given. After 4 courses (1 month) of chelation therapy, there was a complete remission of proteinuria and hematuria, and urine tests remained normal during the 5-year follow-up period. The unique clinical and pathological features of IgA nephropathy with MCD had raised the controversial question of whether MCD and IgA deposition are separate entities or a common pathophysiology. Repeated renal biopsy and similar cases were helpful and should be carried out as far as possible.
.

  7. Minimally invasive percutaneous endovascular therapies in the management of complications of non-alcoholic fatty liver disease (NAFLD): A case report.

    PubMed

    Salsamendi, Jason; Pereira, Keith; Kang, Kyungmin; Fan, Ji

    2015-09-01

    Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disorders from simple steatosis to inflammation leading to fibrosis, cirrhosis, and even hepatocellular carcinoma. With the progressive epidemics of obesity and diabetes, major risk factors in the development and pathogenesis of NAFLD, the prevalence of NAFLD and its associated complications including liver failure and hepatocellular carcinoma is expected to increase by 2030 with an enormous health and economic impact. We present a patient who developed Hepatocellular carcinoma (HCC) from nonalcoholic steatohepatitis (NASH) cirrhosis. Due to morbid obesity, she was not an optimal transplant candidate and was not initially listed. After attempts for lifestyle modifications failed to lead to weight reduction, a transarterial embolization of the left gastric artery was performed. This is the sixth such procedure in humans in literature. Subsequently she had a meaningful drop in BMI from 42 to 36 over the following 6 months ultimately leading to her being listed for transplant. During this time, the left hepatic HCC was treated with chemoembolization without evidence of recurrence. In this article, we wish to highlight the use of minimally invasive percutaneous endovascular therapies such as transarterial chemoembolization (TACE) in the comprehensive management of the NAFLD spectrum and percutaneous transarterial embolization of the left gastric artery (LGA), a novel method, for the management of obesity.

  8. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma.

    PubMed

    Paiva, Bruno; Gutiérrez, Norma C; Rosiñol, Laura; Vídriales, María-Belén; Montalbán, María-Ángeles; Martínez-López, Joaquín; Mateos, María-Victoria; Cibeira, María-Teresa; Cordón, Lourdes; Oriol, Albert; Terol, María-José; Echeveste, María-Asunción; de Paz, Raquel; de Arriba, Felipe; Palomera, Luis; de la Rubia, Javier; Díaz-Mediavilla, Joaquín; Sureda, Anna; Gorosquieta, Ana; Alegre, Adrian; Martin, Alejandro; Hernández, Miguel T; Lahuerta, Juan-José; Bladé, Joan; San Miguel, Jesús F

    2012-01-19

    The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 < 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residual disease by multiparameter flow cytometry at day +100 after HDT/ASCT (hazard ratio 8.0; P = .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated.

  9. [Detection of minimal residual disease in Ph+/bcr-abl+ acute lymphoblast leukemia by cytogenetic analysis, nested-PCR and flow cytometry].

    PubMed

    Xue, Fang; Dong, Zuo-Ren; Zhang, Bing; Gao, Li-Xia

    2003-08-01

    To explore a simple and sensitive method to detect minimal residual disease (MRD) in Ph(+)/bcr-abl(+) ALL patients, the bone marrow samples from 84 de novo ALL patients were detected by cytogenetic analysis, nested-PCR and flow cytometry (FCM). Cytogenetic analysis method is used to detect Ph chromosome, nested-PCR and FCM are used to detect bcr/abl mRNA and an abnormal B-cell differentiation pattern in de novo and complete remission (CR) patients, respectively. The results showed that Ph chromosome has not been found in 14 cases of CR; bcr/abl fusion gene was detected in 11 of 14 CR patients by nested-PCR (78.57%) and bcr/abl fusion gene was positive in 5 of 14 in CR patients (35.71%) by FCM. The sensitivity of nested-PCR was 10(-6)-10(-7), and that of FCM was 10(-4)- 10(-5). It is concluded that the cytogenetic analysis is not sensitive for MRD detection, and the sensitivity of nested-PCR is higher than that of FCM in detecting MRD.

  10. Quantification of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) using amplicon-fusion-site polymerase chain reaction (AFS-PCR).

    PubMed

    Weber, Axel; Taube, Sylvia; Zur Stadt, Udo; Horstmann, Martin; Krohn, Knut; Bradtke, Jutta; Teigler-Schlegel, Andrea; Leiblein, Sabine; Christiansen, Holger

    2012-11-09

    The amplification of putative oncogenes is a common finding within the genome of various cancer types. Identification and further targeting of specific junction sites within the sequence of genomic amplicons (amplicon fusion sites, AFS) by PCR (AFS-PCR) is suitable for quantification of minimal residual disease (MRD). This approach has recently been developed and described for MYCN amplified neuroblastomas. To compare AFS-PCR directly to routinely used MRD diagnostic strategies, we mapped the amplified genomic regions (ampGR) of an iAMP21-amplicon in high resolution of a patient with acute lymphoblastic leukemia (ALL). Successfully, we established AFS-PCR covering junction sites between ampGR within the iAMP21-amplicon. Quantification of MRD by AFS-PCR was directly comparable to IgH/TCR based real time quantitative PCR and fluorescence activated cell sorting (FACS) analysis in consecutive bone marrow (BM) specimens. Our data give an additional proof of concept of AFS-PCR for quantification of MRD. The method could be taken into account for ALL patients with genomic amplifications as alternative MRD diagnostic, if no or qualitatively poor Ig/TCR-PCRs are available.

  11. Minimal Residual Disease (MRD) Detection with Translocations and T-Cell Receptor and Immunoglobulin Gene Rearrangements in Adult Acute Lymphoblastic Leukaemia Patients: A Pilot Study.

    PubMed

    Sayitoğlu, Müge; Ar, M Cem; Hatırnaz, Özden; Öngören, Şeniz; Üre, Ümit; Başlar, Zafer; Sırma, Sema; Aydın, Yıldız; Özbek, Uğur; Ferhanoğlu, Burhan

    2008-09-05

    Monitoring minimal residual disease has become increasingly important in clinical practice of ALL management. Break-point fusion regions of leukaemia related chromosomal aberrations and rearranged immunoglobulin (Ig) and T cell-receptor (TCR) genes, which can be detected by polymerase chain reaction (PCR), are used as leukaemia specific markers in genetic studies of MRD. A total of 31 consecutive patients with newly diagnosed ALL were screened for eligibility criteria. Of those 26 were included in the study. One patient with partial response following induction therapy and four patients who were lost to follow-up after induction were excluded from the study; thus 21 patients were evaluated for MRD. Chromosomal aberrations were detected in 5 (24%) of the patients and were used for MRD monitoring. Three patients had t(9;22) translocation, the other 2 had t(4;11) and t(1;19). MRD-based risk stratification of the 16 patients analysed for Ig/TCR rearrangements revealed 3 low-risk, 11 intermediate-risk and 2 high-risk patients. MRD monitoring is progressively getting to be a more important predictive factor in adult ALL patients. As reported by others confirmed by our limited data there is a good correlation between MRD status and clinical outcome in patients receiving chemotherapy. The pilot-study presented here is the first that systematically and consecutively performs a molecular MRD monitoring of ALL patients in Turkey.

  12. Flow cytometric analysis of CD5+ B cells: a frame of reference for minimal residual disease analysis in chronic lymphocytic leukemia.

    PubMed

    Gupta, Ritu; Jain, Paresh; Deo, S V S; Sharma, Atul

    2004-03-01

    Recent reports suggest that CD5+ B cells constitute up to 47% of the total B cells in normal peripheral blood (PB), a finding that would restrict the sensitivity of the CD5/CD19 flow cytometric assay for minimal residual disease (MRD) analysis in chronic lymphocytic leukemia (CLL). We studied 40 normal samples (PB, 20; bone marrow [BM], 20) using CD5-fluorescein isothiocyanate (FITC)/CD19-phycoerythrin (PE) immunostaining to evaluate the reference range of CD5+ B cells. The mean percentage of CD5+ B cells per total number of B cells was 12.2% (range, 3.6%-23.9%) in PB and 11.7% (range, 4.4%-19.5%) in BM. On serial dilution, this assay could detect 1 CLL cell in 1,000 leukocytes (sensitivity, 0. 1%). A distinct "bright" CD5+ B-cell subpopulation, consistent with a CLL-like-phenotype, was observed in 3 samples. Our results suggest that the CD5-FITC/CD19-PE assay has a clinically useful sensitivity for MRD analysis in CLL. The usefulness of this assay as a screening tool to identify the earliest stage of indolent CLL needs further study.

  13. Minimal residual disease detection by flow cytometry and PARR in lymph node, peripheral blood and bone marrow, following treatment of dogs with diffuse large B-cell lymphoma.

    PubMed

    Aresu, Luca; Aricò, Arianna; Ferraresso, Serena; Martini, Valeria; Comazzi, Stefano; Riondato, Fulvio; Giantin, Mery; Dacasto, Mauro; Guadagnin, Eleonora; Frayssinet, Patrick; Rouquet, Nicole; Drigo, Michele; Marconato, Laura

    2014-05-01

    The most promising techniques for detecting minimal residual disease (MRD) in canine lymphoma are flow cytometry (FC) and polymerase chain reaction amplification of antigen receptor genes (PARR). However, the agreement between these methods has not been established. MRD was monitored by FC and PARR following treatment of dogs affected with diffuse large B-cell lymphoma (DLBCL), comparing results in lymph node (LN), peripheral blood (PB) and bone marrow (BM) samples. The prognostic impact of MRD on time to relapse (TTR) and lymphoma-specific survival (LSS) was also assessed. Fourteen dogs with previously untreated DLBCL were enrolled into the study; 10 dogs eventually relapsed, while four dogs with undetectable MRD were still in remission at the end of the study. At diagnosis, the concordance rate between FC and PARR was 100%, 78.6%, and 64.3% for LN, PB and BM, respectively. At the end of treatment, the agreement rates were 35.7%, 50%, and 57.1% for LN, PB and BM, respectively. At least one of the follow-up samples from dogs experiencing relapse was PARR(+); conversely, FC was not able to detect MRD in seven of the dogs that relapsed. PARR was more sensitive than FC in predicting TTR, whereas the combination of PARR and FC was more sensitive than either technique alone in predicting LSS using PB samples. The results suggest that immunological and molecular techniques should be used in combination when monitoring for MRD in canine DLBCL.

  14. Nanotechnology and stem cell therapy for cardiovascular diseases: potential applications.

    PubMed

    La Francesca, Saverio

    2012-01-01

    The use of stem cell therapy for the treatment of cardiovascular diseases has generated significant interest in recent years. Limitations to the clinical application of this therapy center on issues of stem cell delivery, engraftment, and fate. Nanotechnology-based cell labeling and imaging techniques facilitate stem cell tracking and engraftment studies. Nanotechnology also brings exciting new opportunities to translational stem cell research as it enables the controlled engineering of nanoparticles and nanomaterials that can properly relate to the physical scale of cell-cell and cell-niche interactions. This review summarizes the most relevant potential applications of nanoscale technologies to the field of stem cell therapy for the treatment of cardiovascular diseases.

  15. RNAi applications in therapy development for neurodegenerative disease.

    PubMed

    Maxwell, M M

    2009-01-01

    RNA-mediated interference (RNAi) is a powerful tool for experimental manipulation of gene expression and is widely used to investigate gene function both in vitro and in vivo. RNAi refers to an evolutionarily conserved cellular mechanism for sequence-specific post-transcriptional gene silencing, in which double-stranded RNAs promote selective degradation of homologous cellular mRNAs. Because RNAi-based techniques can be employed to reduce expression of specific genes, this approach holds great promise as a therapy for diverse diseases, including devastating neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis (ALS). Importantly, in recent years RNAi has also emerged as a key tool in target identification and validation studies designed to complement traditional (i.e., small molecule-based) drug development strategies. These studies harness the power of RNAi-mediated reverse genetics to probe disease-associated pathways in both cell-based and animal models, and thus may provide critical data needed to focus drug development efforts around disease-relevant targets. This review highlights recent progress in the preclinical development of RNAi-based therapeutics for neurodegenerative disease and discusses the particular challenges that disorders of the central nervous system (CNS) pose for this approach. It further describes current applications of RNAi techniques for target identification and validation studies and underscores the importance of this methodology to developing treatments for neurological diseases.

  16. Parkinson's disease hand tremor detection system for mobile application.

    PubMed

    Fraiwan, Luay; Khnouf, Ruba; Mashagbeh, Abdel Razaq

    2016-01-01

    Parkinson's disease currently affects millions of people worldwide and is steadily increasing. Many symptoms are associated with this disease, including rest tremor, bradykinesia, stiffness or rigidity of the extremities and postural instability. No cure is currently available for Parkinson's disease patients; instead most medications are for treatment of symptoms. This treatment depends on the quantification of these symptoms such as hand tremor. This work proposes a new system for mobile phone applications. The system is based on measuring the acceleration from the Parkinson's disease patient's hand using a mobile cell phone accelerometer. Recordings from 21 Parkinson's disease patients and 21 healthy subjects were used. These recordings were analysed using a two level wavelet packet analysis and features were extracted forming a feature vector of 12 elements. The features extracted from the 42 subjects were classified using a neural networks classifier. The results obtained showed an accuracy of 95% and a Kappa coefficient of 90%. These results indicate that a cell phone accelerometer can accurately detect and record rest tremor in Parkinson's disease patients.

  17. Tailoring the optimal control cost function to a desired output: application to minimizing phase errors in short broadband excitation pulses.

    PubMed

    Skinner, Thomas E; Reiss, Timo O; Luy, Burkhard; Khaneja, Navin; Glaser, Steffen J

    2005-01-01

    The de facto standard cost function has been used heretofore to characterize the performance of pulses designed using optimal control theory. The freedom to choose new, creative quality factors designed for specific purposes is demonstrated. While the methodology has more general applicability, its utility is illustrated by comparison to a consistently chosen example--broadband excitation. The resulting pulses are limited to the same maximum RF amplitude used previously and tolerate the same variation in RF homogeneity deemed relevant for standard high-resolution NMR probes. Design criteria are unchanged: transformation of I(z)--> I(x) over resonance offsets of +/-20 kHz and RF variability of +/-5%, with a peak RF amplitude equal to 17.5 kHz. However, the new cost effectively trades a small increase in residual z magnetization for improved phase in the transverse plane. Compared to previous broadband excitation by optimized pulses (BEBOP), significantly shorter pulses are achievable, with only marginally reduced performance. Simulations transform I(z) to greater than 0.98 I(x), with phase deviations of the final magnetization less than 2 degrees, over the targeted ranges of resonance offset and RF variability. Experimental performance is in excellent agreement with the simulations.

  18. Application of ''Protocollo di Minima per l'ictus'' (PMIC- Minimal Protocol for Stroke) for inpatient rehabilitation setting.

    PubMed

    Piazzini, D B; Ferrara, P E; Maggi, L; Frasca, G; Aprile, I; Rabini, A; Specchia, A; Bertolini, C

    2008-09-01

    The aim of this study was to describe the baseline characteristics of a sample of stroke patients admitted to rehabilitation settings with the use of a standardised stroke assessment named ''Protocollo di Minima per l'ictus cerebrale'' (PMIC), to verify the usefulness of the application of PMIC and to compare the data of the authors with the international literature. An observational cross sectional study was conducted on a sample of 102 first-time stroke patients (mean age: 71.9 [+/-11.6], 54 men), in three inpatient rehabilitation centres. PMIC. Most patients were enrolled within 14 days of stroke onset. PMIC assessment took on average 20 minutes and provided the following information: 35% had architectural barriers in their homes; 82% of the cases had 1 or more family assistants; the educational level was low for 53%; 72% were retired; most cases were ischemic stroke without any side predominance being shown; 44% had partial anterior circulation infarcts (PACI) ischemic stroke; 18.6% presented dysphagia; 73% had sphincteral incontinence; there was no hypertone in more than 50% of the cases; 87% required assistance; the median Motricity Index Side Score (Miss) value was 44.1; 38% was affected by mood tone alteration. PMIC appeared to be a useful tool for a standardized evaluation of stroke patients. These results provide data with a high correspondence in international reports.

  19. Minimization and Mitigation of Wire EDM Cutting Errors in the Application of the Contour Method of Residual Stress Measurement

    NASA Astrophysics Data System (ADS)

    Ahmad, Bilal; Fitzpatrick, Michael E.

    2016-01-01

    The contour method of residual stress measurement relies on the careful application of wire electro-discharge machining (WEDM) for the cutting stage. Changes in material removal rates during the cut lead to errors in the final calculated values of residual stress. In this study, WEDM cutting parameters have been explored to identify the optimum conditions for contour method residual stress measurements. The influence of machine parameters on the surface roughness and cutting artifacts in the contour cut is discussed. It has been identified that the critical parameter in improving the surface finish is the spark pulse duration. A typical cutting artifact and its impact on measured stress values have been identified and demonstrated for a contour cut in a welded marine steel. A procedure is presented to correct contour displacement data from the influence of WEDM cutting artifacts, and is demonstrated on the correction of a measured weld residual stress. The corrected contour method improved the residual stress magnitude up to 150 MPa. The corrected contour method results were validated by X-ray diffraction, incremental center hole drilling, and neutron diffraction.

  20. Tailoring the optimal control cost function to a desired output: application to minimizing phase errors in short broadband excitation pulses

    NASA Astrophysics Data System (ADS)

    Skinner, Thomas E.; Reiss, Timo O.; Luy, Burkhard; Khaneja, Navin; Glaser, Steffen J.

    2005-01-01

    The de facto standard cost function has been used heretofore to characterize the performance of pulses designed using optimal control theory. The freedom to choose new, creative quality factors designed for specific purposes is demonstrated. While the methodology has more general applicability, its utility is illustrated by comparison to a consistently chosen example—broadband excitation. The resulting pulses are limited to the same maximum RF amplitude used previously and tolerate the same variation in RF homogeneity deemed relevant for standard high-resolution NMR probes. Design criteria are unchanged: transformation of Iz → Ix over resonance offsets of ±20 kHz and RF variability of ±5%, with a peak RF amplitude equal to 17.5 kHz. However, the new cost effectively trades a small increase in residual z magnetization for improved phase in the transverse plane. Compared to previous broadband excitation by optimized pulses (BEBOP), significantly shorter pulses are achievable, with only marginally reduced performance. Simulations transform Iz to greater than 0.98 Ix, with phase deviations of the final magnetization less than 2°, over the targeted ranges of resonance offset and RF variability. Experimental performance is in excellent agreement with the simulations.

  1. Early Detection System of Vascular Disease and Its Application Prospect

    PubMed Central

    2016-01-01

    Markers of imaging, structure, and function reflecting vascular damage, integrating a long time accumulation effect of traditional and unrecognized cardiovascular risk factors, can be regarded as surrogate endpoints of target organ damage before the occurrence of clinical events. Prevention of cardiovascular disease requires risk stratification and treatment of traditional risk factors, such as smoking, hypertension, hyperlipidemia, and diabetes. However, traditional risk stratification is not sufficient to provide accurate assessment of future cardiovascular events. Therefore, vascular injury related parameters obtained by ultrasound or other noninvasive devices, as a surrogate parameter of subclinical cardiovascular disease, can improve cardiovascular risk assessment and optimize the preventive treatment strategy. Thus, we will summarize the research progress and clinical application of early assessment technology of vascular diseases in the present review. PMID:28042567

  2. Aqueous cationic, anionic and non-ionic multi-walled carbon nanotubes, functionalised with minimal framework damage, for biomedical application

    PubMed Central

    Chen, Shu; Hu, Sheng; Smith, Elizabeth F.; Ruenraroengsak, Pakatip; Thorley, Andrew J.; Menzel, Robert; Goode, Angela E.; Ryan, Mary P.; Tetley, Teresa D.; Porter, Alexandra E.; Shaffer, Milo S. P.

    2014-01-01

    The use of a thermochemical grafting approach provides a versatile means to functionalise as-synthesised, bulk multi-walled carbon nanotubes (MWNTs) without altering their inherent structure. The associated retention of properties is desirable for a wide range of commercial applications, including for drug delivery and medical purposes; it is also pertinent to studies of intrinsic toxicology. A systematic series of water-compatible MWNTs, with diameter around 12 nm have been prepared, to provide structurally-equivalent samples predominantly stabilised by anionic, cationic, or non-ionic groups. The surface charge of MWNTs was controlled by varying the grafting reagents and subsequent post-functionalisation modifications. The degree of grafting was established by thermal analysis (TGA). High resolution transmission electron microscope (HRTEM) and Raman measurements confirmed that the structural framework of the MWNTs was unaffected by the thermochemical treatment, in contrast to a conventional acid-oxidised control which was severely damaged. The effectiveness of the surface modification was demonstrated by significantly improved solubility and stability in both water and cell culture medium, and further quantified by zeta-potential analysis. The grafted MWNTs exhibited relatively low bioreactivity on human immortal alveolar epithelial type 1-like cells (TT1) following 24h exposure as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and lactate dehydrogenase release (LDH) assays. The exposure of TT1 cells to MWNTs suppressed the release of the inflammatory mediators, interleukin 6 (IL-6) and interleukin 8 (IL-8). TEM cell uptake studies indicated efficient cellular entry of MWNTs into TT1 cells, via a range of mechanisms. Cationic MWNTs showed a more substantial interaction with TT1 cell membranes than anionic MWNTs, demonstrating a surface charge effect on cell uptake. PMID:24631251

  3. Aqueous cationic, anionic and non-ionic multi-walled carbon nanotubes, functionalised with minimal framework damage, for biomedical application.

    PubMed

    Chen, Shu; Hu, Sheng; Smith, Elizabeth F; Ruenraroengsak, Pakatip; Thorley, Andrew J; Menzel, Robert; Goode, Angela E; Ryan, Mary P; Tetley, Teresa D; Porter, Alexandra E; Shaffer, Milo S P

    2014-06-01

    The use of a thermochemical grafting approach provides a versatile means to functionalise as-synthesised, bulk multi-walled carbon nanotubes (MWNTs) without altering their inherent structure. The associated retention of properties is desirable for a wide range of commercial applications, including for drug delivery and medical purposes; it is also pertinent to studies of intrinsic toxicology. A systematic series of water-compatible MWNTs, with diameter around 12 nm have been prepared, to provide structurally-equivalent samples predominantly stabilised by anionic, cationic, or non-ionic groups. The surface charge of MWNTs was controlled by varying the grafting reagents and subsequent post-functionalisation modifications. The degree of grafting was established by thermal analysis (TGA). High resolution transmission electron microscope (HRTEM) and Raman measurements confirmed that the structural framework of the MWNTs was unaffected by the thermochemical treatment, in contrast to a conventional acid-oxidised control which was severely damaged. The effectiveness of the surface modification was demonstrated by significantly improved solubility and stability in both water and cell culture medium, and further quantified by zeta-potential analysis. The grafted MWNTs exhibited relatively low bioreactivity on transformed human alveolar epithelial type 1-like cells (TT1) following 24 h exposure as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and lactate dehydrogenase release (LDH) assays. The exposure of TT1 cells to MWNTs suppressed the release of the inflammatory mediators, interleukin 6 (IL-6) and interleukin 8 (IL-8). TEM cell uptake studies indicated efficient cellular entry of MWNTs into TT1 cells, via a range of mechanisms. Cationic MWNTs showed a more substantial interaction with TT1 cell membranes than anionic MWNTs, demonstrating a surface charge effect on cell uptake.

  4. Recent advances in the application of metabolomics to Alzheimer's Disease.

    PubMed

    Trushina, Eugenia; Mielke, Michelle M

    2014-08-01

    The pathophysiological changes associated with Alzheimer's Disease (AD) begin decades before the emergence of clinical symptoms. Understanding the early mechanisms associated with AD pathology is, therefore, especially important for identifying disease-modifying therapeutic targets. While the majority of AD clinical trials to date have focused on anti-amyloid-beta (Aβ) treatments, other therapeutic approaches may be necessary. The ability to monitor changes in cellular networks that include both Aβ and non-Aβ pathways is essential to advance our understanding of the etiopathogenesis of AD and subsequent development of cognitive symptoms and dementia. Metabolomics is a powerful tool that detects perturbations in the metabolome, a pool of metabolites that reflects changes downstream of genomic, transcriptomic and proteomic fluctuations, and represents an accurate biochemical profile of the organism in health and disease. The application of metabolomics could help to identify biomarkers for early AD diagnosis, to discover novel therapeutic targets, and to monitor therapeutic response and disease progression. Moreover, given the considerable parallel between mouse and human metabolism, the use of metabolomics provides ready translation of animal research into human studies for accelerated drug design. In this review, we will summarize current progress in the application of metabolomics in both animal models and in humans to further understanding of the mechanisms involved in AD pathogenesis. © 2013.

  5. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232

    PubMed Central

    Wood, Brent L.; Devidas, Meenakshi; Loh, Mignon L.; Raetz, Elizabeth A.; Salzer, Wanda L.; Nachman, James B.; Carroll, Andrew J.; Heerema, Nyla A.; Gastier-Foster, Julie M.; Willman, Cheryl L.; Dai, Yunfeng; Winick, Naomi J.; Hunger, Stephen P.; Carroll, William L.; Larsen, Eric

    2015-01-01

    Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children’s Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725. PMID:26124497

  6. The ZOOM minimization package

    SciTech Connect

    Fischler, Mark S.; Sachs, D.; /Fermilab

    2004-11-01

    A new object-oriented Minimization package is available for distribution in the same manner as CLHEP. This package, designed for use in HEP applications, has all the capabilities of Minuit, but is a re-write from scratch, adhering to modern C++ design principles. A primary goal of this package is extensibility in several directions, so that its capabilities can be kept fresh with as little maintenance effort as possible. This package is distinguished by the priority that was assigned to C++ design issues, and the focus on producing an extensible system that will resist becoming obsolete.

  7. miRNAs: roles and clinical applications in vascular disease.

    PubMed

    Jamaluddin, Md Saha; Weakley, Sarah M; Zhang, Lidong; Kougias, Panagiotis; Lin, Peter H; Yao, Qizhi; Chen, Changyi

    2011-01-01

    miRNAs are small, endogenously expressed noncoding RNAs that regulate gene expression, mainly at the post-transcriptional level, via degradation or translational inhibition of their target mRNAs. Functionally, an individual miRNA can regulate the expression of multiple target genes. The study of miRNAs is rapidly growing and recent studies have revealed a significant role of miRNAs in vascular biology and disease. Many miRNAs are highly expressed in the vasculature, and their expression is dysregulated in diseased vessels. Several miRNAs have been found to be critical modulators of vascular pathologies, such as atherosclerosis, lipoprotein metabolism, inflammation, arterial remodeling, angiogenesis, smooth muscle cell regeneration, hypertension, apoptosis, neointimal hyperplasia and signal transduction pathways. Thus, miRNAs may serve as novel biomarkers and/or therapeutic targets for vascular disease. This article summarizes the current studies related to the disease correlations and functional roles of miRNAs in the vascular system and discusses the potential applications of miRNAs in vascular disease.

  8. Ultrasound treatment of neurological diseases--current and emerging applications.

    PubMed

    Leinenga, Gerhard; Langton, Christian; Nisbet, Rebecca; Götz, Jürgen

    2016-03-01

    Like cardiovascular disease and cancer, neurological disorders present an increasing challenge for an ageing population. Whereas nonpharmacological procedures are routine for eliminating cancer tissue or opening a blocked artery, the focus in neurological disease remains on pharmacological interventions. Setbacks in clinical trials and the obstacle of access to the brain for drug delivery and surgery have highlighted the potential for therapeutic use of ultrasound in neurological diseases, and the technology has proved useful for inducing focused lesions, clearing protein aggregates, facilitating drug uptake, and modulating neuronal function. In this Review, we discuss milestones in the development of therapeutic ultrasound, from the first steps in the 1950s to recent improvements in technology. We provide an overview of the principles of diagnostic and therapeutic ultrasound, for surgery and transient opening of the blood-brain barrier, and its application in clinical trials of stroke, Parkinson disease and chronic pain. We discuss the promising outcomes of safety and feasibility studies in preclinical models, including rodents, pigs and macaques, and efficacy studies in models of Alzheimer disease. We also consider the challenges faced on the road to clinical translation.

  9. Waste Minimization Crosscut Plan

    SciTech Connect

    Not Available

    1992-05-13

    On November 27, 1991, the Secretary of Energy directed that a Department of Energy (DOE) crosscut plan for waste minimization (WMin) be prepared and submitted by March 1, 1992. This Waste Minimization Crosscut Plan responds to the Secretary's direction and supports the National Energy Strategy (NES) goals of achieving greater energy security, increasing energy and economic efficiency, and enhancing environmental quality. It provides a DOE-wide planning framework for effective coordination of all DOE WMin activities. This Plan was jointly prepared by the following Program Secretarial Officer (PSO) organizations: Civilian Radioactive Waste Management (RW); Conservation and Renewable Energy (CE); Defense Programs (DP); Environmental Restoration and Waste Management (EM), lead; Energy Research (ER); Fossil Energy (FE); Nuclear Energy (NE); and New Production Reactors (NP). Assistance and guidance was provided by the offices of Policy, Planning, and Analysis (PE) and Environment, Safety and Health (EH). Comprehensive application of waste minimization within the Department and in both the public and private sectors will provide significant benefits and support National Energy Strategy goals. These benefits include conservation of a substantial proportion of the energy now used by industry and Government, improved environmental quality, reduced health risks, improved production efficiencies, and longer useful life of disposal capacity. Taken together, these benefits will mean improved US global competitiveness, expanded job opportunities, and a better quality of life for all citizens.

  10. Waste Minimization Crosscut Plan

    SciTech Connect

    Not Available

    1992-05-13

    On November 27, 1991, the Secretary of Energy directed that a Department of Energy (DOE) crosscut plan for waste minimization (WMin) be prepared and submitted by March 1, 1992. This Waste Minimization Crosscut Plan responds to the Secretary`s direction and supports the National Energy Strategy (NES) goals of achieving greater energy security, increasing energy and economic efficiency, and enhancing environmental quality. It provides a DOE-wide planning framework for effective coordination of all DOE WMin activities. This Plan was jointly prepared by the following Program Secretarial Officer (PSO) organizations: Civilian Radioactive Waste Management (RW); Conservation and Renewable Energy (CE); Defense Programs (DP); Environmental Restoration and Waste Management (EM), lead; Energy Research (ER); Fossil Energy (FE); Nuclear Energy (NE); and New Production Reactors (NP). Assistance and guidance was provided by the offices of Policy, Planning, and Analysis (PE) and Environment, Safety and Health (EH). Comprehensive application of waste minimization within the Department and in both the public and private sectors will provide significant benefits and support National Energy Strategy goals. These benefits include conservation of a substantial proportion of the energy now used by industry and Government, improved environmental quality, reduced health risks, improved production efficiencies, and longer useful life of disposal capacity. Taken together, these benefits will mean improved US global competitiveness, expanded job opportunities, and a better quality of life for all citizens.

  11. Application of a theoretical model to evaluate COPD disease management

    PubMed Central

    2010-01-01

    Background Disease management programmes are heterogeneous in nature and often lack a theoretical basis. An evaluation model has been developed in which theoretically driven inquiries link disease management interventions to outcomes. The aim of this study is to methodically evaluate the impact of a disease management programme for patients with chronic obstructive pulmonary disease (COPD) on process, intermediate and final outcomes of care in a general practice setting. Methods A quasi-experimental research was performed with 12-months follow-up of 189 COPD patients in primary care in the Netherlands. The programme included patient education, protocolised assessment and treatment of COPD, structural follow-up and coordination by practice nurses at 3, 6 and 12 months. Data on intermediate outcomes (knowledge, psychosocial mediators, self-efficacy and behaviour) and final outcomes (dyspnoea, quality of life, measured by the CRQ and CCQ, and patient experiences) were obtained from questionnaires and electronic registries. Results Implementation of the programme was associated with significant improvements in dyspnoea (p < 0.001) and patient experiences (p < 0.001). No significant improvement was found in mean quality of life scores. Improvements were found in several intermediate outcomes, including investment beliefs (p < 0.05), disease-specific knowledge (p < 0.01; p < 0.001) and medication compliance (p < 0.01). Overall, process improvement was established. The model showed associations between significantly improved intermediate outcomes and improvements in quality of life and dyspnoea. Conclusions The application of a theory-driven model enhances the design and evaluation of disease management programmes aimed at improving health outcomes. This study supports the notion that a theoretical approach strengthens the evaluation designs of complex interventions. Moreover, it provides prudent evidence that the implementation of COPD disease management programmes can

  12. Application of a theoretical model to evaluate COPD disease management.

    PubMed

    Lemmens, Karin M M; Nieboer, Anna P; Rutten-Van Mölken, Maureen P M H; van Schayck, Constant P; Asin, Javier D; Dirven, Jos A M; Huijsman, Robbert

    2010-03-26

    Disease management programmes are heterogeneous in nature and often lack a theoretical basis. An evaluation model has been developed in which theoretically driven inquiries link disease management interventions to outcomes. The aim of this study is to methodically evaluate the impact of a disease management programme for patients with chronic obstructive pulmonary disease (COPD) on process, intermediate and final outcomes of care in a general practice setting. A quasi-experimental research was performed with 12-months follow-up of 189 COPD patients in primary care in the Netherlands. The programme included patient education, protocolised assessment and treatment of COPD, structural follow-up and coordination by practice nurses at 3, 6 and 12 months. Data on intermediate outcomes (knowledge, psychosocial mediators, self-efficacy and behaviour) and final outcomes (dyspnoea, quality of life, measured by the CRQ and CCQ, and patient experiences) were obtained from questionnaires and electronic registries. Implementation of the programme was associated with significant improvements in dyspnoea (p < 0.001) and patient experiences (p < 0.001). No significant improvement was found in mean quality of life scores. Improvements were found in several intermediate outcomes, including investment beliefs (p < 0.05), disease-specific knowledge (p < 0.01; p < 0.001) and medication compliance (p < 0.01). Overall, process improvement was established. The model showed associations between significantly improved intermediate outcomes and improvements in quality of life and dyspnoea. The application of a theory-driven model enhances the design and evaluation of disease management programmes aimed at improving health outcomes. This study supports the notion that a theoretical approach strengthens the evaluation designs of complex interventions. Moreover, it provides prudent evidence that the implementation of COPD disease management programmes can positively influence outcomes of care.

  13. Strategies for minimizing nosocomial measles transmission.

    PubMed Central

    Biellik, R. J.; Clements, C. J.

    1997-01-01

    As a result of the highly contagious nature of measles before the onset of rash, nosocomial transmission will remain a threat until the disease is eradicated. However, a number of strategies can minimize its nosocomial spread. It is therefore vital to maximize awareness among health care staff that an individual with measles can enter a health facility at any time and that a continual risk of the nosocomial transmission of measles exists. The present review makes two groups of recommendations: those which are generally applicable to all countries, and certain additional recommendations which may be suitable only for industrialized countries. PMID:9342896

  14. Waste minimization handbook, Volume 1

    SciTech Connect

    Boing, L.E.; Coffey, M.J.

    1995-12-01

    This technical guide presents various methods used by industry to minimize low-level radioactive waste (LLW) generated during decommissioning and decontamination (D and D) activities. Such activities generate significant amounts of LLW during their operations. Waste minimization refers to any measure, procedure, or technique that reduces the amount of waste generated during a specific operation or project. Preventive waste minimization techniques implemented when a project is initiated can significantly reduce waste. Techniques implemented during decontamination activities reduce the cost of decommissioning. The application of waste minimization techniques is not limited to D and D activities; it is also useful during any phase of a facility`s life cycle. This compendium will be supplemented with a second volume of abstracts of hundreds of papers related to minimizing low-level nuclear waste. This second volume is expected to be released in late 1996.

  15. Minimally invasive mediastinal surgery

    PubMed Central

    Melfi, Franca M. A.; Mussi, Alfredo

    2016-01-01

    In the past, mediastinal surgery was associated with the necessity of a maximum exposure, which was accomplished through various approaches. In the early 1990s, many surgical fields, including thoracic surgery, observed the development of minimally invasive techniques. These included video-assisted thoracic surgery (VATS), which confers clear advantages over an open approach, such as less trauma, short hospital stay, increased cosmetic results and preservation of lung function. However, VATS is associated with several disadvantages. For this reason, it is not routinely performed for resection of mediastinal mass lesions, especially those located in the anterior mediastinum, a tiny and remote space that contains vital structures at risk of injury. Robotic systems can overcome the limits of VATS, offering three-dimensional (3D) vision and wristed instrumentations, and are being increasingly used. With regards to thymectomy for myasthenia gravis (MG), unilateral and bilateral VATS approaches have demonstrated good long-term neurologic results with low complication rates. Nevertheless, some authors still advocate the necessity of maximum exposure, especially when considering the distribution of normal and ectopic thymic tissue. In recent studies, the robotic approach has shown to provide similar neurological outcomes when compared to transsternal and VATS approaches, and is associated with a low morbidity. Importantly, through a unilateral robotic technique, it is possible to dissect and remove at least the same amount of mediastinal fat tissue. Preliminary results on early-stage thymomatous disease indicated that minimally invasive approaches are safe and feasible, with a low rate of pleural recurrence, underlining the necessity of a “no-touch” technique. However, especially for thymomatous disease characterized by an indolent nature, further studies with long follow-up period are necessary in order to assess oncologic and neurologic results through minimally

  16. Early recovery of circulating immature B cells in B-lymphoblastic leukemia patients after CD19 targeted CAR T cell therapy: A pitfall for minimal residual disease detection*().

    PubMed

    Xiao, Wenbin; Salem, Dalia; McCoy, Catherine; Lee, Daniel; Shah, Nirali N; Stetler-Stevenson, Maryalice; Yuan, Constance M

    2017-09-09

    CD19-targeted chimeric-antigen receptor-modified T-cells (CAR-T) are promising in the treatment of refractory B-lymphoblastic leukemia (B-ALL). Minimal residual disease (MRD) detection by multicolor flow cytometry (FCM) is critical to distinguish B-ALL MRD from regenerating, non-neoplastic B-cell populations. FCM was performed on samples from 9 patients with B-ALL treated with CAR-T. All 9 patients showed response to CAR-T. Additionally, FCM revealed circulating CD10+B cells, potentially mimicking MRD. Circulating CD10+ B-cells were detected in blood from 3 days to 3 months after CAR-T, comprising 73% (median) of B-cells (52-83%, 95%CI). They expressed CD19, CD10, CD20, bright CD9, CD22, CD24, moderate CD38 and dim CD58, but were CD34 (-), with bright CD45 and polyclonal surface light chain immunoglobulin (sIg) expression. A similar CD10+B-cell subpopulation was detected by marrow FCM, amidst abundant B-cell precursors. These circulating CD10+B-cells are compatible with immature B-cells, and are a reflection of B-cell recovery within the marrow. They are immunophenotypically distinguishable from residual B-ALL. Expression of light chain sIg and key surface antigens characterizing regenerating B-cell precursors can distinguish immature B-cells from B-ALL MRD and prevent misdiagnosis. This article is protected by copyright. All rights reserved. © 2017 International Clinical Cytometry Society.

  17. Minimal hepatic glucose-6-phosphatase-α activity required to sustain survival and prevent hepatocellular adenoma formation in murine glycogen storage disease type Ia.

    PubMed

    Lee, Young Mok; Kim, Goo-Young; Pan, Chi-Jiunn; Mansfield, Brian C; Chou, Janice Y

    2015-06-01

    Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) activity. In a previous 70-90 week-study, we showed that a recombinant adeno-associated virus (rAAV) vector-mediated gene transfer that restores more than 3% of wild-type hepatic G6Pase-α activity in G6pc (-/-) mice corrects hepatic G6Pase-α deficiency with no evidence of HCA. We now examine the minimal hepatic G6Pase-α activity required to confer therapeutic efficacy. We show that rAAV-treated G6pc (-/-) mice expressing 0.2% of wild-type hepatic G6Pase-α activity suffered from frequent hypoglycemic seizures at age 63-65 weeks but mice expressing 0.5-1.3% of wild-type hepatic G6Pase-α activity (AAV-LL mice) sustain 4-6 h of fast and grow normally to age 75-90 weeks. Despite marked increases in hepatic glycogen accumulation, the AAV-LL mice display no evidence of hepatic abnormalities, hepatic steatosis, or HCA. Interprandial glucose homeostasis is maintained by the G6Pase-α/glucose-6-phosphate transporter (G6PT) complex, and G6PT-mediated microsomal G6P uptake is the rate-limiting step in endogenous glucose production. We show that hepatic G6PT activity is increased in AAV-LL mice. These findings are encouraging for clinical studies of G6Pase-α gene-based therapy for GSD-Ia.

  18. History of consolidation is prognostic in acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplantation in minimal residual disease-negative first complete remission.

    PubMed

    Rashidi, Armin; Linden, Michael A; DeFor, Todd E; Warlick, Erica; Bejanyan, Nelli; Yohe, Sophia; Weisdorf, Daniel J; Ustun, Celalettin

    2017-10-01

    Prognostic factors among acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in minimal residual disease (MRD)-negative first complete remission (CR1) are unknown. We retrospectively attempted to answer the following question: In AML patients undergoing allo-HCT in MRD-negative CR1, does a history of prior consolidation provide additional prognostic information? The inclusion criteria were: (i) Age > 18 years, (ii) AML in CR1 after 1-2 cycles of intensive induction chemotherapy, with or without consolidation, (iii) Allo-HCT between 1/2003 and 4/2016 at our institution, (iv) Available standard-sensitivity 4-color flow cytometry results from a bone marrow aspiration at diagnosis and after completion of all previous chemotherapy within one month prior to HCT, (v) Flow cytometry-based MRD-negative status at the time of HCT. A history of prior consolidation was associated with favorable overall survival (Hazard Ratio [95% Confidence Interval]: 0.59 [0.35-0.99], P = .046), relapse-free survival (0.60 [0.37-0.96], P = .036), and relapse (0.50 [0.27-0.92], P = .025). Analysis of potential sources of bias was unrevealing. In AML patients undergoing allo-HCT in MRD-negative CR1, a history of prior consolidation was associated with favorable outcomes. If the path to pre-HCT MRD negativity includes consolidation, it may identify patients with improved prognosis following HCT in MRD-negative state. These results warrant validation in larger cohorts. © 2017 Wiley Periodicals, Inc.

  19. Clinical outcome and monitoring of minimal residual disease in patients with acute lymphoblastic leukemia expressing the MLL/ENL fusion gene.

    PubMed

    Elia, Loredana; Grammatico, Sara; Paoloni, Francesca; Vignetti, Marco; Rago, Angela; Cenfra, Natalia; Mecarocci, Sergio; Mancini, Marco; Luciani, Matteo; Di Raimondo, Francesco; Cazzaniga, Giovanni; Matarazzo, Mabel; Moleti, Maria Luisa; Santoro, Lidia; Gaidano, Gianluca; Foà, Robin; Mandelli, Franco; Cimino, Giuseppe

    2011-12-01

    We analyzed 12 MLL/ENL positive ALL patients consecutively diagnosed between 1999 and 2009. The MLL/ENL fusion was identified in 4/150 (2.6%), 8/993 (0.8%), and 0/70 of pediatric, adult, and elderly patients, respectively. Eight patients had a WBC count >50 × 10(9) /L. Ten cases had an evaluable immunophenotyping. A B or T precursor ALL occurred in 7 and 3 patients, respectively. Eleven/12 patients (92%) achieved CR. At 48 months, overall survival and event-free survival rates were 73.3% and 67%, respectively. At CR, a parallel RT-PCR evaluation of the MLL/ENL expression was available in 5 cases. Of these latter, 2 tested MLL/ENL-negative and 3 positive. The minimal residual disease molecular monitoring showed that MLL/ENL status did not correlate with outcome. In fact, all the 2 PCR-negative and 1 of the 3 PCR-positive cases relapsed. Further, a MLL/ENL expression, not preceding a relapse, was detected several times during the follow-up of five long-survivors. In conclusion, also in adults, the MLL/ENL fusion identifies a rare leukemic entity with a favorable prognosis. The observed inconsistency between the clinical cure and the presence of detectable MLL/ENL transcript suggests the existence of a MLL/ENL-expressing "preleukemia" stem cells, similar to what demonstrated for the AML1/ETO-positive leukemia setting. Copyright © 2011 Wiley-Liss, Inc.

  20. Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)].

    PubMed

    Perea, G; Lasa, A; Aventín, A; Domingo, A; Villamor, N; Queipo de Llano, M Paz; Llorente, A; Juncà, J; Palacios, C; Fernández, C; Gallart, M; Font, L; Tormo, M; Florensa, L; Bargay, J; Martí, J M; Vivancos, P; Torres, P; Berlanga, J J; Badell, I; Brunet, S; Sierra, J; Nomdedéu, J F

    2006-01-01

    Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.

  1. Weight loss and achievement of minimal disease activity in patients with psoriatic arthritis starting treatment with tumour necrosis factor α blockers

    PubMed Central

    Di Minno, Matteo Nicola Dario; Peluso, Rosario; Iervolino, Salvatore; Russolillo, Anna; Lupoli, Roberta; Scarpa, Raffaele

    2014-01-01

    Objectives To evaluate prospectively the effect of weight loss on the achievement of minimal disease activity (MDA) in overweight/obese patients with psoriatic arthritis (PsA) starting treatment with tumour necrosis factor α (TNFα) blockers. Methods Among subjects with PsA starting treatment with TNFα blockers, 138 overweight/obese patients received a concomitant dietary intervention (69 a hypocaloric diet (HD) and 69 a free-managed diet (FD)). Changes in metabolic variables were measured and a complete clinical rheumatological evaluation was made in all patients at baseline and after a 6-month follow-up to define the achievement of MDA. Results 126 subjects completed the study. MDA was more often achieved by HD than by FD subjects (HR=1.85, 95% CI 1.019 to 3.345, p=0.043). A diet was successful (≥5% weight loss) in 74 (58.7%) patients. Regardless of the type of diet, after 6 months of treatment with TNFα blockers, ≥5% of weight loss was a predictor of the achievement of MDA (OR=4.20, 95% CI 1.82 to 9.66, p<0.001). For increasing weight-loss categories (<5%, 5–10%, >10%), MDA was achieved by 23.1%, 44.8% and 59.5%, respectively. A higher rate of MDA achievement was found in subjects with 5–10% (OR=3.75, 95% CI 1.36 to 10.36, p=0.011) and in those with >10% (OR=6.67, 95% CI 2.41 to 18.41, p<0.001) weight loss in comparison with those with <5% weight loss. Conclusions Regardless of the type of diet, a successful weight loss (≥5% from baseline values) is associated with a higher rate of achievement of MDA in overweight/obese patients with PsA who start treatment with TNFα blockers. PMID:23771989

  2. Safety and Feasibility of a Minimally Fluoroscopic Approach for Ventricular Tachycardia Ablation in Patients With Structural Heart Disease: Influence of the Ventricular Tachycardia Substrate.

    PubMed

    Cano, Óscar; Andrés, Ana; Osca, Joaquín; Alonso, Pau; Sancho-Tello, María-José; Olagüe, José; Martínez-Dolz, Luis

    2016-02-01

    We sought to evaluate the safety and feasibility of a minimally fluoroscopic approach using the CARTOUNIVU module during scar-related ventricular tachycardia (VT) ablation. Consecutive patients with structural heart disease undergoing VT ablation using the CARTOUNIVU module were prospectively included and classified depending on their VT substrate: (1) ischemic VT (IVT) and (2) nonischemic VT and depending on the presence of an epicardial access. Radiation exposure parameters and major and minor procedure-related complications were registered. A near-zero fluoroscopy exposure was defined as those procedures with an effective dose ≤1 mSv. A total of 44 VT ablation procedures were performed in 41 patients (22 IVT and 19 nonischemic VT). The use of the CARTOUNIVU module resulted in low levels of radiation exposure: median total fluoroscopy time and effective dose of 6.08 (1.51-12.36) minutes and 2.15 (0.58-8.22) mSv, respectively. Patients with IVT had lower radiation exposure than patients with nonischemic VT (total fluoroscopy time, 2.53 [1.22-11.22] versus 8.51 [5.55-17.34] minutes; P=0.016). Epicardial access was associated with significantly higher levels of radiation exposure. Complications occurred in 4.9% patients, none of them being related to the use of the image integration tool. A near-zero fluoroscopy ablation could be performed in 14 of 44 procedures (32%), 43% of IVT procedures, and 50% of procedures with endocardial access only. The use of the CARTOUNIVU module during scar-related VT ablation resulted in low levels of radiation exposure. A near-zero fluoroscopy approach can be achieved in up to half of the procedures, especially in IVT patients with endocardial ablation. © 2016 American Heart Association, Inc.

  3. Detailed immunophenotyping of B-cell precursors in regenerating bone marrow of acute lymphoblastic leukaemia patients: implications for minimal residual disease detection.

    PubMed

    Theunissen, Prisca M J; Sedek, Lukasz; De Haas, Valerie; Szczepanski, Tomasz; Van Der Sluijs, Alita; Mejstrikova, Ester; Nováková, Michaela; Kalina, Tomas; Lecrevisse, Quentin; Orfao, Alberto; Lankester, Arjan C; van Dongen, Jacques J M; Van Der Velden, Vincent H J

    2017-07-01

    Flow cytometric detection of minimal residual disease (MRD) in children with B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) requires immunophenotypic discrimination between residual leukaemic cells and B-cell precursors (BCPs) which regenerate during therapy intervals. In this study, EuroFlow-based 8-colour flow cytometry and innovative analysis tools were used to first characterize the immunophenotypic maturation of normal BCPs in bone marrow (BM) from healthy children, resulting in a continuous multiparametric pathway including transition stages. This pathway was subsequently used as a reference to characterize the immunophenotypic maturation of regenerating BCPs in BM from children treated for BCP-ALL. We identified pre-B-I cells that expressed low or dim CD34 levels, in contrast to the classical CD34(high) pre-B-I cell immunophenotype. These CD34(-dim) pre-B-I cells were relatively abundant in regenerating BM (11-85% within pre-B-I subset), while hardly present in healthy control BM (9-13% within pre-B-I subset; P = 0·0037). Furthermore, we showed that some of the BCP-ALL diagnosis immunophenotypes (23%) overlapped with CD34(-dim) pre-B-I cells. Our results indicate that newly identified CD34(-dim) pre-B-I cells can be mistaken for residual BCP-ALL cells, potentially resulting in false-positive MRD outcomes. Therefore, regenerating BM, in which CD34(-dim) pre-B-I cells are relatively abundant, should be used as reference frame in flow cytometric MRD measurements. © 2017 John Wiley & Sons Ltd.

  4. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease.

    PubMed

    Bachanova, V; Marks, D I; Zhang, M-J; Wang, H; de Lima, M; Aljurf, M D; Arellano, M; Artz, A S; Bacher, U; Cahn, J-Y; Chen, Y-B; Copelan, E A; Drobyski, W R; Gale, R P; Greer, J P; Gupta, V; Hale, G A; Kebriaei, P; Lazarus, H M; Lewis, I D; Lewis, V A; Liesveld, J L; Litzow, M R; Loren, A W; Miller, A M; Norkin, M; Oran, B; Pidala, J; Rowe, J M; Savani, B N; Saber, W; Vij, R; Waller, E K; Wiernik, P H; Weisdorf, D J

    2014-03-01

    The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.

  5. Use of minimal disseminated disease and immunity to NPM-ALK antigen to stratify ALK-positive ALCL patients with different prognosis.

    PubMed

    Mussolin, L; Damm-Welk, C; Pillon, M; Zimmermann, M; Franceschetto, G; Pulford, K; Reiter, A; Rosolen, A; Woessmann, W

    2013-02-01

    We studied the prognostic value of minimal disseminated disease (MDD) and anti-ALK immune response in children with NPM-ALK-positive anaplastic-large cell lymphoma (ALCL) and evaluated their potential for risk stratification. NPM-ALK transcripts were analyzed by RT-PCR in bone marrow/peripheral blood of 128 ALCL patients at diagnosis, whereas ALK antibody titers in plasma were assessed using an immunocytochemical approach. MDD was positive in 59% of patients and 96% showed an anti-ALK response. Using MDD and antibody titer results, patients could be divided into three biological risk groups (bRG) with different prognosis: high risk (bHR): MDD-positive and antibody titer ≤ 1/750, 26/128 (20%); low risk (bLR): MDD negative and antibody titer >1/750, 40/128 (31%); intermediate risk (bIR): all remaining patients, 62/128 (48%). Progression-free survival was 28% (s.e., 9%), 68% (s.e., 6%) and 93% (s.e., 4%) for bHR, bIR and bLR, respectively (P<0.0001). Survival was 71% (s.e., 9%), 83% (s.e., 5%) and 98% (s.e., 2%) for bHR, bIR and bLR (P=0.02). Only bHR and histology other than common type were predictive of higher risk of failure (hazard ratio 4.9 and 2.7, respectively) in multivariate analysis. Stratification of ALCL patients based on MDD and anti-ALK titer should be considered in future ALCL trials to optimize treatment.

  6. Microendoscopy-assisted minimally invasive transforaminal lumbar interbody fusion for lumbar degenerative disease: short-term and medium-term outcomes

    PubMed Central

    Yang, Yang; Liu, Bin; Rong, Li-Min; Chen, Rui-Qiang; Dong, Jian-Wen; Xie, Pei-Gen; Zhang, Liang-Ming; Feng, Feng

    2015-01-01

    Objective: To evaluate short-term and medium-term outcomes of microendoscopy-assisted minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and open TLIF for lumbar degenerative disease. Methods: In this prospective, randomized control study, 50 cases received microendoscopy-assisted MIS-TLIF (MIS group), while another well-matched 50 cases accepted open TLIF (open group). Parameters between both groups, including surgical duration, intraoperative blood loss and radiologic exposure, postoperative analgesic usage and ambulatory time, visual analogue scale (VAS) for back and leg, functional scores, self-evaluation of surgical outcome (modified MacNab criteria), interbody fusion rate, adjacent segment degeneration (ASD) rate, as well as complication incidence were compared at 1 month and 24 months postoperatively. Results: Intraoperative blood loss and postoperative analgesic usage were significantly reduced in MIS group (P<0.05). Patients undergoing microendoscopy-assisted MIS-TLIF were able to ambulate earlier postoperatively than those receiving open TLIF (P<0.05). However, it showed prolonged surgical duration and enhanced radiologic exposure in MIS group (P<0.05). At 1 month postoperatively, MIS group was associated with more improvement of VAS and functional scores compared with open group (P<0.05). While at 24 months postoperatively, both groups revealed similar VAS and functional scores (P>0.05). Excellent and perfect scale rating by modified MacNab criteria, interbody fusion rate, ASD rate and complication incidence between both groups were nearly the same (P>0.05). Conclusions: Microendoscopy-assisted MIS-TLIF owns advantages of less iatrogenic injury, decreased blood loss, reduced analgesic usage and earlier rehabilitation, while it has drawbacks of more surgical duration and radiologic exposure. It is superior than open TLIF in terms of short-term clinical outcomes and has similar medium-term clinical outcomes. PMID:26885072

  7. Immunoglobulin and T-cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplant relapse and survival

    PubMed Central

    Logan, Aaron C.; Vashi, Nikita; Faham, Malek; Carlton, Victoria; Kong, Katherine; Buno, Ismael; Zheng, Jianbiao; Moorhead, Martin; Klinger, Mark; Zhang, Bing; Waqar, Amna; Zehnder, James L.; Miklos, David B.

    2017-01-01

    Minimal residual disease (MRD) quantification is an important predictor of outcome after treatment for acute lymphoblastic leukemia (ALL). Bone marrow ALL burden ≥ 10−4 after induction predicts subsequent relapse. Likewise, MRD ≥ 10−4 in bone marrow prior to the initiation of conditioning for allogeneic hematopoietic cell transplantation (allo-HCT) predicts transplant failure. Current methods for MRD quantification in ALL are not sufficiently sensitive for use with peripheral blood specimens and have not been broadly implemented in the management of adults with ALL. Consensus primed immunoglobulin (Ig) and T-cell receptor (TCR) amplification and high-throughput sequencing (HTS) permits use of a standardized algorithm for all patients and can detect leukemia at 10−6 or lower. We applied the Sequenta LymphoSIGHT™ HTS platform to quantification of MRD in 237 samples from 29 adult B-ALL patients before and after allo-HCT. Using primers for the IGH-VDJ, IGH-DJ, IGK, TCRB, TCRD, and TCRG loci, MRD could be quantified in 93% of patients. Leukemia-associated clonotypes at these loci were identified in 52%, 28%, 10%, 35%, 28%, and 41% of patients, respectively. MRD ≥ 10−4 before HCT conditioning predicted post-HCT relapse (HR 7.7, 95% CI 2.0–30, p=0.003). In post-HCT blood samples, MRD ≥ 10−6 had 100% positive predictive value for relapse with median lead-time of 89 days (HR 14; 95% CI 4.7–44, p<0.0001). The use of HTS-based MRD quantification in adults with ALL offers a standardized approach with sufficient sensitivity to quantify leukemia MRD in peripheral blood. Use of this approach may identify a window for clinical intervention prior to overt relapse. PMID:24769317

  8. Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival.

    PubMed

    Logan, Aaron C; Vashi, Nikita; Faham, Malek; Carlton, Victoria; Kong, Katherine; Buño, Ismael; Zheng, Jianbiao; Moorhead, Martin; Klinger, Mark; Zhang, Bing; Waqar, Amna; Zehnder, James L; Miklos, David B

    2014-09-01

    Minimal residual disease (MRD) quantification is an important predictor of outcome after treatment for acute lymphoblastic leukemia (ALL). Bone marrow ALL burden ≥ 10(-4) after induction predicts subsequent relapse. Likewise, MRD ≥ 10(-4) in bone marrow before initiation of conditioning for allogeneic (allo) hematopoietic cell transplantation (HCT) predicts transplantation failure. Current methods for MRD quantification in ALL are not sufficiently sensitive for use with peripheral blood specimens and have not been broadly implemented in the management of adults with ALL. Consensus-primed immunoglobulin (Ig), T cell receptor (TCR) amplification and high-throughput sequencing (HTS) permit use of a standardized algorithm for all patients and can detect leukemia at 10(-6) or lower. We applied the LymphoSIGHT HTS platform (Sequenta Inc., South San Francisco, CA) to quantification of MRD in 237 samples from 29 adult B cell ALL patients before and after allo-HCT. Using primers for the IGH-VDJ, IGH-DJ, IGK, TCRB, TCRD, and TCRG loci, MRD could be quantified in 93% of patients. Leukemia-associated clonotypes at these loci were identified in 52%, 28%, 10%, 35%, 28%, and 41% of patients, respectively. MRD ≥ 10(-4) before HCT conditioning predicted post-HCT relapse (hazard ratio [HR], 7.7; 95% confidence interval [CI], 2.0 to 30; P = .003). In post-HCT blood samples, MRD ≥10(-6) had 100% positive predictive value for relapse with median lead time of 89 days (HR, 14; 95% CI, 4.7 to 44, P < .0001). The use of HTS-based MRD quantification in adults with ALL offers a standardized approach with sufficient sensitivity to quantify leukemia MRD in peripheral blood. Use of this approach may identify a window for clinical intervention before overt relapse. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  9. Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL.

    PubMed

    Bader, P; Hancock, J; Kreyenberg, H; Goulden, N J; Niethammer, D; Oakhill, A; Steward, C G; Handgretinger, R; Beck, J F; Klingebiel, T

    2002-09-01

    We have retrospectively investigated the relationship between the level of minimal residual disease (MRD) detected in bone marrow taken prior to conditioning therapy and outcome following stem cell transplantation for high risk childhood ALL. Forty-one patients, in whom both a molecular marker of MRD and sufficient archival material was available, were included in the study. All were in remission at BMT: eight in CR1, 32 in CR2 and five in greater than CR2. MRD was measured by PCR amplification of antigen receptor gene rearrangements and clone-specific oligoprobing, the median sensitivity of detection being one leukaemic cell in 10000 normals. Results were classified as high-level positive (if a clonal band was evident after electrophoresis), low-level positive (if MRD was detected only after oligoprobing) and negative. MRD was detected at high levels in 17 patients, at low levels in 10 patients and 14 patients were MRD negative at the time of transplant. The 5-year event-free survival for these groups was 23%, 48% and 78%, respectively (P = 0.022). Limited multivariate analysis confirmed the significance of MRD (P = 0.0095) vs CR status, donor type, sex, immunophenotype and acute GvHD. This study confirms the strong relationship between MRD level and outcome following allogeneic transplantation. In contrast to a previous study we observed that a minority of children with high-level pre-BMT MRD can enter long lasting remission. The possible role for acute GVHD coupled with a graft-versus-leukaemia effect in the clearance of high level MRD in patients with ALL is discussed.

  10. Combined use of reverse transcriptase polymerase chain reaction and flow cytometry to study minimal residual disease in Philadelphia positive acute lymphoblastic leukemia.

    PubMed

    Muñoz, L; López, O; Martino, R; Brunet, S; Bellido, M; Rubiol, E; Sierra, J; Nomdedéu, J F

    2000-07-01

    The Philadelphia chromosome in acute lymphoblastic leukemia (Ph+ ALL) is associated with a poor prognosis given the high frequency of chemoresistance and leukemia relapse. Minimal residual disease (MRD) detection before cytogenetic and hematologic relapse could be useful in early therapy. The most suitable methods for detecting MRD in Ph+ ALL are flow cytometry (FC) and reverse transcriptase polymerase chain reaction (RT-PCR). However, since both techniques carry the risk of false-negative results the combined use of these two techniques could overcome this problem. We report our experience using this approach in 47 bone marrow samples obtained from 10 Ph+ ALL patients. Twenty-seven marrow aspirates were taken from patients in clinical remission (CR). The samples were considered positive for MRD by FC when two conditions were met: 1) detection of an abnormal B-cell differentiation pattern and 2) presence of more than 1x10(-3) cells coexpressing CD22/CD34/CD45 or CD66/CD34/CD10. After FC analysis, RNA was purified using standard methods. FC was positive in 23/27 samples in CR (sensitivity 85%). RT-PCR was successfully performed in 23 samples in CR. RT-PCR was positive in 18/23 samples (sensitivity 78%). There were 5 samples with discordant results. FC was positive in 3 samples with a negative RT-PCR and FC was negative in 2 samples with a positive RT. All the 10 patients relapsed and only 1 is currently alive after an allogeneic stem cell transplantation (alloSCT). The median (range) time from MRD detection to relapse in patients treated with chemotherapy was 42 (39-71) days. These data suggest that RT-PCR may be negative despite the presence of neoplastic cells identified by their immunophenotypic traits. We conclude that immunologic and molecular techniques can be used in tandem for monitoring MRD in Ph+ ALL.

  11. Minimal residual disease-guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia 2003 study.

    PubMed

    Yeoh, Allen Eng Juh; Ariffin, Hany; Chai, Elaine Li Leng; Kwok, Cecilia Sze Nga; Chan, Yiong Huak; Ponnudurai, Kuperan; Campana, Dario; Tan, Poh Lin; Chan, Mei Yoke; Kham, Shirley Kow Yin; Chong, Lee Ai; Tan, Ah Moy; Lin, Hai Peng; Quah, Thuan Chong

    2012-07-01

    To improve treatment outcome for childhood acute lymphoblastic leukemia (ALL), we designed the Malaysia-Singapore ALL 2003 study with treatment stratification based on presenting clinical and genetic features and minimal residual disease (MRD) levels measured by polymerase chain reaction targeting a single antigen-receptor gene rearrangement. Five hundred fifty-six patients received risk-adapted therapy with a modified Berlin-Frankfurt-Münster-ALL treatment. High-risk ALL was defined by MRD ≥ 1 × 10(-3) at week 12 and/or poor prednisolone response, BCR-ABL1, MLL gene rearrangements, hypodiploid less than 45 chromosomes, or induction failure; standard-risk ALL was defined by MRD ≤ 1 × 10(-4) at weeks 5 and 12 and no extramedullary involvement or high-risk features. Intermediate-risk ALL included all remaining patients. Patients who lacked high-risk presenting features (85.7%) received remission induction therapy with dexamethasone, vincristine, and asparaginase, without anthracyclines. Six-year event-free survival (EFS) was 80.6% ± 3.5%; overall survival was 88.4% ± 3.1%. Standard-risk patients (n = 172; 31%) received significantly deintensified subsequent therapy without compromising EFS (93.2% ± 4.1%). High-risk patients (n = 101; 18%) had the worst EFS (51.8% ± 10%); EFS was 83.6% ± 4.9% in intermediate-risk patients (n = 283; 51%). Our results demonstrate significant progress over previous trials in the region. Three-drug remission-induction therapy combined with MRD-based risk stratification to identify poor responders is an effective strategy for childhood ALL.

  12. Constrained minimization for monotonic reconstruction

    SciTech Connect

    Rider, W.J.; Kothe, D.B.

    1996-08-20

    The authors present several innovations in a method for monotonic reconstructions. It is based on the application of constrained minimization techniques for the imposition of monotonicity on a reconstruction. In addition, they present extensions of several classical TVD limiters to a genuinely multidimensional setting. In this case the linear least squares reconstruction method is expanded upon. They also clarify data dependent weighting techniques used with the minimization process.

  13. Shapes of embedded minimal surfaces.

    PubMed

    Colding, Tobias H; Minicozzi, William P

    2006-07-25

    Surfaces that locally minimize area have been extensively used to model physical phenomena, including soap films, black holes, compound polymers, protein folding, etc. The mathematical field dates to the 1740s but has recently become an area of intense mathematical and scientific study, specifically in the areas of molecular engineering, materials science, and nanotechnology because of their many anticipated applications. In this work, we show that all minimal surfaces are built out of pieces of the surfaces in Figs. 1 and 2.

  14. Chagas disease diagnostic applications: present knowledge and future steps

    PubMed Central

    Balouz, Virginia; Agüero, Fernán; Buscaglia, Carlos A.

    2017-01-01

    Chagas disease, caused by the protozoan Trypanosoma cruzi, is a life-long and debilitating illness of major significance throughout Latin America, and an emergent threat to global public health. Being a neglected disease, the vast majority of Chagasic patients have limited access to proper diagnosis and treatment, and there is only a marginal investment into R&D for drug and vaccine development. In this context, identification of novel biomarkers able to transcend the current limits of diagnostic methods surfaces as a main priority in Chagas disease applied research. The expectation is that these novel biomarkers will provide reliable, reproducible and accurate results irrespective of the genetic background, infecting parasite strain, stage of disease, and clinical-associated features of Chagasic populations. In addition, they should be able to address other still unmet diagnostic needs, including early detection of congenital T. cruzi transmission, rapid assessment of treatment efficiency or failure, indication/prediction of disease progression and direct parasite typification in clinical samples. The lack of access of poor and neglected populations to essential diagnostics also stress the necessity of developing new methods operational in Point-of-Care (PoC) settings. In summary, emergent diagnostic tests integrating these novel and tailored tools should provide a significant impact on the effectiveness of current intervention schemes and on the clinical management of Chagasic patients. In this chapter, we discuss the present knowledge and possible future steps in Chagas disease diagnostic applications, as well as the opportunity provided by recent advances in high-throughput methods for biomarker discovery. PMID:28325368

  15. Various applications of microRNAs in skin diseases.

    PubMed

    Jinnin, Masatoshi

    2014-04-01

    microRNA (miRNA) is a family of non-coding RNAs, which consists of 19-25 nucleotides and regulates the expression of approximately 30% of human protein-coding mRNAs. miRNAs can bind to complementary sequences of the three prime untranslated regions of target mRNAs, leading to the modulation of gene expression. By altering target expression, miRNAs can affect various cellular activities including cell proliferation and cell development in vitro or carcinogenesis and immune response in vivo. A lot of researches have paid attention to the possibility that miRNAs play a role in the pathogenesis of various human disorders including skin diseases. For example, miR-29a down-regulation is thought to mediate the posttranscriptional up-regulation of collagens, which contributes to the tissue fibrosis in scleroderma. In addition, recent studies indicate that extracellular miRNA levels may be useful for the diagnosis and/or the estimation of disease activity of skin diseases. miR-150 levels were significantly decreased in sera of scleroderma patients, and were inversely correlated with the prevalence of pitting scars/ulcers and the incidence of anti-topoisomerase I antibody. Currently, the therapeutic value of miRNAs for the treatment of human diseases is under evaluation in animal models. let-7a can be overexpressed in the mouse skin by intermittent intraperitoneal miRNA injection, and skin fibrosis induced by bleomycin in mice can be improved by the supplementation of let-7a. This paper discusses the possible applications of miRNAs in the clarification of pathogenesis, diagnosis, evaluation of disease activity and treatment of skin diseases. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  16. Minimizing the Risk of Disease Transmission in Emergency Settings: Novel In Situ Physico-Chemical Disinfection of Pathogen-Laden Hospital Wastewaters

    PubMed Central

    Sozzi, Emanuele; Fabre, Kerline; Fesselet, Jean-François; Ebdon, James E.; Taylor, Huw

    2015-01-01

    ‘Coalition for Cholera Prevention and Control’ recently highlighted the research as meriting serious consideration and further study. Further applications of the method to other emergency settings are being actively explored by the authors through discussion with the World Health Organization with regards to the ongoing Ebola outbreak in West Africa, and with the UK-based NGO Oxfam with regards to excreta-borne disease management in the Philippines and Myanmar, as a component of post-disaster incremental improvements to local sanitation chains. PMID:26110821

  17. Minimizing the Risk of Disease Transmission in Emergency Settings: Novel In Situ Physico-Chemical Disinfection of Pathogen-Laden Hospital Wastewaters.

    PubMed

    Sozzi, Emanuele; Fabre, Kerline; Fesselet, Jean-François; Ebdon, James E; Taylor, Huw

    2015-01-01

    'Coalition for Cholera Prevention and Control' recently highlighted the research as meriting serious consideration and further study. Further applications of the method to other emergency settings are being actively explored by the authors through discussion with the World Health Organization with regards to the ongoing Ebola outbreak in West Africa, and with the UK-based NGO Oxfam with regards to excreta-borne disease management in the Philippines and Myanmar, as a component of post-disaster incremental improvements to local sanitation chains.

  18. Esophagectomy - minimally invasive

    MedlinePlus

    Minimally invasive esophagectomy; Robotic esophagectomy; Removal of the esophagus - minimally invasive; Achalasia - esophagectomy; Barrett esophagus - esophagectomy; Esophageal cancer - esophagectomy - laparoscopic; Cancer of the ...

  19. Applications of CRISPR/Cas9 in retinal degenerative diseases

    PubMed Central

    Peng, Ying-Qian; Tang, Luo-Sheng; Yoshida, Shigeo; Zhou, Ye-Di

    2017-01-01

    Gene therapy is a potentially effective treatment for retinal degenerative diseases. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has been developed as a new genome-editing tool in ophthalmic studies. Recent advances in researches showed that CRISPR/Cas9 has been applied in generating animal models as well as gene therapy in vivo of retinitis pigmentosa (RP) and leber congenital amaurosis (LCA). It has also been shown as a potential attempt for clinic by combining with other technologies such as adeno-associated virus (AAV) and induced pluripotent stem cells (iPSCs). In this review, we highlight the main points of further prospect of using CRISPR/Cas9 in targeting retinal degeneration. We also emphasize the potential applications of this technique in treating retinal degenerative diseases. PMID:28503441

  20. MobileHeart, a mobile smartphone-based application that supports and monitors coronary artery disease patients during rehabilitation.

    PubMed

    Frederix, I; Sankaran, S; Coninx, K; Dendale, P

    2016-08-01

    Conventional center-based cardiac rehabilitation adherence is poor, adversely affecting long-term efficacy. Innovative strategies such as telerehabilitation are perceived as promising alternatives to improve care delivery. This paper presents the results of prior and ongoing work on the design and development of MobileHeart, a telemedical smartphone-based application to be used in secondary prevention for ischemic heart disease patients. Its constituent components are discussed separately, the minimal necessary cardiovascular monitoring requirements are elaborated in more detail. The results are offered starting from a clinical perspective to stress its relevance in the establishment of scientifically/medically sound programs.

  1. Nutritional antioxidants and their applications in cardiometabolic diseases.

    PubMed

    Soory, Mena

    2012-10-01

    There is an increasing global trend in cardiometabolic disorders being a leading cause of morbidity and mortality. Adverse dietary habits and sedentary lifestyles contribute to cardiovascular disease (CVD) and diabetes mellitus (DM). Dietary nutrients in nuts have attracted attention in recent literature due to their beneficial effects on CVD by attenuating lipid profiles, inflammation and oxidative stress. There is well-established evidence of the pharmacological properties of micronutrients that render them therapeutically effective in chronic inflammatory diseases. Although caution should be exercised in using antioxidant supplementation, antioxidant foods as dietary components play an important role in the management of cardiometabolic disorders. There is documented evidence of disease-modifying effects of nutritional compounds with anti-inflammatory and antioxidant effects. They have specific applications in ameliorating oxidative stress- induced inflammatory diseases such as DM and CVD. It is relevant that dietary components that influence risk of DM, have similar effects on inflammatory biomarkers of cardiovascular risk. Polyphenolic compounds such as flavonoids, isoflavones, phenolic acids and lignan contribute to increased plasma antioxidant capacity, decreased oxidative stress markers and reduced total and LDL cholesterol. They modulate genes associated with metabolism, stress defence, detoxification and transporter proteins. Their antioxidant and anti-inflammatory actions have specific applications for pathologies associated with chronic low-grade systemic inflammation that underpins progression of DM and CVD. Mechanisms involved depend on the structure of the compound, redox status of the inflammatory milieu and other interactions. Bioactive phytochemicals play an important therapeutic role in attenuating oxidative damage induced by metabolic syndrome associated with atherogenic dyslipidaemia and a pro-inflammatory, pro-thrombotic state, at a sub

  2. Clinical applications of lightguide diffuse reflectance spectrophotometry in vascular disease

    NASA Astrophysics Data System (ADS)

    Harrison, David K.; Delaney, Colin; Brown, Linda; Newton, David J.; McCollum, Peter T.

    1994-02-01

    There is enormous potential for application of lightguide tissue reflectance spectrophotometry in the diagnosis and treatment of peripheral vascular disease. In the present study, measurements were carried out in 10 such pre-amputation patients to compare the use of micro-lightguide spectrophotometry with the macro-lightguide technique. These preliminary results show excellent agreement between the new, non-invasive micro-lightguide technique and the `gold standard' skin blood flow measurements. This technique could thus provide a more functional, non-invasive assessment of healing potential than skin blood flow measurement.

  3. Progress on conformal microwave array applicators for heating chestwall disease

    NASA Astrophysics Data System (ADS)

    Stauffer, P. R.; Maccarini, P. F.; Juang, T.; Jacobsen, S. K.; Gaeta, C. J.; Schlorff, J. L.; Milligan, A. J.

    2007-02-01

    Previous studies have reported the computer modeling, CAD design, and theoretical performance of single and multiple antenna arrays of Dual Concentric Conductor (DCC) square slot radiators driven at 915 and 433 MHz. Subsequently, practical CAD designs of microstrip antenna arrays constructed on thin and flexible printed circuit board (PCB) material were reported which evolved into large Conformal Microwave Array (CMA) sheets that could wrap around the surface of the human torso for delivering microwave energy to large areas of superficial tissue. Although uniform and adjustable radiation patterns have been demonstrated from multiple element applicators radiating into simple homogeneous phantom loads, the contoured and heterogeneous tissue loads typical of chestwall recurrent breast cancer have required additional design efforts to achieve good coupling and efficient heating from the increasingly larger conformal array applicators used to treat large area contoured patient anatomy. Thus recent work has extended the theoretical optimization of DCC antennas to improve radiation efficiency of each individual aperture and reduce mismatch reflections, radiation losses, noise, and cross coupling of the feedline distribution network of large array configurations. Design improvements have also been incorporated into the supporting bolus structure to maintain effective coupling of DCC antennas into contoured anatomy and to monitor and control surface temperatures under the entire array. New approaches for non-invasive monitoring of surface and sub-surface tissue temperatures under each independent heat source are described that make use of microwave radiometry and flexible sheet grid arrays of thermal sensors. Efforts to optimize the clinical patient interface and move from planar rectangular shapes to contoured vest applicators that accommodate entire disease in a larger number of patients are summarized. By applying heat more uniformly to large areas of contoured anatomy

  4. Construction and applications of rabbit hemorrhagic disease virus replicon.

    PubMed

    Wang, Binbin; Zhe, Mingjia; Chen, Zongyan; Li, Chuanfeng; Meng, Chunchun; Zhang, Miaotao; Liu, Guangqing

    2013-01-01

    The study of rabbit hemorrhagic disease virus (RHDV) has long been hindered by the absence of an in vitro culture system. In this study, using RHDV as a model, a series of DNA-based reporter replicons were constructed in which the firefly luciferase (Fluc) gene was fused in-frame with the open reading frame of the replicon. In this construct, the Fluc gene was inserted where the coding region of viral structural protein was deleted and was under the control of a minimal cytomegalovirus (CMV) immediate-early promoter. Fluc activity analysis showed that these reporter replicons replicate efficiently in mammalian cells. On the basis of the replicon, 5'non-coding regions (5'NCR) and genome-linked protein (VPg) were deleted, and the effect on the expression of replicon was analyzed. The results showed that the expression level of Fluc was reduced in the absence of 5'NCR and VPg, suggesting that the 5'NCR and VPg may play an important role in replication and/or translation of RHDV. To further verify the speculation, we also constructed a replication deficient mutant (pRHDV-luc/Δ3D), and the impact of 5'NCR and VPg deletion on viral translation efficiency was analyzed, our results indicated that both VPg and 5'NCR were involved in RHDV translation.

  5. Application of simple digital methods in the treatment of hemorrhoid disease.

    PubMed

    Hajdarevic, Braco; Slaku, Jasmina; Pandza, Haris; Salihefendic, Nizama; Hadziahmetovic, Zoran

    2009-01-01

    The treatment of patient with relapse of bleeding after application of minimally invasive treatment of hemorrhoidal disease such as elastic band ligation, cryosurgical treatment Hemorrhoidal Arterial Ligation (HAL) can be presented as serious clinical problem in patients with concomitant diseases that can be contraindication for radical surgical treatment. We compared the Simple Digital Method and standard above mentioned minimally invasive ambulatory treatment. We used special proctoscope with Doppler Flowmeter in order to identify all branches of hemorrhoidal artery in the anal canal creating graphical presentation using specially adapted software. HAL method is then used to perform ligation of hemorrhoidal artery branches. The elastic ligatures (called gummiligatures) are then applied to the piles in which most prominent flow was registered using Doppler Flowmeter. Antibiotic prophylaxis and sedation was administered preoperatively. Special computer program registered all steps. Hemorrhoidal ointments and paracetamol were used after surgical procedure. Average number of identified hemorrhoid arteries branches was six, and total duration of the procedure was in average 28 min. We compared patient treatment with our method and standard methods. In tested group we noticed significantly fewer complications (after eight days the number of complications 11% vs. 74%, p<0.001, after 15 days 3% vs. 11%: p=0.101). One year after procedure, the treatment was successful in 91.4%, or 32 out of 35 patients according to proctoscopy and Doppler Flowmeter exam. There were three patients with relapse of symptoms. In 77% of patients hat were treated with rubber bands ligation relapse occurred. Our method is significantly more successful in comparison to classical methods of ambulatory treatment and can be alternative to radical surgical treatment.

  6. Applications of 3D printing in cardiovascular diseases.

    PubMed

    Giannopoulos, Andreas A; Mitsouras, Dimitris; Yoo, Shi-Joon; Liu, Peter P; Chatzizisis, Yiannis S; Rybicki, Frank J

    2016-12-01

    3D-printed models fabricated from CT, MRI, or echocardiography data provide the advantage of haptic feedback, direct manipulation, and enhanced understanding of cardiovascular anatomy and underlying pathologies. Reported applications of cardiovascular 3D printing span from diagnostic assistance and optimization of management algorithms in complex cardiovascular diseases, to planning and simulating surgical and interventional procedures. The technology has been used in practically the entire range of structural, valvular, and congenital heart diseases, and the added-value of 3D printing is established. Patient-specific implants and custom-made devices can be designed, produced, and tested, thus opening new horizons in personalized patient care and cardiovascular research. Physicians and trainees can better elucidate anatomical abnormalities with the use of 3D-printed models, and communication with patients is markedly improved. Cardiovascular 3D bioprinting and molecular 3D printing, although currently not translated into clinical practice, hold revolutionary potential. 3D printing is expected to have a broad influence in cardiovascular care, and will prove pivotal for the future generation of cardiovascular imagers and care providers. In this Review, we summarize the cardiovascular 3D printing workflow, from image acquisition to the generation of a hand-held model, and discuss the cardiovascular applications and the current status and future perspectives of cardiovascular 3D printing.

  7. Association of germline genetic variants in RFC, IL15 and VDR genes with minimal residual disease in pediatric B-cell precursor ALL

    PubMed Central

    Dawidowska, Małgorzata; Kosmalska, Maria; Sędek, Łukasz; Szczepankiewicz, Aleksandra; Twardoch, Magdalena; Sonsala, Alicja; Szarzyńska-Zawadzka, Bronisława; Derwich, Katarzyna; Lejman, Monika; Pawelec, Katarzyna; Obitko-Płudowska, Agnieszka; Pawińska-Wąsikowska, Katarzyna; Kwiecińska, Kinga; Kołtan, Andrzej; Dyla, Agnieszka; Grzeszczak, Władysław; Kowalczyk, Jerzy R.; Szczepański, Tomasz; Ziętkiewicz, Ewa; Witt, Michał

    2016-01-01

    Minimal residual disease (MRD) enables reliable assessment of risk in acute lymphoblastic leukemia (ALL). However, little is known on association between MRD status and germline genetic variation. We examined 159 Caucasian (Slavic) patients with pediatric ALL, treated according to ALL-IC-BFM 2002/2009 protocols, in search for association between 23 germline polymorphisms and MRD status at day 15, day 33 and week 12, with adjustment for MRD-associated clinical covariates. Three variants were significantly associated with MRD: rs1544410 in VDR (MRD-day15); rs1051266 in RFC (MRD-day33, MRD-week12), independently and in an additive effect with rs10519613 in IL15 (MRD-day33). The risk alleles for MRD-positivity were: A allele of VDR (OR = 2.37, 95%CI = 1.07–5.21, P = 0.03, MRD-day15); A of RFC (OR = 1.93, 95%CI = 1.05–3.52, P = 0.03, MRD-day33 and MRD-week12, P < 0.01); A of IL15 (OR = 2.30, 95%CI = 1.02–5.18, P = 0.04, MRD-day33). The risk for MRD-day33-positive status was higher in patients with risk alleles in both RFC and IL15 loci than in patients with risk alleles in one locus or no risk alleles: 2 vs. 1 (OR = 3.94, 95% CI = 1.28–12.11, P = 0.024), 2 vs. 0 (OR = 6.75, 95% CI = 1.61–28.39, P = 0.012). Germline variation in genes related to pharmacokinetics/pharmacodynamics of anti-leukemic drugs and to anti-tumor immunity of the host is associated with MRD status and might help improve risk assessment in ALL. PMID:27427275

  8. Major impact of an early bone marrow checkpoint (day 21) for minimal residual disease in flow cytometry in childhood acute lymphoblastic leukemia.

    PubMed

    Eveillard, Marion; Robillard, Nelly; Arnoux, Isabelle; Garand, Richard; Rialland, Fanny; Thomas, Caroline; Strullu, Marion; Michel, Gérard; Béné, Marie C; Fossat, Chantal; Loosveld, Marie

    2017-06-01

    The early persistence of minimal residual disease (MRD) is considered a poor prognostic factor indicative of chemoresistance in acute lymphoblastic leukemia. In French children, chemosensitivity is assessed at day 21 post-induction by cytomorphology. Here, it was investigated whether a more precise evaluation could be obtained at this time point with multiparameter flow cytometry (MFC). This study enrolled 123 children with de novo acute lymphoblastic leukemia. MRD0 was investigated at day 21 in MFC with a combination of antibodies based on the immunophenotype of diagnosis. It was also evaluated at day 35 by immunoglobulin/T-cell receptor quantitative real-time polymerase chain reaction (MRD1). Three risk groups could be delineated based on MRD0. Patients with MFC/MRD0 levels >10(-2) (n = 25) were considered high risk, those with levels between 10(-2) and 10(-4) (n = 46) intermediate risk, and those <10(-4) (n = 50) low risk. Overall survival (p = 0.048) and event-free survival (EFS, p = 0.00017) were significantly different between these three groups. EFS of the 14 corticoresistant patients strongly depended on their MRD0 level (p = 0.004). Similarly, both EFS (p = 0.0004) and overall survival (p = 0.02) were significantly different in the 109 chemosensitive patients, according to MRD0 levels. MRD0 and MRD1 levels, compared with 112 patients, were consistent (-/- or +/+) in 57.2% of the cases. Both MRD0+/MRD1+ and MRD0+/MRD1- patients had a significantly worse EFS (p = 0.0001) than those with undetectable MRD at both MRD0 and MRD1. This study confirms the usefulness and superiority of an early point of MRD detection by MFC. In addition, MRD0 in MFC identifies a subgroup of patients with poorer prognosis (MRD0+/MRD1-). Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  9. Real-world validation of the minimal disease activity index in psoriatic arthritis: an analysis from a prospective, observational, biological treatment registry.

    PubMed

    Rahman, Proton; Zummer, Michel; Bessette, Louis; Baer, Philip; Haraoui, Boulos; Chow, Andrew; Kelsall, John; Kapur, Suneil; Rampakakis, Emmanouil; Psaradellis, Eliofotisti; Lehman, Allen J; Nantel, Francois; Osborne, Brendan; Tkaczyk, Cathy

    2017-08-30

    To describe the minimal disease activity (MDA) rate over time in patients with psoriatic arthritis (PsA) receiving antitumour necrosis factor agents, evaluate prognostic factors of MDA achievement and identify the most common unmet criteria among MDA achievers. Biologic Treatment Registry Across Canada (BioTRAC): ongoing, prospective registry of patients initiating treatment for rheumatoid arthritis, ankylosing spondylitis or PsA with infliximab (IFX), golimumab (GLM) or ustekinumab. 46 primary-care Canadian rheumatology practices. 223 patients with PsA receiving IFX (enrolled since 2005) and GLM (enrolled since 2010) with available MDA information at baseline, 6 months and/or 12 months. MDA was defined as ≥5 of the following criteria: 28-item tender joint count (TJC28) ≤1, 28-item swollen joint count (SJC28) ≤1, Psoriasis Area and Severity Index (PASI) ≤1 or body surface area≤3, Pain Visual Analogue Scale (VAS) ≤15 mm, patient's global assessment (PtGA) (VAS) ≤20 mm, Health Assessment Questionnaire (HAQ) ≤0.5, tender entheseal points ≤1. Independent prognostic factors of MDA achievement were assessed with multivariate logistic regression. MDA was achieved by 11.7% of patients at baseline, 43.5% at 6 months, 44.8% at 12 months and 48.8% at either 6 or 12 months. Among MDA achievers at 6 months, 75.7% had sustained MDA at 12 months. Lower baseline HAQ (OR=0.210; 95% CI: 0.099 to 0.447) and lower TJC28 (OR=0.880; 95% CI: 0.804 to 0.964), were significant prognostic factors of MDA achievement over 12 months of treatment. The most commonly unmet MDA criteria among MDA achievers was patient reported pain (25%), PtGA (15%) and PASI (12%). Almost 50% of patients treated with IFX or GLM in routine clinical care achieved MDA within the first year of treatment. Lower baseline HAQ and lower TJC28, were identified as significant prognostic factors of MDA achievement. The most commonly unmet criteria in patients who achieved MDA were pain, PtGA and

  10. Association of germline genetic variants in RFC, IL15 and VDR genes with minimal residual disease in pediatric B-cell precursor ALL.

    PubMed

    Dawidowska, Małgorzata; Kosmalska, Maria; Sędek, Łukasz; Szczepankiewicz, Aleksandra; Twardoch, Magdalena; Sonsala, Alicja; Szarzyńska-Zawadzka, Bronisława; Derwich, Katarzyna; Lejman, Monika; Pawelec, Katarzyna; Obitko-Płudowska, Agnieszka; Pawińska-Wąsikowska, Katarzyna; Kwiecińska, Kinga; Kołtan, Andrzej; Dyla, Agnieszka; Grzeszczak, Władysław; Kowalczyk, Jerzy R; Szczepański, Tomasz; Ziętkiewicz, Ewa; Witt, Michał

    2016-07-18

    Minimal residual disease (MRD) enables reliable assessment of risk in acute lymphoblastic leukemia (ALL). However, little is known on association between MRD status and germline genetic variation. We examined 159 Caucasian (Slavic) patients with pediatric ALL, treated according to ALL-IC-BFM 2002/2009 protocols, in search for association between 23 germline polymorphisms and MRD status at day 15, day 33 and week 12, with adjustment for MRD-associated clinical covariates. Three variants were significantly associated with MRD: rs1544410 in VDR (MRD-day15); rs1051266 in RFC (MRD-day33, MRD-week12), independently and in an additive effect with rs10519613 in IL15 (MRD-day33). The risk alleles for MRD-positivity were: A allele of VDR (OR = 2.37, 95%CI = 1.07-5.21, P = 0.03, MRD-day15); A of RFC (OR = 1.93, 95%CI = 1.05-3.52, P = 0.03, MRD-day33 and MRD-week12, P < 0.01); A of IL15 (OR = 2.30, 95%CI = 1.02-5.18, P = 0.04, MRD-day33). The risk for MRD-day33-positive status was higher in patients with risk alleles in both RFC and IL15 loci than in patients with risk alleles in one locus or no risk alleles: 2 vs. 1 (OR = 3.94, 95% CI = 1.28-12.11, P = 0.024), 2 vs. 0 (OR = 6.75, 95% CI = 1.61-28.39, P = 0.012). Germline variation in genes related to pharmacokinetics/pharmacodynamics of anti-leukemic drugs and to anti-tumor immunity of the host is associated with MRD status and might help improve risk assessment in ALL.

  11. Minimal Incision Congenital Cardiac Surgery

    PubMed Central

    del Nido, Pedro J.

    2008-01-01

    Minimally invasive techniques have had limited application in congenital cardiac surgery, primarily due to the complexity of the defects, small working area, and the fact that most defects require exposure to intracardiac structures. Advances in cannula design and instrumentation have allowed application of minimal incision techniques but in most cases, cardiopulmonary bypass is still required. Image guided surgery, which uses non-invasive imaging to guide intracardiac procedures, holds the promise of permitting performance of reconstructive surgery in the beating heart in children. PMID:18395631

  12. Mass spectrometry theory and application to adrenal diseases.

    PubMed

    Wooding, Kerry M; Auchus, Richard J

    2013-05-22

    The diagnosis and management of adrenal diseases hinge upon accurate determination of hormone concentrations in blood and other body fluids. The advent of immunoassays for various steroid hormones has enabled the remarkable progress in adrenal disease over the last several decades, with some limitation. Sequential immunoassay of single analytes is a tedious process, which requires aliquots for each assay. In many complex adrenal diseases, including adrenal cancer and congenital adrenal hyperplasia, the patterns or ratios of multiple steroids rather than the value of any one steroid is more relevant. Although gas chromatography/mass spectrometry of urinary steroid metabolites has been employed to profile steroid production, throughput is slow, and availability is sparse. Recent generations of liquid chromatography-tandem mass spectrometry instruments (LC-MS/MS) provide the throughput and sensitivity required to measure many steroids simultaneously using small samples for commercial and research uses. Even in the best hands, however, LC-MS/MS suffers from limitations and requires diligent attention to detail during method development and implementation. This article reviews the theory, instrumentation principles and terminology, and practical application of mass spectrometry to clinical adrenal disorders.

  13. Application of optical spectroscopic techniques for disease diagnosis

    NASA Astrophysics Data System (ADS)

    Saha, Anushree

    Optical spectroscopy, a truly non-invasive tool for remote diagnostics, is capable of providing valuable information on the structure and function of molecules. However, most spectroscopic techniques suffer from drawbacks, which limit their application. As a part of my dissertation work, I have developed theoretical and experimental methods to address the above mentioned issues. I have successfully applied these methods for monitoring the physical, chemical and biochemical parameters of biomolecules involved in some specific life threatening diseases like lead poisoning and age-related macular degeneration (AMD). I presented optical studies of melanosomes, which are one of the vital organelles in the human eye, also known to be responsible for a disease called age-related macular degeneration (AMD), a condition of advanced degeneration which causes progressive blindness. I used Raman spectroscopy, to first chemically identify the composition of melanosome, and then monitor the changes in its functional and chemical behavior due to long term exposure to visible light. The above study, apart from explaining the role of melanosomes in AMD, also sets the threshold power for lasers used in surgeries and other clinical applications. In the second part of my dissertation, a battery of spectroscopic techniques was successfully applied to explore the different binding sites of lead ions with the most abundant carrier protein molecule in our circulatory system, human serum albumin. I applied optical spectroscopic tools for ultrasensitive detection of heavy metal ions in solution which can also be used for lead detection at a very early stage of lead poisoning. Apart from this, I used Raman microspectroscopy to study the chemical alteration occurring inside a prostate cancer cell as a result of a treatment with a low concentrated aqueous extract of a prospective drug, Nerium Oleander. The experimental methods used in this study has tremendous potential for clinical

  14. Preparation and characterization of semi-refined kappa carrageenan-based edible film for nano coating application on minimally processed food

    NASA Astrophysics Data System (ADS)

    Manuhara, Godras Jati; Praseptiangga, Danar; Muhammad, Dimas Rahadian Aji; Maimuni, Bawani Hindami

    2016-02-01

    Shorter and easier processing of semi-refined kappa carrageenan extracted from Euchema cottonii red seaweed result in cheaper price of the polysaccharide. In this study, edible film was prepared from the semi-refined carrageenan without any salt addition. The effect of the carrageenan concentration (1.0, 1.5, and 2.0% w/v) on physical and mechanical properties of the edible film was studied. Edible film thickness and tensile strength increased but elongation at break and water vapor transmission rate (WVTR) decreased as the concentration increased. Based on the characteristic of the edible film, formulation using 2% carrageenan was recommended. The edible film demonstrated the characteristic as follow: 0.054 mm thickness, 21.14 MPa tensile strength, 12.36% elongation at break, and 9.56 g/m2.hour WVTR. It was also noted the carrageenan-based edible film indicated potential physical and mechanical characteristics for nano coating applications on minimally processed food.

  15. Application of nanomedicine in cardiovascular diseases and stroke.

    PubMed

    Kim, Kye S; Khang, Gilson; Lee, Dongwon

    2011-01-01

    Nanomedicine is using nanotechnology in the medical application, which could range from medical use of nanomaterials in drug delivery and bio-imaging to development of nano-scale devices and sensors for diagnosis and therapy. Nanomedicine could also include methods to evaluate nanomaterials solely to ensure safe use through careful monitoring for potential toxicity. In this review, we will outline some of the potential uses of nanotechnology in different fields of medicine with special emphasis on cardiovascular diseases and stroke, based on pathophysiologic basis. We will also review some of the known nanomaterials that are already being utilized in diagnosis and treatment, commonly the FDA approved nanomaterials and others that have demonstrated to be promising in clinical applications.Finally, we will discuss the potential limitations of using nanotechnology in medical applications. Since nanomedicine is now emerging and still in development, this review is not intended as a comprehensive or conclusive overview of nanomedicine. Instead, we hope to provide examples of what are available currently, and to demonstrate the enormous potentials of nanomedicine in order to meet the unresolved needs and new challenges of medicine.

  16. Seven-year follow-up of allogeneic transplant using BCNU, etoposide, cytarabine and melphalan chemotherapy in patients with Hodgkin lymphoma after autograft failure: importance of minimal residual disease.

    PubMed

    Sobol, Urszula; Rodriguez, Tulio; Smith, Scott; Go, Aileen; Vimr, Ross; Parthasarathy, Mala; Guo, Rong; Stiff, Patrick

    2014-06-01

    Abstract Allogeneic transplant using reduced intensity conditioning is a therapeutic option for patients with Hodgkin lymphoma (HL) who relapse after an autograft. This was a prospective study of 31 consecutive eligible patients with HL who relapsed after an autograft and underwent an allograft using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning. At a median follow-up of 7 years the progression-free survival (PFS) was 36% (95% confidence interval [CI] 19-54%) and overall survival (OS) was 42% (95% CI 23-59%). In multivariate analysis only residual disease at the time of transplant predicted outcome, with a 4-year PFS and OS of 62% and 75% for patients with minimal residual disease versus 8% and 8% for patients with gross residual disease, respectively (p = 0.005 and p = 0.001, respectively). This benefit seemed to be irrespective of chemosensitivity, with an OS for patients with chemorefractory yet minimal disease of 71% at 4 years. BEAM allogeneic transplant is effective in producing long-term remissions after autograft failure. Regardless of chemosensitivity, minimizing tumor burden pre-transplant may improve long-term outcome.

  17. Clinical Application of Pluripotent Stem Cells: An Alternative Cell-Based Therapy for Treating Liver Diseases?

    PubMed

    Tolosa, Laia; Pareja, Eugenia; Gómez-Lechón, Maria José

    2016-12-01

    The worldwide shortage of donor livers for organ and hepatocyte transplantation has prompted the search for alternative therapies for intractable liver diseases. Cell-based therapy is envisaged as a useful therapeutic option to recover and stabilize the lost metabolic function for acute liver failure, end-stage and congenital liver diseases, or for those patients who are not considered eligible for organ transplantation. In recent years, research to identify alternative and reliable cell sources for transplantation that can be derived by reproducible methods has been encouraged. Human pluripotent stem cells (PSCs), which comprise both embryonic and induced PSCs, may offer many advantages as an alternative to hepatocytes for liver cell therapy. Their capacity for expansion, hepatic differentiation and self-renewal make them a promising source of unlimited numbers of hepatocyte-like cells for treating and repairing damaged livers. Immunogenicity and tumorigenicity of human PSCs remain the bottleneck for su