Clinical Path Research Articles

Interference Of The Tumor Supportive Effects Of BCL2 and MCL1 Sensitize Malignant Plasma Cells To The Lethal Effects Of Lenalidomide and Dexamethasone Regimen: An Important Clinical Path For BCL2 Targeting Drugs

BackgroundMultiple myeloma (MM) is the second most common hematologic malignancy in the U.S. and is characterized by increased immunoglobulin production and infiltration of the bone marrow by malignant plasma cells. Myeloma cell growth is supported by both the elements present in the bone marrow microenvironment as well as deregulation of internal cellular systems associated with proliferation and apoptosis. Defective programmed cell death by BCL2 or MCL1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL2 or MCL1. Various strategies to mitigate the effects of increased BCL2 functionality, via small molecule inhibitors or BCL2-specific antisense oligonucleotides have been previously examined in MM. These studies revealed that 1) apart from BCL2, additional anti-apoptotic members belonging to the BCL2 family (i.e. MCL1, BCL-xL) play integral roles in maintenance of the myeloma cell phenotype, 2) drugs, which target only BCL2 offer limited therapeutic advantage and 3) given that survival factors engaged in MM are multifactorial, perhaps isolated targeting of the BCL2 pathways may not be sufficient. We therefore hypothesized that the clinical development of drugs that target various antiapoptotic BCL2 family members will require a partnership with established anti-MM regimens whose activity can potentially be further enhanced with correction of the apoptotic response system. AimSince lenalidomide and dexamethasone (LD) is an established therapy for plasma cell cancers, we investigated if the pan-BCL2 inhibitor AT-101 (BH3 mimetic), which has high binding specificity for BCL2, MCL1 and BCL-xL, can be an effective therapeutic partner to enhance anti-MM effects of LD. MethodsHuman MM (KMS11, U266, OPM2) and WM (BCWM.1) cell lines along with their corresponding bortezomib resistant (BR) clones, (KMS11/BR, U266/BR, OPM2/BR and BCWM.1/BR) which were developed in our laboratory were used in this study. For gene expression profiling, the Illumina HumanHT-12 v3 whole-genome gene expression array and Nanostring nCounter mRNA quantification assays (NanoString, Seattle, WA) were utilized. Statistical analysis was conducted using R-based packages and the MeV software (TIGR). Apoptosis was measured by annexin-v/PI staining, and mitochondrial membrane permeability (MOMP) was assessed using TMRM followed by flow cytometry. Protein profiles were ascertained by western blot. ResultsGene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of various BCL2 family members, notably MCL1 and BCL-xL. In a dose-dependent manner, AT-101 was able to downregulate BCL2 and MCL1 and induced apoptotic cell death in MM and WM cells in a dose dependent manner. Tumor cell death was associated with caspase and PARP-1 cleavage accompanied by an increase in MOMP. This cytotoxic effect and BCL2 downregulation were further potentiated when AT-101 was combined with lenalidomide/dexamethasone (LDA). Nanostring nCounter mRNA quantification and IPA analysis revealed differential changes in the CCNA, FRZB, FYN, IRF1, PTPN11 genes in LDA treated cells. IPA canonical pathway analysis demonstrated the p53 signaling and the cyclins and cell cycle regulation pathways to be the most significantly activated by LDA therapy. SummaryIn summary, we describe for the first time the cellular and molecular events associated with the use of AT-101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy. This study lays the rationale for engaging and handicapping the intrinsic apoptotic system through the pan-BCL2 targeting capabilities of AT-101; thus enhancing the anti-MM effects of lenalidomide/dexamethasone. Disclosures:Foran:Celgene: Research Funding.

Abstract B289: Inhibition of platelet-derived growth factor receptors by ARQ 087, a multi-tyrosine kinase inhibitor.

Abstract Background: The platelet-derived growth factor (PDGF) receptors are receptor tyrosine kinases which contain two isoforms, PDGFRα and β. They form homo- or hetero-dimers and exert different biological functions including organ development and vascularization. Dysregulation of PDGF receptors has been implicated in tumor initiation and progression in addition to playing a major role in epithelial-mesenchymal transition, metastasis, and tumor angiogenesis. ARQ 087, a pan FGF receptor inhibitor inhibits FGFR1, 2, and 3 with IC50 from 2 to 4 nM. Methods: We have performed in vitro kinase profiling to determine percent inhibition of selected kinases and IC50 for PDGFRα and its mutated form. siRNA knockdown was applied to evaluate cell proliferation of the PDGFRα-dependent cancer cell lines NCI-H1703 and A-204. Western blot analysis including phospho PDGFRα/β, pSTAT3, pAKT, pERK together with cell migration and invasion analysis was performed on NCI-H1703 and NIH-3T3 cells. Results: ARQ 087 is an inhibitor of PDGF receptors which is supported by the in vitro kinase profiling results. ARQ 087 but not Imatinib, was equally potent against wild-type PDGFRα and the mutated form of PDGFRα (D842V), indicating a potential clinical implication for Imatinib-resistant PDGFR-driven cancers. Knockdown of PDGFRα using siRNA suppressed PDGFRα-dependent cancer cell line proliferative activity. ARQ 087 inhibition of cell proliferation was accompanied by the reduction of phosphorylation of PDGFRα and its downstream proteins. In addition to the anti-proliferative activity, ARQ 087 suppressed migration and invasion of NCI-H1703 cells through targeting PDGFRα and migration of NIH-3T3 cells through targeting PDGFRβ. Conclusions: ARQ 087 is not only an inhibitor of the FGFR family but also of the PDGFR family, suggesting that targeting cancers driven by PDGF receptors or mutated forms may provide an additional clinical path for ARQ 087. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B289. Citation Format: Yi Yu, Jennifer Lee, Daniel T. Dransfield. Inhibition of platelet-derived growth factor receptors by ARQ 087, a multi-tyrosine kinase inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B289.

Application of clinical pathway in teaching of kidney disease

Objective To evaluate the effects of applying clinical pathway in clinic teaching of kidney diseases. Methods Data of average in-hospital days, costs, percentage of antibiotic drugs, improvement rate and satisfaction of patients who received the clinic pathway in nephrology depart- ment from January 2010 to December 2012 were used to evaluate the quality of clinical pathway and were compared with those of patients not received clinic pathway in 2009. Teaching effects of eight- year clinic medical students whose scores were provided by internal medical teaching section were al- so analyzed. Questionnaire of hospital quality was adopted to assess satisfaction of patients, nurses and doctors and the results were compared with those of 2009 students. All data were analyzed by SPSS 13.0 software. Chi-square test was used for enumeration data and results were expressed as percentage while t test was used for t data and resuhs were expressed as （x ± s）, with P 〈0.05 stand- ing for statistically significant differences. Results After applying clinical pathway, average in-hos- pital days were reduced from 10.7 d in 2009 to 8.7 d in 2012, percentage of medical drugs were de- creased from 86.6% in 2009 to 33.4% in 2012 and percentage of antibiotic drug were reduced from 79.1% to 23.0%. Average in-hospital days and costs of IgA nephropathy and lupus nephritis were de- creased. Satisfaction of patients was increased from 94.1% to 99.0% and scores of students were in- creased from （81.0 ± 2.5） points to （89.5±~ 2.8） points. Conclusions Application of clinical path- way in clinic medical teaching should be encouraged. It can enhance the teaching quality and is help- ful for culturing inno-vative clinic thinking of medical students and cultivate practical medical talents. Key words: Clinical pathway; Clinical teaching; Medical quality; Kidney disease

Pushing the Envelope: “Awake Venoarterial Extracorporeal Membrane Oxygenation” in Pediatric Patients with Acute Cardiac Failure

Objectives: In pediatric patients with cardiogenic shock (CS)/or acute cardiac failure (ACF) extracorporeal membrane oxygenation (ECMO) is often used as a bridging procedure to recovery or further implantation of a ventricular assist device (VAD). Although ECMO has been established as a routine procedure in pediatric tertiary care centers, the clinical path guiding these patients to fully recovery or further VAD implantation is one of the most challenging for pediatric intensivists. Methods: The authors describe the use of venoarterial ECMO (VA-ECMO) as a treatment strategy for ACF in spontaneously breathing and conscious pediatric patients. It presents their experiences with the first five children treated using this new concept. The mean age of the patients was 86 months (range 0 – 226 mo). Mean amount of time on ECMO was 35 days (range 7 – 94 d). Results: Three patients fully recovered with their cardiac function while being treated on “Awake-VA-ECMO,” one was bridged to LVAD and one was successfully bridged to transplantation. Four of the five patients are alive without any recurrences. One patient died before a further heart transplantation while being on intracardiac rotation pump. Although reintubation was necessary in three of our five patients (due to interventional heart catheter) total time breathing spontaneously and being conscious while on ECMO was > 70%. Conclusion: The authors conclude that the concept of “Awake VA-ECMO” is feasible and safe for the treatment of ACF and can be used as a “bridging therapy” to recovery or further VAD implantation in pediatric patients.

クリニカルパスマネジメント専従者・兼任者に求められる役割、知識、技術 : 現在の活動状況から考える今後の課題

クリニカルパスマネジメント専従者・兼任者に求められる役割、知識、技術 : 現在の活動状況から考える今後の課題

Neuron Finding Tracks Path of RNA Decay

A newly discovered mechanism regulating how neurons find their way to the right connections—and how that can go wrong—may lead to better understanding of neurodevelopmental disorders.

The prospects of pazopanib in advanced renal cell carcinoma.

The landscape of treatment for advanced/metastatic renal cell carcinoma (mRCC) has advanced significantly in the last decade and continues to evolve with the approval of new drugs targeting the vascular endothelial growth factor (VEGF) and its receptors and mammalian target of rapamycin (mTOR). Currently available oral VEGF tyrosine kinase inhibitors (TKIs) approved for treatment of mRCC include sorafenib, sunitinib, pazopanib, and axitinib. This review focuses on pazopanib, a multikinase VEGF TKI indicated for patients with treatment-naïve and cytokine-refractory mRCC. This article describes the preclinical and clinical evolution of pazopanib, with an emphasis on its development and role in mRCC. Pivotal trials are discussed that demonstrate the efficacy and safety of pazopanib and its important role in the treatment of patients with mRCC in comparison to other available treatment options. The clinical path of pazopanib continues to develop further, with several ongoing studies exploring its role in neoadjuvant and adjuvant RCC. Furthermore, its potential role in sequential and combination studies with other VEGFR and non-VEGFR targeted agents is discussed. Overall, pazopanib is a unique VEGF TKI, with a different and more favorable safety profile compared with other members of the VEGF TKI family and represents an attractive alternative for patients with mRCC.

Risk of excessive sodium intake in the use of a thickener for dysphagia.

Risk of excessive sodium intake in the use of a thickener for dysphagia.

The application effect of the clinical nursing path management mode in the dermatology department nursing

Objective To investigate the application effect of the clinical nursing path (CNP) management mode in the dermatology department nursing.Methods A total of 120 cases of acute eczema,herpes zoster,acute urticaria and psoriasis patients on admission day single were divided into experimental group and control group with 60 cases in each group,the experimental group used CNP management mode,the control group used conventional nursing model.Duration of hospitalization,hospitalization costs,quality of care,patient satisfaction and health knowledge master degree were compared between the two groups.Results In the experimental group,hospital stay and hospital costs were lower than those in the control group (P ＜ 0.05),quality of care,patient satisfaction and health knowledge grasp degree were higher than those of control group (P ＜ 0.05).Conclusions The implementation of CNP management mode can reduce hospitalization time and costs,improve the quality of care,patient satisfaction and the mastering of health education knowledge.It is a kind of high quality nursing care management mode,is worth popularization and application in dermatology department nursing. Key words: Clinical nursing pathway; Dermatology department; Nursing management

AB1403 Comprehensive target-directed approach for the development of a highly-comparable rituximab biosimilar

BackgroundBiosimilars are successor drug products to a biologic medicine that is already authorized and whose patent is no longer valid. As with their originator products, biosimilars are expressed using living...

Diagnostic tools and technologies for infectious and non-communicable diseases in low-and-middle-income countries

The challenge of changing the healthcare outcomes of many in low- and middle-income countries (LMICs) looms as a major potential cost to all of humankind. A majority of global health initiatives have focused upon increasing access and innovation in treatment options. However, the reliable and appropriate use of candidate treatments must be preceded by diagnoses that ensure the correct clinical path. Foremost in addressing this challenge is the need to develop and distribute appropriate, low cost, accessible diagnostic technologies to engender quality care. Such a need is pressing, for both communicable and non-communicable diseases, which continue to present a growing burden to LMICs. The emergence of paper diagnostics, microfluidic-based total analytical systems (μTAS), BioMEMS, and nano-inspired bioanalytical biosensors; which by their very sophistication promise to render diagnostic tests simple and potentially widely affordable, present exciting options to addressing this need. This paper discusses complementary policy issues in regulation and procurement that must be considered to make low cost, point of care diagnostic technology an accepted step in patient care within LMICs and presents a number of emerging technologies that are poised to address this need.

Effects of clinical nursing pathway on patients with intranasal endoscopic cerebrospinal fluid rhinorrhea repair surgery

Objective To explore the effects of clinical nursing pathway on patients with intranasal endoscopic cerebrospinal fluid rhinorrhea repair surgery.Methods Totals of 69 patients received the implementation of the repair of cerebrospinal fluid rhinorrhea were recruited and randomly divided into intervention group (n =35) and control group (n =34).Control group received traditional preoperative visits and intraoperative coordination,traditional preoperative visits,while intervention group received clinical nursing pathway including preoperative interview pathway,operation day support pathway,and postoperative interview Pathway.Then,anxiety,surgical start time,blood loss,anesthesia recovery time and recovery period of anesthesia complications and patients' satisfaction were observed and compared.Results The SAS score of intervention group in one day before operation and before anesthesia was (46.38 ± 4.77),(49.86 ± 5.59),respectively,lower than that of control group [(50.76 ± 5.81),(53.99 ± 6.59)],and the difference was statistically significant (P ＜ 0.01).After the intervention,blood loss [(199.64 ± 46.72) vs (240.67 ±58.68) ml],anesthesia recovery time [(26.10 ± 5.09) vs (34.50 ± 6.76) min],hospital stay [(20.42 ±2.73) vs (24.61 ± 3.63) d],patients' satisfaction points [(4.56 ± 0.47) vs (3.07 ± 0.52)] in intervention group were significantly lower than that in control group (t =14.152,3.138,3.020,6.056,11.881,respectively;P ＜ 0.01).Conclusions Patients with cerebrospinal fluid rhinorrhea repair treat with surgery clinical care path,can effectively relieve the patient's preoperative anxiety,reduce anesthesia recovery time,blood loss and anesthesia recovery complications and improve the therapeutic effect of perioperative and the patient satisfaction. Key words: Clinical pathway; Endoscopy; Cerebrospinal fluid rhinorrhea; Intraoperative period ; Nursing intervention

PCN60 - Clinical Care Path And Costs Associated With Managing Patients With Prolonged Air Leaks After Thoracic Lung Volume Reduction Surgery: A Review Of The Literature

PCN60 - Clinical Care Path And Costs Associated With Managing Patients With Prolonged Air Leaks After Thoracic Lung Volume Reduction Surgery: A Review Of The Literature

Introduction of Exogenous T-cell Receptors Into Human Hematopoietic Progenitors Results in Exclusion of Endogenous T-cell Receptor Expression

Current tumor immunotherapy approaches include the genetic modification of peripheral T cells to express tumor antigen-specific T-cell receptors (TCRs). The approach, tested in melanoma, has led to some limited success of tumor regression in patients. Yet, the introduction of exogenous TCRs into mature T cells entails an underlying risk; the generation of autoreactive clones due to potential TCR mispairing, and the lack of effective negative selection, as these peripheral cells do not undergo thymic selection following introduction of the exogenous TCR. We have successfully generated MART-1-specific CD8 T cells from genetically modified human hematopoietic stem cells (hHSC) in a humanized mouse model. The advantages of this approach include a long-term source of antigen specific T cells and proper T-cell selection due to thymopoiesis following expression of the TCR. In this report, we examine the molecular processes occurring on endogenous TCR expression and demonstrate that this approach results in exclusive cell surface expression of the newly introduced TCR, and the exclusion of endogenous TCR cell surface expression. This suggests that this stem cell based approach can provide a potentially safer approach for anticancer immunotherapy due to the involvement of thymic selection.

The challenge of teaching Anatomy in a organ‐based curriculum:mistakes made and lessons learned

In 2006 the University of Arizona College of Medicine underwent a curriculum change from the traditional system based format to an organ‐ system based curriculum. Gross Anatomy went from its own separate course to being part of each block through the first two years of the basic sciences. Overall focus on Anatomy was diminished.Challenges encountered. ‐Shortened time for dissections. ‐Anatomy accounting for a minimal percentage of total grade. ‐ Dissection carried on throughout the whole 1st year. ‐When to use prosections instead of student dissections. Innovations ‐ Anatomy elective during the 4th year. ‐ Fresh cadaver based surgeries with emphasis on anatomy for students going into surgical specialties offered in the 4th year. ‐ Fresh cadaver based instruction for all 3rd year students rotating on the surgery clerkship. ‐Fresh cadaver based ultrasound instruction introduced on the surgery clerkship. ‐ Anatomy couse offered to pre‐medical students with medical students acting as instructors. ConclusionsThe change in curriculum to an organ‐based format posed a challenge as to how best to teach Anatomy. New and innovative methods must be introduced to insure graduating medical students have the fundamental knowlege of Anatomy especially focused on the clinical path they will pursue.

Workflow-based Dynamic Modeling for Clinical Path in CDSS

Workflow-based Dynamic Modeling for Clinical Path in CDSS

Application of psychological care clinical pathway in the rehabilitation of patients with facial neuritis

Objective To investigate the efficacy of psychological care clinical pathway on the rehabilitation of patients with facial ncuritis.Methods Analysis from 74 cases of hospitalized patients with facial neuritis in neurology from January 2010 to August 2012.They were randomly divided into the path group and control group,37 cases for each.The control group was treated with conventional care,while the path group received the clinical path of psychological care on the basis of conventional care.Anxiety and severity of depression of patients in the first day to hospital,the second day,and discharge from hospital,length of stay,hospital costs,patients' satisfaction,efficacy and other key indicators were observed and compared between the two groups.Results As compared with the control group,the path group had significantly lower in the anxiety score of the discharged day (43.60 ± 9.32),depression (32.91 ± 4.04),hospital stay (18.9 ± 3.9 days),hospital costs(4325.12 ± 706.9 (￥)),and the difference between the two groups was significantly difference (t =6.757,22.320,8.569,3.253,respectively ; P ＜ 0.01).And the patients' satisfaction (94.59％),treatment effect (97.30％),and health education knowledge score (92.1 ± 6.4) in the path group were significantly higher than that in the control group (x2 =5.232,16.207,respectively; t =13.068 ; P ＜ 0.05).Conclusions Using psychological care clinical path mode to strengthen the psychological care of patients with facial paralysis,can improve the patients with adverse psychological state,promote disease recovery,reduce hospitalization costs,and shorter hospital stay,improve patients' satisfaction,and so on.Standardization and procedures of the clinical path of psychological care,patients can get the best care services and health education effect,while enhancing the nurses' professional knowledge level and job satisfaction. Key words: Facial neuritis; Psychological care; Clinical pathway

Application and effect of clinical nursing path on the improvement of life quality in gastric cancer patients

Objective To study the effect of clinical nursing path on the quality of life of gastric cancer patients.Methods Totals of 60 cases with gastric cancer in Chinese PLA General Hospital between April 2006and August 2010 were divided into clinical nursing path group (n =30) and general nursing group (n =30).And the life quality,motor function and ADL scores were observed.Results The components scores such as emotional health score [(80.2 ± 15.6) vs (65.9 ± 10.4)],general health level [(82.2 ± 15.9) vs (63.7 ±10.0)],effects of drugs on gastric cancer patients[(83.3 ± 14.1) vs (66.9 ± 11.2)],individual cognitive function[(81.7 ± 15.2)vs (66.8 ± 10.9)],social function[(81.5 ± 14.3)vs (67.7 ± 11.8)],the recurrence of gastric cancer anxiety[(81.8 ± 16.6)vs (67.7 ± 10.9)] in clinical nursing path group were better than that in general nursing group,and the differences were statistically significant (t =4.18,5.39,4.99,4.36,4.08,3.89 ; P ＜ 0.05).Meanwhile,the score of motor function and ADL in clinical nursing path group were (75.5 ±9.9) and (73.3-± 16.1),which were superior to the score in general nursing group [(56.4 ± 8.2) and (53.6 ±15.0),respectively,t =8.14,4.90;P ＜0.05].Conclusions The quality of life of gastric cancer patients underwent clinical nursing path are obviously improved,which worthwhile for spreading in clinical practice. Key words: Clinical nursing path ; Gastric cancer; Quality of life

The effect of clinical nursing path on intubation time and complications in hemodialysis patients

Objective To explore the effect of clinical nursing path on indwelling time and complications in hemodialysis patients.Methods A total of 80 hemodialysis patients in our the hospital were divided into the observation group and the control group with 40cases in each.The control group was given conventional nursing,the observation group was given clinical nursing path accordance with the nursing path table plan strictly.The awareness rate of health knowledge,intubation time,complications and nursing satisfaction were compared between two groups.Results Compared with the control group,the health knowledge awareness rate was significantly higher,the intubation time was significantly longer,complications was significantly less in the observation group (P ＜ 0.05).Nursing satisfaction of education,environment,attitude in the observation group were significantly higher than those in the control group (P ＜ 0.05).Conclusions Clinical nursing path is conducive to the promotion of hemodialysis patients to take health behavior,improve the effect of health education,and reduce the incidence of complications. Key words: Clinical nursing pathway; Hemodialysis; Intubation time ; Complications

Present and future of traditional Chinese medicine clinical pharmacy

Traditional Chinese medicine clinical pharmacy is the contact theory of traditional Chinese medicine and herbal application on the bridge, this paper systematically reviews the clinical pharmacy of traditional Chinese medicine the history, current situation of clinical pharmacy to conduct a comprehensive review, put forward the development of Chinese clinical pharmacy path, in order to strengthen the traditional Chinese medicine clinical pharmacy discipline construction and research.