Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial.

BACKGROUND: Trastuzumab (Herceptin(R)) improves disease-free survival (DFS) and overall survival for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess the magnitude of its clinical benefit for subpopulations defined by nodal and steroid hormone receptor status using data from the Herceptin Adjuvant (HERA) study. PATIENTS AND METHODS: HERA is an international multicenter randomized trial comparing 1 or 2 years of trastuzumab treatment with observation after standard chemotherapy in women with HER2-positive breast cancer. In total, 1703 women randomized to 1-year trastuzumab and 1698 women randomized to observation were included in these analyses. Median follow-up was 23.5 months. The primary endpoint was DFS. RESULTS: The overall hazard ratio (HR) for trastuzumab versus observation was 0.64 [95% confidence interval (CI) 0.54-0.76; P < 0.0001], ranging from 0.46 to 0.82 for subgroups. Estimated improvement in 3-year DFS in subgroups ranged from +11.3% to +0.6%. Patients with the best prognosis (those with node-negative disease and tumors 1.1-2.0 cm) had benefit similar to the overall cohort (HR 0.53, 95% CI 0.26-1.07; 3-year DFS improvement +4.6%, 95% CI -4.0% to 13.2%). CONCLUSIONS: Adjuvant trastuzumab therapy reduces the risk of relapse similarly across subgroups defined by nodal status and steroid hormone receptor status, even those at relatively low risk for relapse.

Fertility preservation: Successful transplantation of cryopreserved ovarian tissue in a young patient previously treated for Hodgkin's disease

Cryopreservation of ovarian tissue is now offered as an experimental procedure to preserve the fertility of young patients with a high risk for premature ovarian failure resulting from cancer therapy. This is the only available option to preserve the fertility of prepubertal patients treated with gonadotoxic chemotherapy. At present, thousands of patients all over the world have undergone this procedure with the hope of later restoring their fertility. Although the efficiency of the transplantation of cryopreserved ovarian tissue to restore ovarian function has been established, reports of pregnancy are still very scarce. Here, we describe the second published full-term spontaneous pregnancy after an orthotopic and heterotopic transplantation of cryopreserved ovarian tissue in a 31-year-old woman previously treated by conditioning therapy for bone marrow transplantation for Hodgkin's disease. This birth gives compelling evidence for the graft origin of the gamete and confirms the efficacy of ovarian tissue transplantation in restoring human natural fertility after oncological treatment. This case report stresses the importance of proposing the ovarian tissue cryopreservation procedure to all young patients who require potentially sterilizing treatment, with all alternative options to preserve fertility being duly taken into consideration.

TCR V alpha- and V beta-gene segment use in T-cell subcultures derived from a type-III bare lymphocyte syndrome patient deficient in MHC class-II expression.

Previously, we and others have shown that MHC class-II deficient humans have greatly reduced numbers of CD4+CD8- peripheral T cells. These type-III Bare Lymphocyte Syndrome patients lack MHC class-II and have an impaired MHC class-I antigen expression. In this study, we analyzed the impact of the MHC class-II deficient environment on the TCR V-gene segment usage in this reduced CD4+CD8- T-cell subset. For these studies, we employed TcR V-region-specific monoclonal antibodies (mAbs) and a semiquantitative PCR technique with V alpha and V beta amplimers, specific for each of the most known V alpha- and V beta-gene region families. The results of our studies demonstrate that some of the V alpha-gene segments are used less frequent in the CD4+CD8- T-cell subset of the patient, whereas the majority of the TCR V alpha- and V beta-gene segments investigated were used with similar frequencies in both subsets in the type-III Bare Lymphocyte Syndrome patient compared to healthy control family members. Interestingly, the frequency of TcR V alpha 12 transcripts was greatly diminished in the patient, both in the CD4+CD8- as well as in the CD4-CD8+ compartment, whereas this gene segment could easily be detected in the healthy family controls. On the basis of the results obtained in this study, it is concluded that within the reduced CD4+CD8- T-cell subset of this patient, most of the TCR V-gene segments tested for are employed. However, a skewing in the usage frequency of some of the V alpha-gene segments toward the CD4-CD8+ T-cell subset was noticeable in the MHC class-II deficient patient that differed from those observed in the healthy family controls.

Expert assessments of retrofitting coal-fired power plants with carbon dioxide capture technologies

A set of 13 US based experts in post-combustion and oxy-fuel combustion CO2 capture systems responded to an extensive questionnaire asking their views on the present status and future expected performance and costs for amine-based, chilled ammonia, and oxy-combustion retrofits of coal-fired power plants. This paper presents the experts' responses for technology maturity, ideal plant characteristics for early adopters, and the extent to which R&D and deployment incentives will impact costs. It also presents the best estimates and 95% confidence limits of the energy penalties associated with amine-based systems. The results show a general consensus that amine-based systems are closer to commercial application, but potential for improving performance and lowering costs is limited; chilled ammonia and oxy-combustion offer greater potential for cost reductions, but not without greater uncertainty regarding scale and technical feasibility. © 2011 Elsevier Ltd.

Patient-based outcome assessment instruments in acupuncture research.

BACKGROUND: Outcome assessment can support the therapeutic process by providing a way to track symptoms and functionality over time, providing insights to clinicians and patients, as well as offering a common language to discuss patient behavior/functioning. OBJECTIVES: In this article, we examine the patient-based outcome assessment (PBOA) instruments that have been used to determine outcomes in acupuncture clinical research and highlight measures that are feasible, practical, economical, reliable, valid, and responsive to clinical change. The aims of this review were to assess and identify the commonly available PBOA measures, describe a framework for identifying appropriate sets of measures, and address the challenges associated with these measures and acupuncture. Instruments were evaluated in terms of feasibility, practicality, economy, reliability, validity, and responsiveness to clinical change. METHODS: This study was a systematic review. A total of 582 abstracts were reviewed using PubMed (from inception through April 2009). RESULTS: A total of 582 citations were identified. After screening of title/abstract, 212 articles were excluded. From the remaining 370 citations, 258 manuscripts identified explicit PBOA; 112 abstracts did not include any PBOA. The five most common PBOA instruments identified were the Visual Analog Scale, Symptom Diary, Numerical Pain Rating Scales, SF-36, and depression scales such as the Beck Depression Inventory. CONCLUSIONS: The way a questionnaire or scale is administered can have an effect on the outcome. Also, developing and validating outcome measures can be costly and difficult. Therefore, reviewing the literature on existing measures before creating or modifying PBOA instruments can significantly reduce the burden of developing a new measure.

Communication practices in physician decision-making for an unstable critically ill patient with end-stage cancer.

BACKGROUND: Shared decision-making has become the standard of care for most medical treatments. However, little is known about physician communication practices in the decision making for unstable critically ill patients with known end-stage disease. OBJECTIVE: To describe communication practices of physicians making treatment decisions for unstable critically ill patients with end-stage cancer, using the framework of shared decision-making. DESIGN: Analysis of audiotaped encounters between physicians and a standardized patient, in a high-fidelity simulation scenario, to identify best practice communication behaviors. The simulation depicted a 78-year-old man with metastatic gastric cancer, life-threatening hypoxia, and stable preferences to avoid intensive care unit (ICU) admission and intubation. Blinded coders assessed the encounters for verbal communication behaviors associated with handling emotions and discussion of end-of-life goals. We calculated a score for skill at handling emotions (0-6) and at discussing end of life goals (0-16). SUBJECTS: Twenty-seven hospital-based physicians. RESULTS: Independent variables included physician demographics and communication behaviors. We used treatment decisions (ICU admission and initiation of palliation) as a proxy for accurate identification of patient preferences. Eight physicians admitted the patient to the ICU, and 16 initiated palliation. Physicians varied, but on average demonstrated low skill at handling emotions (mean, 0.7) and moderate skill at discussing end-of-life goals (mean, 7.4). We found that skill at discussing end-of-life goals was associated with initiation of palliation (p = 0.04). CONCLUSIONS: It is possible to analyze the decision making of physicians managing unstable critically ill patients with end-stage cancer using the framework of shared decision-making.

Automatic segmentation of seven retinal layers in SDOCT images congruent with expert manual segmentation.

Segmentation of anatomical and pathological structures in ophthalmic images is crucial for the diagnosis and study of ocular diseases. However, manual segmentation is often a time-consuming and subjective process. This paper presents an automatic approach for segmenting retinal layers in Spectral Domain Optical Coherence Tomography images using graph theory and dynamic programming. Results show that this method accurately segments eight retinal layer boundaries in normal adult eyes more closely to an expert grader as compared to a second expert grader.

Biochemical Characterization a virus isolate from a patient with Herpes Keratitis clinically-resitant to Acyclovir

info:eu-repo/semantics/published

Comparative effectiveness studies to improve clinical outcomes in end stage renal disease: the DEcIDE patient outcomes in end stage renal disease study.

BACKGROUND: Evidence is lacking to inform providers' and patients' decisions about many common treatment strategies for patients with end stage renal disease (ESRD). METHODS/DESIGN: The DEcIDE Patient Outcomes in ESRD Study is funded by the United States (US) Agency for Health Care Research and Quality to study the comparative effectiveness of: 1) antihypertensive therapies, 2) early versus later initiation of dialysis, and 3) intravenous iron therapies on clinical outcomes in patients with ESRD. Ongoing studies utilize four existing, nationally representative cohorts of patients with ESRD, including (1) the Choices for Healthy Outcomes in Caring for ESRD study (1041 incident dialysis patients recruited from October 1995 to June 1999 with complete outcome ascertainment through 2009), (2) the Dialysis Clinic Inc (45,124 incident dialysis patients initiating and receiving their care from 2003-2010 with complete outcome ascertainment through 2010), (3) the United States Renal Data System (333,308 incident dialysis patients from 2006-2009 with complete outcome ascertainment through 2010), and (4) the Cleveland Clinic Foundation Chronic Kidney Disease Registry (53,399 patients with chronic kidney disease with outcome ascertainment from 2005 through 2009). We ascertain patient reported outcomes (i.e., health-related quality of life), morbidity, and mortality using clinical and administrative data, and data obtained from national death indices. We use advanced statistical methods (e.g., propensity scoring and marginal structural modeling) to account for potential biases of our study designs. All data are de-identified for analyses. The conduct of studies and dissemination of findings are guided by input from Stakeholders in the ESRD community. DISCUSSION: The DEcIDE Patient Outcomes in ESRD Study will provide needed evidence regarding the effectiveness of common treatments employed for dialysis patients. Carefully planned dissemination strategies to the ESRD community will enhance studies' impact on clinical care and patients' outcomes.

An active learning approach for rapid characterization of endothelial cells in human tumors.

Currently, no available pathological or molecular measures of tumor angiogenesis predict response to antiangiogenic therapies used in clinical practice. Recognizing that tumor endothelial cells (EC) and EC activation and survival signaling are the direct targets of these therapies, we sought to develop an automated platform for quantifying activity of critical signaling pathways and other biological events in EC of patient tumors by histopathology. Computer image analysis of EC in highly heterogeneous human tumors by a statistical classifier trained using examples selected by human experts performed poorly due to subjectivity and selection bias. We hypothesized that the analysis can be optimized by a more active process to aid experts in identifying informative training examples. To test this hypothesis, we incorporated a novel active learning (AL) algorithm into FARSIGHT image analysis software that aids the expert by seeking out informative examples for the operator to label. The resulting FARSIGHT-AL system identified EC with specificity and sensitivity consistently greater than 0.9 and outperformed traditional supervised classification algorithms. The system modeled individual operator preferences and generated reproducible results. Using the results of EC classification, we also quantified proliferation (Ki67) and activity in important signal transduction pathways (MAP kinase, STAT3) in immunostained human clear cell renal cell carcinoma and other tumors. FARSIGHT-AL enables characterization of EC in conventionally preserved human tumors in a more automated process suitable for testing and validating in clinical trials. The results of our study support a unique opportunity for quantifying angiogenesis in a manner that can now be tested for its ability to identify novel predictive and response biomarkers.

Caring for Alaska Native prostate cancer survivors in primary care: a survey of Alaska Tribal Health System providers.

BACKGROUND: Little is known about the constraints of optimizing health care for prostate cancer survivors in Alaska primary care. OBJECTIVE: To describe the experiences and attitudes of primary care providers within the Alaska Tribal Health System (ATHS) regarding the care of prostate cancer survivors. DESIGN: In late October 2011, we emailed a 22-item electronic survey to 268 ATHS primary care providers regarding the frequency of Prostate Specific Antigen (PSA) monitoring for a hypothetical prostate cancer survivor; who should be responsible for the patient's life-long prostate cancer surveillance; who should support the patient's emotional and medical needs as a survivor; and providers' level of comfort addressing recurrence monitoring, erectile dysfunction, urinary incontinence, androgen deprivation therapy, and emotional needs. We used simple logistic regression to examine the association between provider characteristics and their responses to the survivorship survey items. RESULTS: Of 221 individuals who were successfully contacted, a total of 114 responded (52% response rate). Most ATHS providers indicated they would order a PSA test every 12 months (69%) and believed that, ideally, the hypothetical patient's primary care provider should be responsible for his life-long prostate cancer surveillance (60%). Most providers reported feeling either "moderately" or "very" comfortable addressing topics such as prostate cancer recurrence (59%), erectile dysfunction (64%), urinary incontinence (63%), and emotional needs (61%) with prostate cancer survivors. These results varied somewhat by provider characteristics including female sex, years in practice, and the number of prostate cancer survivors seen in their practice. CONCLUSIONS: These data suggest that most primary care providers in Alaska are poised to assume the care of prostate cancer survivors locally. However, we also found that large minorities of providers do not feel confident in their ability to manage common issues in prostate cancer survivorship, implying that continued access to specialists with more expert knowledge would be beneficial.

Effect of ritonavir-induced cytochrome P450 3A4 inhibition on plasma fentanyl concentrations during patient-controlled epidural labor analgesia: a pharmacokinetic simulation.

BACKGROUND: Ritonavir inhibition of cytochrome P450 3A4 decreases the elimination clearance of fentanyl by 67%. We used a pharmacokinetic model developed from published data to simulate the effect of sample patient-controlled epidural labor analgesic regimens on plasma fentanyl concentrations in the absence and presence of ritonavir-induced cytochrome P450 3A4 inhibition. METHODS: Fentanyl absorption from the epidural space was modeled using tanks-in-series delay elements. Systemic fentanyl disposition was described using a three-compartment pharmacokinetic model. Parameters for epidural drug absorption were estimated by fitting the model to reported plasma fentanyl concentrations measured after epidural administration. The validity of the model was assessed by comparing predicted plasma concentrations after epidural administration to published data. The effect of ritonavir was modeled as a 67% decrease in fentanyl elimination clearance. Plasma fentanyl concentrations were simulated for six sample patient-controlled epidural labor analgesic regimens over 24 h using ritonavir and control models. Simulated data were analyzed to determine if plasma fentanyl concentrations producing a 50% decrease in minute ventilation (6.1 ng/mL) were achieved. RESULTS: Simulated plasma fentanyl concentrations in the ritonavir group were higher than those in the control group for all sample labor analgesic regimens. Maximum plasma fentanyl concentrations were 1.8 ng/mL and 3.4 ng/mL for the normal and ritonavir simulations, respectively, and did not reach concentrations associated with 50% decrease in minute ventilation. CONCLUSION: Our model predicts that even with maximal clinical dosing regimens of epidural fentanyl over 24 h, ritonavir-induced cytochrome P450 3A4 inhibition is unlikely to produce plasma fentanyl concentrations associated with a decrease in minute ventilation.

Patient education preferences in ophthalmic care.

BACKGROUND: The learning preferences of ophthalmology patients were examined. METHODS: Results from a voluntary survey of ophthalmology patients were analyzed for education preferences and for correlation with race, age, and ophthalmic topic. RESULTS: To learn about eye disease, patients preferred one-on-one sessions with providers as well as printed materials and websites recommended by providers. Patients currently learning from the provider were older (average age 59 years), and patients learning from the Internet (average age 49 years) and family and friends (average age 51 years) were younger. Patients interested in cataracts, glaucoma, macular degeneration, and dry eye were older; patients interested in double vision and glasses were younger. There were racial differences regarding topic preferences, with Black patients most interested in glaucoma (46%), diabetic retinopathy (31%), and cataracts (28%) and White patients most interested in cataracts (22%), glaucoma (22%), and macular degeneration (19%). CONCLUSION: MOST OPHTHALMOLOGY PATIENTS PREFERRED PERSONALIZED EDUCATION: one-on-one with their provider or a health educator and materials (printed and electronic) recommended by their provider. Age-related topics were more popular with older patients, and diseases with racial risk factors were more popular with high risk racial groups.

Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis.

While blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) T cell regulatory receptor has become a commonly utilized strategy in the management of advanced melanoma, many questions remain regarding the use of this agent in patient populations with autoimmune disease. We present a case involving the treatment of a patient with stage IV melanoma and ulcerative colitis (UC) with anti-CTLA-4 antibody immunotherapy. Upon initial treatment, the patient developed grade III colitis requiring tumor necrosis factor-alpha (TNF-α) blocking antibody therapy, however re-treatment with anti-CTLA-4 antibody following a total colectomy resulted in a rapid complete response accompanied by the development of a tracheobronchitis, a previously described extra-intestinal manifestation of UC. This case contributes to the evolving literature on the use of checkpoint inhibitors in patients also suffering from autoimmune disease, supports future clinical trials investigating the use of these agents in patients with autoimmune diseases, and suggests that an understanding of the specific molecular pathways involved in a patient's autoimmune pathology may provide insight into the development of more effective novel combinatorial immunotherapeutic strategies.

Preoperative pain level and patient expectation predict hospital length of stay after total hip arthroplasty.

The purpose of this study was to identify preoperative predictors of length of stay after primary total hip arthroplasty in a patient population reflecting current trends toward shorter hospitalization and using readily obtainable factors that do not require scoring systems. A retrospective review of 112 consecutive patients was performed. High preoperative pain level and patient expectation of discharge to extended care facilities (ECFs) were the only significant multivariable predictors of hospitalization extending beyond 2 days (P=0.001 and P<0.001 respectively). Patient expectation remained significant after adjusting for Medicare's 3-day requirement for discharge to ECFs (P<0.001). The study was adequately powered to analyze the variables in the multivariable logistic regression model, which had a concordance index of 0.857.