Current and emerging therapies for the treatment of pancreatic cancer

Pancreatic adenocarcinoma carries a dismal prognosis and remains a significant cause of cancer morbidity and mortality. Most patients survive less than 1 year; chemotherapeutic options prolong life minimally. The best chance for long-term survival is complete resection, which offers a 3-year survival of only 15%. Most patients who do undergo resection will go on to die of their disease. Research in chemotherapy for metastatic disease has made only modest progress and the standard of care remains the purine analog gemcitabine. For resectable pancreatic cancer, presumed micrometastases provide the rationale for adjuvant chemotherapy and chemoradiation (CRT) to supplement surgical management. Numerous randomized control trials, none definitive, of adjuvant chemotherapy and CRT have been conducted and are summarized in this review, along with recent developments in how unresectable disease can be subcategorized according to the potential for eventual curative resection. This review will also emphasize palliative care and discuss some avenues of research that show early promise

Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database

CCA Mortality Rate by Year among Asians; raw data file with query terms. (TXT 6 kb

Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers

Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. Implications for Practice: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents

Effect of trimetazidine dihydrochloride therapy on exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy: A randomized clinical trial

Importance: Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy. Objective: To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy. Design, Setting, and Participants: This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018. Interventions: Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months. Main Outcomes and Measures: The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro-brain natriuretic peptide level, and troponin T level. Results: Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, -2.58 to -0.11 mL/kg per minute; P = .03) in the intervention group after 3 months. Conclusions and Relevance: In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited. Trial Registration: ClinicalTrials.gov identifier: NCT01696370

UK clinical guideline for the prevention and treatment of osteoporosis

The National Osteoporosis Guideline Group (NOGG) has revised the UK guideline for the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. Accredited by NICE, this guideline is relevant for all healthcare professionals involved in osteoporosis management. INTRODUCTION The UK National Osteoporosis Guideline Group (NOGG) first produced a guideline on the prevention and treatment of osteoporosis in 2008, with updates in 2013 and 2017. This paper presents a major update of the guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. METHODS Where available, systematic reviews, meta-analyses and randomised controlled trials were used to provide the evidence base. Conclusions and recommendations were systematically graded according to the strength of the available evidence. RESULTS Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment and intervention thresholds, management of vertebral fractures, non-pharmacological and pharmacological treatments, including duration and monitoring of anti-resorptive therapy, glucocorticoid-induced osteoporosis, and models of care for fracture prevention. Recommendations are made for training; service leads and commissioners of healthcare; and for review criteria for audit and quality improvement. CONCLUSION The guideline, which has received accreditation from the National Institute of Health and Care Excellence (NICE), provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals involved in its management. This position paper has been endorsed by the International Osteoporosis Foundation and by the European Society for the Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases

Experimental assessment of unvalidated assumptions in classical plasticity theory.

This report investigates the validity of several key assumptions in classical plasticity theory regarding material response to changes in the loading direction. Three metals, two rock types, and one ceramic were subjected to non-standard loading directions, and the resulting strain response increments were displayed in Gudehus diagrams to illustrate the approximation error of classical plasticity theories. A rigorous mathematical framework for fitting classical theories to the data, thus quantifying the error, is provided. Further data analysis techniques are presented that allow testing for the effect of changes in loading direction without having to use a new sample and for inferring the yield normal and flow directions without having to measure the yield surface. Though the data are inconclusive, there is indication that classical, incrementally linear, plasticity theory may be inadequate over a certain range of loading directions. This range of loading directions also coincides with loading directions that are known to produce a physically inadmissible instability for any nonassociative plasticity model

Domain Specific Self-Efficacy Mediates the Impact of Pain Catastrophizing on Pain and Disability in Overweight and Obese Osteoarthritis Patients

This study examined whether self-efficacy mediated the relationship between pain catastrophizing and pain and disability. Participants were 192 individuals diagnosed with osteoarthritis (OA) of the knees who were overweight or obese. Multiple mediator analyses were conducted to simultaneously test self-efficacy for pain control, physical function, and emotional symptoms as mediators while controlling for demographic and medical status variables. Higher pain catastrophizing was associated with lower self-efficacy in all three domains (ps< .05). Self-efficacy for pain control fully mediated the relationship between pain catastrophizing and pain (Beta=.08, Sobel test Z=1.97, p<.05). The relationship between pain catastrophizing and physical disability was fully mediated by self-efficacy for physical function (Beta=.06, Sobel test Z=1.95, p=.05). Self-efficacy for emotional symptoms partially mediated the relationship between pain catastrophizing and psychological disability (Beta=. 12, Sobel test Z=2.92, p<.05). These results indicate that higher pain catastrophizing contributed to greater pain and disability via lower domain-specific self-efficacy. Efforts to reduce pain and improve functioning in OA patients should consider addressing pain catastrophizing and domain specific selfefficacy. Pain catastrophizing may be addressed through cognitive therapy techniques and selfefficacy may be enhanced through practice of relevant skills and personal accomplishments. Perspective- This paper found that higher pain catastrophizing contributed to great pain and disability via domain specific self-efficacy. These results suggest that treatment efforts to reduce pain and improve functioning in OA patients who are overweight or obese should consider addressing both pain catastrophizing and self-efficacy. Originally published Journal of Pain, Vol. 9, No. 10, Oct 200

Microglia regulate myelin growth and integrity in the central nervous system

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health(1), it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease(2,3)