A systemic review and meta-analysis of Aflibercept plus FOLFIRI regimen as a second-line treatment for metastatic colorectal cancer: A PRISMA compliant pooled analysis of randomized controlled trials and single arm studies to assess efficacy and safety.

BACKGROUND AND OBJECTIVE: Aflibercept; a decoy receptor for vascular endothelial growth factors (VEGFs) and placental growth factor (PLGF), in combination with FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride) chemotherapy regime, was FDA approved in 2012 as second-line salvage chemotherapy for metastatic colorectal cancer (mCRC). This is the first systematic review, and meta-analysis-based evidence to determine the efficacy and safety of Aflibercept plus FOLFIRI regimen pooling randomized controlled trials and single-arm studies. METHOD: PubMed, Cochrane library, Embase, and Clinical trial.gov were systematically searched for published randomized controlled trials, single-arm studies, and national patient programs on aflibercept plus FOLFIRI chemotherapy for the treatment of mCRC till 11/10/2022. RESULT: Ten studies met the inclusion criteria comprising 1075 patients for efficacy studies and 2027 patients for safety studies. The pooled prevalences were 18% (95% CI, 5%-37%, p = 0.00) for 12 m PFS and 61% (95% CI, 53-68%, p = 0.00) for 12 m OS. The pooled prevalences were 69% (95% CI, 55-82%, p = 0.00) for any grade 3-4 toxicities, 10% (95% CI, 5-16%, p = 0.00) for grade 3-4 diarrhea, 13% (95% CI, 5-24%, p = 0.00) for grade 3-4 hypertension, 31% (95% CI, 22-40%, p = 0.00) for grade 3-4 neutropenia and 5% (95% CI, 2-7%, p = 0.00) for grade 3-4 venous thromboembolic event. CONCLUSION: Our meta-analysis shows that the aflibercept plus FOLFIRI combination shows better survival efficacies however; it is also associated with more high-grade adverse events.

Current investigative modalities for detecting and staging lung cancers: a comprehensive summary.

This narrative review compares the advantages and drawbacks of imaging and other investigation modalities which currently assist with lung cancer diagnosis and staging, as well as those which are not routinely indicated for this. We examine plain film radiography, computed tomography (CT) (alone, as well as in conjunction with positron emission tomography (PET)), magnetic resonance imaging (MRI), ultrasound, and newer techniques such as image-guided bronchoscopy (IGB) and robotic bronchoscopy (RB). While a chest X-ray is the first-line imaging investigation in patients presenting with symptoms suggestive of lung cancer, it has a high positive predictive value (PPV) even after negative X-ray findings, which calls into question its value as part of a potential national screening programme. CT lowers the mortality for high-risk patients when compared to X-ray and certain scoring systems, such as the Brock model can guide the need for further imaging, like PET-CT, which has high sensitivity and specificity for diagnosing solitary pulmonary nodules as malignant, as well as for assessing small cell lung cancer spread. In practice, PET-CT is offered to everyone whose lung cancer is to be treated with a curative intent. In contrast, MRI is only recommended for isolated distant metastases. Similarly, ultrasound imaging is not used for diagnosis of lung cancer but can be useful when there is suspicion of intrathoracic lymph node involvement. Ultrasound imaging in the form of endobronchial ultrasonography (EBUS) is often used to aid tissue sampling, yet the diagnostic value of this technique varies widely between studies. RB is another novel technique that offers an alternative way to biopsy lesions, but further research on it is necessary. Lastly, thoracic surgical biopsies, particularly minimally invasive video-assisted techniques, have been used increasingly to aid in diagnosis and staging.

Medication Safety Principles and Practice in CKD.

Ensuring patient safety is a priority of medical care because iatrogenic injury has been a primary concern. Medications are an important source of medical errors, and kidney disease is a thoroughfare of factors threatening safe administration of medicines. Principal among these is reduced kidney function because almost half of all medications used are eliminated via the kidney. Additionally, kidney patients often suffer from multimorbidity, including diabetes, hypertension, and heart failure, with a range of prescribers who often do not coordinate treatments. Patients with kidney disease are also susceptible to further kidney injury and metabolic derangements from medications, which can worsen the disease. In this review, we will present the key issues and threats to safe medication use in kidney disease, with a focus on predialysis CKD, as the scope of medication safety in ESKD and transplantation are unique and deserve their own consideration. We discuss drugs that need to be avoided or dose modified, and review the complications of a range of medications routinely administered in CKD, as these also call for cautious use.

The Role of PCSK9 Inhibitors in the Treatment of Hypercholesterolemia.

OBJECTIVE: To evaluate the efficacy, safety, and cost-effectiveness of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and describe its place in therapy for the treatment of hypercholesterolemia. DATA SOURCES: A search of MEDLINE, CINAHL, and Clinicaltrials.gov was performed from January 2012 to March 2018 to identify literature pertaining to PCSK9 inhibitors using pre-specified search terms. Additional references were identified from citations of the literature. STUDY SELECTION AND DATA EXTRACTION: Only articles in English were reviewed. Phase II, phase III, pooled, post hoc, and cardiovascular (CV) trials were included. Cost-effectiveness studies and conference materials were also reviewed. DATA SYNTHESIS: All trials evaluating alirocumab and evolocumab demonstrated significant low-density lipoprotein cholesterol (LDL-C) lowering versus comparators. Two trials revealed a decrease in the major adverse cardiovascular events (MACE) end point with PCSK9 inhibitor use; 1 of these 2 trials revealed a decrease in all-cause mortality with alirocumab use. No significant safety concerns apart from injection site reactions were noted. Despite these results, 4 cost-effectiveness analyses failed to meet acceptable thresholds. Relevance to Patient Care and Clinical Practice: This review describes the most up-to-date evidence regarding PCSK9 inhibitors. A discussion on LDL-C lowering potential, effect on CV events and mortality, safety considerations, feasibility of administration, and cost are included to guide clinicians on future use. CONCLUSION: The PCSK9 inhibitor drug class is an effective LDL-C lowering option for patients with the highest risk of CVD events and high LDL-C despite the use of statin therapy. For more widespread use, significant cost reductions are needed.

Lixisenatide (Adlyxin): A Once-Daily Incretin Mimetic Injection for Type-2 Diabetes.

Lixisenatide (Adlyxin), a once-daily incretin mimetic injection for type-2 diabetes.

The Current Landscape of Transitions of Care Practice Models: A Scoping Review.

Transitions of care (TOC) are a set of actions to ensure patient coordination and continuity of care as patients transfer between different locations or levels. During transitions associated with chronic or acute illness, vulnerable patients may be placed at risk with fragmented systems compromising their health and safety. In addition, poor care transitions also have an enormous impact on health care spending. The primary objective of this scoping review is to summarize the current landscape of practice models that deliver TOC services in the United States. The secondary objective is to use the information to characterize the current state of best practice models. A search of the PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Web of Science, International Pharmaceutical Abstracts, National Center for Biotechnology Information at the U.S. National Library of Medicine, and Cochrane Library databases (January 1, 2000-April 13, 2015) for articles pertaining to TOC models, limited to U.S. studies published in the English language with human subjects, gleaned 1362 articles. An additional 26 articles were added from the gray literature. Articles meeting inclusion criteria underwent a second review and were categorized into four groups: background information, original TOC research articles not evaluating practice model interventions, original TOC research articles describing practice models, and systematic or Cochrane reviews. The reviewers met weekly to discuss the challenges and resolve disagreements regarding literature reviews with consensus before progressing. A total of 188 articles describing TOC practice models met the inclusion criteria. Despite the strengths of several quality TOC models, none satisfied all the components recommended by leading experts. Multimodal interventions by multidisciplinary teams appear to represent a best practice model for TOC to improve patient outcomes and reduce readmissions, but one size does not fit all. Best model TOC services must include services along the TOC continuum: pretransition and posttransition, as well as at home and in outpatient health care settings. Studies clearly show that single-modal interventions are rarely successful in reducing readmissions and that successful TOC services must be multimodal and multidisciplinary, and continue throughout the care transition. Utilizing best practice TOC models described in this article as a starting point, practitioners interested in developing their own TOC program should test these tools in new practice environments and add to the body of literature by publishing their findings.

Therapeutic Management of Familial Hypercholesterolemia: Current and Emerging Drug Therapies.

Familial hypercholesterolemia (FH) is a genetic disorder characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) concentrations that result from mutations of the LDL receptor, apolipoprotein B (apo B-100), and proprotein convertase subtilisin/kexin type 9 (PCSK9). Early and aggressive treatment can prevent premature atherosclerotic cardiovascular disease in these high-risk patients. Given that the cardiovascular consequences of FH are similar to typical hypercholesterolemia, traditional therapies are utilized to decrease LDL-C levels. Patients with FH should receive statins as first-line treatment; high-potency statins at high doses are often required. Despite the use of statins, additional treatments are often necessary to achieve appropriate LDL-C lowering in this patient population. Novel drug therapies that target the pathophysiologic defects of the condition are continuously emerging. Contemporary therapies including mipomersen (Kynamro, Genzyme), an oligonucleotide inhibitor of apo B-100 synthesis; lomitapide (Juxtapid, Aegerion), a microsomal triglyceride transfer protein inhibitor; and alirocumab (Praluent, Sanofi-Aventis/Regeneron) and evolocumab (Repatha, Amgen), PCSK9 inhibitors, are currently approved by the U.S. Food and Drug Administration for use in FH. This review highlights traditional as well as emerging contemporary therapies with supporting clinical data to evaluate current recommendations and discuss the future direction of FH management.

Prevalence of and factors associated with therapeutic failure-related hospitalizations in the elderly.

OBJECTIVE: A therapeutic failure (TF) is defined as a failure to accomplish the goals of treatment attributable to inadequate therapy, a drug-drug interaction that results in a subtherapeutic level for a drug, or medication nonadherence. The objective of this study was to evaluate the prevalence of and factors associated with TF-related hospitalizations in older adults. DESIGN: This investigation was a retrospective cohort study. SETTING: This study was conducted within a university-based hospital setting. PATIENTS: This investigation included patients with a primary care physician from the University of Pittsburgh Medical Center (UPMC) Senior Care Institute admitted to any UPMC hospital between September 1, 2011, and December 1, 2011. INTERVENTIONS: Chart abstracts of patient records were screened for a TF using a validated tool called the Therapeutic Failure Questionnaire (TFQ). Covariate data were also obtained. Descriptive statistics and bivariate analyses using Fisher's exact tests were conducted to assess the association between the covariates and the primary outcome. MAIN OUTCOME MEASURE(S): The primary outcome was the presence of a TF as measured by the TFQ. Secondary outcomes included associations between covariates and the presence of a TF. RESULTS: Of the 93 hospitalizations screened, 57 met inclusion criteria, and 18% of hospitalizations were as a result of preventable TFs. On bivariate analyses, both congestive heart failure (P = 0.03) and dependency for medication management (P = 0.04) were significantly associated with occurrence of TF. CONCLUSIONS: TFs are a potentially preventable cause of hospitalization in the elderly population and are commonly caused by omission of therapy.

Control of the timing and dosage of IGF-I delivery from encapsulated cells.

We report here on the development and characterization of a cell-based system for the regulated delivery of bioactive insulin-like growth factor I (IGF-I). A stable mammalian cell line, CHO-K1 Tet-IGFI, was genetically modified to have tetracycline-induced transcription of the human IGF-I gene. Cells were activated to express IGF-I in the presence of doxycycline (DOX), a tetracycline derivative, while expression was inactivated in the absence of DOX. Temporal, or on-off, release of IGF-I from cells encapsulated within Ca²âº-alginate hydrogels was demonstrated in a pilot study over the course of 10 days in culture. Released growth factor was bioactive, exhibiting a proliferative effect comparable to recombinant purified IGF-I protein. The dosage levels and temporal control of IGF-I release from encapsulated cells meet the requirements of orthopedic wound repair, making this approach an attractive means for the controlled synthesis and delivery of growth factors in situ for wound healing.

Doxycycline delivery from PLGA microspheres prepared by a modified solvent removal method.

We report on the development of a modified solvent removal method for the encapsulation of hydrophilic drugs within poly(lactic-co-glycolic acid) (PLGA). Using a water/oil/oil double emulsion, hydrophilic doxycycline was encapsulated within PLGA spheres with particle diameters ranging from approximately 600 nm to 19 µm. Encapsulation efficiencies of up to 74% were achieved for theoretical loadings from 1% to 10% (w/w), with biphasic release over 85 days with nearly complete release at the end of this time course. About 1% salt was added to the formulations to examine its effects on doxycycline release; salt modulated release only by increasing the magnitude of initial release without altering kinetics. Fourier transform infrared spectroscopy indicated no characteristic differences between doxycycline-loaded and control spheres. Differential scanning calorimetry and X-ray diffraction suggest that there may be a molecular dispersion of the doxycycline within the spheres and the doxycycline may be in an amorphous state, which could explain the slow, prolonged release of the drug.

A localizable, biological-based system for the delivery of bioactive IGF-1 utilizing microencapsulated genetically modified human fibroblasts.

Insulin-like growth factor 1 (IGF-1) is a potent mitogen and differentiation factor with particular relevance to orthopedic tissue engineering. A biologically based Ca2+-alginate microcapsule vehicle, utilizing genetically modified primary normal human fibroblasts (NHFs), was developed and characterized for localized synthesis and delivery of human IGF-1 (hIGF-1). Normal human fibroblasts were transfected to overexpress the hIGF-1 gene, leading to cells that expressed 4 ng of hIGF-1 per 10(6) cells per 24 hours. Encapsulation within alginate led to a six-fold enhancement in the generation and release of hIGF-1 to 22 ng of hIGF-1 per 10(6) cells per 24 hours. Release was constitutive, predictable, and exhibited highly repeatable first-order kinetics with no initial burst. Released growth factor was biologically active and exhibited a proliferative effect comparable to commercially available recombinant hIGF-1. The magnitude of hIGF-1 release met the requirements of orthopedic tissue generation, and this approach is considered an attractive alternative to other proposed methods of growth factor delivery.