Patient and Family Caregiver Considerations When Selecting Early Breast Cancer Treatment: Implications for Clinical Pathway Development.

BACKGROUND: While clinical pathways have been widely adopted to decrease variation in cancer treatment patterns, they do not always incorporate patient and family caregiver perspectives. We identified shared patient and family caregiver considerations influencing treatment preferences/decision making to inform development of a shared decision pathway. METHODS: We conducted qualitative interviews with women who completed initial definitive treatment for stage I-III breast cancer and their family caregivers. As part of a broader interview, we asked participants what they considered when choosing a treatment option for themselves/their loved one. We coded transcribed interviews, analyzed patient and family caregiver datasets separately, and compared findings. Findings Patients' (n = 22) mean age was 55.7 years, whereas family caregivers' (n = 20) mean age was 59.5 years, with most (65%) being patients' spouses/partners. Considerations reported by both groups included cancer status, treatment issues, physical/psychosocial/family consequences, and provider/health care system issues. Data revealed three key tensions that arise during treatment decision making: (1) having enough information to set expectations but not so much as to be overwhelming; (2) balancing the highest likelihood of cure with potential physical/emotional/social/financial consequences of the chosen treatment; and (3) wanting to make data-driven decisions while having a personalized treatment plan. DISCUSSION: Patients and family caregivers identified several considerations of shared relevance reflecting different perspectives. Efforts to balance considerations can produce tensions that may contribute to decision regret if unaddressed. CONCLUSION: Clinical pathways can increase exposure to decision regret if treatment options are selected without consideration of patients' priorities. A shared decision pathway that incorporates patient-centeredness could facilitate satisfactory decision making.

A clinical pathway is a tool used by doctors and nurses to help them plan how they will take care of patients. Clinical pathways do not always include what is important to patients and their families. We spoke with patients with breast cancer and their family members. We wanted to learn what is important to them when they are making decisions about how the patient will be treated for cancer. They reported thinking about the kind of cancer the patient had and about pros and cons of different treatment choices. They also thought about how much is known about different treatment choices. Other patients' stories were important. Patients and family members wanted to know how a treatment would affect their bodies, feelings, normal roles in life, and families. They also thought about their relationship with their doctors and nurses and about how they would pay for their care. It was seen as hard to balance these things when making decisions. Patients and family members wanted to make decisions they would be happy with later. We will use this information to create a new clinical pathway. This tool will help patients with breast cancer, family members, doctors, and nurses work together to make the best decisions about the patient's cancer.

Comparative effectiveness of first-line nab-paclitaxel versus paclitaxel monotherapy in triple-negative breast cancer.

Aim: This observational study evaluated the effectiveness of nab-paclitaxel versus paclitaxel monotherapy as first-line (1L) treatment for metastatic triple-negative breast cancer (mTNBC). Materials & methods: 200 patients from the US Flatiron Health electronic health record-derived database (mTNBC diagnosis, January 2011-October 2016) who received 1L nab-paclitaxel (n = 105) or paclitaxel (n = 95) monotherapy were included. Overall survival and time to next treatment were evaluated. Results: The adjusted overall survival hazard ratio was 0.98 (95% CI: 0.67-1.44), indicating a similar risk of death between groups. Adjusted time to next treatment hazard ratio was 0.89 (95% confidence interval: 0.62-1.29). Conclusion: Nab-paclitaxel and paclitaxel monotherapy showed similar efficacy, suggesting their interchangeability as 1L treatments for mTNBC.

Private sector risk-sharing agreements in the United States: trends, barriers, and prospects.

OBJECTIVES: Risk-sharing agreements (RSAs) between drug manufacturers and payers link coverage and reimbursement to real-world performance or utilization of medical products. These arrangements have garnered considerable attention in recent years. However, greater use outside the United States raises questions as to why their use has been limited in the US private sector, and whether their use might increase in the evolving US healthcare system. STUDY DESIGN: To understand current trends, success factors, and challenges in the use of RSAs, we conducted a review of RSAs, interviews, and a survey to understand key stakeholders' experiences and expectations for RSAs in the US private sector. METHODS: Trends in the numbers of RSAs were assessed using a database of RSAs. We also conducted in-depth interviews with stakeholders from pharmaceutical companies, payer organizations, and industry experts in the United States and European Union. In addition, we administered an online survey with a broader audience to identify perceptions of the future of RSAs in the United States. RESULTS: Most manufacturers and payers expressed interest in RSAs and see potential value in their use. Due to numerous barriers associated with outcomes-based agreements, stakeholders were more optimistic about financial-based RSAs. In the US private sector, however, there remains considerable interest--improved data systems and shifting incentives (via health reform and accountable care organizations) may generate more action. CONCLUSIONS: In the US commercial payer markets, there is continued interest among some manufacturers and payers in outcomes-based RSAs. Despite continued discussion and activity, the number of new agreements is still small.

Targeted erlotinib for first-line treatment of advanced non-small cell lung cancer: a budget impact analysis.

OBJECTIVES: A recent phase III trial showed that patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor specific EGFR mutations significantly benefit from first-line treatment with erlotinib compared to chemotherapy. This study sought to estimate the budget impact if coverage for EGFR testing and erlotinib as first-line therapy were provided in a hypothetical 500,000-member managed care plan. METHODS: The budget impact model was developed from a US health plan perspective to evaluate administration of the EGFR test and treatment with erlotinib for EGFR-positive patients, compared to non-targeted treatment with chemotherapy. The eligible patient population was estimated from age-stratified SEER incidence data. Clinical data were derived from key randomized controlled trials. Costs related to drug, administration, and adverse events were included. Sensitivity analyses were conducted to assess uncertainty. RESULTS: In a plan of 500,000 members, it was estimated there would be 91 newly diagnosed advanced NSCLC patients annually; 11 are expected to be EGFR-positive. Based on the testing and treatment assumptions, it was estimated that 3 patients in Scenario 1 and 6 patients in Scenario 2 receive erlotinib. Overall health plan expenditures would increase by $0.013 per member per month (PMPM). This increase is largely attributable to erlotinib drug costs, in part due to lengthened progression-free survival and treatment periods experienced in erlotinib-treated patients. EGFR testing contributes slightly, whereas adverse event costs mitigate the budget impact. The budget impact did not exceed $0.019 PMPM in sensitivity analyses. CONCLUSIONS: Coverage for targeted first-line erlotinib therapy in NSCLC likely results in a small budget impact for US health plans. The estimated impact may vary by plan, or if second-line or maintenance therapy, dose changes/interruptions, or impact on patients' quality-of-life were included.

Characterization of hairpin ribozyme reactions.

Hairpin ribozymes are small RNA catalytic motifs naturally found in the satellite RNAs of tobacco ringspot virus (TRsV), chicory yellow mottle virus (CYMoV), and arabis mosaic virus (ArMV). The catalytic activity of the hairpin ribozyme extends to both cleavage and ligation reactions. Here we describe methods for the kinetic analysis of the self-cleavage reaction under transcription reaction conditions. We also describe methods for the generation of DNA templates for subsequent in vitro transcription reaction of hairpin ribozymes. This is followed by a description of the preparation of the suitable RNA molecules for ligation reaction and their kinetic analysis.

Visuomotor learning enhanced by augmenting instantaneous trajectory error feedback during reaching.

We studied reach adaptation to a 30° visuomotor rotation to determine whether augmented error feedback can promote faster and more complete motor learning. Four groups of healthy adults reached with their unseen arm to visual targets surrounding a central starting point. A manipulandum tracked hand motion and projected a cursor onto a display immediately above the horizontal plane of movement. For one group, deviations from the ideal movement were amplified with a gain of 2 whereas another group experienced a gain of 3.1. The third group experienced an offset equal to the average error seen in the initial perturbations, while a fourth group served as controls. Learning in the gain 2 and offset groups was nearly twice as fast as controls. Moreover, the offset group averaged more reduction in error. Such error augmentation techniques may be useful for training novel visuomotor transformations as required of robotic teleoperators or in movement rehabilitation of the neurologically impaired.

A risk-benefit analysis of factor V Leiden testing to improve pregnancy outcomes: a case study of the capabilities of decision modeling in genomics.

PURPOSE: We sought to assess the benefits, risks, and personal utility of factor V Leiden mutation testing to improve pregnancy outcomes and to assess the utility of decision-analytic modeling for complex outcomes in genomics. METHODS: We developed a model to evaluate factor V Leiden testing among women with a history of recurrent pregnancy loss, including heparin therapy during pregnancy in mutation-positive women. Outcomes included venous thromboembolism, major bleeds, pregnancy loss, maternal mortality, and quality-adjusted life-years. RESULTS: Factor V Leiden testing in a hypothetical cohort of 10,000 women led to 7 fewer venous thromboembolic events, 90 fewer pregnancy losses, and an increase of 17 major bleeding events. Small improvements in quality-adjusted life-years were largely attributable to reduced mortality but also to improvements in health-related quality of life. However, sensitivity analyses indicate large variance in results due to data uncertainty. Furthermore, the complexity of outcomes limited our ability to fully capture the repercussions of testing in the quality-adjusted life-year measure. CONCLUSION: Factor V Leiden testing involves tradeoffs between clinical and personal utility, and additional effectiveness data are needed for heparin use to prevent pregnancy loss. Decision-analytic methods offer somewhat limited value in assessing these tradeoffs, suggesting that evaluation of complex outcomes will require novel approaches to appropriately capture patient-centered outcomes.Genet Med 2013:15(5):374-381.

Insights into the substrate specificity of a thioesterase Rv0098 of mycobacterium tuberculosis through X-ray crystallographic and molecular dynamics studies.

The crystal structure of Rv0098, a long-chain fatty acyl-CoA thioesterase from Mycobacterium tuberculosis with bound dodecanoic acid at the active site provided insights into the mode of substrate binding but did not reveal the structural basis of substrate specificities of varying chain length. Molecular dynamics studies demonstrated that certain residues of the substrate binding tunnel are flexible and thus modulate the length of the tunnel. The flexibility of the loop at the base of the tunnel was also found to be important for determining the length of the tunnel for accommodating appropriate substrates. A combination of crystallographic and molecular dynamics studies thus explained the structural basis of accommodating long chain substrates by Rv0098 of M. tuberculosis.

Sequence elements outside the catalytic core of natural hairpin ribozymes modulate the reactions differentially.

Abstract Hairpin ribozymes occur naturally only in the satellite RNAs of tobacco ringspot virus (TRsV), chicory yellow mottle virus (CYMoV) and arabis mosaic virus (ArMV). The catalytic centre of the predominantly studied sTRsV hairpin ribozyme, and of sArMV is organised around a four-way helical junction. We show here that sCYMoV features a five-way helical junction instead. Mutational analysis indicates that the fifth stem does not influence kinetic parameters of the sCYMoV hairpin ribozyme in vitro reactions, and therefore seems an appendix to that junction in the other ribozymes. We report further that all three ribozymes feature a three-way helical junction outside the catalytic core in stem A, with Watson-Crick complementarity to loop nucleotides in stem B. Kinetic analyses of cleavage and ligation reactions of several variants of the sTRsV and sCYMoV hairpin ribozymes in vitro show that the presence of this junction interferes with their reactions, particularly the ligation. We provide evidence that this is not due to a presumed interaction of the afore-mentioned elements in stems A and B. The evolutionary survival of this cis-inhibiting element seems rather to be caused by the coincidence of its position with that of the hammerhead ribozyme in the other RNA polarity.

Noninvasive assessment of glycosaminoglycan production in injectable tissue-engineered cartilage constructs using magnetic resonance imaging.

The glycosaminoglycan (GAG) content of engineered cartilage is a determinant of biochemical and mechanical quality. The ability to measure the degree to which GAG content is maintained or increases in an implant is therefore of importance in cartilage repair procedures. The gadolinium exclusion magnetic resonance imaging (MRI) method for estimating matrix fixed charge density (FCD) is ideally suited to this. One promising approach to cartilage repair is use of seeded injectable hydrogels. Accordingly, we assess the reliability of measuring GAG content in such a system ex vivo using MRI. Samples of the photopolymerizable hydrogel, poly(ethylene oxide) diacrylate, were seeded with bovine chondrocytes (approximately 2.4 million cells/sample). The FCD of the constructs was determined using MRI after 9, 16, 29, 36, 43, and 50 days of incubation. Values were correlated with the results of biochemical determination of GAG from the same samples. FCD and GAG were found to be statistically significantly correlated (R2 = 0.91, p < 0.01). We conclude that MRI-derived FCD measurements of FCD in injectable hydrogels reflect tissue GAG content and that this methodology therefore has potential for in vivo monitoring of such constructs.

Optimal methods for the preservation of cartilage samples in MRI and correlative biochemical studies.

MRI studies of cartilage require the prevention of sample degradation before and during scanning and during shipment for correlative studies. Methods to achieve this include immersion in protease inhibitors (PIs), refrigeration, and freezing. In this study, bovine nasal cartilage (BNC) samples were stored in Dulbecco's phosphate-buffered saline (DPBS), DPBS with standard PIs, or PI solution with GM6001, a potent metalloproteinase inhibitor. For each buffer, three samples were scanned at +4 degrees C and stored at +4 degrees C or at -20 degrees C with thawing prior to imaging. T2 and magnetization transfer (MT) rate, km, were measured weekly over 4 months, after which time water and glycosaminoglycan (GAG) contents were compared with those of matching tissue excised pre-storage. Samples in DPBS exhibited increased T2 (+33.6% after 1 month at +4 degrees C, P = 0.040) and decreased km (-20.6%, P = 0.004), while refrigeration in DPBS with PI and GM6001 yielded good stability (T2: +2.7%, P = 0.874; km: -4.2%, P = 0.654 after 108 days at +4 degrees C). Water content increased while GAG content markedly decreased in all samples. Thus, stability in cartilage MRI parameters can be optimized with appropriate storage conditions, but storage time should nonetheless be minimized.

Comparison of smear cytology with histopathology of the CT guided stereotactic brain biopsy.

The study was undertaken to determine the accuracy of cytological diagnosis of CNS lesions by comparing it with the final histopathological diagnosis of CT guided stereotactic brain biopsy. Squash preparations were prepared from 25 cases of CNS lesions operated in two years. These included 18 astrocytomas, 1 metastatic deposits, 1 epidermoid cyst, 1 Toxoplasmosis, 1 granulomatous inflammation and 3 cases showing normal brain parenchyma. The cytological diagnosis was available to the neurosurgeon within 10 minutes. The cytohistological correlation with paraffin block sections worked out to be 92%. Thus, this proved to be a fairly reliable and rapid method for immediate intra-operative diagnosis.

Crystal structure of dimeric FabZ of Plasmodium falciparum reveals conformational switching to active hexamers by peptide flips.

The crystal structure of beta-hydroxyacyl acyl carrier protein dehydratase of Plasmodium falciparum (PfFabZ) has been determined at a resolution of 2.4 A. PfFabZ has been found to exist as a homodimer (d-PfFabZ) in the crystals of the present study in contrast to the reported hexameric form (h-PfFabZ) which is a trimer of dimers crystallized in a different condition. The catalytic sites of this enzyme are located in deep narrow tunnel-shaped pockets formed at the dimer interface. A histidine residue from one subunit of the dimer and a glutamate residue from the other subunit lining the tunnel form the catalytic dyad in the reported crystal structures. While the position of glutamate remains unaltered in the crystal structure of d-PfFabZ compared to that in h-PfFabZ, the histidine residue takes up an entirely different conformation and moves away from the tunnel leading to a His-Phe cis-trans peptide flip at the histidine residue. In addition, a loop in the vicinity has been observed to undergo a similar flip at a Tyr-Pro peptide bond. These alterations not only prevent the formation of a hexamer but also distort the active site geometry resulting in a dimeric form of FabZ that is incapable of substrate binding. The dimeric state and an altered catalytic site architecture make d-PfFabZ distinctly different from the FabZ structures described so far. Dynamic light scattering and size exclusion chromatographic studies clearly indicate a pH-related switching of the dimers to active hexamers.