Patient experience and quality of life during neoadjuvant therapy for pancreatic cancer: a systematic review and study protocol.

PURPOSE: Neoadjuvant therapy (NT) is increasingly being offered to patients with pancreatic ductal adenocarcinoma (PDAC) prior to surgical resection. However, the experience and quality of life (QOL) of patients undergoing NT are poorly understood. METHODS: A systematic review of the Cinahl, Embase, Medline, Pubmed, Scopus, and Web of Science databases was conducted to evaluate the available literature pertaining to the experience and QOL of patient's undergoing NT for PDAC. RESULTS: Among 6041 articles screened, only six met criteria for full-text review including three prospective clinical trials of NT with QOL secondary endpoints. Overall, global QOL during or following NT did not significantly change from baseline. Pain scores seemed to improve during NT while the impact of NT on physical functioning varied across studies. No studies were identified evaluating other aspects of the patient experience. CONCLUSION: Although NT appears to have a minor impact on the QOL of patients with PDAC, this systematic review identified significant evidence gaps in the literature. A protocol of a prospective observational cohort study utilizing a digital smartphone app that aims to evaluate the patient experience and longitudinal QOL of patients with PDAC undergoing NT is presented.

Patient and caregiver preferences for the potential benefits and risks of a seizure forecasting device: A best-worst scaling.

BACKGROUND: Epilepsy is the 4th most common neurological disorder and is characterized by recurrent, unpredictable seizures. The ability to forecast seizures is a significant unmet need and would have a transformative effect on the lives of people living with epilepsy. In an effort to address this need, the Epilepsy Foundation has committed effort and resources to promote the development of seizure forecasting devices (SFD). OBJECTIVE: To promote user-centered design of future SFD, we sought to quantify patient and caregiver preferences for the potential benefits and risks of SFD. METHODS: A community-centered approach was used to develop a survey incorporating a novel best-worst scaling (BWS) to assess preferences for SFD. A main-effect orthogonal array was used to design and generate 18 "prototypes" that systematically varied across six attributes: seizure forecasting probability, seizure forecasting range, inaccuracy of forecasting, amount of time required to use the device, how the device is worn, and cost. The dependent variable was the attributes that respondents selected the best and worst in each profile, and a choice model was estimated using conditional logistic regression, which was also stratified and compared across patients and caregivers. Respondents also indicated that they would accept each of the prototype SFDs if it were real. These acceptance data and net monetary benefits (relative to the least preferred SFD) were explored. RESULTS: There were 633 eligible respondents; 493 (78%) completed at least one task. Responses indicated that 346 (68%) had epilepsy, and 147 (29%) were primary caregivers or family members of someone with epilepsy. The data show that short forecasting range is the most favored among experimental attributes, followed by mid forecasting range and notification of high chance of seizure. Having the device implanted is the least favorable attribute. Stated preferences differed between patients and caregivers (p < 0.001) for range of forecasting and inaccuracy of device. Caregivers preferred any range of forecasting, regardless of length, more than patients. Patients cared less about inaccuracy of the device compared to caregivers. The groups also differ in impact of fear of having seizures (versus actually having seizures) (p = 0.034) and on device acceptance. The acceptance of devices ranged from 42.3% to 95%, with caregivers being more likely to use a device (p < 0.05) for the majority of device profiles. Acceptance of devices varied with net monetary benefit of the best device being $717.44 more per month relative to the least preferred device. CONCLUSION: Our finding extends previous calls for seizure forecasting devices by demonstrating the value that they might provide to patients and caregivers affected by epilepsy and the feature that might be most and least desirable. In addition to guiding device development, the data can help inform regulatory decisions makers.

Parent clinical trial priorities for fragile X syndrome: a best-worst scaling.

An expansion in the availability of clinical drug trials for genetic neurodevelopmental conditions is underway. Delineating patient priorities is key to the success of drug development and clinical trial design. There is a lack of evidence about parent decision-making in the context of clinical drug trials for genetic neurodevelopmental conditions. We assessed parents' priorities when making a decision whether to enroll their child with fragile X syndrome (FXS) in a clinical drug trial. An online survey included a best-worst scaling method for parents to prioritize motivating and discouraging factors for child enrollment. Parents were recruited through the National Fragile X Foundation and FRAXA. Sequential best-worst with conditional logit analysis was used to determine how parents prioritize motivating and discouraging factors about trial enrollment decisions. Respondents (N = 354) were largely biological mothers (83%) of an individual with FXS who ranged in age from under 5 to over 21 years. The highest motivating factor was a trial to test a drug targeting the underlying FXS mechanism (coeff = 3.28, p < 0.001), followed by the potential of the drug to help many people (coeff = 3.03, p < 0.001). Respondents rated requirement of blood draws (coeff = -3.09, p < 0.001), loss of access to the drug post trial (coeff = -3.01, p < 0.001), and drug side effects (coeff = -2.96, p < 0.001) as most discouraging. The priorities defined by parents can be incorporated into evidence-based trial design and execution to enhance the enrollment process.

Tuning isoform selectivity and bortezomib sensitivity with a new class of alkenyl indene PDI inhibitor.

Protein disulfide isomerase (PDI, PDIA1) is an emerging therapeutic target in oncology. PDI inhibitors have demonstrated a unique propensity to selectively induce apoptosis in cancer cells and overcome resistance to existing therapies, although drug candidates have not yet progressed to the stage of clinical development. We recently reported the discovery of lead indene compound E64FC26 as a potent pan-PDI inhibitor that enhances the cytotoxic effects of proteasome inhibitors in panels of Multiple Myeloma (MM) cells and MM mouse models. An extensive medicinal chemistry program has led to the generation of a diverse library of indene-containing molecules with varying degrees of proteasome inhibitor potentiating activity. These compounds were generated by a novel nucleophilic aromatic ring cyclization and dehydration reaction from the precursor ketones. The results provide detailed structure activity relationships (SAR) around this indene pharmacophore and show a high degree of correlation between potency of PDI inhibition and bortezomib (Btz) potentiation in MM cells. Inhibition of PDI leads to ER and oxidative stress characterized by the accumulation of misfolded poly-ubiquitinated proteins and the induction of UPR biomarkers ATF4, CHOP, and Nrf2. This work characterizes the synthesis and SAR of a new chemical class and further validates PDI as a therapeutic target in MM as a single agent and in combination with proteasome inhibitors.