Desmoid Tumors: A Comprehensive Review.

Desmoid tumors (DT) are rare, locally aggressive, fibroblastic soft-tissue tumors that are characterized by infiltrative growth and can affect organs and adjacent structures, resulting in substantial clinical burden impacting patients' health-related quality of life. Searches of PubMed, Embase, Cochrane, and key conferences were conducted in November 2021 and updated periodically through March 2023 to identify articles describing the burden of DT. Of 651 publications identified, 96 relevant ones were retained. Diagnosis of DT is challenging because of its morphologic heterogeneity and variable clinical presentation. Patients visit multiple healthcare providers, often facing delays in correct diagnosis. The low incidence of DT (estimated 3-5 cases per million person-years) limits disease awareness. Patients with DT experience a high symptom burden: up to 63% of patients experience chronic pain, which leads to sleep disturbance (73% of cases), irritability (46% of cases), and anxiety/depression (15% of cases). Frequently mentioned symptoms are pain, limited function and mobility, fatigue, muscle weakness, and swelling around the tumor. Overall, quality of life in patients with DT is lower than in healthy controls. There is no treatment approved by the US Food and Drug Administration for DT; however, treatment guidelines reference available options, such as active surveillance, surgery, systemic therapy, and locoregional therapy. Choice of active treatment may depend on tumor location, symptoms, and risk of morbidity. The substantial burden of illness of DT is related to difficulties in timely and accurate diagnosis, high symptom burden (pain and functional limitations), and decreased quality of life. There is a high unmet need for treatments that specifically target DT and improve quality of life.

GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS©): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial.

PURPOSE: The GODDESS© tool was developed to assess Desmoid Tumor/Aggressive Fibromatosis (DT/AF) symptom severity and impact on patients' lives. This study evaluated GODDESS©'s cross-sectional and longitudinal measurement properties. METHODS: The Phase 3, randomized placebo-controlled, DeFi study (NCT03785964) of nirogacestat in DT/AF was used to assess GODDESS©'s reliability, construct validity, responsiveness, and estimate of meaningful change thresholds (MCTs). Other patient-reported outcome (PRO) measures included Patient Global Impression of Severity (PGIS) in DT/AF symptoms, EORTC QLQ-C30, Brief Pain Inventory Short Form, and PROMIS Physical Function short-form 10a v2.0 plus 3 items. RESULTS: DeFi participants (N = 142) had a median age of 34 years (range: 18-76) and were mostly female (64.8%), with extra-abdominal (76.8%) or intra-abdominal tumors (23.2%). The GODDESS© symptom/impact scales showed internal consistency at baseline, cycles 4 and 7 (Cronbach's α > 0.70) and test-retest reliability (intra-class correlation coefficient > 0.85). GODDESS© scales correlated moderately to highly with PRO measures capturing similar content and differentiated among PGIS and Eastern Cooperative Oncology Group groups. GODDESS© scales detected improvement over time. For the total symptom score, a 1.30-point decrease was estimated as the within-person MCT and a 1.00-point decrease as the between-group MCT. For the physical functioning impact score, estimated within- and between-group MCTs were 0.60-point and 0.50-point decreases, respectively. Few participants exhibited symptom worsening. CONCLUSION: GODDESS© was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses. TRIAL REGISTRATION NUMBER AND REGISTRATION DATE: NCT03785964; December 24, 2018.

Overall and complete response rates as potential surrogates for overall survival in relapsed/refractory multiple myeloma.

Aim: The correlation between response and survival has not been well-studied in relapsed or refractory multiple myeloma (RRMM). Materials & methods: A systematic literature review of Medline, Embase and Cochrane databases (2010-06/2020) and relevant congresses (2018-2020) was performed to identify randomized clinical trials in RRMM reporting median overall survival (mOS), progression-free survival and response end points. The relationship between mOS and response end points was analyzed using Pearson's product-moment correlation. Results: A total of 81 records for 65 original studies, representing 12,827 patients were included. The correlation was moderate for mOS with overall response rate (Pearson r = 0.79), very good partial response (r = 0.73) and duration of response (r = 0.78); all were statistically significant. In linear regression models, estimated mOS gain was 0.48, 0.47 and 1.94 months per percentage point of overall response rate, very good partial response and complete response, respectively (all p < 0.001). Significance was maintained after adjustment for age, relapsed versus refractory multiple myeloma and study year. The analysis was limited by small sample sizes and inconsistent reporting of study-level covariates. Conclusion: These findings support short-term response-based end points as surrogates to survival in RRMM.

Treatments for multiple myeloma may not work for every patient and the cancer may come back. In clinical trials, it is difficult to find out how well new treatments work in allowing patients to live longer. This is especially true when patients have advanced disease that has returned or has not responded to treatment. How well a patient responds to treatment (i.e., has a decreased extent of disease) could indicate whether the drug will help the patient live longer, but the relationship between response to treatment and survival is not fully understood. We conducted a systematic review and meta-analysis to better understand how response rates and survival are related. A systematic review collects all the published research on a specific subject, and a meta-analysis is a statistical method that creates a single finding from several separate studies. This study found a moderate relationship between how long patients live after receiving treatment for multiple myeloma and their response to treatment. This would allow response-to-treatment data from clinical trials to be used to predict better survival and show the drug can help patients.

Disease and economic burden of surgery in desmoid tumors: a review.

INTRODUCTION: Desmoid tumors (DT) are soft-tissue tumors that infiltrate into surrounding structures with ill-defined margins. Although surgery is a potential treatment option, complete excision with negative margins is not often possible, the postsurgery recurrence rate is high, and surgery can result in disfigurement and/or loss of function. AREAS COVERED: We conducted a literature review to assess the burden of surgery in patients with DT, focusing on recurrence rates and functional deficits resulting from surgeries. Since economic data related to DT surgery is lacking, reviews of surgery costs in soft-tissue sarcomas and of general costs of amputations were conducted. Risk factors for DT recurrence after surgery are young age (<30 years), tumor location (extremities), tumor size (>5 cm in greatest diameter), positive resection margins, and history of trauma in the area of the primary tumor. Tumors in the extremities have the highest risk of recurrence (30%-90%). Lower rates of recurrences have been reported when radiotherapy was used after surgery (14%-38%). EXPERT OPINION: Although effective in specific cases, surgery may be associated with poor long-term functional outcomes and higher economic costs. Therefore, it is imperative to find alternative treatments with acceptable efficacy and safety profiles that do not adversely affect functional aspects in patients.

Multi-omics analysis identifies drivers of protein phosphorylation.

BACKGROUND: Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. The abundance of a phosphorylated peptide (phosphopeptide) is determined by the abundance of its parent protein and the proportion of target sites that are phosphorylated. RESULTS: We quantified phosphopeptides, proteins, and transcripts in heart, liver, and kidney tissue samples of mice from 58 strains of the Collaborative Cross strain panel. We mapped ~700 phosphorylation quantitative trait loci (phQTL) across the three tissues and applied genetic mediation analysis to identify causal drivers of phosphorylation. We identified kinases, phosphatases, cytokines, and other factors, including both known and potentially novel interactions between target proteins and genes that regulate site-specific phosphorylation. Our analysis highlights multiple targets of pyruvate dehydrogenase kinase 1 (PDK1), a regulator of mitochondrial function that shows reduced activity in the NZO/HILtJ mouse, a polygenic model of obesity and type 2 diabetes. CONCLUSIONS: Together, this integrative multi-omics analysis in genetically diverse CC strains provides a powerful tool to identify regulators of protein phosphorylation. The data generated in this study provides a resource for further exploration.

Characterizing the Patient Journey in Multiple Myeloma: Qualitative Review.

BACKGROUND: The patient experience of multiple myeloma (MM) is multifaceted and varies substantially between individuals. Current published information on the patient perspective and treatment of MM is limited, making it difficult to gain insights into patient needs regarding the condition. OBJECTIVE: In this review, a combined research method approach (ie, the review of published literature and social media posts) was undertaken to provide insight into patients' perspectives on the burden and treatment of MM, the impact of the COVID-19 pandemic, and the impact of MM on caregivers of patients with MM. METHODS: Targeted searches of PubMed and PsycINFO were conducted from November 16, 2010, to November 16, 2020; in parallel, patient-reported information derived from social media posts from 6 patient advocacy websites and YouTube were searched. The review of patient advocacy websites and YouTube targeted patient-reported information from patients with a self-reported diagnosis of MM who discussed their experience of MM and its treatments. RESULTS: A total of 27 articles and 138 posts were included (patient-reported information included data from 76 individuals), and results from both sources showed that patients experienced a variety of symptoms and treatment side effects, including neuropathy, fatigue, nausea, and back pain. These can affect areas of health-related quality of life (HRQOL), including physical functioning; emotional, psychological, and social well-being; the ability to work; and relationships. Patients valued involvement in treatment decision-making, and both the patient-reported information and the literature indicated that efficacy and tolerability strongly influence treatment decision-making. For patients, caregivers, and physicians, the preference for treatments was strongest when associated with increased survival. Caregivers can struggle to balance care responsibilities and jobs, and their HRQOL is affected in several areas, including emotional-, role-, social-, and work-related aspects of life. The COVID-19 pandemic has challenged patients' ability to manage MM because of limited hospital access and restrictions that negatively affected their lives, psychological well-being, and HRQOL. Unmet patient needs identified in the literature and patient-reported information were for more productive appointments with health care professionals, better-tolerated therapies, and more support for themselves and their caregivers. CONCLUSIONS: The combination of published literature and patient-reported information provides valuable and rich details on patient experiences and perceptions of MM and its treatment. The data highlighted that patients' HRQOL is impeded not only by the disease but also by treatment-related side effects. Patients in the literature and patient-reported information showed a strong preference for treatments that prolong life, and patients appeared to value participation in treatment decisions. However, there remain unmet needs and areas for further research, including treatment, caregiver burden, and how to conduct appointments with health care professionals. This may help improve the understanding of the journey of patients with MM. PLAIN LANGUAGE SUMMARY: Multiple Myeloma (MM) is the second most common cancer that affects blood cells. In this study, researchers wanted to know patients' views on the effects of MM and the treatments they received. Researchers also looked at the impact of the COVID-19 pandemic on patients' treatment and the impact of MM on caregivers. To this end, the researchers reviewed information from 27 published studies and 138 social media posts by 76 patients with MM. Patients commonly reported nerve pain, tiredness, feeling sick, and back pain caused by MM and the treatments they received. The effects of MM and treatments affected patients' physical function; emotional, psychological, and social well-being; ability to work; and relationships. The researchers found that patients wanted to be involved in decisions related to their treatment. The effectiveness against MM and known negative effects strongly influenced the choice of treatments for patients. Increased survival was the strongest factor in the choice of treatment for patients, caregivers, and doctors. Researchers found that the emotional-, role-, social-, and work-related aspects of caregivers' lives were affected by caring for patients with MM. The COVID-19 pandemic also affected the ability of patients to manage their MM because of limited hospital access and the effects of restrictions that impacted their lives and psychological well-being. Finally, the researchers identified some areas requiring improvement, including unproductive appointments with health care professionals, the need for treatments with fewer negative effects, and more support for patients with MM and their caregivers. This information may be useful to improve and understand the experience of patients with MM.

Patient, Family Member and Physician Perspectives and Experiences with AML Treatment Decision-Making.

INTRODUCTION: Treatment decisions in older adults with acute myeloid leukemia (AML) are challenging, particularly for those who are not candidates for intensive chemotherapy (IC), and the trade-offs patients, their families and physicians consider when choosing a treatment option are not well understood. This qualitative research explored the value of extending survival and the treatment decision-making process from a multi-stakeholder perspective. METHODS: Overall, 28 patients with AML (≥ 65 years old, unsuitable for IC), 25 of their relatives and 10 independent physicians from the US, UK and Canada took part in one-on-one, 60-minute qualitative interviews. RESULTS: Across all stakeholders, improved health-related quality of life (HRQoL), extended survival and relief of AML symptoms were recognized as most important in AML treatment decision-making. However, extending survival in 'good health' was more important than extending survival alone, particularly because of the extra time it gives patients and their relatives together, and allows patients to achieve important goals. Patients' limited understanding of available treatment options, paired with incorrect perceptions of treatment side effects, impacted their involvement in the treatment decision-making process. Patients and physicians perceived physicians to have the most influence in the decision-making process despite their priorities not always aligning. CONCLUSION: These findings illustrate the importance of having structured discussions which explicitly assess patients' goals and their understanding and expectations of treatments and also the need for patient friendly resources about the lived experience of AML and available treatment options. These measures will help to ensure that patients are fully involved in the shared decision-making process.

Response rates and minimal residual disease outcomes as potential surrogates for progression-free survival in newly diagnosed multiple myeloma.

Progression-free survival (PFS) is a common primary endpoint in newly diagnosed multiple myeloma (NDMM). Patients with NDMM typically have longer PFS and are more likely to achieve minimal residual disease (MRD) or complete response (CR) compared to patients with relapsed or refractory multiple myeloma. Response-based surrogate endpoints may hold value given the longer follow-up time required to evaluate PFS in NDMM. In this work, systematic literature reviews of Medline, Embase, and Cochrane databases (2010-06/2020) and relevant congresses (2018-2020) were performed to identify randomized clinical trials (RCTs) and real-world studies in NDMM reporting median PFS and objective response. Associations between PFS and each response endpoint were evaluated using Pearson's product-moment correlation weighted by sample size in each RCT arm. Unadjusted and adjusted weighted linear regression models were applied to estimate the gain in median PFS associated with each response endpoint. Statistically significant correlations were identified for median PFS with overall response rate (ORR; Pearson r = 0.59), CR (r = 0.48), stringent CR (sCR; r = 0.68), and MRD (r = 0.69). The unadjusted models estimated 0.50 (95% CI: 0.36, 0.64; p<0.001), 0.42 (95% CI: 0.25, 0.58; p<0.001), 1.05 (95% CI: 0.58, 1.52; p<0.001), and 0.35 (95% CI: 0.12, 0.58; p = 0.006) months of median PFS gained per point of ORR, CR, sCR, and MRD, respectively. Associations for median PFS remained statistically significant in models adjusted for age and treatment type with ORR (0.35, 95% CI: 0.21, 0.49; p<0.001), and adjusted for age and International Staging System risk stage with CR (0.29, 95% CI: 0.16, 0.41; p<0.001). Due to small sample size, adjusted models could not be constructed for sCR or MRD. Nevertheless, evidence of significant survival benefit (p<0.05) associated with MRD negativity and sCR was identified across real-world studies. These findings provide support for the use of response outcomes as surrogate endpoints to estimate PFS benefit in NDMM.

Patterns of undertreatment among patients with acute myeloid leukemia (AML): considerations for patients eligible for non-intensive chemotherapy (NIC).

Acute myeloid leukemia (AML) is a life-threatening malignancy that is more prevalent in the elderly. Because the patient population is heterogenous and advanced in age, choosing the optimal therapy can be challenging. There is strong evidence supporting antileukemic therapy, including standard intensive induction chemotherapy (IC) and non-intensive chemotherapy (NIC), for older patients with AML, and guidelines recommend treatment selection based on a patient's individual and disease characteristics as opposed to age alone. Nonetheless, historic evidence indicates that a high proportion of patients who may be candidates for NIC receive no active antileukemic treatment (NAAT), instead receiving only best supportive care (BSC). We conducted a focused literature review to assess current real-world patterns of undertreatment in AML. From a total of 25 identified studies reporting the proportion of patients with AML receiving NAAT, the proportion of patients treated with NAAT varied widely, ranging from 10 to 61.4% in the US and 24.1 to 35% in Europe. Characteristics associated with receipt of NAAT included clinical factors such as age, poor performance status, comorbidities, and uncontrolled concomitant conditions, as well as sociodemographic factors such as female sex, unmarried status, and lower income. Survival was diminished among patients receiving NAAT, with reported median overall survival values ranging from 1.2 to 4.8 months compared to 5 to 14.4 months with NIC. These findings suggest a proportion of patients who are candidates for NIC receive NAAT, potentially forfeiting the survival benefit of active antileukemic treatment.

Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia.

Background: Two combination therapies recently approved and recommended for use in combination with low-dose cytarabine (LDAC) in acute myeloid leukemia patients unfit for intensive chemotherapy are glasdegib+LDAC and venetoclax+LDAC. Materials & methods: An indirect treatment comparison used median overall survival, overall survival hazard ratios, complete remission (CR), CR+CR with incomplete blood count recovery and transfusion independence to assess comparative effectiveness, and a simulated treatment comparison accounted for differences in patient characteristics between trials. Results: Differences in efficacy between glasdegib+LDAC and venetoclax+LDAC were suggestive and not statistically significant. Conclusion: With no significant differences in comparative effectiveness, considerations such as safety profiles, burden of administration and patient preference are likely to guide treatment decisions.

The cost-effectiveness of glasdegib in combination with low-dose cytarabine, for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are not eligible to receive intensive induction chemotherapy in Canada.

AIM: The clinical efficacy and safety of DAURISMO (glasdegib) combined with low-dose cytarabine (LDAC) were demonstrated in the BRIGHT AML 1003 study among newly diagnosed acute myeloid leukemia patients who are not eligible to receive intensive chemotherapy. This study aims to evaluate its cost-effectiveness versus LDAC alone and azacitidine from a Canadian payer perspective. MATERIALS AND METHODS: A partitioned-survival model was developed with three health states: progression-free survival (PFS), relapse/progression and death. Clinical inputs were obtained from the BRIGHT AML 1003 study for glasdegib and LDAC, and from the two trial publications and indirect treatment comparison for azacitidine. Drug acquisition/administration, disease management, adverse event and end-of-life costs were considered. All costs were measured in Canadian dollars. Cost-effectiveness of glasdegib + LDAC was assessed against LDAC alone in main population, and against azacitidine by bone marrow blasts (BMB). A weighted average ICER was calculated to represent the current treatment use of Canadian clinical practice. The reference-case analysis was conducted probabilistically, and numerous probabilistic scenario analyses were conducted. RESULTS: The incremental cost-effectiveness ratios (ICERs) compared to LDAC alone was CAD $177,065 (a mean gain of 0.41 QALYs and an incremental cost of CAD $72,695), to azacitidine in 20-30% and >30% BMB group were CAD $178,201 (a mean gain of 0.34 QALYs and an incremental cost of CAD $59,889) and dominant (a mean gain of 0.28 QALYs while reducing costs by CAD $7,856) respectively, resulting in a weighted average ICER of CAD $81,310 per QALY. LIMITATIONS AND CONCLUSIONS: Though uncertainties remain with the generated PFS curve, the derived azacitidine curves, administration and vial wastage, the model has been built under the best available evidence and relied on clinical opinions where there were data gaps. The weighted average ICER suggests that glasdegib + LDAC is cost-effective at a CAD $100,000 willingness-to-pay threshold.

A quality-adjusted survival time without symptoms or toxicities analysis of glasdegib plus low-dose cytarabine versus low-dose cytarabine as initial therapy for acute myeloid leukemia in patients who are not considered candidates for intensive chemotherapy.

BACKGROUND: In a randomized study, glasdegib (a hedgehog inhibitor) plus low-dose cytarabine (LDAC) significantly prolonged survival in comparison with LDAC in patients with acute myeloid leukemia (AML). A quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) approach was used to evaluate comparative quality-adjusted survival. METHODS: Overall survival was partitioned into the following: time with any treatment-emergent grade 3 or higher adverse events (TOX); time without symptoms of disease progression or toxicity (TWiST); and time after treatment discontinuation due to insufficient clinical response, relapse, or death time after progression (REL). Q-TWiST was calculated by multiplying the restricted mean time in each state by respective utilities and then summing up the utility-adjusted time. RESULTS: At 20 months of follow-up, the survival probabilities for the glasdegib-LDAC arm and the LDAC arm were 28.2% and 7.9%, respectively. Glasdegib-LDAC patients (n = 78), in comparison with LDAC patients (n = 38), had significantly longer mean TWiST (+3.4 months; 95% confidence interval [CI], 1.8-5.2 months) and TOX (+0.8 months; 95% CI, 0.1-1.6 months) and longer but nonsignificant REL (+0.3 months; 95% CI, -1.9 to 2.3 months). Q-TWiST was 4.0 months (95% CI, 2.1-5.8 months) longer with glasdegib plus LDAC, and this translated into a 75% relative improvement in quality-adjusted survival with respect to LDAC. Results were robust to the length of follow-up (6-24 months) and remained significant when all adverse events, regardless of grade, were included. CONCLUSIONS: These results suggest that most of the survival benefit from glasdegib plus LDAC versus LDAC alone is TWiST, and this represents added time in relatively "good" health. These results support the clinical value of glasdegib plus LDAC as initial therapy for AML in patients for whom intensive chemotherapy is not an option.

Dissecting the Genetic Architecture of Cystatin C in Diversity Outbred Mice.

Plasma concentration of Cystatin C (CysC) level is a biomarker of glomerular filtration rate in the kidney. We use a Systems Genetics approach to investigate the genetic determinants of plasma CysC concentration. To do so we perform Quantitative Trait Loci (QTL) and expression QTL (eQTL) analysis of 120 Diversity Outbred (DO) female mice, 56 weeks of age. We performed network analysis of kidney gene expression to determine if the gene modules with common functions are associated with kidney biomarkers of chronic kidney diseases. Our data demonstrates that plasma concentrations and kidney mRNA levels of CysC are associated with genetic variation and are transcriptionally coregulated by immune genes. Specifically, Type-I interferon signaling genes are coexpressed with Cst3 mRNA levels and associated with CysC concentrations in plasma. Our findings demonstrate the complex control of CysC by genetic polymorphisms and inflammatory pathways.

Patient-Centered Insights on Treatment Decision Making and Living with Acute Myeloid Leukemia and Other Hematologic Cancers.

Expectations relating to treatment and survival, and factors influencing treatment decisions are not well understood in adult patients with acute myeloid leukemia. This study analyzed combined findings from a targeted literature review with patient-reported information shared on YouTube to further understand patient perspectives in hematologic cancers and, in particular, acute myeloid leukemia. The targeted literature review included articles concerning patient (aged ≥ 18 years) experiences or perspectives in acute myeloid leukemia or other hematologic cancers. YouTube video selection criteria included patients (aged ≥ 60 years) with self-reported acute myeloid leukemia. In total, 26 articles (13 acute myeloid leukemia-specific and 14 other hematologic cancers, with one relevant to both populations) and 28 videos pertaining to ten unique patients/caregivers were identified. Key concepts reported by patients included the perceived value of survival for achieving personal and/or life milestones, the emotional/psychological distress of their diagnosis, and the uncertainties about life expectancy/prognosis. Effective therapies that could potentially delay progression and extend life were of great importance to patients; however, these were considered in terms of quality-of-life impact and disruption to daily life. Many patients expressed concerns regarding the lack of treatment options, the possibility of side effects, and how their diagnosis and treatment would affect relationships, daily lives, and ability to complete certain tasks. Both data sources yielded valuable and rich information on the patient experience and perceptions of hematologic cancers, in particular for acute myeloid leukemia, and its treatments. Further understanding of these insights could aid discussions between clinicians, patients, and their caregivers regarding treatment decisions, highlight outcomes of importance to patients in clinical studies, and ultimately, inform patient-focused drug development and evaluation.

Using Social Media to Uncover Treatment Experiences and Decisions in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome Who Are Ineligible for Intensive Chemotherapy: Patient-Centric Qualitative Data Analysis.

BACKGROUND: Until recently, treatment options were limited for patients with acute myeloid leukemia and myelodysplastic syndrome (AML and MDS) who are ineligible for intensive chemotherapy. Owing to the condition's rapid progression, it is difficult to identify what is most important to patients when making treatment decisions. Patients' needs can be better addressed by gaining a deeper understanding of their perspectives, which is valuable in the decision-making process. The Food and Drug Administration recently encouraged the use of social media as a tool to gain insight on patients' perspectives regarding symptoms experienced and the impacts of their disease. OBJECTIVE: This study aimed to use disease-specific social media posts by patients with AML or MDS who are ineligible for intensive chemotherapy and their caregivers to capture factors they feel are most important, and to provide current evidence to inform and characterize these perspectives. METHODS: Posts by patients with AML or MDS and their caregivers were extracted from publicly available discussions on 3 large AML- or MDS-specific sites. These posts were manually reviewed to only include patients who are ineligible for intensive chemotherapy. A total of 1443 posts from 220 AML patients/caregivers and 2733 posts from 127 MDS patients/caregivers met the study inclusion criteria. A qualitative data analysis (QDA) of a sample of 85 patients'/caregivers' posts was conducted to identify themes, and a targeted QDA of posts from 79 users focused on treatment decision discussions. Posts were manually reviewed, and relevant text segments were coded and grouped into categories and overall themes. RESULTS: Eighty-six percent (73/85) of users in the overall QDA had relevant information about the key objectives. The most commonly discussed treatment experience theme was the humanistic burden of AML or MDS in terms of emotional/physical impact and impact on family (86%, 63/73 of users), followed by treatment decisions (56%, 41/73) and unmet needs (50%, 37/73). In the QDA of treatment decisions, 60 posts from 45 users contained relevant information. Patients commonly reported the desire to reach specific milestones, including birthdays and weddings. They wished for a better quality of life over quantity of life, did not want the risk of suffering from side effects, and expressed a clear preference to be at home rather than in a hospital or care home. CONCLUSIONS: This study was a novel application of disease-specific social media. It highlighted experiences in the current treatment of AML and MDS, including information gaps, patient/caregiver uncertainty, and the importance of understanding patients'/caregivers' goals and opinions. A clear finding from this research was the importance of reaching certain personal life goals and being at home with family and friends. The analysis showed that patients/caregivers face additional challenges, including humanistic impacts and a lack of information regarding treatment options.

Overall survival of glasdegib in combination with low-dose cytarabine, azacitidine, and decitabine among adult patients with previously untreated AML: comparative effectiveness using simulated treatment comparisons.

BACKGROUND: Until recently, treatments for older patients with AML ineligible to receive intensive chemotherapies were limited to hypomethylating agents, low-dose cytarabine (LDAC), or clinical trials. In 2018, the FDA approved combination glasdegib (GLAS) plus LDAC based on Phase II results demonstrating improved overall survival (OS) versus LDAC alone in previously untreated AML. However, no randomized clinical trials have directly compared GLAS + LDAC with other AML treatments. OBJECTIVE: Using both indirect treatment comparison (ITC) and simulated treatment comparison (STC), which adjusts for baseline differences between trials, the comparative effectiveness of GLAS + LDAC was compared with hypomethylating agent azacitidine (AZA) or decitabine (DEC). METHODS: A systematic literature review identified published trials of AZA or DEC versus LDAC among older AML patients ineligible for high-intensity chemotherapy. In addition to standard and covariate-adjusted ITC, STC was performed following guidance from the NICE Decision Support Unit (DSU). Using individual patient data from the Phase II GLAS + LDAC study, population-specific OS hazard ratios (HR) for GLAS + LDAC versus AZA or DEC were compared. Furthermore, covariate-adjusted ITC (Cox multivariate models) and STC were repeated using GLAS + LDAC versus LDAC data propensity-weighted for within-trial mean cytogenetic risk. As this initial step was not specified in the DSU, results from this second method were compared to the first STC following DSU guidance only. RESULTS: Standard ITC and STC both demonstrated significantly improved OS for GLAS + LDAC versus either AZA or DEC. Adjusting for key covariates, STC stepwise exponential models demonstrated GLAS + LDAC superiority to both AZA (HR=0.424; 95% CI: 0.228, 0.789) and DEC (HR=0.505; 95% CI: 0.269, 0.949). These significant results held using full or step-wise approaches, following DSU guidance only or the weighted STC approach. CONCLUSION: Using ITC and STC, GLAS + LDAC demonstrated superior OS to AZA or DEC in an adult population with previously untreated AML for whom intensive chemotherapy is not an option.

Glasdegib plus intensive/nonintensive chemotherapy in untreated acute myeloid leukemia: BRIGHT AML 1019 Phase III trials.

Glasdegib, an oral Hedgehog pathway inhibitor, has been associated with significantly improved survival when combined with low-dose cytarabine in patients with untreated acute myeloid leukemia (AML) who were unsuitable for intensive chemotherapy, when compared with low-dose cytarabine alone. BRIGHT AML 1019 (NCT03416179) comprises two independently powered Phase III, randomized (1:1), double-blind global trials evaluating oral glasdegib 100 mg once daily or placebo plus one of two standard chemotherapy regimens in adults with untreated AML. The intensive trial combines glasdegib/placebo with cytarabine and daunorubicin (7 + 3), while the nonintensive trial combines glasdegib/placebo with azacitidine. The primary end point of both studies is overall survival. Secondary end points include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Trial registration number: ClinicalTrials.gov identifier: NCT03416179.

Long-term Follow-up of Cheilectomy for Treatment of Hallux Rigidus.

BACKGROUND: Hallux rigidus is the most common arthritic condition in the foot. First metatarsophalangeal joint cheilectomy produces satisfactory results in retrospective studies with reported good to excellent results in up to 97% and pain relief and function in 92%. The results of cheilectomy for higher grades of hallux rigidus are less favorable. The purpose of this study was to evaluate the long-term functional results and survivorship of cheilectomy for treatment of hallux rigidus. METHODS: This was a retrospective, questionnaire-based study investigating the long-term results of cheilectomy for treatment of hallux rigidus. The preoperative arthritic grade was graded retrospectively according to the Hattrup and Johnson (H&J) grading system. A questionnaire was administered via email or telephone that included questions regarding pain recurrence following surgery, current functional status, and satisfaction with the operation. Kaplan-Meier survival analysis was performed to estimate survival time between arthritic grades. We reviewed 165 patients (169 feet) with an average follow-up of 6.6 (5.0-10.9) years. RESULTS: The overall survival rate (painless at the time of last follow-up) was 70.4% (119 feet), with no significant difference between the 3 H&J arthritic grades. Most of the recurrences (28 feet, 75%) were at the first 2 years following the surgery. Nine feet (5.3%) had a second procedure at a mean postoperative time of 3.6 (range, 1.6-7.4) years. Of the 169 feet, 117 (69.3%) reported being satisfied or very satisfied and 127 (75.1%) indicated they would repeat the operation under the same circumstances. CONCLUSION: Our study supports the use of cheilectomy for treatment of hallux rigidus (grade 1-3 Coughlin and Shurnas) as a reliable procedure with favorable results. At long-term follow-up, patients who underwent cheilectomy had a low revision rate and a moderately low rate of pain recurrence. LEVEL OF EVIDENCE: Level IV, retrospective case-series.

Risk Factors of QTc Prolongation in Women With Hormone Receptor‒positive/Human Epidermal Growth Factor Receptor 2‒negative Metastatic Breast Cancer: A Retrospective Analysis of Health Care Claims Data.

PURPOSE: In addition to biomarker status, treatment selection for metastatic breast cancer (mBC) includes individual patient and clinical characteristics such as tumor burden, timing of disease recurrence, and comorbidities. Women with mBC may take medications that can increase the risk of drug-induced toxicities, including prolongation of cardiac repolarization (prolongation of QT interval). Corrected QT (QTc) prolongation, a toxicity associated with many cancer treatments, can lead to potentially life-threatening ventricular arrhythmias. As such, it is important to identify patients at risk for QTc prolongation due to comorbid conditions, concomitant medications, or electrolyte abnormalities. This real-world study estimated the proportion of women with hormone receptor‒positive (HR+)/human epidermal growth factor receptor 2‒negative (HER2‒) mBC who may be at risk of developing QTc prolongation. Results in the elderly are also included. METHODS: This retrospective, cross-sectional cohort study used the Truven Health MarketScan and Optum Clinformatics administrative claims databases. Patients' medical and pharmacy data were evaluated to assess the risk of QTc prolongation. Prescription and medication administration claims were evaluated during the 7-day period before the index date (ie, first secondary neoplasm diagnosis). In addition, International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification, codes were evaluated 12 months before the index date to describe congenital long QT syndrome, cardiac disease, and electrolyte abnormalities. FINDINGS: A cohort of 24,340 women with HR+/HER2‒ mBC were identified, including 5059 women aged 65-74 years and 4851 aged ≥75 years. Based on an overall analysis of risk factors (congenital long QT syndrome, cardiovascular disease, electrolyte abnormalities, or concomitant medications), 29.5% of all patients, 33.2% of patients aged 65-74 years, and 40.5% of patients aged ≥75 years had risk factors for QTc prolongation. IMPLICATIONS: This analysis of real-world data indicates that almost 1 in 3 women with HR+/HER2‒ mBC had congenital long QT syndrome, cardiovascular disease, and/or electrolyte abnormalities or received a concomitant medication that could increase the risk of developing QTc prolongation. The risk factors for congenital long QT syndrome, cardiovascular disease, or electrolyte abnormalities were more common in older patients. This analysis emphasizes the importance of individualized benefit/risk assessment during treatment decisions, especially when considering drugs with known or possible QTc prolongation risk.

Health-related quality of life in acute myeloid leukemia patients not eligible for intensive chemotherapy: results of a systematic literature review.

BACKGROUND: AML is a rapidly progressing bone marrow cancer, with poor survival rates compared to other types of leukemia. IC and NIC as well as BSC treatment options are available; however, there is scant published literature on the impact of disease and treatment on the HRQoL in patients receiving NIC. AIM: This study determined the HRQoL among NIC AML patients. MATERIALS AND METHODS: Embase, Medline, Cochrane database, and conference abstracts were searched using the prespecified PICOS criteria from January 2000 to November 2017 for studies reporting HRQoL and patient preference utilities in NIC AML. Studies on patients with RAEB-t MDS, randomized clinical trials (RCTs), prospective observational studies, and patient surveys were included, while systematic reviews and meta-analyses were used for bibliographic searching. RESULTS: Thirteen records from 12 original studies were identified. These included five records from four RCTs, three prospective studies, four patient survey studies, and one cost-effectiveness analysis. At baseline, NIC AML patients had poor HRQoL scores especially in fatigue (33) and GHS (50) on a 0-100 scale, with higher scores indicating better health. Low baseline HRQoL scores, especially PF and fatigue (<50) were shown to be significant independent predictors of poor survival. Clinical responders demonstrated meaningful improvements, especially in PF and fatigue, along with other health domains after being treated with NIC agents across several studies. CONCLUSION: HRQoL is poor for patients with NIC AML; measures such as fatigue and PF at baseline have been identified as independent prognostic factors for overall survival with several studies showing improvement in both domains with treatment. RCTs should incorporate evaluation of treatment impact on patients' PF and fatigue as important measures of effectiveness.