Synthesis, and anti-malarial screening, of 1-diethylamino-4- (dihydroartemisinin-10-yl)amino pentane

Artemisinin and its derivatives have become antimalarial drugs of choice because they are effective against most stages in the life cycle of  plasmodium and are safe for all, including pregnant women. World Health Organisation (WHO) has nevertheless recommended artemisinin based combination therapy (ACT) to guard against possible development of resistance, as observed with chloroquine. In this study we coupled dihydroartemisinin with 2-amino- 5-diethyl aminopentane (the chloroquine handle) by using the Mitsunobu coupling (an SN2 reaction). This involvesthe use of diisopropylazodicarboxylate (DIAD), triphenyl phosphine (Ph3P), 2-amino-5-diethylaminopentane and dihydroartemisinin (DHA) at room temperature to synthesize the target compound, 1-diethylamino-4-(dihydroartemisinin-10-yl)amino pentane {coded: DHA-CQ; IUPAC Name: N1,N1-diethyl-N4-(3,6,9- trimethyldecahydro- 3,12-epoxy[1,2]dioxepino[4,3-i] isochromen-10-yl) pentane-1,4-diamine}. The structure of DHA-CQ was determined from spectroscopic data (IR, 1H & 13C NMR, MS). The compound was screened at three dose levels of 3 mg/kg, 10 mg/kg and 30 mg/kg, for in vivo curative antimalarial activity against mice infected with Plasmodium berghei berghei. The target  compound also had an LD50 of 330 mg/kg in mice by the oral route. Asingle dose kinetics study was carried out and three different metabolites were identified.Keywords: Artemisinin; Chloroquine; Dihydroartemisinin; Plasmodium berghei berghei; Mitsunobu couplin

Financial Toxicity, Symptom Burden, Illness Perceptions, and Communication Confidence in Cancer Clinical Trial Participants

PURPOSE: Cancer clinical trial (CCT) participants are at risk for experiencing adverse associations from financial toxicity, but these remain understudied. METHODS: From July 2015 to July 2017, we prospectively enrolled CCT participants referred for financial assistance and a group of patients matched by age, sex, cancer type, trial, and trial phase. We assessed financial burden of cancer care, cost concerns about CCTs, physical (Edmonton Symptom Assessment Scale [ESAS]) and psychologic (Patient Health Questionnaire-4 [PHQ-4]) symptoms, illness perceptions (Brief Illness Perception Questionnaire), and communication confidence (Perceived Efficacy in Patient-Physician Interactions). Adjusting for age, sex, race, performance status, marital status, income, insurance, and disease status, we examined associations of financial burden and cost concerns with patients' symptoms, illness perceptions, and communication confidence. RESULTS: Of 198 patients, 112 (56.6%) reported financial burden and 82 (41.4%) reported cost concerns. Higher ESAS-total (odds ratio [OR] = 1.03; 95% CI, 1.01 to 1.06; P = .001), PHQ-4 depression (OR = 1.58; 95% CI, 1.20 to 2.08; P &lt; .001), PHQ-4 anxiety (OR = 1.26; 95% CI, 1.02 to 1.55; P = .025), and more negative illness perceptions (OR = 1.04; 95% CI, 1.00 to 1.07; P = .029) were associated with financial burden, but not communication confidence (OR = 0.98; 95% CI, 0.02 to 1.05; P = .587). Higher ESAS-total (OR = 1.03; 95% CI, 1.01 to 1.05; P = .004), PHQ-4 depression (OR = 1.36; 95% CI, 1.08 to 1.71; P = .03), PHQ-4 anxiety (OR = 1.26; 95% CI, 1.03 to 1.53; P = .018), more negative illness perceptions (OR = 1.06; 95% CI, 1.02 to 1.10; P = .001), and decreased communication confidence (OR = 0.93; 95% CI, 0.86 to 1.00; P = .029) were associated with cost concerns. CONCLUSION: In this study of CCT participants, greater symptom burden, more negative illness perceptions, and lower communication confidence were associated with financial toxicity, underscoring the importance of addressing these issues when seeking to alleviate adverse associations of financial toxicity. </jats:sec

Patient-reported care satisfaction and symptom burden in hospitalized patients with cancer.

2013 Background: Hospitalized patients with cancer often experience high symptom burden, which may impact their care satisfaction and use of health care services. Yet, studies describing these patients’ care satisfaction, symptom burden, and health care utilization are lacking. Methods: We prospectively enrolled patients with cancer and unplanned hospitalizations from 9/2014-4/2017. Upon admission, patients self-reported their care satisfaction (FAMCARE items asking about satisfaction regarding speed with which symptoms are treated and coordination of care) and physical (Edmonton Symptom Assessment System [ESAS]) and psychological (Patient Health Questionnaire 4 [PHQ4]) symptom burden. We used regression models to identify patient factors associated with care satisfaction. We also explored associations between patients’ care satisfaction, symptom burden, and hospital length of stay (LOS) in models adjusted for age, sex, marital status, comorbidity score, cancer type, cancer documented as curable/incurable, time since cancer diagnosis, and admission to a dedicated oncology service. Results: We enrolled 1,576 of 1,749 (90.1%) consecutive patients (mean age = 63.19±13.39 years, 46.3% female). Most reported being very satisfied/satisfied with the speed with which symptoms are treated (89.0%) and coordination of care (90.1%). Older age (B = 0.01, P &lt; .02 for both) and admission to a dedicated oncology service (B = 0.20, P &lt; .01 for both) were each independently associated with higher satisfaction with the speed with which symptoms are treated and coordination of care. Higher satisfaction with the speed with which symptoms are treated was associated with lower PHQ4 depression (B = -0.14, P = .01), PHQ4 anxiety (B = -0.11, P &lt; .01), ESAS physical (B = -1.30, P &lt; .01), and ESAS total (B = -2.44, P &lt; .01) symptoms. Higher satisfaction with coordination of care was associated with lower PHQ4 depression (B = -0.14, P = .02), PHQ4 anxiety (B = -0.16, P &lt; .01), ESAS physical (B = -1.30, P &lt; .01), and ESAS total (B = -2.75, P &lt; .01) symptoms. Satisfaction with the speed with which symptoms are treated (B = -0.47, P = .03) and coordination of care (B = -0.50, P = .03) were both associated with shorter hospital LOS. Conclusions: Most hospitalized patients with cancer reported high care satisfaction, which was associated with older age and admission to a dedicated oncology service. We found relationships among higher care satisfaction, lower symptom burden, and shorter hospital LOS, underscoring the importance of efforts to enhance symptom management and care coordination in this population. </jats:p

Randomized trial of a symptom monitoring intervention for hospitalized patients with advanced cancer (NCT03396510).

12014 Background: Hospitalized patients with advanced cancer experience a high symptom burden, which is associated with poor clinical outcomes and increased health care use. Symptom monitoring interventions are increasingly becoming standard of care in oncology, but studies of these interventions in the hospital setting are lacking. We evaluated the impact of a symptom monitoring intervention in hospitalized patients with advanced cancer. Methods: We randomly assigned hospitalized patients with advanced cancer who were admitted to the oncology service to a symptom monitoring intervention or usual care. Patients in both arms reported their symptoms (Edmonton Symptom Assessment System [ESAS] and Patient Health Questionnaire 4 [PHQ4], higher scores on both indicate greater symptom severity) daily via tablet computers. Patients assigned to the intervention had their symptom reports presented graphically with alerts for moderate/severe symptoms during daily oncology rounds. The primary endpoint was the proportion of days with improved symptoms for those who completed two or more days of symptoms. Secondary endpoints included hospital length of stay (LOS) and readmission rates. Results: From 2/2018-10/2019, we randomized 390 patients (76.2% enrollment rate); 320 completed two or more days of symptoms (median age=65.6 [range 18.8-93.2]; 43.8% female). The most common cancers were gastrointestinal (36.9%), lung (18.8%), and genitourinary (12.2%). Nearly half of patients (48.5%) had one or more comorbid conditions in addition to cancer. We found no significant differences between intervention and usual care regarding the proportion of days with improved ESAS total (B=-0.05, P=.17), ESAS physical (B=-0.02, P=.52), PHQ4 anxiety (B=-0.03, P=.33), and PHQ4 depression (B=-0.02, P=.44) symptoms. Intervention patients also did not differ from usual care with respect to secondary endpoints of hospital LOS (7.50 v 7.59 days, P=.88) and readmission rates within 30 days of discharge (32.5% v 25.6%, P=.18). Conclusions: For hospitalized patients with advanced cancer, this symptom monitoring intervention did not have a significant impact on their symptom burden and health care use. These findings do not support the routine integration of this type of symptom monitoring intervention for hospitalized patients with advanced cancer. The positive outcomes seen in previous studies of symptom monitoring interventions may not be reproduced in other patient populations and care settings. Support: UG1CA189823; Clinical trial information: NCT03396510 . </jats:p

Communicating the components of informed treatment decision-making in patients with pancreatic cancer receiving preoperative therapy.

147 Background: Preoperative therapy for localized pancreatic cancer represents an emerging treatment paradigm with the potential to provide significant benefits, yet with complex risks. Research is lacking about whether clinicians effectively communicate key components of informed decision-making for patients considering this treatment. Methods: From 2017-2019, we conducted a two-part, mixed methods study. In part 1, we conducted interviews with clinicians (medical/radiation/surgical oncology, n = 13) and patients with pancreatic cancer who had received preoperative therapy (n = 18) to explore perceptions of information needed to make informed decisions about preoperative therapy, from which we generated a list of key elements. In part 2, we audio recorded the initial multidisciplinary visits of patients with pancreatic cancer eligible for preoperative therapy (n = 20). Two coders (94% concordance) independently identified whether clinicians discussed key elements from part 1. Patients also completed a post-visit survey reporting whether clinicians discussed the key elements. We explored discordance between audio recordings and patient reports using qualitative, explanatory themes. Results: In part 1, we identified 13 key elements of informed treatment decision-making, including treatment logistics, alternatives, and potential risks/benefits. In part 2, recordings showed that most visits included discussions about logistics, such as the chemotherapy schedule (n = 20) and use of a port-a-cath (n = 20), whereas few included discussions about risks, such as the potential for hospitalizations (n = 7), urgent visits (n = 6), or needing help with daily tasks (n = 6). Patients reported hearing about potential benefits, such as likelihood of achieving surgery (n = 10) and cure (n = 7), even when these were not discussed. Qualitative themes across these discordant cases included clinician optimism regarding present day results versus historical findings and mentions of positive outcomes from prior patients without citing specific data or potential adverse outcomes. Conclusions: We identified key elements of information patients with pancreatic cancer need to make informed decisions about preoperative therapy. Although clinicians frequently disclosed much of this information, we found multiple cases of patient-clinician discordance for certain key elements, which underscores the need for interventions to enhance patient-clinician communication regarding pancreatic cancer treatment decisions. </jats:p

Patient-reported care satisfaction and symptom burden in hospitalized patients with cancer.

180 Background: Hospitalized patients with cancer often experience a high symptom burden, which may impact care satisfaction and healthcare utilization. However, research describing these patients’ care satisfaction, symptom burden, and health care use is lacking. We sought to investigate relationships among care satisfaction, physical and psychological symptom burden, and hospital length of stay (LOS) in hospitalized patients with cancer. Methods: We prospectively enrolled patients with cancer and unplanned hospitalizations from 9/2014 to 4/2017. Upon admission, we assessed patients’ care satisfaction (FAMCARE items: satisfaction with care coordination and the speed with which symptoms are treated) as well as their physical (Edmonton Symptom Assessment System [ESAS]) and psychological (Patient Health Questionnaire-4 [PHQ-4]) symptoms. We used regression models to identify factors associated with care satisfaction, and we also examined associations of care satisfaction with patients’ symptom burden and hospital length of stay (LOS). Results: Among 1,576 participants (median age = 65.0 years [range:19-96], 46.3% female, 70.9% with incurable cancer, 58.4% admitted to a dedicated oncology service), most reported being “satisfied” or “very satisfied” with care coordination (90.1%) and the speed with which symptoms are treated (89.0%). Older age (care coordination: B &lt; 0.01, P = 0.022, speed with which symptoms are treated: B = 0.01, P = 0.001) and admission to a dedicated oncology service (B = 0.20, P &lt; 0.001 for each) were associated with higher care satisfaction. Higher satisfaction with care coordination was associated with lower ESAS-physical (B = -1.28, P = 0.007), ESAS-total (B = -2.73, P &lt; 0.001), PHQ4-depression (B = -0.14, P = 0.022), and PHQ4-anxiety (B = -0.16, P = 0.008) symptoms. Higher satisfaction with the speed with which symptoms are treated was associated with lower ESAS-physical (B = -1.32, P = 0.003), ESAS-total (B = -2.46, P &lt; 0.001), PHQ4-depression (B = -0.14, P = 0.014), and PHQ4-anxiety (B = -0.17, P = 0.004) symptoms. Greater satisfaction with care coordination (B = -0.48, P = 0.040) and the speed with which symptoms are treated (B = -0.44, P = 0.041) were both associated with shorter LOS. Conclusions: Hospitalized patients with cancer report high care satisfaction, which correlates with older age and admission to a dedicated oncology service. Significant associations among higher care satisfaction, lower symptom burden, and shorter hospital LOS highlight the importance of improving symptom management and care coordination in this population. </jats:p

Associations of Skeletal Muscle With Symptom Burden and Clinical Outcomes in Hospitalized Patients With Advanced Cancer

Background: Low muscle mass (quantity) is common in patients with advanced cancer, but little is known about muscle radiodensity (quality). We sought to describe the associations of muscle mass and radiodensity with symptom burden, healthcare use, and survival in hospitalized patients with advanced cancer. Methods: We prospectively enrolled hospitalized patients with advanced cancer from September 2014 through May 2016. Upon admission, patients reported their physical (Edmonton Symptom Assessment System [ESAS]) and psychological (Patient Health Questionnaire-4 [PHQ-4]) symptoms. We used CT scans performed per routine care within 45 days before enrollment to evaluate muscle mass and radiodensity. We used regression models to examine associations of muscle mass and radiodensity with patients’ symptom burden, healthcare use (hospital length of stay and readmissions), and survival. Results: Of 1,121 patients enrolled, 677 had evaluable muscle data on CT (mean age, 62.86 ± 12.95 years; 51.1% female). Older age and female sex were associated with lower muscle mass (age: B, –0.16; P&lt;.001; female: B, –6.89; P&lt;.001) and radiodensity (age: B, –0.33; P&lt;.001; female: B, –1.66; P=.014), and higher BMI was associated with higher muscle mass (B, 0.58; P&lt;.001) and lower radiodensity (B, –0.61; P&lt;.001). Higher muscle mass was significantly associated with improved survival (hazard ratio, 0.97; P&lt;.001). Notably, higher muscle radiodensity was significantly associated with lower ESAS-Physical (B, –0.17; P=.016), ESAS-Total (B, –0.29; P=.002), PHQ-4-Depression (B, –0.03; P=.006), and PHQ-4-Anxiety (B, –0.03; P=.008) symptoms, as well as decreased hospital length of stay (B, –0.07; P=.005), risk of readmission or death in 90 days (odds ratio, 0.97; P&lt;.001), and improved survival (hazard ratio, 0.97; P&lt;.001). Conclusions: Although muscle mass (quantity) only correlated with survival, we found that muscle radiodensity (quality) was associated with patients’ symptoms, healthcare use, and survival. These findings underscore the added importance of assessing muscle quality when seeking to address adverse muscle changes in oncology.</jats:p

Patient-reported outcomes (PROs) in older adults with gastrointestinal (GI) cancer undergoing surgery.

159 Background: Older adults with GI cancer often experience poor surgical outcomes, yet little is known about their PROs, such as physical function, quality of life (QOL), and physical and psychological symptom burden. Methods: As part of a randomized trial of perioperative geriatric care, we prospectively enrolled adults age ≥65 with GI cancer planning to undergo surgical resection. We asked patients preoperatively to self-report their physical function (activities of daily living [ADLs] and instrumental ADLs [IADLs]), QOL (EORTC QLQ-C30), symptom burden (Edmonton Symptom Assessment System [ESAS], scores &gt; 3 considered moderate/severe [mod/sev]), depression symptoms (Geriatric Depression Scale [GDS], scores &gt; 4 represent a positive screen for depression), and comorbidities. We used regression models to explore relationships among PROs and clinical outcomes (receiving planned surgery, postoperative complications [Clavien-Dindo], hospital readmissions within 90 days, and survival). Results: From 9/2016 - 4/2019, we enrolled 160 of 221 (72.4%) patients approached (median age: 72, range: 65-92). At baseline, most (53.1%) reported at least one comorbidity and required assistance with ADLs (94.8%) and IADLs (52.3%). Patients reported an average of 2.56 mod/sev ESAS symptoms, and 27.7% screened positive for depression. For surgical outcomes, 137 patients (85.6%) underwent planned surgery, and 99 (72.2%) of these had at least one postoperative complication. Greater independence with ADLs was associated with undergoing planned surgery (OR = 1.21, P = .02), lower risk of complications (OR = 0.81, P &lt; .01), and improved survival (HR = 0.87, P = .02), but not readmissions. Greater independence with IADLs was associated with undergoing planned surgery (OR = 1.30, P = .03) and improved survival (HR = 0.73, P &lt; .01), but not other outcomes. Higher baseline QOL was only associated with lower risk of postoperative complications (OR = 0.97, P = .04). Higher depression scores were only associated with worse survival (HR = 1.13, P = .02). Higher baseline symptom burden predicted for shorter time to readmission (HR = 1.13, p = .03). Patient-reported number of comorbidities was associated with shorter time to readmission (HR = 1.49, p = .03) and higher risk of complications (OR = 1.70, P = .03). Conclusions: Older adults with GI cancer often have baseline functional limitations and a high symptom burden, all of which are associated with worse clinical outcomes. Future work should study whether addressing preoperative PROs could improve older patients’ surgical outcomes. Clinical trial information: NCT02810652 . </jats:p