Cancer research is not correlated with driver gene mutation burdens.

BACKGROUND: Cancer research is pursued with the goal of positively impacting patients with cancer. Decisions regarding how to allocate research funds reflect a complex balancing of priorities and factors. Even though these are subjective decisions, they should be made with consideration of all available objective facts. An accurate estimate of the affected cancer patient population by mutation is one variable that has only recently become available to inform funding decisions. METHODS: We compared the overall incident burden of mutations within each cancer-associated gene with two measures of cancer research efforts: research grant funding amounts and numbers of academic manuscripts. We ask to what degree the aggregate set of cancer research efforts reflects the relative burdens of the different cancer genetic drivers. We thoroughly investigate the design of our queries to ensure that the presented results are robust and conclusions are well justified. FINDINGS: We find cancer research is generally not correlated with the relative burden of mutation within the different genetic drivers of cancer. CONCLUSIONS: We suggest that cancer research would benefit from incorporating, among other factors, an epidemiologically informed mutation-estimate baseline into a larger framework for funding and research allocation decisions. FUNDING: This work was supported in part by the National Institutes of Health (NIH) P30CA014195 and NIH DP2AT011327.

Cost-effectiveness of sutimlimab in cold agglutinin disease.

Primary cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by cold-reactive antibodies that bind to red blood cells and lead to complement-mediated hemolysis. Patients with primary CAD experience the burden of increased health resource utilization and reduced quality of life. The standard-of-care (SOC) in patients with primary CAD has included cold avoidance, transfusion support, and chemoimmunotherapy. The use of sutimlimab, a humanized monoclonal antibody that selectively inhibits C1-mediated hemolysis, was shown to reduce transfusion-dependence and improve quality of life across two pivotal phase 3 studies, further supported by 2-year extension data. Using data from the transfusion-dependent patient population that led to sutimlimab's initial FDA approval, we performed the first-ever cost-effectiveness analysis in primary CAD. The projected incremental cost-effectiveness ratio (ICER) in our Markov model was $2 340 000/QALY, significantly above an upper-end conventional US willingness-to-pay threshold of $150 000/QALY. These results are consistent across scenarios of higher body weight and a pan-refractory SOC patient phenotype (i.e., treated sequentially with bendamustine-rituximab, bortezomib, ibrutinib, and eculizumab). No parameter variations in deterministic sensitivity analyses changed our conclusion. In probabilistic sensitivity analysis, SOC was favored over sutimlimab in 100% of 10 000 iterations. Exploratory threshold analyses showed that significant price reduction (>80%) or time-limited treatment (<18 months) followed by lifelong clinical remission off sutimlimab would allow sutimlimab to become cost-effective. The impact of sutimlimab on health system costs with longer term follow-up data merits future study and consideration through a distributional cost-effectiveness framework.

Cost-effectiveness of prophylaxis with recombinant vs plasma-derived VWF in severe von Willebrand disease in the United States.

ABSTRACT: We evaluated the cost-effectiveness of prophylaxis with recombinant von Willebrand factor (rVWF) vs with plasma-derived von Willebrand factor (pdVWF) for patients with severe Von Willebrand disease. We found that rVWF is a cost-saving factor replacement compared with pdVWF across all willingness-to-pay thresholds in the United States.

Cost-effectiveness of bevacizumab therapy in the care of patients with hereditary hemorrhagic telangiectasia.

ABSTRACT: No US Food and Drug Administration- or European Medicines Agency-approved therapies exist for bleeding due to hereditary hemorrhagic telangiectasia (HHT), the second-most common inherited bleeding disorder worldwide. The current standard of care (SOC) includes iron and red cell supplementation, alongside the necessary hemostatic procedures, none of which target underlying disease pathogenesis. Recent evidence has demonstrated that bleeding pathophysiology is amenable to systemic antiangiogenic therapy with the anti-vascular endothelial growth factor bevacizumab. Despite its high cost, the addition of longitudinal bevacizumab to the current SOC may reduce overall health care resource use and improve patient quality of life. We conducted, to our knowledge, the first cost-effectiveness analysis of IV bevacizumab in patients with HHT with the moderate-to-severe phenotype, comparing bevacizumab added to SOC vs SOC alone. The primary outcome was the incremental net monetary benefit (iNMB) reported over a lifetime time horizon and across accepted willingness-to-pay thresholds, in US dollar per quality-adjusted life year (QALY). Bevacizumab therapy accrued 9.3 QALYs while generating $428 000 in costs, compared with 8.3 QALYs and $699 000 in costs accrued in the SOC strategy. The iNMB of bevacizumab therapy vs the SOC was $433 000. No parameter variation and no scenario analysis, including choice of iron supplementation product, changed the outcome of bevacizumab being a cost-saving strategy. Bevacizumab therapy also saved patients an average of 133 hours spent receiving HHT-specific care per year of life. In probabilistic sensitivity analysis, bevacizumab was favored in 100% of all 10 000 Monte Carlo iterations across base-case and all scenario analyses. Bevacizumab should be considered for more favorable formulary placement in the care of patients with moderate-to-severe HHT.

Cost-effectiveness of rapid vs in-house vs send-out ADAMTS13 testing for immune thrombotic thrombocytopenic purpura.

ABSTRACT: While awaiting confirmatory results, empiric therapy for patients suspected to have immune thrombotic thrombocytopenic purpura (iTTP) provides benefits and also accrues risks and costs. Rapid assays for ADAMTS13 may be able to avoid the cost and risk exposure associated with empiric treatment. We conducted, to our knowledge, the first cost-effectiveness evaluation of testing strategies with rapid vs traditional ADAMTS13 assays in patients with intermediate- to high-risk PLASMIC scores, with and without caplacizumab use. We built a Markov cohort simulation with 4 clinical base-case analyses: (1) intermediate-risk PLASMIC score with caplacizumab; (2) intermediate-risk PLASMIC score without caplacizumab; (3) high-risk PLASMIC score with caplacizumab; and (4) high-risk PLASMIC score without caplacizumab. Each of these evaluated 3 testing strategies: (1) rapid assay (<1-hour turnaround); (2) in-house fluorescence resonance energy transfer (FRET)-based assay (24-hour turnaround); and (3) send-out FRET-based assay (72-hour turnaround). The primary outcome was the incremental net monetary benefit reported over a 3-day time horizon and across accepted willingness-to-pay thresholds in US dollars per quality-adjusted life-year (QALY). While accruing the same amount of QALYs, the rapid assay strategy saved up to $46 820 (95% CI, $41 961-$52 486) per patient tested. No parameter variation changed the outcome. In probabilistic sensitivity analyses, the rapid assay strategy was favored in 100% (3 base cases and scenario analyses) and 99% (1 base-case and scenario analysis) across 100 000 Monte Carlo iterations within each. Rapid ADAMTS13 testing for patients with intermediate- or high-risk PLASMIC scores yields significant per patient cost savings, achieved by reducing the costs associated with unnecessary therapeutic plasma exchange and caplacizumab therapy in patients without iTTP.

Decreasing alloimmunization-specific mortality in sickle cell disease in the United States: Cost-effectiveness of a shared transfusion resource.

Red blood cell alloimmunization and consequent delayed hemolytic transfusion reaction (DHTR) incidence and mortality in patients with sickle cell disease (SCD) are high. A shared transfusion resource has decreased both in other countries, while in the United States cost concerns persist. We conducted a Markov cohort simulation of a birth cohort of alloimmunized patients with SCD to estimate lifetime DHTR incidence, DHTR-specific mortality, quality-adjusted life expectancy (QALE), and costs with the implementation of a shared transfusion resource to identify antibody history versus without (i.e., status quo). We conducted our analysis using a lifetime analytic time horizon and from a United States health system perspective. Implementation of shared transfusion resource projects to decrease cumulative DHTR-specific mortality by 26% for alloimmunized patients with SCD in the United States, relative to the status quo. For an average patient population of 32 000, this intervention would generate a discounted increment of 4000 QALYs at an incremental discounted cost of $0.3 billion, resulting in an incremental cost-effectiveness ratio of $75 600/QALY [95% credible interval $70 200-81 400/QALY]. The results are most sensitive to the baseline lifetime medical expenditure of patients with SCD. Alloantibody data exchange is cost-effective in 100% of 10 000 Monte Carlo simulations. The resource would theoretically need a minimum patient population of 1819 patients or cost no more than $5.29 million annually to be cost-effective. By reducing DHTR-specific mortality, a shared transfusion resource in the United States projects to be a life-saving and cost-effective intervention for patients with SCD in the United States.

Association of the Stanford Integrated Psychosocial Assessment for Transplant and 1-Year Outcome of Living Kidney Transplantation in Japan.

BACKGROUND: Because most kidney transplantations in Japan are performed on the basis of living donors, after-transplant outcomes should achieve optimum results, overcoming participants' possible reduced adherence. OBJECTIVE: To investigate the association between the Japanese version of the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT-J) and outcomes, 1 year after the patient's living kidney transplant (LKT). METHODS: The prospective cohort study was undertaken at Tokyo Women's Medical University Hospital from January 2020 to July 2021, with a 1-year follow-up period. The SIPAT-J assesses 18 psychosocial risk factors: (1) Patient's Readiness Level and Illness Management (SIPAT A), (2) Social Support System Level of Readiness (SIPAT B), (3) Psychological Stability and Psychopathology (SIPAT C), and (4) Lifestyle and Effect of Substance Use (SIPAT D). The evaluators, a psychiatrist and 3 clinical psychologists, conducted an independent, blinded application of the SIPAT-J using participants' medical records. The study focused on physical composite outcomes, psychiatric outcomes, and nonadherent behaviors. RESULTS: The participants were 173 LKT recipients (median age [interquartile range], 51 [38-59]); 67.1% were male and 67.1% were employed. The median (interquartile range) SIPAT scores were SIPAT A [7 (5-9)], SIPAT B [7 (5-9)], SIPAT C [2 (0-4)], SIPAT D [3 (3-4)], and SIPAT total [20 (16-23)]. The physical composite outcome was 25 (14.5%), psychiatric outcome 9 (5.2%), and nonadherent behavior 17 (9.8%). SIPAT C (odds ratio = 1.34, 95% confidence interval = 1.06-1.72, P = 0.02) was significantly associated with the psychiatric outcome. SIPAT B (odds ratio = 1.49, 95% confidence interval = 1.12-1.98, P = 0.01) and SIPAT total (odds ratio = 1.13, 95% confidence interval = 1.03-1.24, P = 0.01) were significantly associated with nonadherent behaviors. There was no significant association between the SIPAT and physical composite outcomes. CONCLUSION: This study is the first to examine the association between SIPAT and physical and psychiatric outcomes 1 year after LKT, controlling for follow-up periods and factors other than SIPAT. Comprehensive psychosocial assessment before LKT and early identification of factors that may negatively affect transplant success can allow targeted interventions to be implemented and increase the likelihood of favorable recipient outcomes.

Leucine zipper protein 1 (LUZP1) regulates the constriction velocity of the contractile ring during cytokinesis.

There has been a great deal of research on cell division and its mechanisms; however, its processes still have many unknowns. To find novel proteins that regulate cell division, we performed the screening using siRNAs and/or the expression plasmid of the target genes and identified leucine zipper protein 1 (LUZP1). Recent studies have shown that LUZP1 interacts with various proteins and stabilizes the actin cytoskeleton; however, the function of LUZP1 in mitosis is not known. In this study, we found that LUZP1 colocalized with the chromosomal passenger complex (CPC) at the centromere in metaphase and at the central spindle in anaphase and that these LUZP1 localizations were regulated by CPC activity and kinesin family member 20A (KIF20A). Mass spectrometry analysis identified that LUZP1 interacted with death-associated protein kinase 3 (DAPK3), one regulator of the cleavage furrow ingression in cytokinesis. In addition, we found that LUZP1 also interacted with myosin light chain 9 (MYL9), a substrate of DAPK3, and comprehensively inhibited MYL9 phosphorylation by DAPK3. In line with a known role for MYL9 in the actin-myosin contraction, LUZP1 suppression accelerated the constriction velocity at the division plane in our time-lapse analysis. Our study indicates that LUZP1 is a novel regulator for cytokinesis that regulates the constriction velocity of the contractile ring.

Family functioning before kidney transplantation from living-related donors: Perspectives of donors and recipients in Japan.

INTRODUCTION: In Japan, approximately 90% of kidney transplantations involve living donors who are relatives. Selection of a living donor from potential family member donors could affect the entire family. However, reports focusing on preliving-related kidney transplant (LRKT) family functioning are lacking. Family functioning comprises ways that family members communicate and cooperate with each other. The Family Assessment Device (FAD) was used to measure family functioning from the perspective of donors and recipients just prior to LRKT. METHOD: A total of 122 donor-recipient pairs (244 participants in total) who planned to have LRKT were recruited consecutively from July 2020 to July 2021 and included in the analysis. RESULTS: There was no significant difference in FAD scores between donors and recipients, with approximately 20% of both groups reporting poor family functioning. Differences in family functioning according to types of relatives were shown in recipients. The rate of poor family functioning was significantly lower in the spouse group than in the parent-to-child group (recipient: 6.6%, 29.3%; donor: 8.2%, 34.1%, respectively). However, agreement regarding good or poor family functioning assessment was high in the parent-to-child pairs and low in the spouse pairs. DISCUSSION: Most LRKT donors and recipients reported good family functioning; however, some perceived poor family functioning. Evaluations by donors did not always align with that of recipients, especially among spouse pairs. It is important to treat them as independent entities. Preoperative assessment to connect them with appropriate support can enhance recovery after LRKT. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Global Health Resource Utilization and Cost-Effectiveness of Therapeutics and Diagnostics in Immune Thrombotic Thrombocytopenic Purpura (TTP).

In this review, we examine the current landscape of health resource utilization and cost-effectiveness data in the care of patient populations with immune thrombotic thrombocytopenic purpura. We focus on the therapeutic (therapeutic plasma exchange, glucocorticoids, rituximab, caplacizumab) and diagnostic (ADAMTS13 assay) health technologies employed in the care of patients with this rare disease. Health resource utilization and cost-effectiveness data are limited to the high-income country context. Measurement of TTP-specific utility weights in the high-income country context and collection of health resource utilization data in the low- and middle-income country settings would enable an evaluation of country-specific quality-adjusted life expectancy and cost-effectiveness of these therapeutic and diagnostic health technologies. This quantification of value is one way to mitigate cost concerns where they exist.

Characterization of the stanford integrated psychosocial assessment for transplant for heart, liver, and kidney transplant candidates in Japan.

BACKGROUND: The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a comprehensive psychosocial assessment proven useful for predicting the outcomes of organ transplantation that is expected to be useful in Japan. However, the characteristics of organ-specific SIPAT scores for organ transplant recipient candidates in Japan are unclear and, to date, the SIPAT has not been properly utilized in clinical practice. The purpose of this study was to present basic data that can be used to establish the relation between SIPAT scores and post-transplantation psychosocial outcomes as well as organ-specific outcomes. METHODS: This study included 167 transplant recipient candidates (25 heart, 71 liver, and 71 kidney) who completed a semi-structured interview based on the Japanese version of SIPAT (SIPAT-J) prior to transplantation. The differences between organs in terms of SIPAT scores and differences in SIPAT scores based on demographic data were comparatively analyzed. RESULTS: The total SIPAT scores were higher for liver recipient candidates than for heart recipient candidates (P = .019). Regarding the subscales, SIPAT B (social support system) scores were higher for liver and kidney recipient candidates than for heart recipient candidates (P = .021), whereas SIPAT C (psychological stability and psychopathology) scores were higher for liver recipient candidates than for kidney recipient candidates (P = .002). Recipient candidates with a history of psychiatric treatment and those who were unemployed had higher SIPAT scores, regardless of the transplant organ, than recipient candidates without a history of psychiatric treatment and those who were employed (P < .001, P = .016, respectively). CONCLUSIONS: There were notable differences in the total SIPAT-J and subscale scores among the liver, heart, and kidney recipient candidates. Each organ was associated with specific psychosocial issues that should be addressed before transplantation. Interventions such as information provision and patient education based on SIPAT assessment results for each organ may improve recipient post-transplant outcomes.

Congenital Echovirus 11 Infection in a Neonate.

Neonates infected with enterovirus in utero would be fulminant at birth or develop symptoms within a few days. Echovirus 11 causes life-threatening hepatic necrosis with coagulopathy and adrenal hemorrhagic necrosis. The prognosis depends on the enterovirus serotype and the absence of serotype-specific maternal antibodies at the time of delivery. We describe a fatal neonatal case of congenital echovirus 11 infection.

Cost-effectiveness of prophylactic emicizumab versus prophylactic recombinant factor VIII in patients with moderate or mild hemophilia A without inhibitors in the United States.

Prophylactic emicizumab is cost-ineffective in adults with moderate or mild hemophilia A without inhibitors at current pricing. The price of prophylactic emicizumab would need to decrease by >35% to become cost-effective in this patient population.

Distributional Cost-Effectiveness of Equity-Enhancing Gene Therapy in Sickle Cell Disease in the United States.

BACKGROUND: Gene therapy is a potential cure for sickle cell disease (SCD). Conventional cost-effectiveness analysis (CEA) does not capture the effects of treatments on disparities in SCD, but distributional CEA (DCEA) uses equity weights to incorporate these considerations. OBJECTIVE: To compare gene therapy versus standard of care (SOC) in patients with SCD by using conventional CEA and DCEA. DESIGN: Markov model. DATA SOURCES: Claims data and other published sources. TARGET POPULATION: Birth cohort of patients with SCD. TIME HORIZON: Lifetime. PERSPECTIVE: U.S. health system. INTERVENTION: Gene therapy at age 12 years versus SOC. OUTCOME MEASURES: Incremental cost-effectiveness ratio (ICER) (in dollars per quality-adjusted life-years [QALYs] gained) and threshold inequality aversion parameter (equity weight). RESULTS OF BASE-CASE ANALYSIS: Gene therapy versus SOC for females yielded 25.5 versus 15.7 (males: 24.4 vs. 15.5) discounted lifetime QALYs at costs of $2.8 million and $1.0 million (males: $2.8 million and $1.2 million), respectively, with an ICER of $176 000 per QALY (full SCD population). The inequality aversion parameter would need to be 0.90 for the full SCD population for gene therapy to be preferred per DCEA standards. RESULTS OF SENSITIVITY ANALYSIS: SOC was favored in 100.0% (females) and 87.1% (males) of 10 000 probabilistic iterations at a willingness-to-pay threshold of $100 000 per QALY. Gene therapy would need to cost less than $1.79 million to meet conventional CEA standards. LIMITATION: Benchmark equity weights (as opposed to SCD-specific weights) were used to interpret DCEA results. CONCLUSION: Gene therapy is cost-ineffective per conventional CEA standards but can be an equitable therapeutic strategy for persons living with SCD in the United States per DCEA standards. PRIMARY FUNDING SOURCE: Yale Bernard G. Forget Scholars Program and Bunker Endowment.

Cross-cultural comparison of continuous deep sedation for advanced cancer patients in East Asian countries: prospective cohort study.

OBJECTIVE: Cultural, social, and legal factors have been known to affect physicians' practice of continuous deep sedation. There have been few quantitative studies to compare continuous deep sedation practice in Asian countries. We aimed to describe and compare clinical characteristics of continuous deep sedation in Japan, Korea and Taiwan. METHODS: Patients with advanced cancer admitted to participating palliative care units were enrolled from January 2017 to September 2018. We evaluated and compared (i) the prevalence of continuous deep sedation, (ii) the characteristics of sedated and non-sedated groups in each country, and (iii) continuous deep sedation administration patterns among the three countries. RESULTS: A total of 2158 participants were included in our analysis, and 264 received continuous deep sedation. The continuous deep sedation prevalence was 10, 16 and 22% in Japan, Korea and Taiwan, respectively. Delirium was the most frequent target symptom in all countries, along with dyspnoea (in Japan) and psychological symptoms (in Korea). Midazolam was most frequently used in Japan and Taiwan, but not in Korea (P < 0.001). Among the patients receiving continuous deep sedation, the hydration amount on the final day was significantly different, with median volumes of 200, 500 and 0 mL in Japan, Korea and Taiwan, respectively (P < 0.001). In Korea, 33% of the continuous deep sedation administration caused a high degree of physicians' discomfort, but 3% in Japan and 5% in Taiwan (P < 0.001). CONCLUSIONS: Clinical practices of continuous deep sedation and physicians' discomfort related to continuous deep sedation initiation highly varied across countries. We need to develop optimal decision-making models of continuous deep sedation and hydration during continuous deep sedation in each country.

[A new therapeutic target for patent ductus arteriosus].

The ductus arteriosus (DA) maintains the fetal circulation by connecting the aorta and pulmonary arteries. Patent ductus arteriosus (PDA) occurs in >70% extremely-low-birth-weight infants. Patients with PDA exhibit circulatory failure, which is caused by left-to-right shunt. The DA immediately contracts after birth in response to the elevation of blood oxygen tension and to the decline in circulating prostaglandin E2 (PGE2). Cyclooxygenase inhibitors targeting smooth muscle cell (SMC) contraction represent only pharmacological treatment for PDA. However, it is important for DA anatomical closure that intimal thickening (IT) is appropriately formed between SMC layer and endothelial cells (EC). IT begins to form before the second-trimester and becomes prominent toward the end of third-trimester as an increase in placenta-derived PGE2. Immature DAs frequently fail to be close due to poorly formed IT. IT consists of extracellular matrices (ECM) and migrated DA-SMCs from the tunica media. A glycoprotein fibulin-1 is expressed in developing cardiovascular system and binds to multiple ECMs. We found that PGE2 increased fibulin-1 via EP4 in DA-SMCs, and Fbln1-deficient mice exhibited PDA with poor IT formation. Although EP4 is a Gs-coupled GPCR, fibulin-1 was secreted from DA-SMCs through the phospholipase C-protein kinase C-non-canonical NFκB signaling pathway. Fibulin-1 bound to DA-EC-derived versican which is a binding partner of hyaluronan, which promoted directional DA-SMC migration toward ECs and contributed to IT formation in the DA. Fibulin-1 upregulation by the activation of specific downstream pathway of EP4 may serve a new pharmacological strategy for PDA.

Low potency of fecal immunological surveillance testing soon after negative colonoscopy or resection of low-risk adenoma in average-risk patients.

BACKGROUND: Postcolonoscopy surveillance colonoscopy based on positive fecal occult blood testing (FOBT) is often performed, although its long-term efficacy has not been established. The aim of this study was to clarify the low potency of FOBT surveillance at short intervals after colonoscopy. METHODS: Colonoscopy was performed in 1308 average-risk patients, based on positive results of immunological FOBT [fecal immunological test (FIT)]. Patients were stratified according to the length of time since their last colonoscopy and their colonoscopy results [no adenoma or 1-2 small (<10 mm) adenomas]. Tumor detection rates were determined. RESULTS: The baseline patients characteristics did not differ between the groups. The advanced lesion detection rate (ALDR) among the patients who had never undergone a colonoscopy was 21.9% [95% confidence interval (CI), 19.1-25.0%]. Among the patients who had no adenoma detected in the previous colonoscopy within the past 5 years, the past 5-10 years and over 10 years, the ALDRs were 2.5% (95% CI, 1.0-5.5%), 4.1% (95% CI, 1.5-9.4%) and 9.3% (95% CI, 3.1-22.2%), respectively. Among the patients who had 1-2 small adenomas, the ALDRs were 7.4% (95% CI, 3.4-14.8%), 12.1% (95% CI, 4.2-27.9%) and 27.8% (95% CI, 12.2-51.2%), respectively. Invasive cancer was not observed in any patients within 5 years since the prior colonoscopy. CONCLUSION: In average-risk patients whose prior colonoscopy detected no adenomas or low-risk adenomas, postcolonoscopy surveillance by FIT has a low positive predictive value within a 5-year interval.

Incidence and associated factors of sudden unexpected death in advanced cancer patients: A multicenter prospective cohort study.

PURPOSE: A sudden unexpected death has significant negative impacts on patients, family caregivers, and medical staff in hospice/palliative care. This study aimed to clarify the incidence and associated factors of sudden unexpected death according to four definitions in advanced cancer patients. METHODS: We performed a prospective cohort study in 23 inpatient hospices/palliative care units in Japan. Advanced cancer patients aged ≥18 years who were admitted to inpatient hospices/palliative care units were included. The incidence and associated factors of sudden unexpected death were evaluated in all enrolled patients according to four definitions: (a) rapid decline death, defined as a sudden death preceded by functional decline over 1-2 days; (b) surprise death, defined if the primary responsible palliative care physician answered "yes" to the question, "Were you surprised by the timing of the death?"; (c) unexpected death, defined as a death that occurred earlier than the physicians had anticipated; and (d) performance status (PS)-defined sudden death, defined as a death that occurred within 1 week of functional status assessment with an Australia-modified Karnofsky PS ≥50. RESULTS: Among 1896 patients, the incidence of rapid decline death was the highest (30-day cumulative incidence: 16.8%, 95% CI: 14.8-19.0%), followed by surprise death (9.6%, 8.1-11.4%), unexpected death (9.0%, 7.5-10.8%), and PS-defined sudden death (6.4%, 5.2-8.0%). Male sex, liver metastasis, dyspnea, malignant skin lesion, and fluid retention were significantly associated with the occurrence of sudden unexpected death. CONCLUSION: Sudden unexpected death is not uncommon even in inpatient hospices/palliative care units, with range of 6.4-16.8% according to the different definitions.

Efficacy of Proportional Sedation and Deep Sedation Defined by Sedation Protocols: A Multicenter, Prospective, Observational Comparative Study.

PURPOSE: To investigate the efficacy of two types of palliative sedation: proportional and deep sedation, defined by sedation protocols. METHODS: From a multicenter prospective observational study, we analyzed the data of those patients who received the continuous infusion of midazolam according to the sedation protocol. The primary endpoint was goal achievement at 4 hours: in proportional sedation, symptom relief (Integrated Palliative care Outcome Scale: IPOS ≤ 1) and absence of agitation (modified Richmond Agitation-Sedation Scale: RASS ≤ 0); in deep sedation, the achievement of deep sedation (RASS ≤ -4). Secondary endpoints included deep sedation as a result of proportional sedation, communication capacity (Communication Capacity Scale item 4 ≤ 2), IPOS and RASS scores, and adverse events. RESULTS: A total of 81 patients from 14 palliative care units were analyzed: proportional sedation (n = 64) and deep sedation (n = 17). At 4 hours, the goal was achieved in 77% (n = 49; 95% confidence interval: 66-87) with proportional sedation; and 88% (n = 15; 71-100) with deep sedation. Deep sedation was necessary in 45% of those who received proportional sedation. Communication capacity was maintained in 34% with proportional sedation and 10% with deep sedation. IPOS decreased from 3.5 to 0.9 with proportional sedation, and 3.5 to 0.4 with deep sedation; RASS decreased from +0.3 to -2.6, and +0.4 to -4.2, respectively. Fatal events related to the treatment occurred in 2% (n = 1) with proportional and none with deep sedation. CONCLUSION: Proportional sedation achieved satisfactory symptom relief while maintaining some patients' consciousness, and deep sedation achieved good symptom relief while the majority of patients lost consciousness.