Identification of novel drug targets for multiple sclerosis by integrating plasma genetics and proteomes.

BACKGROUND: Genome-wide association studies (GWAS) have revealed numerous loci associated with multiple sclerosis (MS). However, the challenge lies in deciphering the mechanisms by which these loci influence the target traits. Here, we employed an integrative analytical pipeline to efficiently transform genetic associations to identify novel proteins for MS. METHODS: We systematically integrated MS GWAS data (N = 115,803) with human plasma proteome data (N = 7213) and conducted proteome-wide association studies (PWAS) to identify MS-associated pathogenic proteins. Following this, we employed Mendelian randomization and Bayesian colocalization analyses to verify the causal relationship between these significant plasma proteins and MS. Lastly, we utilized the Drug-Gene Interaction Database (DGIdb) to identify potential drug targets for MS. RESULTS: The PWAS identified 25 statistically significant cis-regulated plasma proteins associated with MS at a false discovery rate of P < 0.05. Further analysis revealed that the abundance of 7 of these proteins (PLEK, TNXB, CASP3, CD59, CR1, TAPBPL, ATXN3) was causally related to the incidence of MS. Our findings indicated that genetically predicted higher levels of TNXB and CD59 were associated with a lower risk of MS, whereas higher levels of PLEK, CASP3, CR1, TAPBPL, and ATXN3 were associated with an increased risk of MS. Three plasma proteins (PLEK, CR1, CD59) were validated by colocalization analysis. Among these, CR1 was prioritized as a target for Eculizumab due to its significant association with MS risk. Additionally, PLEK, CR1, and CD59 were identified as druggable target genes. CONCLUSIONS: Our proteomic analysis has identified PLEK, CR1, and CD59 as potential drug targets for MS treatment. Developing pharmacological inducers or inhibitors for these proteins could pave the way for new therapeutic approaches, potentially improving outcomes for MS patients.

Real-world treatment patterns and clinical outcomes from a retrospective chart review study of patients with recurrent or advanced endometrial cancer who progressed following prior systemic therapy in Europe.

OBJECTIVE: To evaluate real-world treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer patients who progressed following prior systemic therapy in clinical practice in Europe. DESIGN: Endometrial Cancer Health Outcomes-Europe (ECHO-EU) is a retrospective patient chart review study. SETTING: ECHO-EU is a multicentre study conducted in the UK, Germany, Italy, France and Spain. PARTICIPANTS: Patients with recurrent/advanced endometrial cancer who progressed between 1 July 2016 and 30 June 2019 following prior first-line systemic therapy were eligible and data were collected until last available follow-up through November 2021. PRIMARY AND SECONDARY OUTCOME MEASURES: Data collected included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed since initiation of second-line therapy to estimate time to treatment discontinuation, real-world progression-free survival (rwPFS) and overall survival (OS). RESULTS: A total of 475 patients were included from EU5 countries. Median age was 69 years at advanced endometrial cancer diagnosis, 78.7% had stage IIIB-IV disease, 45.9% had Eastern Cooperative Oncology Group status ≥2 at second-line therapy initiation. In second line, a majority of patients initiated either non-platinum-based chemotherapy (55.6%) or endocrine therapy (16.2%). Physician-reported real-world overall response rate (classified as complete or partial response) to second-line therapy was 34.5%, median rwPFS was 7.4 months (95% CI 6.2 to 8.0) and median OS was 11.0 months (95% CI 9.9 to 12.3). CONCLUSIONS: Patients had poor clinical outcomes with a median OS of <1 year and rwPFS of approximately 7 months, highlighting the significant unmet medical need in pretreated recurrent/advanced endometrial cancer patients. Novel therapies with potential to improve PFS and OS over conventional therapies could provide significant clinical benefit.

Durvalumab After Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer.

Importance: The PACIFIC trial established consolidation durvalumab as the standard of care following chemoradiotherapy (CRT) for patients with unresectable stage III non-small cell lung cancer (NSCLC). Understanding its benefit in routine US clinical practice is critical. Objective: To report characteristics, treatment patterns, and outcomes of patients who did or did not receive durvalumab. Design, Setting, and Participants: Two prespecified cohorts were curated in this retrospective cohort study (SPOTLIGHT). Deidentified patient-level data from a US database (Flatiron Health) were analyzed. Patients had unresectable stage III NSCLC, were diagnosed on or after January 1, 2011, had 2 or more visits on or afterward, and received CRT. Data were analyzed from May 2021 to October 2023. Exposures: Patients started durvalumab after CRT (durvalumab cohort) or ended CRT without durvalumab (nondurvalumab cohort) by June 30, 2019, to allow 15 or more months of follow-up from CRT end. Main Outcomes and Measures: End points included progression-free survival (PFS), overall survival (OS), time to first subsequent therapy or death (TFST), and time to distant metastasis or death (TTDM). Results: The durvalumab cohort included 332 patients (median [IQR] age, 67.5 [60.8-74.0] years; 187 were male [56.3%], 27 were Black [8.7%], 33 were other races [10.7%], and 249 were White [80.6%]) and the nondurvalumab cohort included 137 patients (median (IQR) age, 70.0 [64.0-75.0] years; 89 [65.0%] were male, 11 [8.9%] were Black, 19 [15.4%] were other races, and 93 [75.6%] were White). Most patients had a smoking history (durvalumab, 316 patients [95.2%] and nondurvalumab, 132 patients [96.4%]) and Eastern Cooperative Oncology Group performance status 0 through 1 (durvalumab, 251 patients [90.9%] and nondurvalumab, 88 patients [81.5%]). Median (IQR) CRT duration was 1.6 (1.4-1.8) months for the durvalumab cohort and 1.5 (1.4-1.8) months for the nondurvalumab cohort. Median time to durvalumab discontinuation was 9.5 months (95% CI, 7.8-10.6 months). Median TFST and TTDM were not reached (NR) in the durvalumab cohort and 8.3 months (95% CI, 4.8-11.8 months) and 11.3 months (95% CI, 6.4-14.5 months), respectively, in the nondurvalumab cohort. Median PFS and OS were 17.5 months (95% CI, 13.6-24.8 months) and NR in the durvalumab cohort and 7.6 months (95% CI, 5.2-9.8 months) and 19.4 months (95% CI, 11.7-24.0 months) in the nondurvalumab cohort. In Cox regression analyses of patients who completed concurrent CRT without progression, durvalumab was associated with a lower risk of progression or death (hazard ratio [HR], 0.36; 95% CI, 0.26-0.51) and lower risk of death (HR, 0.27; 95% CI, 0.16-0.43), adjusted for prior platinum agent and patient characteristics. Conclusions and Relevance: In this cohort study, findings were consistent with PACIFIC, and durvalumab was associated with a lower risk of progression and/or death. Further investigation is warranted to explain why patients did not receive durvalumab after its approval.

Building Block Metal Nanocluster-Based Growth in 1D Direction.

Metal nanoclusters with precisely modulated structures at the nanoscale give us the opportunity to synthesize and investigate 1D nanomaterials at the atomic level. Herein, it realizes selective 1D growth of building block nanocluster "Au13 Cd2 " into three structurally different nanoclusters: "hand-in-hand" (Au13 Cd2 )2 O, "head-to-head" Au25 , and "shoulder-to-shoulder" Au33 . Detailed studies further reveals the growth mechanism and the growth-related tunable properties. This work provides new hints for the predictable structural transformation of nanoclusters and atomically precise construction of 1D nanomaterials.

Quality-adjusted time without symptoms or toxicity analysis of nivolumab plus chemotherapy versus chemotherapy alone for the management of previously untreated patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma.

BACKGROUND: The phase 3 CheckMate 649 established superior overall survival of nivolumab in combination with chemotherapy (NIVO + chemo) compared with chemotherapy (chemo) alone as a first-line treatment for patients with Her2-negative advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC). This post hoc trial analysis aimed to evaluate the benefit of NIVO + chemo using quality-adjusted time without symptoms or toxicity (Q-TWiST) to further account for quality of life (QoL) in different health states depending on disease progression and treatment toxicity. METHODS: Using data from CheckMate 649, we evaluated the quality-adjusted survival gain associated with NIVO + chemo compared with chemo alone among all randomized patients and repeated similar analyses among those with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5. Relative Q-TWiST gains of ≥ 10% were predefined as clinically important. RESULTS: In all randomized patients, those receiving NIVO + chemo had a mean Q-TWiST gain of 1.8 (95% CI 0.9, 2.7) months compared with those receiving chemo alone. The relative Q-TWiST gain was estimated to be 12.8%. Patients with PD-L1 CPS ≥ 5 had greater quality-adjusted survival gain from NIVO + chemo with an estimated Q-TWiST gain of 2.8 (95% CI 1.5, 4.1) months, representing a relative gain of 20.6%. Subgroup analyses and sensitivity analyses with various QoL utility values yielded consistent findings in favor of NIVO + chemo compared with chemo alone. Q-TWiST gain from NIVO + chemo increased with longer duration of follow-up. CONCLUSIONS: NIVO + chemo was associated with a statistically significant and clinically important gain in quality-adjusted survival compared with chemo alone among previously untreated patients with advanced GC/GEJC/EAC.

Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma.

The quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology provides a comprehensive framework for treatment comparison that partitions survival time into distinct health states reflecting both treatment toxicity and disease progression. ZUMA-7 (ClinicalTrials.gov identifier NCT03391466), a phase 3 randomized open-label multicenter study, was conducted to evaluate the efficacy of axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor T cell therapy, compared with standard of care (SOC) involving platinum-based salvage chemotherapy with autologous stem cell transplantation (ASCT) consolidation as a second-line treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL), and met its primary endpoint of improved event-free survival (EFS). We aimed to use the Q-TWiST method to compare the quality-adjusted survival of R/R LBCL patients treated with axi-cel and those treated with SOC who were enrolled in ZUMA-7. The preplanned analysis of overall survival (OS) was partitioned into 3 mutually exclusive health states: time with grade ≥3 adverse events before the event as defined in the EFS analysis (TOX), time without severe toxicity before the event (TWiST), and time after the event (REL). Q-TWiST was computed as a weighted sum of mean TOX, TWiST, and REL values multiplied by state-specific quality of life (QoL) utility scores. Q-TWiST was evaluated in the intention-to-treat cohort at median follow-up. A relative Q-TWiST gain of 10% was deemed "clinically important" and a gain of ≥15% was deemed "clearly clinically important" based on established categorization. Sensitivity analyses with follow-up ranging from 3 months to the maximum follow-up and subgroup analyses by age and R/R status were explored. At a median follow-up of 23.5 months, the axi-cel cohort showed a significantly longer time without severe toxicity compared with the SOC cohort, with a mean TWiST duration of 11.18 months versus 5.39 months, respectively. The mean TOX was 1.16 months versus .74 months, and mean REL was 6.02 months versus 10.66 months. Quality-adjusted survival was significantly longer with axi-cel by 3.7 months (95% CI, 2.3 to 5.2 months), representing a relative gain of 21.9%. This was reflected across all subgroups, with estimated Q-TWiST gains of 3.1 months (95% CI, 1.5 to 4.9 months) for patients age <65 years, 5.2 months (95% CI, 2.4 to 7.9 months) for those age ≥65 years, 3.2 months (95% CI, 1.4 to 4.9 months) for those with primary refractory disease, 9.1 months (95% CI, 3.9 to months 13.5) for those who relapsed within 6 months, and 4.1 months (95% CI, 1.1 to 7.1 months) for those who relapsed between 6 and 12 months. The Q-TWiST gain for axi-cel also was statistically significant across follow-up durations, increasing from .2 month (95% CI, .1 to .3 month) at a 3-month follow-up to 4.9 months (95% CI, 2.4 to 7.8 months) at the maximum follow-up of 37.7 months. Axi-cel was associated with a statistically significant and "clearly clinically important" gain in quality-adjusted survival, regardless of the relative decline in QoL associated with treatment toxicity, disease progression, or additional cancer treatment. This finding adds to the existing evidence supporting a benefit for axi-cel as a second-line treatment for patients with R/R LBCL.

Clinical and Economic Burden of Out-of-Hospital Cardiac Arrest in US Commercial Insurance Population (2014 to 2019).

Little is known about the economic burden incurred by out-of-hospital cardiac arrest (OHCA) in the US commercial insurance setting. We used IBM MarketScan Commercial Claims and Encounters Database (January 2014 to March 2019) to identify patients hospitalized with OHCA based on the International Classification of Diseases codes. Patients who survived the initial OHCA episode were stratified by prognosis based on discharge setting and classified into mild (discharged home), moderate (skilled nursing facility), severe (inpatient rehabilitation or long-term hospital), and very severe (hospice) prognosis groups, respectively. Patients were followed up for 12 months after discharge for health care resource utilization and medical costs, which were inflated to year 2020. Overall, 23,512 patients with OHCA hospitalization were identified, of whom 14,667 were <65 years and 60.5% were men. The incidence of OHCA per 100,000 was steady in patients <65 years over the years (17.9 in 2014; 17.5 in 2018) but among those ≥65 years, decreased from 139.7 in 2014 to 111.1 in 2018. Total medical costs 12 months after discharge generally increased with severity of prognosis, with an average for the mild, moderate, and severe prognosis group, respectively, estimated to be $52,746, $100,394, and $130,530 among patients <65 years, and $63,194, $65,794, and $70,973 among those ≥65 years. Costs were lower for those with very severe prognosis ($7,102 for <65 years; $2,553 for ≥65 years), possibly due to high mortality. In conclusion, OHCA continues to pose a substantial clinical and economic burden on patients and the US health care system, which increases with the severity of disease prognosis.

Preterm disparities between foreign and Swedish born mothers depend on the method used to estimate gestational age. A Swedish population-based register study.

This study aims to examine whether disparities in gestational age outcomes between foreign and Swedish-born mothers are contingent on the measure used to estimate gestational age and, if so, to identify which maternal factors are associated with the discrepancy. Using population register data, we studied all singleton live births in Sweden from 1992-2012 (n = 1,317,265). Multinomial logistic regression was performed to compare gestational age outcomes classified into very (<32 weeks) and late preterm (32-36 weeks), term and post-term derived from the last menstrual period (LMP) and ultrasound estimates in foreign- and Swedish-born women. Compared to Swedish-born women, foreign-born women had similar odds of very preterm birth (OR: 0.98 [95% CI: 0.98, 1.01]) and lower odds of moderately preterm birth (OR: 0.95 [95% CI: 0.92, 0.98]) based on ultrasound, while higher risks based on LMP (respectively, OR: 1.10 [95% CI: 1.07, 1.14] and 1.09 [95% CI: 1.06, 1.13]). Conclusions on disparities in gestational age-related outcomes by mother's country of origin depend on the method used to estimate gestational age. Except for very preterm, foreign-born women had a health advantage when gestational age is based on ultrasound, but a health disadvantage when based on LMP. Studies assessing disparities in very preterm birth by migration status are not affected by the estimation method but caution should be taken when interpreting disparities in moderately preterm and preterm birth rates.

Hyperkalemia and Acute Kidney Injury with Spironolactone Use Among Patients with Heart Failure.

OBJECTIVE: To quantify the risk of hyperkalemia and acute kidney injury (AKI) when spironolactone use is added on to loop diuretic use among patients with heart failure, and to evaluate whether the risk is modified by level of kidney function. METHODS: We identified 17,110 patients with heart failure treated with loop diuretics between January 1, 2004, and December 31, 2016 within the Geisinger Health System. We estimated the incidence of hyperkalemia and AKI associated with spironolactone initiation, and used target trial emulation methods to minimize confounding by indication. RESULTS: During a mean follow-up of 134 mo, 3229 of 17,110 patients (18.9%) initiated spironolactone. Incidence rates of hyperkalemia and AKI in patients using spironolactone with a loop diuretic were 2.9 and 10.1 events per 1000 person-months, respectively. In propensity score-matched analyses, spironolactone initiation was associated with higher hyperkalemia and AKI risk compared with loop alone (hazard ratio, 1.69; 95% CI, 1.35 to 2.10; P<.001, and hazard ratio, 1.12; 95% CI, 1.00 to 1.26; P=.04, respectively). There were no differences in the relative risk of either outcome associated with spironolactone by level of kidney function. CONCLUSION: The addition of spironolactone to loop diuretics in patients with heart failure was associated with higher risk of hyperkalemia and AKI; these risks must be weighed against the potential benefits of spironolactone.

Association of Albuminuria Levels With the Prescription of Renin-Angiotensin System Blockade.

Multiple clinical guidelines recommend an ACE (angiotensin-converting enzyme) inhibitor or angiotensin II receptor blocker (ARB) in patients with elevated albuminuria, which can be measured through urine albumin-to-creatinine ratio (ACR), protein-to-creatinine ratio, or dipstick. However, how albuminuria test results relate to the prescription of ACE inhibitor/ARB is uncertain. We identified individuals with an ACR measurement between January 1, 2004, and June 30, 2018, and no contraindications or allergy to ACE inhibitor/ARB. We performed multivariable logistic regression analyses to evaluate the association between ACR level and prescription of ACE inhibitor/ARB within 6 months after the test. We applied similar methods to investigate the association of protein-to-creatinine ratio and dipstick measurement results with the prescription of ACE inhibitor/ARB. Among 67 237 individuals with an ACR measurement, 47.7% were already taking an ACE inhibitor or ARB at the time of first ACR measurement. Among the 35 138 individuals who were not on ACE inhibitor/ARB, those with higher ACR levels were more likely to be prescribed ACE inhibitor/ARB in the following 6 months, with steep increases in prescriptions until ACR 300 mg/g, after which the association plateaued. The majority (80.9%) of ACE inhibitor/ARB prescriptions were made by family medicine and internal medicine. A similar pattern held in the cohorts tested by protein-to-creatinine ratio and dipstick measurement. Our study provides evidence that albuminuria test results change patient care, suggesting that adherence to albuminuria testing is a key step in optimal medical management.

Association Between Renin-Angiotensin System Blockade Discontinuation and All-Cause Mortality Among Persons With Low Estimated Glomerular Filtration Rate.

Importance: It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR). Objective: To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD). Design, Setting, and Participants: This retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019. Exposures: Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2. Main Outcomes and Measures: The association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD. Results: Of the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65). Conclusions and Relevance: The findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.

Are population-based patient-reported outcomes associated with overall survival in patients with advanced pancreatic cancer?

BACKGROUND: Advanced pancreatic cancer (APC) patients often have substantial symptom burden. In Ontario, patients routinely complete the Edmonton Symptom Assessment Scale (ESAS), which screens for nine symptoms (scale: 0-10), in cancer clinics. We explored the association between baseline patient-reported outcomes, via ESAS, and overall survival (OS). METHODS: Advanced pancreatic cancer patients with ESAS records prior to receiving publicly funded drugs from November 2008 to March 2016 were retrospectively identified from Cancer Care Ontario's administrative databases. We examined three composite ESAS scores: total symptom distress score (TSDS: 9 symptoms), physical symptom score (PHS: 6/9 symptoms), and psychological symptom score (PSS: 2/9 symptoms); Composite scores greater than defined thresholds (TSDS ≥36, PHS ≥24, PSS ≥8) were considered as high symptom burden. Crude OS was assessed using Kaplan-Meier method. Hazard ratios (HRs) were assessed using multivariable Cox models. Analysis was repeated in a sub-cohort with Eastern Cooperative Oncology Group (ECOG) status and metastasis. RESULTS: We identified 2199 APC patients (mean age 64 years, 55% male) with ESAS records prior to receiving chemotherapy. Crude median survival was 4.5 and 7.3 months for high and low TSDS, respectively. High TSDS was associated with lower OS (HR = 1.47, 95% CI: 1.33, 1.63). In the sub-cohort (n = 393) with ECOG status and metastasis, high TSDS was also associated with lower OS (HR = 1.34, 95% CI: 1.04, 1.73). Similar trends were observed for PHS and PSS. CONCLUSIONS: Higher burden of patient-reported outcome was associated with reduced OS among APC patients. The effect was prominent after adjusting for ECOG status.

Discontinuation of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Chronic Kidney Disease.

OBJECTIVE: To assess the patterns of angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACE-I/ARB) discontinuation in the setting of chronic kidney disease (CKD) progression in real-world clinical practice. PATIENTS AND METHODS: We identified incident ACE-I/ARB users with a baseline estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2 and without end-stage renal disease in the Geisinger Health System between January 1, 2004, and December 31, 2015. We investigated the associations of CKD stage, hospitalizations with and without acute kidney injury (AKI), serum potassium, bicarbonate level, thiazide, and loop diuretic use with ACE-I/ARB discontinuation. RESULTS: Among the 53,912 ACE-I/ARB users, the mean age was 59.9 years, and 50.6% were female. More than half of users discontinued ACE-I/ARB within 5 years of therapy initiation. The risk of ACE-I/ARB discontinuation increased with more advanced CKD stage. For example, patients who initiated ACE-I/ARB with CKD stage G4 (eGFR: 15-29 mL/min/1.73 m2) were 2.09-fold (95% CI, 1.87-2.34) more likely to discontinue therapy than those with eGFR ≥ 90 mL/min/1.73 m2. Potassium level greater than 5.3 mEq/L, systolic blood pressure ≤ 90 mm Hg, bicarbonate level < 22 mmol/L, and intervening hospitalization-particularly AKI-related-were also strong risk factors for ACE-I/ARB discontinuation. Thiazide diuretic use was associated with lower risk, whereas loop diuretic use was associated with higher risk of discontinuation. CONCLUSION: In a real-world cohort, discontinuation of ACE-I/ARB was common, particularly in patients with lower eGFR. Hyperkalemia, hypotension, low bicarbonate level, and hospitalization (AKI-related, in particular) were associated with a higher risk of ACE-I/ARB discontinuation. Additional studies are needed to evaluate the risk-benefit balance of discontinuing ACE-I/ARB in the setting of CKD progression.

Globalization of clinical trials: Variation in estimated regional costs of pivotal trials, 2015-2016.

BACKGROUND/AIMS: Despite the increasing globalization of clinical trials, little is known regarding how the trial site costs vary around the world. We quantified the geographical distribution and regional cost differences for the clinical trials that established the benefits for new therapeutic drugs approved by the US Food and Drug Administration in 2015 and 2016. METHODS: We included all pivotal clinical trials for 59 new molecular entities approved by the US Food and Drug Administration in 2015 and 2016 that included at least one site in North America. We derived cost estimates from IQVIA's CostPro, a global clinical trial cost-estimating tool used by pharmaceutical sponsors. We assessed the patient and site allocation of these trials across eight geographic regions. To quantify the region-specific cost differences, we conducted a within-trial comparison by expressing the estimated regional costs associated with the sites in each global region as a percent of the same costs in North America. We also estimated the percentage breakdown of regional cost components (pass-through, site management, regulatory, and study conduct costs) for each trial and for all endpoints reported the median and interquartile range. RESULTS: Overall, 127 pivotal clinical trials enrolled 91,415 patients from 13,264 sites. Most patients (60.3%) and sites (57.3%) were outside North America. A median of 66% of the total estimated trial costs (interquartile range: 60%-72%) were spent on regional tasks, with the largest share (53.3%) going directly to trial sites and the remainder going to other regional trial management tasks. Differences were greatest in four lower cost regions: Africa, with an estimated regional cost per site of 49% of North America (interquartile range: 44%-56%), Central Europe 50% (interquartile range: 41%-63%), Middle East 53% (interquartile range: 42%-64%) and Latin America 59% (interquartile range: 50%-70%). Overall, 90 (71%) of the 127 pivotal trials had a total of 3160 sites in these lower cost regions. In contrast, savings were more limited in Western Europe, Oceania, and Asia, where estimated regional costs were 78% of North America (interquartile range: 67%-89%). One-quarter of the trials with sites in Asia and Oceana did not achieve cost savings in those regions relative to North America. CONCLUSION: Among this sample of pivotal trials for recently approved US Food and Drug Administration products, most patients and sites enrolled were outside of North America, with selection of regional sites having a significant impact on total trial costs.

Improved survival in overweight and obese patients with aggressive B-cell lymphoma treated with rituximab-containing chemotherapy for curative intent.

The association between obesity and survival in non-Hodgkin lymphoma is unclear. Using the Ontario Cancer Registry we conducted a retrospective analysis of incident cases of aggressive-histology B-cell lymphoma treated with a rituximab-containing regimen with curative intent between 2008-2016. 6246 patients were included. On multivariable analysis the rate of all-cause mortality was lower for the overweight body mass index (BMI 25-29.9 kg/m2) (HR 0.85; 95%CI 0.77-0.95) and obese BMI (≥30 kg/m2) (HR 0.75; 95%CI 0.67-0.85) groups compared to the normal weight group (18.5-24.9 kg/m2). Binomial logistic regression analysis revealed a lower odds ratio (OR) of admission to hospital during treatment in the overweight (OR 0.84; 95%CI 0.75-0.95) compared to normal weight BMI group. In the largest cohort to date of aggressive-histology B-cell lymphoma patients treated with rituximab, increased BMI is associated with a survival advantage, and the magnitude of this effect increases from overweight to obese BMI.

Cost-effectiveness analysis of treatment with non-curative or palliative intent for hepatocellular carcinoma in the real-world setting.

Hepatocellular carcinoma (HCC) presentation is heterogeneous necessitating a variety of therapeutic interventions with varying efficacies and associated prognoses. Poor prognostic patients often undergo non-curative palliative interventions including transarterial chemoembolization (TACE), sorafenib, chemotherapy, or purely supportive care. The decision to pursue one of many palliative interventions for HCC is complex and an economic evaluation comparing these interventions has not been done. This study evaluates the cost-effectiveness of non-curative palliative treatment strategies such as TACE alone or TACE+sorafenib, sorafenib alone, and non-sorafenib chemotherapy compared with no treatment or best supportive care (BSC) among patients diagnosed with HCC between 2007 and 2010 in a Canadian setting. Using person-level data, we estimated effectiveness in life years and quality-adjusted life years (QALYs) along with total health care costs (2013 US dollars) from the health care payer's perspective (3% annual discount). A net benefit regression approach accounting for baseline covariates with propensity score adjustment was used to calculate incremental net benefit to generate incremental cost-effectiveness ratio (ICER) and uncertainty measures. Among 1,172 identified patients diagnosed with HCC, 4.5%, 7.9%, and 5.6%, received TACE alone or TACE+sorafenib, sorafenib, and non-sorafenib chemotherapy clone, respectively. Compared with no treatment or BSC (81.9%), ICER estimates for TACE alone or TACE+sorafenib was $6,665/QALY (additional QALY: 0.47, additional cost: $3,120; 95% CI: -$18,800-$34,500/QALY). The cost-effectiveness acceptability curve demonstrated that if the relevant threshold was $50,000/QALY, TACE alone or TACE+sorafenib, non-sorafenib chemotherapy, and sorafenib alone, would have a cost-effectiveness probability of 99.7%, 46.6%, and 5.5%, respectively. Covariates associated with the incremental net benefit of treatments are age, sex, comorbidity, and cancer stage. Findings suggest that TACE with or without sorafenib is currently the most cost-effective active non-curative palliative treatment approach to HCC. Further research into new combination treatment strategies that afford the best tumor response is needed.

Cost-effectiveness analysis of potentially curative and combination treatments for hepatocellular carcinoma with person-level data in a Canadian setting.

Patients with early-stage hepatocellular carcinoma (HCC) are potential candidates for curative treatments such as radiofrequency ablation (RFA), surgical resection (SR), or liver transplantation (LT), which have demonstrated a significant survival benefit. We aimed to estimate the cost-effectiveness of curative and combination treatment strategies among patients diagnosed with HCC during 2002-2010. This study used Ontario Cancer Registry-linked administrative data to estimate effectiveness and costs (2013 USD) of the treatment strategies from the healthcare payer's perspective. Multiple imputation by logistic regression was used to handle missing data. A net benefit regression approach of baseline important covariates and propensity score adjustment were used to calculate incremental net benefit to generate incremental cost-effectiveness ratio (ICER) and uncertainty measures. Among 2,222 patients diagnosed with HCC, 10.5%, 14.1%, and 10.3% received RFA, SR, and LT monotherapy, respectively; 0.5-3.1% dual treatments; and 0.5% triple treatments. Compared with no treatment (53.2%), transarterial chemoembolization (TACE) + RFA (average $2,465, 95% CI: -$20,000-$36,600/quality-adjusted life years [QALY]) or RFA monotherapy ($15,553, 95% CI: $3,500-$28,500/QALY) appears to be the most cost-effective modality with lowest ICER value. The cost-effectiveness acceptability curve showed that if the relevant threshold was $50,000/QALY, RFA monotherapy and TACE+ RFA would have a cost-effectiveness probability of 100%. Strategies using LT delivered the most additional QALYs and became cost-effective at a threshold of $77,000/QALY. Our findings found that TACE+ RFA dual treatment or RFA monotherapy appears to be the most cost-effective curative treatment for patients with potential early stage of HCC in Ontario. These findings highlight the importance of identifying and measuring differential benefits, costs, and cost-effectiveness of alternative HCC curative treatments in order to evaluate whether they are providing good value for money in the real world.

Application of the sequential quadratic programming algorithm for reconstructing the distribution of optical parameters based on the time-domain radiative transfer equation.

Sequential quadratic programming (SQP) is used as an optimization algorithm to reconstruct the optical parameters based on the time-domain radiative transfer equation (TD-RTE). Numerous time-resolved measurement signals are obtained using the TD-RTE as forward model. For a high computational efficiency, the gradient of objective function is calculated using an adjoint equation technique. SQP algorithm is employed to solve the inverse problem and the regularization term based on the generalized Gaussian Markov random field (GGMRF) model is used to overcome the ill-posed problem. Simulated results show that the proposed reconstruction scheme performs efficiently and accurately.

Effect of socioeconomic status on hepatocellular carcinoma incidence and stage at diagnosis, a population-based cohort study.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) incidence is increasing worldwide and cirrhosis is the most important risk factor predominantly caused by chronic viral hepatitis infection. We studied the impact of socioeconomic status (SES) on HCC incidence and stage at diagnosis among viral hepatitis cases. METHODS: A population-based retrospective cohort study was conducted through the Ontario Cancer Registry linked data. Incidence rates were calculated using person-time methodology. Association between SES (income quintile) and HCC incidence was assessed using proportional-hazards regression. The impact of SES on HCC stage was investigated using logistic regression. RESULTS: Among 11 350 individuals diagnosed with viral hepatitis between 1991 and 2010, a crude HCC incidence rate of 21.4 cases per 1000 person-years was observed. Adjusting for age, gender, urban/rural residence and year of viral hepatitis diagnosis, a significant association was found between SES and HCC incidence, with an increased risk among individuals in the lowest three income quintiles (incidence rate ratio, IRR = 1.235; 95% CI: 1.074-1.420; IRR = 1.183; 95% CI: 1.026-1.364; IRR = 1.158; 95% CI: 1.000-1.340 respectively). No significant association between SES and HCC incidence was found after additionally adjusting for risk factors associated with HCC. However, HCC risk factors such as cirrhosis and HIV are associated with SES. Furthermore, no association was found between SES and HCC stage. CONCLUSIONS: The association between SES and HCC incidence is likely because of differences in risk factors across income quintiles. Investigating how SES affects HCC incidence facilitates an understanding of which populations are at elevated risk for HCC.

Surveillance in Patients With Barrett's Esophagus for Early Detection of Esophageal Adenocarcinoma: A Systematic Review and Meta-Analysis.

OBJECTIVES: Although endoscopic surveillance of patients with Barrett's esophagus (BE) has been widely implemented for early detection of esophageal adenocarcinoma (EAC), its justification has been debated. This systematic review aimed to evaluate benefits, safety, and cost effectiveness of surveillance for patients with BE. METHODS: MEDLINE, EMBASE, EconLit, Scopus, Cochrane, and CINAHL were searched for published human studies that examined screening practices, benefits, safety, and cost effectiveness of surveillance among patients with BE. Reviewers independently reviewed eligible full-text study articles and conducted data extraction and quality assessment, with disagreements resolved by consensus. Random effects meta-analyses were performed to assess the incidence of EAC, EAC/high-grade dysplasia (HGD), and annual stage-specific transition probabilities detected among BE patients under surveillance, and relative risk of mortality among EAC patients detected during surveillance compared with those not under surveillance. RESULTS: A total of 51 studies with 11,028 subjects were eligible; the majority were of high quality based on the Newcastle-Ottawa quality scale. Among BE patients undergoing endoscopic surveillance, pooled EAC incidence per 1,000 person-years of surveillance follow-up was 5.5 (95% confidence interval (CI): 4.2-6.8) and pooled EAC/HGD incidence was 7.7 (95% CI: 5.7-9.7). Pooled relative mortality risk among surveillance-detected EAC patients compared with nonsurveillance-detected EAC patients was 0.386 (95% CI: 0.242-0.617). Pooled annual stage-specific transition probabilities from nondysplastic BE to low-grade dysplasia, high-grade dysplasia, and EAC were 0.019, 0.003, and 0.004, respectively. There was, however, insufficient scientific evidence on safety and cost effectiveness of surveillance for BE patients. CONCLUSIONS: Our findings confirmed a low incidence rate of EAC among BE patients undergoing surveillance and a reduction in mortality by 61% among those who received regular surveillance and developed EAC. Because of knowledge gaps, it is important to assess safety of surveillance and health-care resource use and costs to supplement existing evidence and inform a future policy decision for surveillance programs.