Exploratory Multivariate Analysis Research Articles

The influence of factors in the internal control system on financial reporting quality at administrative and public service units in Vietnam

The objective of the project is to measure the influence of factors in the internal control system on financial reporting quality at administrative and public service units in Vietnam. The author inherits five internal control components from the Committee of Sponsoring Organization [COSO], 2013: control environment, risk assessment, communication information, and supervision that affect financial reporting quality. The author uses a mixed research method including qualitative and quantitative, with primary data collected through a survey of 400 units with 30 observed variables, resulting in 350 valid survey forms. From there, the study analyzed EFA exploratory factor analysis and multivariate regression analysis with support from SPSS 27.0 software. Research results show that the internal control system has an impact on administrative and public service units in Vietnam, with the level of influence of the components gradually decreasing: (1) information and communication, (2) control environment, (3) control activities, (4) risk assessment, (5) monitoring. With the results of this research, it helps administrative and public service units to improve and enhance the financial reporting quality while helping to reduce and eliminate weaknesses in the internal control implementation process, in order to strengthen the internal foundation and influence positive impact on governance.

Considerations for protein and amino acids in standardized reference diet for parthenogenetic marbled crayfish Procambarus virginalis model organism

The concept of a standardized reference diet (SRD) is used in laboratory model organisms to ensure nutritional control between studies and laboratories. Although models using the genetically identical, all female parthenogenetic marbled crayfish (Procambarus virginalis) are growing in popularity, research into nutrition in this species still has many knowledge gaps. To fast track the development of a SRD in terms of protein and amino acids (SRDprotein) for this species, we first analyzed the composition of its body amino acids to determine the ideal protein concept (IPC) of indispensable amino acids in wild-caught P. virginalis (which had an unusually high preponderance of leucine and arginine). Then, we strategically evaluated three common clusters of types of fish feed: (1) ornamental fish feed (SER) fortified with a naturally occurring alga (Spirulina). This type of feed was protein-high in arginine and leucine (SER + SPI) that fulfils the species’ IPC for iso-protein (~ 40%), iso-phosphorus (~ 0.8%) and near iso-energetic (~ 475 kcal 100 g−1); (2) freeze-dried live feed consisting of chironomid larvae (CHI) fortified with Spirulina (CHI + SPI) that fulfils the IPC for iso-protein (~ 46%), iso-phosphorus (~ 0.7%) and near iso-energetic (~ 405 kcal 100 g−1); and (3) a commercially standardized ‘starter diet’ for carnivorous fish larvae (FISH) and post-larval shrimps (SHRIMP) with iso-protein (~ 56%) and iso-phosphorus (~ 1.6%). A total of six diets, embracing a diverse range of proteinaceous feeds, were used in a 100-day ad libitum feeding and growth trial. The FISH group outperformed all the other groups (p < 0.05) and our exploratory multivariate analysis revealed an ideal demand of > 44% protein (tailored to deliver high arginine 3% and leucine 4%, followed by the usual lysine > 3.5% and methionine 1.2%) but also the lowest carbohydrate level (21%). For SRDprotein, our findings show that the FISH diet is ideal and suggest the possibilities of using a CHI + SPI diet for further optimization (more economic use of protein and phosphorus).

Chemical characterization of the hydrophilic fraction of (geo)propolis from brazilian stingless bees

Stingless bees make propolis and geopropolis; the latter is characterized by the presence of small portions of soils besides the usual plant resins. These propolis are consumed by rural and indigenous communities to heal or prevent diseases and have complex chemical composition; then to get a full understanding of their chemicals it is necessary the use of complementary analytical tools. Herein the hydrophilic fraction of 50 samples of Brazilian (geo)propolis (this way referring to either propolis or geopropolis from stingless bees) was derivatised and analysed by GC-MS. Therefore, the presence of semi-volatile and non-volatile compounds belonging to chemical classes such as flavonoids, esters, terpenoids, phenolic compounds, organic acids, phenylpropanoids, fatty acids, fatty acyls, and other lipids was confirmed. Exploratory multivariate analysis indicated that bee species affects the chemical composition of (geo)propolis. It was observed that (geo)propolis from Tetragonisca angustula from the states of Paraná and São Paulo have similar chemical composition suggesting that in both regions this stingless bee have gathered similar vegetal resins to make its (geo)propolis. Alternatively, Melipona quadrifasciata and Melipona marginata have generalist collection patterns as their (geo)propolis show a variable composition depending on the geographical origin.

Breast Cancer With HER2 Immunohistochemical Score 2 and Average HER2 Signals/Cell 6 or More and HER2/CEP17 Ratio Less Than 2 ('ISH Group 3'): A Multiinstitutional Cohort Analysis Emphasizing Outcome and Molecular Subtype

Breast cancer (BC) with average human epidermal growth factor receptor 2 (HER2) signals/cell ≥6 and HER2/chromosome enumeration probe 17 (CEP17) ratio <2 (in situ hybridization [ISH] group 3) is very rare, accounting for 0.4% to 3.0% of cases sent for the dual-probe ISH assay. Although such patients are currently eligible for treatment with HER2-targeted therapy, their characteristics and outcomes remain poorly understood. Sixty-two BCs with equivocal HER2 immunohistochemical score (2+) and reflex ISH group 3 results were identified across 4 institutions. Available clinicopathologic characteristics, MammaPrint and BluePrint molecular results, and follow-up information were retrospectively analyzed. Most BCs with HER2 equivocal immunohistochemical and ISH group 3 results were histologic grade 2 or 3 (100%), estrogen receptor (ER) positive (90.3%), with an average HER2 signals/cell of 7.3. Molecular profiles revealed that 80% (16/20) of tumors were luminal subtypes, and HER2 molecular subtype was identified in 10% of tumors (2/20). Twelve (19.4%) out of 62 patients developed local recurrence and/or distant metastasis with a median follow-up of 50 months. One (10%) of 10 patients achieved pathologic complete response after neoadjuvant chemotherapy. Forty-nine (79%) out of 62 patients completed anti-HER2 agents, and exploratory analysis showed no statistically significant difference in disease outcomes between patients who completed anti-HER2 treatment and those who did not. Univariate analysis revealed advanced clinical stage, and ER/progesterone receptor negativity was associated with unfavorable disease outcomes, and exploratory multivariate analysis demonstrated that clinical stage was the most significant factor associated with disease outcomes in the studied population. These findings increase our understanding of this rare, but clinically important HER2 category. Large-scale prospective randomized studies are needed to further evaluate the role of perioperative HER2-targeted therapy in this patient population.

Use of Different Anti-PD-1 Checkpoint Combination Strategies for First-Line Advanced NSCLC Treatment-The Experience of Ion Chiricuță Oncology Institute.

Different combination modalities between an anti-PD-1/PD-L1 agent and a platinum-based chemotherapy or another checkpoint inhibitor (with or without a short course or full course of a platinum doublet) proved superior to chemotherapy alone in multiple clinical trials, but these strategies were not directly compared. The aim of this study is to report the real-world data results with different immunotherapy combinations in a series of patients treated in consecutive cohorts at the Ion Chiricuță Oncology Institute. A total of 122 patients were successively enrolled in three cohorts: (1A) nivolumab + ipilimumab (18 patients), (1B) nivolumab + ipilimumab + short-course chemotherapy (33 patients), and (2) pembrolizumab plus full-course chemotherapy (71 patients). Endpoints included overall survival (OS), progression-free survival (PFS), objective response (ORR), and univariate and multivariate exploratory analysis of prognostic factors. Median follow-up in the consecutive cohorts 1A, 1B, and 2 was 83 versus 59 versus 14.2 months. Median OS and PFS for all patients were 22.2 and 11.5 months, respectively, and 2-year actuarial OS and PFS were 49% and 35%, respectively. For the nivolumab + ipilimumab (cohorts 1A and 1B) versus pembrolizumab combinations (cohort 2), median OS was 14 vs. 24.8 months (p = 0.18) and 2-year actuarial survival 42% vs. 53%; median PFS was 8.6 vs. 12.7 months (p = 0.41) and 2-year actuarial PFS 34% vs. 35%; response rates were 33.3% vs. 47.9% (p = 0.22). Older age, impaired PS (2 versus 0-1), corticotherapy in the first month of immunotherapy, and >3.81 neutrophils to lymphocytes ratio were independent unfavorable prognostic factors in the multivariate analysis of survival (limited to 2 years follow-up). The 5-year long-term survival was 30.5% and 18.8% for cohorts 1A and 1B, respectively (not enough follow-up for cohort 2). Efficacy results using different immunotherapy combination strategies were promising and not significantly different between protocols at 2 years. Real-world efficacy and long-term results in our series were in line with those reported in the corresponding registration trials.

The Public's Intended Uptake of Hypothetical Esophageal Adenocarcinoma Screening Scenarios: A Nationwide Survey.

Screening for early esophageal adenocarcinoma (EAC) may potentially reduce EAC-related mortality and morbidity. This study aimed to examine the Dutch population's intended uptake of 3 hypothetical EAC screening test scenarios and preferences for potential future organization. A total of 8,350 Dutch individuals aged 45-75 years were invited, of whom 2,258 completed a web-based survey. Participants were randomly assigned to 1 of 3 hypothetical screening test scenarios (i.e., transnasal endoscopy, ingestible cell collection device, or breath analysis). The primary outcome was intended uptake. Secondary outcomes included acceptance of screening eligibility criteria and preferences regarding invitation, counseling, and diagnostic follow-up. We performed exploratory univariable and multivariable regression analyses to assess which determinants were associated with EAC screening intent. Intended uptake of screening was highest in the breath analysis scenario (95%), followed by conventional upper endoscopy (78%), an ingestible cell collection device (75%), and transnasal endoscopy (68%) ( P < 0.001). Anticipating discomfort was most strongly associated with decreased intention to undergo transnasal endoscopy (odds ratio 0.18, 95% confidence interval 0.11-0.29) or swallow a cell collection device (odds ratio 0.20, 95% confidence interval 0.13-0.32). Cancer worry and high acceptance of test sensitivity/specificity were consistently associated with a positive intention to participate in screening. Inviting persons for screening based on gastroesophageal reflux disease symptoms, age, or the output of a risk prediction model was acceptable to 74%, 69%, and 66%, respectively. Inviting only men was acceptable for only 41% of women. The majority (58%) preferred to be invited by a public health organization, and 32% of the participants preferred to discuss their decision to participate with a healthcare professional. Participants in this study self-selected through a web-based survey, potentially introducing selection bias. Participants generally intended to participate in EAC screening, although the level of intent depended on the discomfort and performance associated with the offered screening test. Determining eligibility based on gastroesophageal reflux disease symptoms, age, or a risk calculator, but not sex, would be acceptable to most individuals.

Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial

We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group’s change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: −32.3% [95% CI: −49.2%, −9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

Listeria monocytogenes-associated spontaneous bacterial peritonitis in France: a nationwide observational study of 208 cases

Listeriosis is a foodborne infection caused by Listeria monocytogenes. Three main forms of listeriosis are well characterised, but little is known about L monocytogenes-associated spontaneous bacterial peritonitis. We used data from the French national surveillance of listeriosis to perform a nationwide retrospective study. All patients with L monocytogenes isolated by culture from a peritoneal fluid sample in France between April 1, 1993, and Dec 31, 2022, were included. Individuals for whom bacterial peritonitis was not confirmed and those who also had another type of invasive listeriosis were excluded. A standardised checklist was used to collect demographic, clinical, and biological data as well as antibiotic treatment and follow-up data. The primary outcome was to determine the characteristics of L monocytogenes-associated spontaneous bacterial peritonitis. We did descriptive analyses and assessed risk factors for 1-month mortality using an exploratory multivariable Cox model analysis. Among the 8768 L monocytogenes cases reported, 208 (2%) were patients with L monocytogenes-associated spontaneous bacterial peritonitis. Mean age was 65 years (SD 13), 50 (24%) of 208 patients were female, and 158 (76%) were male (no data on race or ethnicity were available). 200 (98%) of 205 patients with L monocytogenes-associated spontaneous bacterial peritonitis with available data had immunosuppressive comorbidities, including cirrhosis (148 [74%] of 201 with available data), ongoing alcoholism (58 [62%] of 94), and ongoing neoplasia (60 [31%] of 195). Causes of ascites included cirrhosis (146 [70%] of 208), ongoing neoplasia (26 [13%]), end-stage heart failure (13 [6%]), and peritoneal dialysis (11 [5%]). Among those with available data, presentation was pauci-symptomatic and non-specific; only 67 (50%) of 135 patients presented with fever, 49 (37%) of 132 with abdominal pain, and 27 (21%) of 129 with diarrhoea. 61 (29%) of 208 patients were dead at 1 month, 92 (44%) were dead at 3 months, and 109 (52%) were dead at 6 months after diagnosis. Ongoing neoplasia (hazard ratio 2·42 [95% CI 1·05-5·56]; p=0·039), septic shock (8·03 [2·66-24·02]; p=0·0021), and high blood leukocyte count (1·05 [1·00-1·09]; p=0·045) were independently associated with 1-month mortality. Despite the non-specific and mild presentation of L monocytogenes-associated spontaneous bacterial peritonitis, the outcome is poor and similar to that of neurolisteriosis, and so identification of L monocytogenes in ascitic fluid samples requires urgent parenteral amoxicillin-based treatment to avoid a fatal outcome. Institut Pasteur, Inserm, and French Public Health Agency. For the French translation of the abstract see Supplementary Materials section.

Multivariate data analysis for semen quality in two frog species

Despite the growing body of research on frog reproduction and semen quality, studies employing statistical methods and analyses are scarce. The present study aimed to examine the use of exploratory multivariate data analysis for evaluating the seminal quality of frogs, determining a possible hierarchy among frog species based on semen characteristics, and identifying the most effective clustering strategy. Data on the seminal quality of the butter frog (Leptodactylus ocellatus, native specie) were collected from seven samples, and for the bullfrog (Lithobates catesbeianus, exotic specie), five samples were used, all derived from a literature review. Four distinct clustering strategies were tested: Single Linkage, Unweighted Pair Group Method with Arithmetic Mean (UPGMA), Complete Linkage, and Ward’s method. Exploratory multivariate data analysis could effectively evaluate frog seminal quality, allowing the classification of frog species (both native and exotic) based on semen. Among the tested strategies, UPGMA emerged as the most suitable grouping method.

Factors affecting marketing on sustainable tourism development in the coastal provinces of Vietnam

The article "Marketing factors affecting sustainable tourism development in Vietnam's coastal provinces" focuses on researching the role of Marketing in promoting sustainable tourism in Vietnam's coastal provinces. The study aims to identify and evaluate the impact of marketing factors such as tourism products, prices, distribution channels, marketing communications, people, processes and physical evidence on the sustainable development of the industry travel in this area. Through the use of primary and secondary data collection methods, along with descriptive statistical analysis techniques, exploratory factor analysis (EFA) and multivariate regression analysis, the study has clarify the current status of sustainable tourism development in Vietnam's coastal provinces and point out marketing factors that have a significant influence on this process. Based on the research results, the article proposes practical recommendations for tourism managers and businesses to orient and optimize marketing activities to promote sustainable tourism. At the same time, the article also frankly points out the limitations of the research and opens up new research directions for the future.

Acute Angiotensin II Receptor Blockade Facilitates Parahippocampal Processing During Memory Encoding in High-Trait-Anxious Individuals

BackgroundAngiotensin II receptor blockers (ARBs) have been associated with preventing posttraumatic stress disorder symptom development and improving memory. However, the underlying neural mechanisms are poorly understood. This study investigated ARB effects on memory encoding and hippocampal functioning that have previously been implicated in posttraumatic stress disorder development. MethodsIn a double-blind randomized design, 40 high-trait-anxious participants (33 women) received the ARB losartan (50 mg) or placebo. At drug peak level, participants encoded images of animals and landscapes before undergoing functional magnetic resonance imaging, where they viewed the encoded familiar images and unseen novel images to be memorized and classified as animals/landscapes. Memory recognition was assessed 1 hour after functional magnetic resonance imaging. To analyze neural effects, whole-brain analysis, hippocampus region-of-interest analysis, and exploratory multivariate pattern similarity analysis were employed. ResultsARBs facilitated parahippocampal processing. In the whole-brain analysis, losartan enhanced brain activity for familiar images in the parahippocampal gyrus (PHC), anterior cingulate cortex, and caudate. For novel images, losartan enhanced brain activity in the PHC only. Pattern similarity analysis showed that losartan increased neural stability in the PHC when processing novel and familiar images. However, there were no drug effects on memory recognition or hippocampal activation. ConclusionsGiven that the hippocampus receives major input from the PHC, our findings suggest that ARBs may modulate higher-order visual processing through parahippocampal involvement, potentially preserving intact memory input. Future research needs to directly investigate whether this effect may underlie the preventive effects of ARBs in the development of posttraumatic stress disorder.

Durvalumab-Associated Pneumonitis in Patients with Locally Advanced Non-Small Cell Lung Cancer: A Real-World Population Study.

The PACIFIC trial led to a new standard of care for patients with locally advanced lung cancer, but real-world practice has demonstrated that immune checkpoint inhibitor (ICI) pneumonitis can lead to significant clinical complications. This study aimed to examine the clinical predictors, outcomes, and healthcare utilization data in patients who received consolidation durvalumab. Using the Alberta Immunotherapy Database, NSCLC patients who received durvalumab in Alberta, Canada, from January 2018 to December 2021 were retrospectively evaluated. We examined incidence and predictive values of severe pneumonitis, with overall survival (OS) and time-to-treatment failure (TTF) using exploratory multivariate analyses. Of 189 patients, 91% were ECOG 0-1 and 85% had a partial response from chemoradiation prior to durvalumab. Median TTF and OS were not reached; 1-year OS was 82%. An amount of 26% developed any grade of pneumonitis; 9% had ≥grade 3 pneumonitis. Male gender and a pre-existing autoimmune condition were associated with severe pneumonitis. V20 was associated with any grade of pneumonitis. Pneumonitis development was found to be an independent risk factor for worse OS (p = 0.038) and TTF (p = 0.007). Our results suggest clinical and dosimetric predictive factors of durvalumab-associated pneumonitis. These results affirm the importance of careful patient selection for safe completion of consolidation durvalumab in real-world LA-NSCLC population.

Predictors and outcomes of perioperative cardiac arrest in children undergoing noncardiac surgery

BackgroundPerioperative cardiac arrest continues to occur. This study aims to identify risk factors for perioperative cardiac arrest in children presenting for noncardiac surgery and characterise its outcomes. MethodsUsing the National Surgical Quality Improvement Program (NSQIP) Pediatric Database 2019 and 2020, 261 276 patients were included. Patients ≥18 yr and cardiac surgical procedures were excluded. Exploratory multivariable analysis was performed to identify independent predictors of perioperative cardiac arrest and associated outcomes. ResultsThe overall rate of cardiac arrest was 0.1%, with an intraoperative rate of 0.05% and 48-h postoperative rate of 0.06%. Significant risk factors for perioperative cardiac arrest included age <12 months (adjusted odds ratios [aOR] 3.07, P<0.001), American Society of Anesthesiology Physical Status classification (ASA-PS 3 aOR=2.57, P<0.001; ASA-PS 4 aOR=5.27, P<0.001; ASA-PS 5 aOR=13.1, P<0.001), admission through the emergency room (aOR 1.7, P=0.003), inpatient (aOR 2.19, P=0.008), major and severe cardiac disease (aOR 1.58, P=0.008), impaired cognitive status (aOR 1.54, P=0.009), and longer anaesthesia duration (aOR 1.1 per 30 min, P<0.001). Perioperative cardiac arrest was significantly associated with longer hospital length of stay, reoperation, differences in discharge destination, and 30-day mortality. In addition, patients experiencing postoperative cardiac arrest had a significantly higher rate of in-hospital and 30-day mortality than those experiencing intraoperative cardiac arrest. ConclusionsThe incidence of cardiac arrest in this study is higher than previously reported. This may be related to selection bias and the rigorous data collection required by NSQIP. Lower 30-day mortality after intraoperative cardiac arrest could be related to prompt recognition and rapid initiation of intraoperative resuscitation. Identification of perioperative risk factors for cardiac arrest is crucial to improve the safety and quality of patient care.

Phenotypic Analysis of Baseline T cell Subsets and Third Generation CD20 Targeted CAR T cell Products for Treatment of Relapsed/Refractory Follicular Lymphoma

Background: Chimeric antigen receptor (CAR) T cell therapy achieves high response rates in the treatment of follicular lymphoma (FL), with two FDA-approved therapies to date. However, some patients (pts) fail to achieve a complete response and others experience early relapse, and the reasons for this are unclear. One potential explanation for treatment failure is poor persistence or exhaustion of CAR T cells. Indeed, in other settings of CAR T cell (CAR-T) therapy, phenotypic differences in the CAR-T product and even pre-manufacturing T cells can predict duration of anti-tumor CAR-T function and antigen-responsive cytotoxicity. Methods: We previously reported promising efficacy and safety in a cohort of pts with relapsed/refractory FL treated with a fully-human 3 rd generation CD20-targeted CAR (Shadman et al., ICML 2023). In pt samples from this trial, we quantified CD4 + and CD8 + T cell subsets in screening blood samples at study entry (n=20), based on CD45RA, CD45RO, CCR7, CD62L, CD27, and/or CD95 expression (naïve [T N], central memory [T CM], effector memory, stem cell memory, effector, etc.) We also analyzed various combinations of markers from exhaustion (PD-1, Tim-3, Lag-3, CD39, and CD57) and memory (CD45RA, CD45RO, CCR7, CD62L, and CD127) panels in CAR-T products (measured 1 day prior to infusion) (n=19; 1 pt had insufficient cells in the infusion product [IP] to analyze). These were recorded as both percent expression (of total CD4 + or CD8 + cells) compared to isotype controls and calculated absolute cell counts per µl at apheresis or in IP. We performed a univariate analysis of hypothesis-driven biomarkers (7 at baseline, 10 in IP) (Table 1) capturing combinations of T N / T CM markers (screening and IP) and absence of exhaustion markers (IP only) with endpoints of complete remission (CR) at 6 months, progression-free survival (PFS), CAR-T expansion (area under the curve [AUC] and peak), and cytokine release syndrome (CRS) (no pts developed neurologic toxicity). Due to the small sample size, we performed multivariable analysis using a novel high dimensional inference (HDI) approach to rank potential biomarkers of interest with primary endpoint CR at 6 months and secondary endpoint CAR-T cell AUC. HDI provides “de-biased” estimates for coefficients, confidence intervals, and p-values without refitting, which is easier to interpret. Biomarker combinations comprising &amp;lt;1% cells were excluded. Results: We did not find any significant association between baseline or IP hypothesis-driven markers and CR at 6 months or CRS in univariate analysis. We noted a possible association with baseline absolute counts of CD45RO +CD62L +CD8 + cells for PFS; however, this was largely driven by an outlier pt with a short remission due to CD20-negative relapse. Baseline % of CD45RA +CD62L + in CD8 + cells was associated with higher peak CAR-T expansion, and infused absolute counts of CD8 + CAR T cells with CD45RA +CD62L +, CD45RO +CD62L +, CD39 -PD-1 -, or Lag3 -PD-1 - phenotypes were found to be associated with both higher CAR-T AUC and peak CAR-T expansion. The multivariable HDI analysis revealed a rank list of markers of interest associated with CR at 6 months and CAR-T AUC, with the top 5 combinations for each association shown in Table 2. Conclusion: We found that higher infused numbers of CD8 + CAR T cells with T N or T CM phenotypes, or low expression of certain exhaustion phenotype marker combinations, were associated with improved CAR-T expansion. We did not find any notable phenotypic signatures at baseline or in the IP that were predictive of prolonged CR, PFS, or toxicity, though the analysis was limited by a relatively small sample size. In FL, where a response to CAR-T therapy is almost universal, pre-manufacture and IP T cell phenotypes appear to have a lower importance for achieving an initial response than what has been reported in other settings with lower response rates (chronic lymphocytic leukemia, large B cell lymphoma). Our lack of clear association between T cell phenotypes and prolonged CR or PFS suggests that later treatment failures in FL may be driven primarily by factors other than T cell fitness, such as tumor biology. However, our exploratory multivariable analysis did identify some potential phenotypic signatures that may prove to be predictive with further validation, and future studies incorporating duration of B cell aplasia may show that phenotypes are important for functional CAR T cell persistence.

A Matching-Adjusted Indirect Comparison of Acalabrutinib with and without Obinutuzumab Versus Zanubrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia

Introduction The second-generation Bruton tyrosine kinase inhibitors acalabrutinib (acala) and zanubrutinib (zanu) have not been compared with each other in a head-to-head randomized controlled trial (RCT). Acala with and without obinutuzumab (obin) was evaluated in the ELEVATE-TN RCT in treatment-naïve patients with chronic lymphocytic leukemia (CLL). Zanu was evaluated in treatment-naïve patients with CLL/small lymphocytic leukemia (SLL) in cohorts 1 and 2 of the SEQUOIA RCT. We used an unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acala ± obin versus zanu in patients with treatment-naïve CLL/SLL without del(17p). Datasets were derived from comprehensive individual patient data (IPD) from ELEVATE-TN and published aggregate data from cohort 1 in SEQUOIA. Methods In this unanchored MAIC, we weighted IPD for the acala + obin and acala monotherapy arms from ELEVATE-TN to match zanu baseline data from SEQUOIA. We excluded patients with del(17p) in ELEVATE-TN to match cohort 1 in SEQUOIA, which excluded patients with del(17p). Patients were matched based on variables considered prognostic and/or predictive of investigator-assessed progression-free survival (INV-PFS) in an exploratory multivariate Cox-regression analysis of ELEVATE-TN. These were age, ECOG status, Binet stage, bulky disease, B2 microglobulin, cytopenia, del(11q), trisomy 12, IGHV status,and TP53 mutation. The efficacy analysis assessed INV-PFS in randomized patients (acala + obin, n = 162; acala monotherapy, n = 163; zanu, n = 241) using the Oct 2021 data cut-off (DCO) for ELEVATE-TN and the Oct 2022 DCO for SEQUOIA (median follow-up 58 versus 44 months). Pseudo-IPD for INV-PFS for zanu were obtained from Kaplan-Meier curves. The safety analysis assessed the incidence of adverse events (AEs) and reported the odds ratios (ORs) of AEs in treated patients (acala + obin, n = 162; acala monotherapy, n = 162; zanu, n = 240). To compare the incidence of AEs, the ELEVATE-TN Sep 2020 DCO was used to match the median follow-up from the SEQUOIA Oct 2022 DCO (47 versus 44 months). Results In the efficacy analysis, the acala + obin and acala monotherapy effective sample sizes (ESSs) post-matching were 124 (76%) and 105 (64%), respectively. Matching had little impact on acala + obin and acala monotherapy INV-PFS (Figure 1). Post-matching, 36-month INV-PFS was higher with acala + obin (95%; 95% CI: 90-97) than with zanu (84%; 95% CI: 79-88). The MAIC-weighted Cox hazard ratio (HR) found INV-PFS to be superior with acala + obin versus zanu (HR: 0.41; 95% CI: 0.23-0.74; Figure 1). No evidence of a difference between acala monotherapy post-matching and zanu was found when looking at 36-month INV-PFS (86%; 95% CI: 78-91 versus 84%; 95% CI: 79-88; HR: 0.91; 95% CI: 0.53-1.56). In the safety analysis, the acala + obin and acala monotherapy ESSs post-matching were 123 (76%) and 103 (64%), respectively. There were no significant differences in the odds of having most types of AE with acala + obin versus zanu, except for higher odds of having any grade neutropenia (OR: 2.19; 95% CI: 1.33-3.60) and arthralgia (OR: 2.33; 95% CI: 1.37-3.96). Acala monotherapy showed lower odds of having any grade hypertension (OR: 0.44, 95% CI: 0.20-0.99; Figure 2) and no significant differences in the odds of having other types of AEs versus zanu. Conclusions In this MAIC of ELEVATE-TN and SEQUOIA evaluating patients with treatment-naïve CLL/SLL without del(17p), acala + obin had a longer INV-PFS versus zanu, while there was no evidence of a difference between acala monotherapy and zanu. Acala + obin and acala monotherapy generally had similar safety profiles to zanu. However, acala monotherapy was associated with lower odds of any grade hypertension versus zanu, while acala + obin was associated with higher odds of any grade neutropenia and arthralgia versus zanu. Although the results of MAIC analyses can only be hypothesis-generating, these results address an important data gap by systematically comparing these two commonly used regimens where randomized, prospective data are not available.

Receipt of work accommodations related to longer job tenure among working breast cancer survivors.

485 Background: Receiving accommodations at work (e.g. flexible hours) can help cancer survivors transition to and maintain employment. There is limited knowledge, however, about occupational and personal factors that influence receiving accommodations. We hypothesize that the longer an employee worked at an organization, the higher the odds of receiving accommodations likely due to enhanced awareness (e.g. policies, processes) and interpersonal connections (e.g. relationships, managerial support). Methods: We analyzed data from the PinkWorks Study, a self-reported, cross-sectional online survey of 154 female breast cancer survivors. Participants were ≥18 years of age, fluent in English, had completed treatment within the past 36 months, and were working ≥ 20 hours per week at the time of cancer diagnosis and currently. Logistic Regression was performed to evaluate if job tenure (&lt; 5 yrs, versus ≥ 5 yrs) was associated with receipt of accommodations (yes, no) in the full sample and then stratified by having taken leave from work (n=79) or not (n=77) based on our prior work. Due to small sample sizes in key cells, however, only exploratory multivariate analyses were conducted. Results: In analyses of the total sample, there was a suggested association of higher job tenure (≥5 years) with receipt of accommodations compared to those with fewer years (&lt; 5 yrs) at the company (OR=1.76, 95% CI 0.72-4.22, p=0.22). Among those who took a leave of absence, participants with higher job tenure (≥5 years) were far more likely to receive work accommodations (OR = 3.50 95% CI 1.04-11.8, p=0.04). In contrast, among those who did not take a leave, there was no evidence of an effect related to job tenure (p=0.58). Analysis from preliminary multivariate adjustment (e.g., age, stage of disease, race) did not appreciably vary from the univariate results. However, we did observe that participants identifying as non-Hispanic white were more likely to receive accommodations than other race/ethnic groups (OR = 3.42 95% CI 0.90-12.9, p=0.07) in multivariate analyses of the entire sample. Conclusions: Our findings suggest that length of time with an employer predicts receipt of work accommodation possibly limited to those who took medical leave. This difference in work leave suggests preferential awarding of real-time accommodations and leave. From a clinical perspective, these results should guide discussions about work accommodations, especially early in treatment and for patients with shorter job tenure or from diverse racial backgrounds. They underscore the critical need for organizational policy interventions to ensure equal support for all employees following a cancer diagnosis. The cross-sectional design and small sample sizes in this exploratory study limit interpretation. Future analyses are suggested to explore underlying reasons (e.g., enhanced awareness of policies) and racial disparities in receiving accommodations.

Real-world experience with CLAIRYG® 50 mg/mL (intravenous immunoglobulin) in children under 12 years with primary immunodeficiency or immmune thrombocytopenia: a post-approval safety study.

This study presents the results of a real-life, multicenter, prospective, post-approval safety evaluation of Clairyg® 50 mg/mL, a 5% intravenous immunoglobulin (IVIg) liquid, in 59 children (aged < 12 years) with primary immunodeficiency diseases (PID) (n = 32) or immune thrombocytopenia (ITP) (n = 27) in France. The primary objective of the study was to assess the safety and tolerability of Clairyg®, recording all serious and non-serious adverse events (AEs), whether related (rAEs) or not related to the product. Secondary objectives aimed at evaluating the administration of Clairyg® under routine conditions and the available efficacy data to better document the benefit/risk ratio in this pediatric population. An exploratory objective was added to evaluate the potential factors associated with the occurrence of rAEs. Patients received Clairyg® according to the approved dosage under normal conditions of prescriptions over a median follow-up period of 11.8 months. A total of 549 infusions (PID: n = 464 and ITP: n = 85), were administered, of which 58.8% were preceded by premedication. The most frequent rAEs were headache, vomiting, and pyrexia in both indications. Most of them were considered non-serious and mild or moderate in intensity. A severe single rAE was observed (aseptic meningitis) in a 4-year-old girl presenting with chronic ITP. The exploratory multivariate analysis of potential co-factors showed that the occurrence of rAEs is significantly linked to high IVIg doses and possibly to female gender. The annualized rate of serious bacterial infections was 0.11 for patients with PID. For patients with ITP, 74.1% experienced at least one bleeding episode during the follow-up, mostly a cutaneous one, and none had gastrointestinal, genitourinary, or central nervous system bleeding. Clairyg® was well tolerated and allowed for control of serious bacterial infection in PID and serious bleeding in ITP, which are the main complications in these respective pediatric disorders. No new safety signal was detected in children less than 12 years-old in real-life conditions of use.

The Possible Role of Anti- and Protumor-Infiltrating Lymphocytes in Pathologic Complete Response in Early Breast Cancer Patients Treated with Neoadjuvant Systemic Therapy.

The tumor microenvironment, composed of pro- and antitumor immune cells, affects cancer cell behavior. We aimed to evaluate whether tumor-infiltrating lymphocyte (TIL) density and TIL subtypes in core biopsies at the diagnosis of breast cancer patients could predict a pathologic complete response (pCR; ypT0/is ypN0) from neoadjuvant systemic therapy (NST). The TIL subtypes were determined based on the proportions of presumably antitumor (CD8+, CXCL13+) and protumor (PD-1+, FOXP3+) immune cells. A prospective, noninterventional study, including 171 participants undergoing NST, was performed. The median TIL density for the entire cohort was 10% (IQR: 3.5-23.8), and 59 (35%) patients achieved pCR. TIL density was positively associated with pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR (p = 0.012, OR 1.27; 95% CI 1.05-1.54) when controlled for age (p = 0.232), Ki-67 (p = 0.001), node-negative status (p = 0.024), and HER2+/triple negative vs. luminal B-like subtype (p < 0.001). In our sample, higher proportions of PD-1+ TILs and FOXP3+ TILs were associated with a higher probability of pCR but the association was not statistically significant and we could not make any conclusions on the direction of associations in the model with all four biomarkers. In the exploratory multivariable analysis, we showed that only higher CD8+ TILs were associated with pCR. In conclusion, TIL density and its subtypes are associated with pCR.

Monitoring settling of anaerobic digestates using low-field MRI profiling and NMR relaxometry measurements

Dewatering of anaerobic digestate from red meat processing was assessed using low field MRI profiling and NMR relaxometry. Samples were flocculated using a cationic flocculant (EM640CT) at dosing range (0 to 1.6% v/v) and monitored during the initial 30 min of settling via MRI profiling to assess changes in water fraction, settling time and initial settling velocity. The profiles showed decreasing settling time and increasing initial settling velocity with increased dosing, while sample porosity was observed to increase up to the optimal dosing point (0.8% v/v). Significant increases in sample variability were observed past this point due to flocculant overdosing. The samples were then analysed in terms of turbidity and NMR relaxometry. Increasing flocculant concentration caused turbidity to decrease from 210 to 13 NTU. The relaxation rate of free water showed a strong positive correlation with turbidity. T2 peaks observed before overdosing could be assigned to different water structures (free, interstitial, vicinal and hydration). An additional T2 population emerged in the T2 distributions at the optimal dosing point. Multivariate exploratory data analysis (MEDA) showed that this T2 population from the solids layer was strongly correlated with the total solids layer height and turbidity of the watery layer. This T2 peak formation may therefore be used to study opaque flocculated solids to monitor for water structures associated with flocculant overdosing. Further studies using this technique will aim to assess the potential of low field T2 relaxometry monitoring inline before mechanical dewatering, to monitor optimal flocculant dosing during continuous operations on systems with high solids concentration.

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer

The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated. To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy. The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022. After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen. The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile. Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]). The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC. ClinicalTrials.gov Identifier: NCT02404935.