Long-term Benefits Research Articles

Abstract PO2-04-01: Predictors of exceptional response to first line HER2-targeted therapy for metastatic breast cancer

Abstract Background HER2-targeted therapies have transformed the trajectory of HER2-positive (HER2+) metastatic breast cancer (MBC), with a subgroup of responders remaining on first line (1L) therapy for many years (yrs). Despite these promising outcomes, the paradigm remains palliative, with some patients (pts) receiving therapy indefinitely. Opportunities to interrupt therapy are controversial and anecdotal in the setting of a limited understanding of long-term responders and lack of predictive biomarkers. Methods We identified prevalent pts with HER2+ MBC seen and consented at Dana-Farber Cancer Institute between 2010 and 2023, regardless of the original date of MBC diagnosis. Exceptional responders (ExRes) were pts without evidence of progressive disease (PD) 3 yrs from initiation of 1L therapy for MBC. Conventional responders (ConRes) were pts who experienced PD within 3 yrs of 1L treatment initiation. We compared clinicopathological characteristics and treatment patterns between ExRes and ConRes using Chi-square or Wilcoxon test. We analyzed median time to treatment switch due to PD (TTS-PD) – i.e., time from metastatic diagnosis to 1L treatment end due to PD - and overall survival, via the Kaplan-Meier method and with a landmark analysis at year 3 (Y3). Our primary aim was to identify predictors of exceptional response to 1L anti-HER2 therapy. Results Of 635 pts with HER2+ MBC, we identified 147 ExRes and 370 ConRes and excluded 118 pts due to follow up ≤ 3 yrs and no PD events. Median follow up was 7.1 yrs (IQR 5.5-11.0) for ExRes and 7.1 yrs (IQR 4.0-11.4) for ConRes. Median age at MBC diagnosis was 50.7 yrs (range 21.9-91.9) for ExRes and 49.8 yrs (26.9-82.3) for ConRes. ExRes presented more often with de novo MBC than ConRes (52.1 vs 30.6%, p< 0.0001). On metastatic samples, more ExRes than ConRes had HER2 3+ tumors by immunohistochemistry (IHC) (93.7 vs 81.0%, p=0.002), whereas the proportion of ER-positive disease was similar between the two groups (45.6 vs 53.4%, p=0.1). Most pts received (neo)adjuvant anti-HER2 agents in both groups (62.5 vs 72.7%, p=0.1). More ExRes than ConRes (55.8 vs 42.7% p=0.007) received 1L chemotherapy (CT) plus trastuzumab (H)/pertuzumab (P). Alternative 1L treatments were CT plus H (26.5 vs 25.7%), H +/- P +/- endocrine therapy (8.2 vs 10.5%), T-DM1 (2 vs 9.2%), tyrosine kinase inhibitors-based regimens (7.5 vs 10.8%). For pts with recurrent MBC, disease-free interval was longer for ExRes than ConRes (median 4.7 vs 3.4 yrs, p=0.01). Visceral involvement at MBC relapse was similar for ExRes and ConRes (78.2 vs 77.8%, p=0.9). Brain metastases at any timepoint were less frequent among ExRes than ConRes (42.9 vs 55.1%, p=0.01). Among ExRes, 70 (47.6%) pts experienced PD after Y3, with a median TTS-PD of 4.6 (4.1-5.1) yrs. In a landmark analysis at Y3, the 2-year TTS-PD was 68.5% (95% CI: 59.8%-75.7%) (5 yrs from treatment start), and 4-year overall survival was 86.5% (95% CI: 78.1%-91.9%) (7 yrs from treatment start). ConRes received a median of 5 (1-19) treatment regimens for MBC, with a median 1L TTS-PD of 12 (10.8-13) mo. A total of 89 (60.5%) ExRes and 214 (57.8%) ConRes underwent tumor sequencing. Data comparing genomic features between ExRes and ConRes will be presented. Conclusions In this prospective cohort, 28% of pts with HER2+ MBC had exceptional response to 1L anti-HER2 therapy. Consistent with prior data, ExRes present more frequently with de novo disease and HER2 IHC 3+ tumors. In our cohort, ExRes had a median follow-up of 7.1 years and 52.4% never experienced PD. Although a significant proportion of pts with HER2+ MBC derive long-term benefit from anti-HER2 therapy, the treatment paradigm remains palliative, and it is unknown whether biomarkers may reliably predict exceptional response and guide future treatment. Ongoing work will explore whether genomic features vary between ExRes and ConRes. Citation Format: Stefania Morganti, Tianyu Li, Katheryn Santos, Melissa Hughes, Nolan Priedigkeit, Yvonne Li, Marla Lipsyc-Sharf, Gregory Kirkner, Janet Files, Julie Kasparian, Elizabeth Grant, Gunjan Gupta, Giuseppe Curigliano, Sara Tolaney, Andrew Cherniack, Nabihah Tayob, Nancy Lin, Heather Parsons. Predictors of exceptional response to first line HER2-targeted therapy for metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-01.

Latent-Transforming Growth Factor β-Binding Protein 1/Transforming Growth Factor β1 Complex Drives Antitumoral Effects upon ERK5 Targeting in Melanoma

Melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. Available treatments have improved the survival, although long-term benefits are still unsatisfactory. The mitogen-activated protein kinase ERK5 promotes melanoma growth, and ERK5 inhibition determines cellular senescence and the senescence-associated secretory phenotype. Here, latent-transforming growth factor β-binding protein 1 (LTBP1) mRNA was found to be upregulated in A375 and SK-Mel-5 BRAFV600E melanoma cells after ERK5 inhibition. In keeping with a key role of LTBP1 in regulating transforming growth factor β (TGF-β), TGF-β1 protein levels were increased in lysates and conditioned media of ERK5-knock down (KD) cells, and were reduced upon LTBP1 KD. Both LTBP1 and TGF-β1 proteins were increased in melanoma xenografts in mice treated with the ERK5 inhibitor XMD8-92. Moreover, treatment with conditioned media from ERK5-KD melanoma cells reduced cell proliferation and invasiveness, and TGF-β1-neutralizing antibodies impaired these effects. In silico datasets revealed that higher expression levels of both LTBP1 and TGFB1 mRNA are associated with better overall survival of melanoma patients, and that increased LTBP1 or TGF-β1 expression proved a beneficial role in patients treated with anti-PD1 immunotherapy, making unlikely a possible immunosuppressive role of LTBP1/TGF-β1 upon ERK5 inhibition. This study, therefore, identifies additional desirable effects of ERK5 targeting, providing evidence of an ERK5-dependent tumor suppressive role of TGF-β in melanoma.

Young Trauma-Exposed Women with Low Sleep Effciency have Blunted Sympathetic Baroreflex Sensitivity and Higher Muscle Sympathetic Nerve Activity

Introduction: Poor sleep, a known risk factor for cardiovascular disease (CVD) and one of the American Heart Association’s essential 8th, is common after trauma-exposure. Although premenopausal women are thought to be protected from CVD, trauma exposure might increase their CVD risk. In a recent large epidemiological study examining sleep-related CVD comorbidities, the empirical cut off point for optimal sleep effciency (SE) was set at 83%, distinguishing between good and poor sleep effciency. Studies have suggested an overactive sympathetic nervous system and an impaired baroreflex sensitivity (BRS) as potential mechanisms of increased CVD risk. However, the impact of poor sleep effciency on muscle sympathetic nerve activity (MSNA) and BRS in young trauma-exposed women is unknown. We hypothesized that young trauma-exposed women with poor sleep effciency will present with impaired BRS and increased MSNA at rest. Methods: We collected data on 30 women (18 – 40 years) from diverse backgrounds who had been exposed to trauma. Sleep data was acquired via ActiWatch for 7 days and used to categorize our participants into two groups: good effciency (SE > 83%, n=17) and poor effciency (SE < 83%, n=13), with SE calculated as the percentage of time spent asleep while in bed. Additionally, we collected continuous noninvasive blood pressure (BP), heart rate (HR), and MSNA (burst frequency, incidence, and total activity) during 10 minutes of quiet rest. Sympathetic BRS was determined as the slope of the regression between individual sympathetic bursts and diastolic BP bins (3 mmHg), weighted against the number of cardiac cycles, utilizing an automated program (Ensemble, NZ). Results: There were no significant differences in trauma symptom severity, resting BP and HR between the two groups (p>0.05 for all). However, resting sympathetic BRS was blunted in the poor SE (-0.10±0.88 bursts/100hb/mmHg) compared to the good SE (-1.44±1.58 bursts/100hb/mmHg, p=0.006) group, even after adjusting for age (p=0.009). Likewise, resting total MSNA was higher in the poor SE compared to the good SE after adjusting for age (p=0.028). MSNA burst frequency and burst incidence were comparable between the groups (p>0.05). Conclusion: Our analyses revealed that poor sleep effciency is associated with decreased sympathetic baroreflex sensitivity and higher total muscle sympathetic activity at rest, regardless of age. Blunted sympathetic BRS may contribute to increased sympathetic activity in young women with poor sleep effciency. Future studies testing strategies to improve sleep effciency in this population could provide potential long-term cardiovascular benefits. UL1TR002494 and NIH K01HL161027 No disclosure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Can a specific deep brain stimulation paradigm slow motor progression and provide long-term motor benefit in Parkinson’s disease?

Can a specific deep brain stimulation paradigm slow motor progression and provide long-term motor benefit in Parkinson’s disease?

Laparoscopic Spleen-Preserving Hilar Lymphadenectomy for Advanced Proximal Gastric Cancer Without Greater Curvature Invasion

Splenic hilar lymphadenectomy has been recommended for locally advanced proximal gastric cancer (APGC) involving the greater curvature. However, it is unclear whether laparoscopic spleen-preserving splenic hilar lymphadenectomy (LSPSHL) is associated with a long-term survival benefit for APGC without greater curvature invasion. To present the 5-year follow-up data from a randomized clinical trial that compared laparoscopic total gastrectomy (D2 group) with D2 plus LSPSHL (D2 + No. 10 group) among patients with resectable APGC. This is a post hoc secondary analysis of a randomized clinical trial that enrolled 536 patients with potentially resectable APGC (cT2-4a, N0 or N+, and M0) without greater curvature invasion from January 5, 2015, to October 10, 2018. All patients were tracked for at least 5 years. The final follow-up was on October 30, 2023. Patients were randomly assigned in a 1:1 ratio to the D2 + No. 10 or D2 groups. The 5-year disease-free survival (DFS) and overall survival (OS) rates were measured. Recurrence patterns and causes of death were compared. A total of 526 patients (392 men [74.5%]; mean [SD] age, 60.6 [9.6] years) were included in the modified intent-to-treat analysis, with 263 patients in each group. The 5-year DFS rate was 63.9% (95% CI, 58.1%-69.7%) for the D2 + No. 10 group and 55.1% (95% CI, 49.1%-61.1%) for the D2 group (log-rank P = .04). A statistically significant difference was observed in the 5-year OS between the D2 + No. 10 group and the D2 group (66.2% [95% CI, 60.4%-71.9%] vs 57.4% [95% CI, 51.4%-63.4%]; log-rank P = .03). The No. 10 lymph node exhibited a therapeutic value index (TVI) of 6.5, surpassing that of Nos. 8a (TVI, 3.0), 11 (TVI, 5.8), and 12a (TVI, 0.8). A total of 86 patients in the D2 + No. 10 group (cumulative incidence, 32.7%) and 111 patients in the D2 group (cumulative incidence, 42.2%) experienced recurrence (hazard ratio, 0.72; 95% CI, 0.54-0.95; P = .02). The multivariable competing risk regression model demonstrated that D2 + No. 10 remained an independent protective factor for a lower 5-year cumulative recurrence rate after surgery (hazard ratio, 0.75; 95% CI, 0.56-1.00; P = .05). There was a significant difference in the 5-year cumulative recurrence rate at the No. 10 lymph node area between the 2 groups (D2 + No. 10 group vs D2 group: 0% vs 2.3% [n = 6]; P = .01). This post hoc secondary analysis of a randomized clinical trial found that laparoscopic total gastrectomy with LSPSHL can improve the prognosis and reduce recurrence for APGC without greater curvature invasion. Future multicenter studies are warranted to validate these findings. ClinicalTrials.gov Identifier: NCT02333721.

TEN YEAR FOLLOW-UP OF PATIENTS WITH RESISTANT HYPERTENSION RANDOMIZED TO RENAL DENERVATION OR ANTIHYPERTENSIVE DRUG TREATMENT

Objective: Renal denervation (RDN) is a treatment option in resistant hypertension. The procedure is considered safe, although randomized trials only demonstrate a moderate blood pressure (BP) lowering effect, when considering medication adherence. Some observational studies describe reduction in BP several years after the procedure. The aim of the study was to describe long-term safety and potential benefits of RDN after ten years, compared to optimized drug treatment, measuring serum concentration of antihypertensive drugs to ensure adherence. Design and method: We report data from ten year follow-up of patients randomized to RDN (n=9) or drug adjustment (n=10). Initially the patients had treatment-resistant hypertension, defined as daytime systolic ambulatory BP >= 135 mmHg after witnessed intake (directly observed therapy, DOT) of >= 3 antihypertensive drugs including a diuretic and therefore considered as adherent. One year after RDN or drug adjustment, we optimized antihypertensive medication for all patients. Thereafter, patients received appropriate antihypertensive treatment in primary or secondary care, according to their BPs. Patients were informed of serum concentration measurements performed at the 7-year visit. At the 10-year visit, serum drug measurements before DOT and ambulatory BP measurement (ABPM) were used for evaluation of adherence. Antihypertensive agents were registered, glomerular filtration rate (eGFR) was estimated by the CKD-EPI formula using creatinine and Cystatin C, and renal arteries were examined by CT or MRI. Results: All living patients (n=18) attended the 10-year visit, now mean age 69 years, using 4±2 antihypertensive agents, with no difference between groups. Serum concentrations confirmed that all patients were adherent to reported medication. There were significant and similar BP reductions in both groups compared to baseline; daytime ABPM -22±15/9±8 mmHg in the RDN group, and -20±15/13±7 mmHg in the control group (figure). No patients developed renal artery stenosis. The decrease in eGFR was similar in both groups. Conclusions: To our knowledge this is the RCT with the longest follow-up supporting long-term safety of RDN in patients with resistant hypertension. Daytime ABPM improved during 10 years of follow-up, not explained by RDN, but due to adjustments in antihypertensive regimens and probably better adherence to medication.

Advancing Organizational Science With Computational Process Theories

Organizational scholars commonly refer to organizations as complex systems unfolding as a function of work processes. Consequently, the direct study of work processes necessitates our attention. However, organizational scholars tend not to study work processes directly. Instead, organizational scholars commonly develop theories about relationships among psychological construct phenomena that indirectly reference people’s affective, behavioral, cognitive, and/or social processes as underlying explanations. Specifically, construct-oriented theories summarize processes in operation across actors, time, and contexts, and thus, provide limited insights into how focal phenomena manifest directly as a function of process operations. Construct theories remain one-step removed from articulating sequences of actions and two-steps removed from describing generative mechanisms responsible for observed actions. By “missing the action,” construct theories offer incomplete explanatory accounts and imprecise interventions. We assert that researchers in organizational science can make progress towards addressing these concerns by directing greater attention to developing computational process theories. We begin by presenting a framework for differentiating theories based on their focus (constructs versus processes) and modality (narrative versus computational). We use the framework to contrast narrative construct theories to computational process theories. We then describe key design principles for developing computational process theories and explain those principles using a leadership example. We use simulated data, from the computational process model we develop, to explicitly demonstrate the differences between construct and process thinking. We then discuss how computational process theories advance theory development. We conclude with a discussion of the long-term benefits of computational process theories for organizational science.

Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization

Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G ± P). Chemomobilization (CM) can be used as a salvage regimen after G ± P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefits. At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell (PC) burden or MM-related biomarkers. Given the lack of efficacy of non-ICM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary PC leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G ± P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n = 45; hyper-CVAD-based, n = 16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved free light chains. Among those evaluated with longitudinal peripheral blood flow cytometry (n = 8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34+ cells (10.8 versus 10.2 × 10⁶/kg, P = .018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (hazard ratio [HR] 0.30, 95% CI 0.14 to 0.67, P = .003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, P = .2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, P < .001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, P < .001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, P = .031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, P = .018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, P = .018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, P = .012). ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity.

Development and interpretation of a pathomics-driven ensemble model for predicting the response to immunotherapy in gastric cancer

BackgroundOnly a subset of patients with gastric cancer experience long-term benefits from immune checkpoint inhibitors (ICIs). Currently, there is a deficiency in precise predictive biomarkers for ICI efficacy. The aim...

EFFECT OF HIGH DOSE APROCITENTAN IN PATIENTS WITH RESISTANT HYPERTENSION NOT CONTROLLED BY LOW DOSE

Objective: The phase 3 PRECISION study in patients with resistant hypertension tested 12.5 mg and 25 mg aprocitentan during the 4-week DB placebo-controlled part, in addition to a fixed-dose combination of amlodipine, valsartan, hydrochlorothiazide. No differences in primary endpoint (SiSBP) were observed between the two doses. This post-hoc exploratory analysis evaluates the observed long-term benefit of increasing to a higher dose (25 mg) in patients not achieving a blood pressure control after 4 weeks on the lower dose (12.5 mg). Design and method: In PRECISION, after completion of the 4-week DB part 1, all randomized patients received 25 mg aprocitentan during the 32-week SB part 2. This subgroup analysis includes 93 subjects who were still uncontrolled at week 4 (SiSBP &gt; 140 mm/Hg) in the 12.5 mg aprocitentan group (n=223). The % of patients achieving control (&lt;140 or &lt; 130 for SiSBP and &lt; 90 or &lt; 85 mm/Hg for SiDBP) or showing a response of &gt;/= -10 or &gt;/= -15 mmHg in SiSBP or &gt;/= -5 or &gt;/= -10 mm/Hg in SiDBP vs week 4 at week 6, 12 and 36 (i.e., after 2 to 32 weeks of treatment with 25 mg) were calculated. Results: Among the patients in the aprocitentan 12.5 mg group with uncontrolled SiSBP at 4 weeks, after 2 weeks of treatment with 25 mg (at study Week 6), 39.8% (37/93) of subjects achieved SiSBP &lt; 140 mmHg. This increased to 49.3% (37/73) after 32 weeks of aprocitentan 25 mg treatment, at study week 36. The control rate set at the 130 mm Hg threshold and the response rates also increased over time. Also, for SiDBP the increase in the dose of aprocitentan resulted in a high proportion of patients being controlled (45% to 68% depending on the threshold) and responders (45 to 68%) after 32 weeks of treatment. Conclusions: These additional exploratory analyses show that switching from 12.5 mg to 25 mg aprocitentan can achieve further BP control or response not obtained with the lower dose.

Are changes in malocclusion associated with adulthood psychosocial well-being?

The purpose of this study was to investigate the longitudinal psychosocial effects of changes in malocclusion from adolescence to adulthood on oral health-related quality of life (OHRQOL), self-rated dental appearance, and overall life satisfaction. The Dunedin Multidisciplinary Health and Development Study is a longitudinal birth cohort study of 1037 children born at Queen Mary Hospital, Dunedin, New Zealand, between April 1, 1972 and March 31, 1973. Data on their health and development, including dental examinations, has since been collected periodically. Malocclusion severity was measured using the Dental Aesthetic Index in participants aged 15 and 45 years (data collected at age 18 years was supplemented for data missing at age 15 years). Other data collected included clinically assessed oral health (dental caries and periodontal disease experience) and self-rated dental appearance, OHRQOL, life satisfaction, and personality traits. Malocclusion data were available for 868 participants in adolescence and 834 aged 45 years. For those with a severe handicapping malocclusion at 15 years old, 46.6% who received orthodontic treatment transitioned to a resolved (ie, mild-moderate) malocclusion when aged 45 years, whereas only 16.2% of those who did not receive orthodontic treatment made that transition. A transition to a worse malocclusion was associated with impacts on OHRQOL when aged 45 years in the subdomains of functional limitation, psychological discomfort, and physical disability as well as worse self-ratings of dental appearance, and these findings were held after adjusting for potential confounders. Malocclusion was not associated with overall life satisfaction. Maintenance of acceptable occlusion after orthodontic treatment requires a strong emphasis on achieving and maintaining excellent dental health and avoiding chronic oral conditions such as dental caries and tooth loss. The long-term benefits of orthodontic treatment may diminish by midlife unless good dental health is maintained. Orthodontists have the responsibility to raise awareness among their patients on how to maintain good oral health after orthodontic treatment.

The moderating role of tourism intensity on residents’ intentions towards pro-tourism behaviours

This study analysed the complex dynamics of tourism based on perspectives and intentional behaviours of residents. The analysis focused on how residents perceive the effects of tourism, their satisfaction with it, their subjective well-being, and their inclinations towards pro-tourism behaviours. By merging social exchange theory and bottom-up spillover theory, it also investigates tourism intensity (TI) as a moderator, which has been understudied. A representative sample of 990 residents, in both high and low TI municipalities of the Algarve region, was surveyed. The model was estimated using PLS-SEM. The results revealed significant differences in residents’ perceptions based on TI. Residents in high TI areas perceived stronger effects on satisfaction due to negative and positive impacts of tourism. However, TI did not affect the relationships between satisfaction with tourism, subjective well-being, and intentions for pro-tourism behaviours. The economic gains created by tourism may differ from the social and psychological factors shaping residents’ well-being. These outcomes offer valuable insights for destination managers and politicians, aiding in the development of strategies to alleviate the adverse effects of tourism. Directing efforts towards improving residents’ satisfaction with tourism, subjective well-being, and support for tourism can also contribute to securing long-term and sustainable benefits for host communities.

Internal Management Strategy of Chinese Internet Enterprises and Business Performance: A Study of Tencent Internet Enterprises in China

The objective of this research is to examine the relationship between the internal management strategy of Chinese internet enterprises and business performance. The research results in the fields of business models and innovations, internet business models and their innovation theories and practices, and business ethics are analyzed and discussed, while the internet development process of China is reviewed. Then, the existing problems are analyzed, and the concerned field and concepts in this study are clarified. Based on previous theoretical research and market research, the research methodology is designed, the research hypotheses are proposed, and the research models are constructed to perform quantitative and qualitative research. Next, the cases of Baidu, Alibaba and Tencent are engaged to conduct empirical analysis and verify the conclusions. The correlation analysis show that the impact on corporate financial performance is positive when social responsibility to shareholders, creditors, users, and government is undertaken, which is consistent with the original hypothesis. However, fulfilling social responsibility to employees and suppliers is significantly and negatively related to financial performance, which is inconsistent with the original hypothesis. Therefore, companies should take a long-term perspective and not just see short-term benefits at the expense of long-term social benefits. Companies pay attention to and carry out a series of social responsibility activities can establish stable emotional ties with the public, so that the company can gain the support and trust of many parties in society, and can enhance market competitiveness and bring good development opportunities, thus improving the viability of the company and increasing social and economic value for the company

Importance of Early Detection in Early Psychosis

Early psychosis is the term coined in the hope that early intervention and treatment would benefit the long-term clinical outcomes of patients with psychosis. According to the clinical staging of psychosis, clinical high risk for psychosis and first-episode psychosis are allocated to early psychosis. Here, we described several clinical issues regarding the importance of early detection in early psychosis. As for clinical high risk for psychosis, we addressed the prevalence and clinical courses of clinical high risk for psychosis and whether early intervention services can lower the risk of psychosis onset in individuals with clinical high risk for psychosis. Regarding first-episode psychosis, we showed the prevalence of first-episode psychosis, the patterns, definitions, and clinical implications of the duration of untreated psychosis, and whether early intervention services can reduce the duration of untreated psychosis. With further research, we hope to achieve convincing evidence that early intervention can provide longterm benefits to patients with psychosis.

Computed tomography benefits and cost in hemodynamically stable patients with blunt abdominal trauma at an Egyptian University Hospital

BackgroundTrauma is a significant cause of mortality, especially among individuals aged between 15 and 44 years, with a substantial burden falling on economically active populations. Low- and middle-income countries (LMICs) bear the burden of trauma-related deaths, accounting for over 90 % globally. In Egypt, trauma rates are increasing, primarily due to road traffic crashes (RTC), affecting males disproportionately. Blunt abdominal trauma, often caused by RTC, can lead to missed intra-abdominal injuries (IAIs) due to atypical symptoms. Computed Tomography (CT) offers high sensitivity and specificity in detecting IAIs, but concerns about cost and radiation exposure exist. MethodologyThis study investigates the roles of Focused Assessment with Sonography for Trauma (FAST) and CT in managing blunt abdominal trauma. A retrospective cohort study was conducted on hemodynamically stable patients. Data included patient demographics, trauma details, healthcare decisions, costs, and outcomes. ResultsComputed tomography significantly reduced unnecessary laparotomies (12.3% vs. 24.8 %, p = 0.001), shortened hospital stays (4.83±0.71 days vs. 6.15±1.28 days, p = 0.005), and reduced ICU admissions (8 vs. 32, p = 0.023) compared to FAST alone. Overall costs were lower in the CT & FAST Group ($2055.95 vs. $3488.7, p = 0.0001), with no significant difference in missed IAIs. ConclusionThis study highlights the limitations of relying solely on FAST for IAIs and underscores the value of CT in guiding healthcare decisions. Incorporating CT led to reduced negative laparotomies, shorter hospital stays, and fewer ICU admissions. While CT incurs initial costs, its long-term benefits outweigh expenditures, particularly in LMICs. This study provides insights into optimizing diagnostic approaches for blunt abdominal trauma in low-resource settings.

Effective Treatment of Solar Facial Porokeratosis in One Patient with Topical Atorvastatin/Cholesterol Cream.

We report a rare case of solar facial porokeratosis (SFP) treated topically with atorvastatin/cholesterol or cholesterol alone for 48 weeks. The patient reported no obvious skin irritation and was delighted with the outcome. This study supported the effectiveness of a pathogenesis-directed treatment for SFP. Moreover, we point out that topical statins combined with cholesterol might have a long-term benefit in the treatment of SFP.

A retrospective study of postoperative adjuvant therapy following immunotherapy combined with targeted therapy and sequential curative surgical procedures for initially unresectable hepatocellular carcinoma

Objective: To report the clinical efficacy of adjuvant therapy based on pathological results following immunotherapy combined with targeted therapy and sequential curative surgical procedures in patients with initially unresectable hepatocellular carcinoma. Methods: This is a retrospective case series study. Data from 100 patients who underwent adjuvant therapy based on pathological results following immunotherapy combined with targeted therapy and sequential curative surgical procedures with long-term survival were collected from December 2018 to December 2022 at the Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese People's Liberation Army General Hospital. According to inclusion and exclusion criteria, 47 cases were included, among which patients who met the discontinuation criteria and maintained a drug-free tumor-free status. Thirty-nine male and eight female patients were included, with an age of (54.2±18.8)years(range:38 to 73 years) at initial diagnosis. At the time of initial diagnosis, 43 cases (91.5%) were classified as Barcelona Clinic Liver Cancer(BCLC) stage C. Survival curves were made using Kaplan Meier method. Results: Forty-seven patients underwent R0 resection, all achieved a drug-free tumor-free state through postoperative adjuvant therapy based on pathological examination results. Thirty-six patients(76.6%) maintained a drug-free tumor-free survival status for more than 6 months,28 patients(59.6%) for more than 12 months,and 8 patients(17.0%) for more than 24 months. The longest drug-free tumor-free survival in this cohort reached 48 months. The median follow-up time in this study was 32 months. After diagnosis, the overall survival rates at 1- and 3- years were 97.7%(95%CI:93.4% to 100%) and 90.7%(95%CI:82.5% to 99.8%). The postoperative recurrence-free survival rates at 1- and 3- years were 91.0%(95%CI:83.0% to 99.8%) and 71.3%(95%CI:58.7% to 86.5%). Conclusions: The adjuvant therapy based on pathological results following immunotherapy combined with targeted therapy and sequential curative surgical approach provides long-term survival benefits for patients with initially unresectable hepatocellular carcinoma. Standardized adjuvant therapy maybe sustain long-term tumor-free status,and achieve drug-free tumor-free survival.

Discretionary investment managers evaluation in pension fund: Shared input dynamic network DEA approach

Investment trust corporations (ITCs) constitute one of the financial industry's subsectors, and their evaluations of fund management performance play a crucial role. With the recent increase in the number of ITCs and their assets, how the Public Service Pension Fund management board (PSPFMB) of Taiwan makes investment decisions regarding multiple companies has become a critical issue. Using the shared input dynamic network data envelopment analysis approach (SDNDEA), we empirically estimate the performance efficiency scores of the funds of 34 ITCs and analyze the performance of the manufacturing structures of their internal networks. Our results indicate that the PSPFMB should consider the effects of being entrusted with decisions on efficiency. Employing K-means clustering techniques, we investigate the operational characteristics of each group and identify the differences among them. Moreover, this research identifies significant externalities related to ownership structures, indicating that the PSPFMB should consider the effects of such structures on efficiency in the context of entrusting decisions. Thus, the PSPFMB can make optimal investment decisions based on our ITC evaluation and selection model and help pension funds achieve stable long-term investment benefits.

Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling.

We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13-3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08-7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95-1.91], p = 0.10), which did not translate into a significant survival benefit. We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.

Optimization of Frequency Modulation Energy Storage Configuration in Power Grid Based on Equivalent Full Cycle Model

This paper aims to meet the challenges of large-scale access to renewable energy and increasingly complex power grid structure, and deeply discusses the application value of energy storage configuration optimization scheme in power grid frequency modulation. Based on the equivalent full cycle model and a large number of actual operation data, various energy storage technologies are technically analyzed, and the economic and environmental performance of different energy storage configuration schemes are comprehensively evaluated. On this basis, this paper puts forward a set of efficient and economical energy storage configuration optimization strategies to meet the demand of power grid frequency modulation and promote the wide application of energy storage technology. After an in-depth analysis, it is found that the optimized energy storage configuration scheme is excellent in technology, economy, and environmental protection. Specifically, in terms of technical performance, the optimization scheme has significantly improved key indicators such as energy storage efficiency, capacity and power, and response speed, which can better meet the requirements of power grid frequency modulation. Through the verification of actual operation data, it is found that the overall efficiency of the optimized energy storage configuration scheme is above 55%, which is helpful to the stability and efficiency of power grid frequency modulation. In terms of economic performance, although the initial investment cost of the optimization scheme may be high, it is found that it has good economy through the evaluation of long-term operation benefits. Considering that the energy storage system can reduce the operating cost of the power grid, improve the energy utilization rate, and achieve the optimization of cost-effectiveness in the long run, this scheme is economically feasible and attractive. In terms of environmental performance, the optimization scheme effectively reduces the negative impact on the environment by improving energy storage efficiency, reducing emissions, and optimizing resource utilization. This is not only conducive to the sustainable development of the power grid but also in line with the current global trend of promoting green and low-carbon transformation. To sum up, this paper not only provides an efficient and economical energy storage allocation optimization strategy for power grid frequency modulation but also provides a scientific basis for relevant decision-making departments. By promoting the practical application and development of energy storage technology, this paper is helpful to improve the frequency modulation ability of power grid, optimize energy structure, and reduce environmental pollution, and thus achieve the goal of sustainable energy development. The data results and in-depth analysis of this paper provide strong support for the practical application of energy storage configuration optimization scheme and also provide important reference for the further innovation and development of energy storage technology.