Advanced Stages Of Disease Research Articles

Papillary microcarcinoma of the thyroid gland: Evaluation of TERT and BRAFV-600E expression and their relationship with clinicopathological findings

Papillary microcarcinomas (PMCs) are papillary carcinomas ≤1 cm in size, with an increasing incidence. Although generally indolent, some cases exhibit aggressive behavior. Recently, active surveillance has been recommended to avoid surgical treatment. Identifying molecular changes that predict aggressiveness in PMCs has gained importance, but studies are limited. We aimed to demonstrate TERT expression and BRAF V600E positivity immunohistochemically in PMCs and correlate them with histomorphological features, subtypes, and clinicopathological findings. We included 95 PMC cases diagnosed between 2010 and 2019 at the Department of Pathology, Faculty of Medicine, XXX University. We investigated TERT expression using RT-PCR. We evaluated BRAF V600E mutation immunohistochemically. We evaluated the relationship between genetic, histomorphological, and clinicopathological findings. In patients with multifocality and those with a tumor size ≥0.5 cm, the frequency of lymph node metastasis was significantly higher. A positive correlation was shown between BRAF V600E positivity and lymph node metastasis, lymphovascular invasion, advanced disease stage, and classical subtype by univariate analyses. We detected TERT expression in 18 of 95 patients (7.8 %). No relationship could be detected between TERT expression alone or combined with BRAF positivity and clinicopathological features. Although TERT mutations are associated with aggressiveness in thyroid cancers, this association was absent in PMCs. The presence of TERT expression was demonstrated in some cases. However, TERT expression could not be associated with clinicopathological findings, which is consistent with the literature suggesting that TERT plays a role in advanced stages of carcinogenesis.

Challenges and Opportunities in Accessing Surgery for Glioblastoma in Low-Middle Income Countries: A Narrative Review.

Glioblastoma: a highly aggressive brain tumor, presents substantial challenges in treatment and management, with surgical intervention playing a pivotal role in improving patient outcomes. Disparities in access to brain tumor surgery arise from a multitude of factors, including socioeconomic status, geographical location, and healthcare resource allocation. Low- and middle-income countries (LMICs) often face significant barriers to accessing surgical services, such as shortages of specialized neurosurgical expertise, limited healthcare infrastructure, and financial constraints. Consequently, glioblastoma patients in LMICs experience delays in diagnosis, suboptimal treatment, and poorer clinical outcomes compared to patients in high-income countries (HICs). The clinical impact of these disparities is profound. Patients in LMICs are more likely to be diagnosed at advanced disease stages, receive less effective treatment, and have lower survival rates than their counterparts in HICs. Additionally, disparities in access to surgical care exacerbate economic and societal burdens, emphasizing the urgent need for targeted interventions and health policy reforms to address healthcare inequities. This review highlights the importance of addressing global disparities in access to brain tumor surgery for glioblastoma through collaborative efforts, policy advocacy, and resource allocation, aiming to improve outcomes and promote equity in surgical care delivery for all glioblastoma patients worldwide.

Treosulfan-Versus Melphalan-Based Reduced Intensity Conditioning in HLA-Haploidentical Transplantation for Patients ≥ 50 Years with Advanced MDS/AML.

Relapse and regimen-related toxicities remain major challenges in achieving long-term survival, particularly among older patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have demonstrated the feasibility of treosulfan-based conditioning, noting stable engraftment and low non-relapse mortality (NRM) in patients undergoing HLA-matched allo-HSCT. However, data on treosulfan-based conditioning in the HLA-haploidentical transplantation (HaploT) setting are limited. We retrospectively compared conditioning with fludarabine-cyclophosphamide (FC)-melphalan (110 mg/m2) and FC-treosulfan (30 g/m2) prior to HaploT using post-transplantation cyclophosphamide (PTCy) in patients with high-risk MDS/AML patients ≥ 50 years, transplanted from 2009-2021 at our institution (n = 80). After balancing patient characteristics by a matched-pair analysis, we identified twenty-one matched pairs. Two-year OS and LFS were similar among the groups (OS 66% and LFS 66%, p = 0.8 and p = 0.57). However, FC-melphalan was associated with a significantly lower probability of relapse compared to FC-treosulfan (0% vs. 24%, p = 0.006), counterbalanced by a higher NRM (33% vs. 10%, p = 0.05). Time to engraftment and incidences of acute and chronic graft-versus-host disease (GvHD) did not differ significantly. In conclusion, HaploT using FC-treosulfan in combination with PTCy in patients aged ≥50 years with MDS/AML appears safe and effective, particularly in advanced disease stages. We confirm the favorable extramedullary toxicity profile, allowing for potential dose intensification to enhance antileukemic activity.

Dilemma in patients with amyotrophic lateral sclerosis and expectations from brain–machine interfaces

Objective We hypothesized that patients with amyotrophic lateral sclerosis (ALS) face a dilemma between motivation to live and difficulty in living, and brain–machine interfaces (BMIs) can reduce this dilemma. This study aimed to investigate the present situation of patients with ALS and their expectations from BMIs. Materials and methods Our survey design consisted of an anonymous mail-in questionnaire comprising questions regarding the use of tracheostomy positive pressure ventilation (TPPV), motivation to live, anxiety about the totally locked-in state (TLS), anxiety about caregiver burden, and expectations regarding the use of BMI. Primary outcomes were scores for motivation to live and anxiety about caregiver burden and the TLS. Outcomes were evaluated using the visual analogue scale. Results Among 460 participants, 286 (62.6%) were already supported by or had decided to use TPPV. The median scores for motivation to live, anxiety about TLS, and anxiety about caregiver burden were 8.0, 9.0, and 7.0, respectively. Overall, 49% of patients intended to use BMI. Among patients who had refused TPPV, 15.9% intended to use BMI and TPPV. Significant factors for the use of BMI were motivation to live (p = .003), anxiety about TLS (p < .001), younger age (p < .001), and advanced disease stage (p < .001). Conclusions These results clearly revealed a serious dilemma among patients with ALS between motivation to live and their anxiety about TLS and caregiver burden. Patients expected BMI to reduce this dilemma. Thus, the development of better BMIs may meet these expectations.

Blood Astrocyte Biomarkers in Alzheimer Disease: A Systematic Review and Meta-Analysis.

Neuroinflammation, particularly early astrocyte reactivity, is a significant driver of Alzheimer disease (AD) pathogenesis. It is unclear how the levels of astrocyte biomarkers change in patients across the AD continuum and which best reflect AD-related change. We performed a systematic review and meta-analysis of 3 blood astrocyte biomarkers (glial fibrillary acidic protein [GFAP], chitinase-3-like protein 1 [YKL-40], and S100B) in patients clinically diagnosed with AD. MEDLINE and Web of Science were searched on March 23, 2023, without restrictions on language, time, or study design, for studies reporting blood levels of the astrocyte biomarkers GFAP, YKL-40, or S100B in patients on the AD continuum (including those with mild cognitive impairment [MCI] and dementia) and a cognitively unimpaired (CU) control population. AD diagnosis was based on established diagnostic criteria and/or comprehensive multidisciplinary clinical consensus. Studies reporting indirect biomarker measures (e.g., levels of biomarker autoantibodies) were excluded. Risk of bias assessment was performed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. Pooled effect sizes were determined using the Hedge g method with a random-effects model. The review was prospectively registered on PROSPERO (registration number CRD42023458305). The search identified 1,186 studies; 36 met inclusion criteria (AD continuum n = 3,366, CU n = 4,115). No study was assessed to have a high risk of bias. Compared with CU individuals, patients on the AD continuum had higher GFAP and YKL-40 levels (GFAP effect size 1.15, 95% CI 0.94-1.36, p < 0.0001; YKL-40 effect size 0.38, 95% CI 0.28-0.49, p < 0.0001). Both biomarkers were elevated in more advanced clinical stages of the disease (i.e., in AD dementia compared with MCI due to AD: GFAP effect size 0.48, 95% CI 0.19-0.76, p = 0.0009; YKL-40 effect size 0.34, 95% CI 0.10-0.57, p = 0.0048). No significant differences in blood S100B levels were identified. We demonstrated significant elevations in blood GFAP and YKL-40 levels in patients on the AD continuum compared with CU individuals. Furthermore, within the AD clinical spectrum, significant elevation correlated with more advanced disease stage. Our findings suggest that both biomarkers reflect AD-related pathology. Our findings are limited by the lack of cultural and linguistic diversity in the study populations meta-analyzed. Future meta-analyses using a biomarker-defined AD population are warranted.

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Our comprehensive analysis revealed that adrenoceptor alpha 2A (ADRA2A) was downregulated in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

Dyadic coping and related factors among couples with colorectal cancer: A latent profile analysis

ObjectiveThis study aimed to identify latent subgroups of dyadic coping (DC) among colorectal cancer (CRC) patients and their spousal caregivers, and to explore the factors associated with these subgroups. MethodsWe conducted a cross-sectional study involving 268 pairs of CRC patients and their spousal caregivers. Participants completed the General Information Questionnaire, the Dyadic Coping Inventory, the Cancer-Related Communication Problems Scale, and the Fear of Progress Questionnaire-Short Form. Latent profile analysis (LPA) of DC among CRC couples was performed using Mplus 8.3. We compared couple illness communication, fear of cancer recurrence (FCR), and demographic characteristics between the identified subgroups and conducted ordinal logistic regression analysis to examine factors associated with these subgroups. ResultsThe 268 pairs of CRC patients and their spousal caregivers were classified into four subgroups based on their coping levels: low-DC group (12.3%), low common-DC group (7.1%), moderate-DC group (52.6%), and high-DC group (28.0%). Disease stage, couple illness communication, and spouse's FCR were significantly associated with the four subgroups. ConclusionsThere is considerable variability in DC levels among CRC patients and their spousal caregivers. Patients with advanced disease stages, inadequate communication between spouses, and severe RCR exhibit lower levels of DC. These findings provide a theoretical basis for nursing personnel to develop personalized intervention strategies tailored to the characteristics of these subgroups.

Detecting heart stress using NT-proBNP in patients with type 2 diabetes mellitus and hypertension or high-normal blood pressure: a cross-sectional multicentric study

BackgroundWe evaluated the prevalence of “heart stress” (HS) based on NT-proBNP cut-points proposed by the 2023 Consensus of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in asymptomatic patients with T2DM and hypertension or high-normal blood pressure (BP) eligible for SGLT2 inhibitors (SGLT2i) and/or GLP-1 receptor agonists (GLP1-RA), drugs with proven benefits on reducing the incidence of HF, hospitalizations, cardiovascular events and mortality.MethodsA cross-sectional multicentric study was conducted on 192 consecutive outpatients, aged ≥ 55 years, with hypertension or high-normal BP, referred to three diabetology units. NT-proBNP was collected before starting new anti-diabetic therapy. Patients with known HF were excluded, and participants were classified based on the age-adjusted NT-proBNP cut-points.ResultsMean age: 70.3 ± 7.8 years (67.5% males). Patients with obesity (BMI ≥ 30 Kg/m2): 63.8%. Median NT-proBNP: 96.0 (38.8–213.0) pg/mL. Prevalence of chronic kidney disease (CKD, eGFR < 60 mL/min/1.73m2): 32.1%. Mean arterial BP: 138.5/77.0 ± 15.8/9.9 mmHg. The NT-proBNP values, according to the proposed age-adjusted cut-points, classified 28.6% of patients as “HS likely” (organize elective echocardiography and specialist evaluation), 43.2% as “HS not likely” (a grey area, repeat NT-proBNP at six months) and 28.2% as “very unlikely HS” (repeat NT-proBNP at one year). The presence of CKD and the number of anti-hypertensive drugs, but not glycemic parameters, were independently associated with HS.ConclusionsAccording to NT-proBNP, over a quarter of T2DM patients with hypertension/high-normal BP, among those eligible for SGLT2i and/or GLP1-RA, were already at risk of cardiac damage, even subclinical. Most would receive an indication to echocardiogram and be referred to a specialist, allowing the early implementation of effective strategies to prevent or delay the progression to advanced stages of cardiac disease and overt HF.

ITGB3 is a Novel Prognostic Biomarker and Correlates with Aberrant Methylation and Tumor Immunity in Clear Cell Renal Cell Carcinoma.

Current evidence highlights clear cell renal carcinoma (ccRCC) as the most prevalent form of kidney cancer despite ongoing challenges in treating advanced-stage disease. Integrin subunit beta 3 (ITGB3) has recently emerged as a critical player in tumorigenesis, prompting our investigation into its role in ccRCC. This study aimed to elucidate the mechanisms responsible for ITGB3 downregulation and evaluate its clinical significance, particularly regarding its impact on the immune landscape within ccRCC. We first conducted analyses utilizing data from both TCGA and GEO datasets to explore ITGB3 expression in ccRCC tissues. Subsequently, we evaluated the association between ITGB3 expression levels and patient prognosis and pathological staging. Pathway and functional enrichment analyses were performed to assess correlations between ITGB3 and immune and methylation-related pathways. Additionally, we examined the relationship between ITGB3 transcriptional expression and DNA hypermethylation. A prognostic risk model was developed using LASSO-based analysis on selected ITGB3-associated DNA methylation probes. Immunohistochemistry (IHC) analysis, alongside TIMER and ssGSEA results, was utilized to investigate ITGB3 expression and its association with immune cell infiltration. Our analyses revealed significant downregulation of ITGB3 mRNA expression in ccRCC tissues compared to other members of the ITGB family, consistent across TCGA and GEO datasets. Higher ITGB3 expression correlated with improved prognosis and lower pathological stage in ccRCC patients. Pathway and functional enrichment analyses demonstrated positive correlations between ITGB3 and immune and methylation-related pathways, while ITGB3 transcriptional expression showed a negative correlation with DNA hypermethylation. The established prognostic risk model identified a high-risk group with poorer survival probabilities than the low-risk group. Immunohistochemical quantification revealed a positive correlation between CD4+ and CD8+ immune cell infiltration and ITGB3 expression. Overall, our study provides compelling evidence supporting the significant role of ITGB3 in ccRCC immunity. The downregulation of ITGB3, coupled with its association with better prognosis and immune activation, suggests its potential as a therapeutic target and prognostic marker for this patient population.

Addressing ovarian cancer research gaps in under-resourced settings using individual initiatives: The OVANORDEST pilot project in Morocco.

183 Background: In Morocco, ovarian cancer (OC) is a neglected women’s cancer. To bridge this gap, early-career cancer researchers might develop and engage in individual initiatives to enhance research outcomes. In this perspective, I recently launched the OVANORDEST project as an individual initiative. This plan outlines a three-step strategy designed to promote OC research, highlighting specific milestones. This abstract presents the findings from the initial feasibility study, which focuses on real-world evidence, implementing inexpensive precision medicine approaches, supporting women in oncology, and enhancing meta-research. Methods: Initially, a bibliometric study was conducted to find research gaps in the field of OC in Morocco. A 16-year real-world retrospective study was conducted at the Hassan II Oncology Center (October 2005-June 2020). To implement precision medicine approaches, quality evidence on several potentially inexpensive blood-based biomarkers such as Pan-Immune Inflammation-Value (PIIV) were explored using a PROSPERO-registered umbrella systematic review and then investigated in an original cohort. Cox regression analyses were applied to identify the effects of different biomarkers on survival outcomes. Meta-research was developed by publishing two special thematic issues and one edited book on OC biomarkers. The project also included a mentorship program designed to empower women oncologists. Results: A total of 258 patients with OC were included. Most patients had advanced FIGO stages at diagnosis. The median overall survival (OS) for the entire cohort was 32 months, with a median progression-free survival (PFS) of 14.6 months. CA-125 positivity, advanced disease stage, and presence of residual disease after surgery were prognostic factors that adversely affected survival. In the multivariable analysis after adjustment for the FIGO stage, high PIIV was an independent predictive factor of OS (HR= 1.83; 95% CI: 1.18-2.84, p=0.007). Two specialized thematic issues were published alongside a book dedicated to ovarian cancer biomarkers. Additionally, careers of a group of women oncologists were boosted and a local patient advocacy group was supported in adopting supportive strategies for patients. Conclusions: Engaging early-career cancer researchers through individual initiatives in under-resourced settings may considerably improve research outcomes. In this context, I propose that sharing this experience, which has been successfully applied in Morocco, could empower health systems and facilitate the generation of research outputs in low- and middle-income countries.

Efficacy assessment of a novel pan-RAS inhibitor in KRAS-mutant and wild type colorectal 3D bioprinted organoid tumor tissue.

91 Background: Colorectal cancer (CRC) is the third leading type of cancer worldwide, with ~150,000 new cases in the US annually and a grim 14% 5-year survival for patients diagnosed at a late stage. A lack of treatment options leads to persistently poor prognosis for patients with advanced stage disease. KRAS mutations are well known drivers of CRC and other GI cancers. Multiple KRAS mutations occur in CRC, including G12D (34%), G12V (21%), G13D (20%), G12C (8%), and others (18%). Existing KRAS-targeted therapies have limited use in CRC, underscoring the need for pan-RAS inhibitors in treating CRC and other RAS driven cancers. Objective: Assess activity of ADT-007, our pan-RAS inhibitor, on wild-type (WT) and KRAS-mutant 3D bioprinted organoid tumor (BOT) tissue using our high-throughput ex vivo platform. Methods: Using previously established bioprinting protocols, WT and mutant BOTs were printed with HT29 and HCT116 cells, respectively. HT29 is an established human WT CRC cell line with known sensitivity to proteosome and survivin inhibitors. HCT116 is a KRASG13D mutant human CRC cell line. 3 sets of BOTs were generated and acclimated for 24h. One set was treated for 72h with proteosome inhibitor Bortezomib, another with survivin inhibitor YM155, and the third with our novel pan-RAS inhibitor ADT-007. Dose response curves were generated from both conventional ATP luminescence readouts and high-content imaging. Results: BOT tissue microarchitecture was validated and &gt;200 µm diffusion in BOTs was confirmed using high-content imaging. Differential response was quantified using Cell TiterGlo endpoint assay as well as advanced image processing of high-content live/dead nuclear stained images captured at multiple z-plains. ADT-007 IC50 was found to be substantially lower for mutant HCT116 compared to that for WT HT29 cell line BOTs, which was consistent with separately conducted in vitro and in vivo studies. Conclusions: A pan-RAS inhibitor, such as ADT-007 with high selectivity for cancer cells with activated RAS that is not limited to a specific KRAS mutant allele or RAS isozyme, could have broader use for CRC and other RAS-driven cancers. Further, due to their potential to replicate biophysical characteristics of a tumor and its microenvironment, BOT based precision and personalized medicine platforms can provide more accurate drug efficacy readout compared to in vitro cancer models.

Detailed pathological characteristics and survival prognosis of patients with penile cancer from a high-capacity tertiary referral centre over a 20-year period.

120 Background: Penile cancer is a rare cancer that affects 0.1-1 per 100,000 men in developed countries. However, data on this cancer in developing countries, particularly in Asian populations, are lacking. A retrospective study is needed to determine the characteristics of penile cancer patients, tumor-related treatments, and prognosis. The objective of our study was to present statistical results that are applicable to an Asian population under the most recent staging system. Additionally, we aimed to report on the pathological characteristics and prognosis of a large sample of patients with penile cancer who underwent long-term follow-up with the standard extent of radical dissection. Methods: This study retrospectively analyzed clinical and pathological data from 1017 patients who were diagnosed with penile cancer at Sun Yat-sen University Cancer Center between October 2001 and October 2023. The primary study endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Survival curves were plotted using the Kaplan‒Meier method, and differences were compared using the log-rank test. Univariate and multivariate Cox proportional risk models were used to analyze the factors associated with tumor survival. Results: The average follow-up time was 50 months (range: 0.6-232.8 months). The 5- and 10-year OS rates were 67.3% and 62.7%, respectively, and the 5- and 10-year PFS rates were 63.9% and 61.1%, respectively. After excluding 127 Tx patients and 23 TIS stage patients, the 10-year OS rates of pTa stage (29 patients), pT1 (305 patients), pT2 stage (217 patients), pT3 stage (271 patients), and pT4 stage (45 patients) patients were 96.3%, 80.1%, 61.7%, 55.4%, and 14.2%, respectively. A total of 690 patients underwent standard lymph node dissection. The 10-year OS rates of pN0 (376 patients), pN1 (111 patients), pN2 (78 patients), and pN3 (125 patients) patients were 92.7%, 62.5%, 48.1% and 31.3%, respectively. The results of the multifactorial analysis revealed that T stage (T4 stage versus Ta-T1 stage: HR=2.38, 95% CI: 1.00~5.66, P=0.05), pathological grade (G3~4 grade versus G1~2 grade: HR=1.63, 95% CI: 1.05~2.53, P=0.027), N stage (pN+ versus pN0: HR=14.11, 95% CI: 7.83~25.43, P&lt;0.001), and white blood cell count (WBC&gt;8.5: HR=1.71, 95% CI: 1.17~2.51, P=0.006) were independent prognostic factors in penile cancer patients. Conclusions: Patients with penile cancer had better long-term OS after standard lymph node dissection. The adverse factors were T stage, pathological grade, extent of lymph node metastasis, and preoperative WBC count. Identifying high-risk patients through preoperative evaluation can improve long-term survival rates. Radical lymph node dissection in the early stage has more curative value, and adjuvant therapy should be provided in patients with advanced-stage disease after surgery.

Unveiling the Intricacies of Monoamine Oxidase-A (MAO-A) Inhibition in Colorectal Cancer: Computational Systems Biology, Expression Patterns, and the Anticancer Therapeutic Potential.

Colorectal cancer (CRC) remains a significant health burden globally, necessitating a deeper understanding of its molecular intricacies for effective therapeutic interventions. Elevated monoamine oxidase-A (MAO-A) expression has been consistently observed in CRC tissues, correlating with advanced disease stages and a poorer prognosis. This research explores the systems biology effects of MAO-A inhibition with small molecule inhibitor clorgyline regarding CRC. The applied systems biology approach starts with a chemocentric informatics approach to derive high-confidence hypotheses regarding the antiproliferative effects of MAO-A inhibitors and ends with experimental validation. Our computational results emphasized the anticancer effects of MAO-A inhibition and the chemogenomics similarities between clorgyline and structurally diverse groups of apoptosis inducers in addition to highlighting apoptotic, DNA-damage, and microRNAs in cancer pathways. Experimental validation results revealed that MAO inhibition results in antiproliferative antimigratory activities in addition to synergistic effects with doxorubicin. Moreover, the results demonstrated a putative role of MAO-A inhibition in commencing CRC cellular death by potentially mediating the induction of apoptosis.

2248 Clinical relevance of Donanemab treatment

Abstract Objective To assess in Alzheimer’s disease (ad), the treatment impact of donanemab, an amyloid plaque-reducing monoclonal antibody, on readily interpretable item-measures and constructs that matter to patients, care-partners, and clinicians. Background Positive outcomes were reported from TRAILBLAZER-ALZ2, a randomised, double-blind, placebo-controlled, 18-month, phase 3 study evaluating donanemab as an investigational treatment for mild cognitive impairment (MCI) or mild dementia due to ad. In 1736 participants, donanemab significantly slowed the rate of clinical decline (by 22–36%) as measured by the integrated ad Rating Scale (iADRS) and the Clinical Dementia Rating Scale—Sum-of-Boxes (CDR-SB); both measures of cognition and function as indications of global clinical severity. In these subsequent post-hoc exploratory analyses, the impact of donanemab treatment on individual iADRS cognition and function items, CDR domains, and risks of advancing to greater disease severity were assessed. Methods Mixed model repeated measures and Cox proportional hazard modelling methodology assessed treatment effects on iADRS items and CDR domains. Results Donanemab treatment was associated with significant beneficial effects on: 1) iADRS cognitive items related to episodic memory and executive function, and instrumental activities of daily living items related to communication and others (e.g. being left alone, making a meal, using household appliances); 2) all CDR-SB cognitive and functional domains (i.e. memory, orientation, judgement/problem solving, community affairs, home/hobbies, and personal care); and 3) lowering risk of progression to a more advanced clinical stage of disease. Conclusions These analyses explored the impact of donanemab treatment on constructs that matter to and are considered more readily interpretable by patients, care-partners, and clinicians. These results provide further support that treating those with MCI or mild dementia due to ad with donanemab can meaningfully reduce risk of progression to more severe clinical stages (e.g. moderate stage dementia), and potentially allow greater independence for a longer period of time.

Gender-Related Aspects of Laryngeal Squamous Cell Carcinoma: A Retrospective Cohort Study.

Laryngeal squamous cell carcinoma (SCC) is a predominantly male illness. Although the rate of female patients increased, a knowledge gap exists in the medical literature regarding gender-based differences. Retrospective cohort study. Adult patients treated for laryngeal SCC in a tertiary medical centre between 2006 and 2020. Data were collected on demographics, clinical presentation, treatment modalities, disease recurrence and survival status. Two hundred ninety-one patients with laryngeal SCC, 50 (17.2%) females and 241 (82.8%) males. Disease-specific survival (DSS), overall survival (OS) and disease-free survival (DFS), as well as differences in disease characteristics and treatment modalities. Tumour subsites differed significantly between females and males (36% vs. 19.5% supraglottic, 62% vs. 80.5% glottic and 2% vs. 0% subglottic, respectively; p = 0.006). Females were diagnosed at younger ages (61.7 ± 10.58 vs. 65.87 ± 11.11 years, p = 0.016) and advanced-stage disease (58% vs. 39.4%, p = 0.018). Females were treated with combined modalities at higher rates (36% vs. 54.8% for single modality, p = 0.031). DSS rates did not differ between genders (log-rank p = 0.12). Despite being diagnosed at more advanced disease stages, females demonstrated prolonged median OS compared to males (130.17 vs. 106.17 months, log-rank p = 0.017). No significant differences in DFS were observed (log-rank p = 0.32). In a multivariate Cox proportional hazards model, male gender remained an independent negative OS predictor (HR = 2.08; CI, 1.10-3.96; p = 0.025), along with increasing age (HR = 1.06; CI, 1.04-1.09; p < 0.001) and advanced disease stage (HR = 1.7; CI, 1.08-2.67; p = 0.023). Our findings suggest the importance of considering gender-specific factors in the management of laryngeal SCC.

Prognostic Significance of Caudal-type Homeobox Gene 2 and Sex-determining Region Y-Box 2 Immunohistochemistry Markers in Gastric Cancer – A Clinicopathological Study

Abstract Background: Gastric cancer is one of the most commonly diagnosed cancers and the third leading cause of cancer-related deaths in the world as it has a poor prognosis due to its delayed presentation. Adenocarcinoma (intestinal or diffuse type) is the most common type histologically, and tumor, node, and metastasis staging is essential for prognosis and treatment planning. Gastric cancer patients may have different clinical presentation even within the same cancer stage group, hence it is important to evaluate additional markers in such patients which can help in prognosticating them to aid in effective management of such patients. This study evaluates two new immunohistochemistry (IHC) markers and their clinical correlation which will help in prognosticating gastric cancer patients. Materials and Methods: Biopsy tissues from 30 patients between April 2016 and April 2019, who underwent upper gastrointestinal endoscopy in a tertiary care center of Armed Forces and were found to have gastric cancer, were studied. Caudal-type homeobox gene 2 (CDX2) and sex-determining region Y-box 2 (SOX2) immunoreactivity was correlated with histomorphology, clinical presentation, and staging of tumor. Results: CDX2 positivity (P = 0.002) as well as SOX2 negativity (P = 0.058) was associated with an advanced stage of disease in our study. CDX2+/SOX2− profile was also noted to be statistically correlating (P = 0.014) with poor prognosis in gastric cancer. Conclusion: Loss of SOX2 together with positive CDX2 expression had a good correlation with advanced disease and poor outcome. Further studies should be undertaken for targeted therapy for these IHC markers.

Integrated analysis of disulfidoptosis-related genes identifies NRP1 as a novel biomarker promoting proliferation of gastric cancer via glutamine mediated energy metabolism

The incidence and mortality of gastric cancer rank fifth and fourth worldwide among all malignancies, respectively. Additionally, disulfidoptosis, a recently identified form of cellular demise, is closely linked to the initiation and advancement of malignancies. This study aims to create a novel signature of disulfidptosis-related genes (DRGs) and to further explore its association with the tumor immune microenvironment. Based on our comprehensive study, a prognostic signature consisting of 31 DRGs in stomach adenocarcinoma (STAD) was identified and characterized. Through the integrative analyses involving gene expression profiling, machine learning algorithms, and Cox regression models, the prognostic significance of these DRGs was demonstrated. Our findings highlight their strong predictive power in assessing overall survival across diverse patient datasets, and their better performance than traditional clinicopathological factors. Moreover, the DRGs signature showed association with the characteristics of the tumor microenvironment, which has implications for the immune modulation and therapeutic strategies in STAD. Specifically, NRP1 emerged as a key DRG with elevated expression in STAD, showing correlation with the advanced stages of diseases and poorer outcomes. Functional studies further revealed the role of NRP1 in promoting STAD cell proliferation through the modulation of glutamine metabolism. Overall, our study underscores the clinical relevance of DRGs as biomarker and potential therapeutic targets in STAD management, providing insights into disease biology and personalized treatments.

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils.

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ∼50% of treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.

Sociodemographic and Clinical Characteristics Associated with Genetic Testing among Cancer Survivors: Evidence from Three Cancer Registries.

Genetic tests, including germline and tumor (somatic) testing, can optimize the clinical care and outcomes for cancer patients and their family members. However, evidence on cancer patients' use of genetic testing and discussions about it with healthcare providers is limited. Study participants included cancer survivors aged 18 or older, drawn from the 2021 Health Information and National Trends Survey (HINTS)-Surveillance, Epidemiology, and End Results (SEER) linked database, which comprises three US cancer registries: Iowa, New Mexico, and the Greater Bay Area. Sociodemographic factors (e.g., age, sex, income, education) at the time of the survey and clinical characteristics (e.g., cancer site, stage) at the time of diagnosis were compared based on self-reported genetic testing status and provider discussions, using survey design-adjusted analysis. The weighted study sample comprised 415,978 cancer survivors with a mean age of 70.5 years at the time of the survey. Overall, 17.0% reported having germline testing, 8.5% having tumor testing, and 8.6% discussing tumor testing with their healthcare providers. Higher proportions of germline genetic testing were observed among survivors under age 65 at the time of the survey, females, holding college degrees, and with private insurance coverage compared to their respective counterparts - males, aged 65 or above when surveyed, with lower educational attainment, and with public insurance or uninsured. The proportion of those who reported tumor testing was greater for those diagnosed in recent years (2015-2017 vs. before 2002). Regarding clinical characteristics, survivors with ovarian and breast cancers had a 7.0-36.4% higher prevalence of both testing compared to those with other cancer types lacking germline indication. More cancer survivors diagnosed at distant stages (vs. regional) or between 2015 and 2017 (vs. 2003-2010) reported having provider discussions about tumor testing. Findings showed that the highest reports of germline testing were among young female cancer survivors and those with higher education and private insurance. Survivors diagnosed in recent years or with advanced-stage disease were more likely to report discussing tumor testing with providers. Further research is warranted to better understand the barriers and educational needs of cancer patients, caregivers, and providers to optimize genetic testing strategies.

CIED-based remote monitoring in heart failure using the HeartLogic™ algorithm: Which patients benefit most?

Background & Aims: Early identification of worsening HF enables timely adjustments to prevent hospitalization. Recent studies show the HeartLogic™ algorithm detects congestion and reduces HF events. However, it is unclear which patients benefit most. Therefore, this study aims to identify and characterize HF patients who benefit most from CIED-based remote monitoring with HeartLogic™. Methods: In this multicenter retrospective study, patients with a CIED and HeartLogic™ algorithm under structured follow-up were included. Patients were classified as having “substantial benefit” or “no benefit” from monitoring. Results: In total, 242 patients were included (male n = 190, 79%, median age 61 years [IQR 61–77]). Median follow-up was 1.2 years [IQR 1.1–2.7]. Among 378 alerts, 266 were true positive (70%) and 112 false positive (30%). Of the 242 patients, 69 (29%) were classified as having “substantial benefit”, while 173 (71%) had “no benefit” from HeartLogic™ monitoring. Univariate and multivariate analysis showed that patients with “substantial benefit” had higher NYHA functional class (OR 2.64, P = 0.004), higher NT-ProBNP (OR 1.02, P = 0.003), higher serum creatinine (OR 1.10, P < 0.001), lower LVEF (OR 1.19, P = 0.004), more severe mitral regurgitation (OR 2.16, P = 0.006), higher right ventricular end diastolic volume (OR 1.05, P = 0.040), higher pulmonary artery pressures (OR 1.19, P = 0.003), and were more likely to use loop diuretics (OR 2.79, P = 0.001). Among patients with “substantial benefit,” the positive predictive value (PPV) of HeartLogic™ to detect congestion was 92%. Conclusion: The utilization of CIED-based HeartLogic™ driven HF care demonstrated pronounced efficacy, predominantly in patients exhibiting characteristics of HF at a more advanced disease stage.