Lower limit of normal of cross-sectional area of peripheral muscles and diaphragm measurements performed with ultrasound in full-term and preterm infants.

To stratify groups of infants by gestational age and identify the lower limit of normal (LLN) of the cross-sectional area of peripheral muscles as well as diaphragmatic excursion and thickness and parasternal activation during spontaneous respiration in full-term and preterm newborns. A cross-sectional study was conducted at a neonatal unit. Preterm newborns (PTNBs) with gestational age of 28 to 366/7 weeks and full-term newborns (NBs) with gestational age of 37 to 416/7 weeks, clinically and hemodynamically stable, breathing ambient air with no signs of respiratory distress were included. NBs on oxygen therapy, those with known genetic syndromes, malformations of the nervous system and those having undergone surgery were excluded. Ultrasound was performed over the rectus femoris, tibialis anterior, and biceps brachii muscles (cross-sectional area) and diaphragm (thickness and excursion). One hundred twenty NBs were stratified based on gestational age (< 30 weeks [n = 25]; 31 to 35 weeks [n = 51]; 37 to 41 6/7 weeks [n = 44]). Significant differences were found in the cross-sectional area of the rectus femoris muscles and thigh circumference of NBs > 37 weeks compared to the other 2 groups (p < 0.05). Differences were found in diaphragm thickness and excursion between the groups with gestational age > 37 weeks and < 30 weeks. Greater activation of the parasternal muscles was found in the PTNBs. With regard to LLN, significant differences were found between the groups with gestational age > 37 weeks and < 30 weeks for all variables analyzed and between the group with gestational age > 37 weeks and other 2 groups for the cross-sectional area of the rectus femoris, diaphragmatic excursion, and diaphragm contraction velocity. Differences were found among the groups in the size of peripheral muscles as well as diaphragm thickness and excursion. Moreover, greater activation of the parasternal muscle was found in NBs with gestational age < 30 weeks. This study establishes normal values of ultrasound measures for full-term and preterm newborns.

Language Matters: Exploring Preferred Terms for Diverse Populations.

This article explores the significance of employing preferred terms and inclusive language in research practices concerning diverse populations. It highlights how inappropriate terminology can lead to labeling, stereotyping, and stigma, particularly for equity-denied groups. The study aimed to identify and analyze terminology preferences for diverse communities by major international organizations. Through a systematic environmental scan methodology, data were collected from 12 prominent organizations. The results indicate a concerted effort toward adopting inclusive language, with organizations favoring respectful and accurate terminology. For instance, terms like "people made vulnerable by systemic inequities" and "migrant workers" were preferred over outdated or stigmatizing alternatives. The discussion emphasizes the importance of identifying conflicting terms and trends in terminology preferences over time. We recommend prioritizing the use of preferred terms to promote respectful and accurate discourse, with a focus on person-centered language. Ultimately, the findings underscore the critical role of language in shaping perceptions and attitudes toward diverse communities, and advocate for continued efforts to promote inclusivity and equity in research, policy, and practice.

Sexual Health Implications of Return Migration for Women and Their Partners in Rural Mexico: A Critical Ethnography.

ABSTRACT: The return of a migrant partner can negatively impact the sexual health of women who stayed in their communities. Understanding their sexual health needs is crucial for developing targeted interventions and support systems. Our study used a critical ethnographic approach in Agua Dulce, a rural community in Mexico, involving 50 key informants: women who stayed behind (n = 20), returnees (n = 12), community leaders (n = 12), and health care professionals (n = 6). We used participant observation, policy analysis, and interviews, using purposeful and snowball sampling methods. A gender-based thematic analysis revealed economic hardships and early separations affect the sexual well-being of women who stay behind. Infidelity, discovered through social media or calls, causes emotional distress and family disruptions. Male migrants spend an average of 8.85 years abroad, leading to fears of risky sexual behaviors. Our study highlights the urgent need for specialized support centers and comprehensive health interventions.

Translating Open-Ended Questions in Cross-Cultural Qualitative Research: A Comprehensive Framework.

INTRODUCTION: Globalization has increased the importance of multicultural research to address health disparities and improve healthcare outcomes for underrepresented communities. The International Nursing Network for HIV Research (The Network) serves as a platform for researchers to collaborate on cross-cultural and cross-national HIV studies. This article discusses the Network's approach to overcoming barriers in multicultural and multinational research in a qualitative context. METHODS: The network created a protocol to guide decision-making throughout the translation process of qualitative data collected from participants in their native languages. The protocol includes aspects of why, when, what, who, how, where, and by what means the translation is completed. RESULTS: The protocol has allowed researchers to enhance the validity, reliability, and cultural sensitivity of translation process, ensuring the clarity and impact of their research findings. DISCUSSION: Rigorous translation practices promote cross-cultural understanding and respect for participants' perspectives, fostering global collaborations and knowledge exchange.

Deciphering the effect of a Cu(II)-hydrazone complex on intracellular cell signalling pathways in a human osteosarcoma 2D and 3D models.

New therapeutic strategies for osteosarcoma (OS) have demonstrated the potential efficacy of copper compounds as anticancer drugs and as a substitute for the often used platinum compounds. OS is a type of bone cancer, primarily affecting young adults and children..The main objective of this work is to discover the molecular targets and cellular pathways related to the antitumor properties of a Cu(II)-hydrazone toward human OS  2D and 3D systems. Cell viability study using MG-63 cells was evaluated in OS monolayer and spheroids. CuHL significantly reduced cell viability in OS models (IC50 2D: 2.6 ± 0.3 µM; IC50 3D: 9.9 ± 1.4 µM) (p<0.001). Also, CuHL inhibits cell proliferation and it induces cells to apoptosis. The main mechanism of action found for CuHL are the interaction with DNA, genotoxicity, the ROS generation and the proteasome activity inhibition. Besides, 67 differentially expressed proteins were found using proteomic approaches. Of those 67 proteins, 40 were found overexpressed and 27 underexpressed. The response to stress and to unfolded protein, as well as ATP synthesis were the most affected biological process among upregulated proteins, whilst proteins related to DNA replication and redox homeostasis were downregulated.

Prospective Outcomes After Serial Platelet-Rich Plasma (PRP) Injection in Vocal Fold Scar and Sulcus.

OBJECTIVE: Vocal fold scar and sulcus pose significant treatment challenges with no current optimal treatment. Platelet-rich plasma (PRP), an autologous concentration of growth factors, holds promise for regenerating the superficial lamina propria. This study aims to evaluate the potential benefits of serial PRP injections on mucosal wave restoration and vocal function. METHODS: In a prospective clinical trial across two institutions, patients with vocal fold scar underwent four serial PRP injections, one month apart. Blinded independent laryngologists and expert listeners used pretreatment and one-month post-fourth injection videostroboscopy and CAPE-V assessments to evaluate mucosal wave and voice quality changes, respectively. Additionally, patient reported outcome measures (PROMs) were evaluated. RESULTS: In the study, 15 patients received 55 PRP injections without adverse effects. Eight patients (53.3%) had mild, three patients (20%) had moderate, and four patients (26.7%) had severe scar. There was an average reduction of 8.7 points in post-treatment VHI-10 scores (p = 0.007). The raters observed an improvement in post-treatment voice in 73.4% of cases, and CAPE-V scores showed a reduction of 18.8 points on average (p = 0.036). The videostroboscopic VALI ratings showed an improvement in mucosal wave rating from 2.0 to 4.0. On average, the raters perceived the post-PRP exams to be better in 56.7% of cases. CONCLUSIONS: PRP has been validated as a safe autologous option for treatment of vocal fold scar. While results for mucosal wave and voice quality varied, there was a consistent improvement in PROMs. LEVEL OF EVIDENCE: Level 3: Prospective cohort study, with blinded analysis Laryngoscope, 2024.

Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins.

BACKGROUND: Deferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimers disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO, and other chelators do enter the brain despite some contrary reports. OBJECTIVE: Low dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid precursor protein (APP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice. METHODS: Iron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and APP processing by Western blot. RESULTS: DFO decreased brain iron by 18% (MRI) and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. APP and secretase enzymes also decreased by 30%. CONCLUSIONS: WT mice respond to DFO with decreased APP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered APP and secretase enzymes.

An Examination of Perceptions among Black Women on Their Awareness of and Access to Pre-Exposure Prophylaxis (PrEP).

Cisgender Black women (CBW) experience 67% of new HIV diagnoses among women in the South. Progress toward ending the HIV epidemic requires researchers to explore perceptions of factors related to the decision to initiate pre-exposure prophylaxis (PrEP) among CBW. Qualitative methods were used to explore how social and structural constructs influence individual decisions to use PrEP among 20 CBW through focus groups. The thematic data analysis identified how facilitators and barriers to PrEP uptake aligned with an external locus of control (LOC) [e.g., media influences on understanding of PrEP] or an internal LOC (e.g., awareness of personal vulnerability to HIV). Several participants highlighted that their PrEP knowledge was rooted in an external LOC, such as media campaigns. A participant stated, 'But even with the commercial, it wasn't representation for me.' Another participant described her personal HIV vulnerability in her sexual relationship as an internal LOC, stating, 'Not ignorance, it's maybe just not accepting the true reality of this can be contracted even from someone that you believe that you trust.' Due to gaps in media marketing, healthcare providers should be aware that some female patients may perceive that PrEP is not for them. Provider-led sexual health discussions are urgently needed to bridge the gap between PrEP eligibility and initiation.

Breast Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

The Expression of Genes Related to Reverse Cholesterol Transport and Leptin Receptor Pathways in Peripheral Blood Mononuclear Cells Are Decreased in Morbid Obesity and Related to Liver Function.

Obesity is frequently accompanied by non-alcoholic fatty liver disease (NAFLD). These two diseases are associated with altered lipid metabolism, in which reverse cholesterol transport (LXRα/ABCA1/ABCG1) and leptin response (leptin receptor (Ob-Rb)/Sam68) are involved. The two pathways were evaluated in peripheral blood mononuclear cells (PBMCs) from 86 patients with morbid obesity (MO) before and six months after Roux-en-Y gastric bypass (RYGB) and 38 non-obese subjects. In the LXRα pathway, LXRα, ABCA1, and ABCG1 mRNA expressions were decreased in MO compared to non-obese subjects (p < 0.001, respectively). Ob-Rb was decreased (p < 0.001), whereas Sam68 was increased (p < 0.001) in MO. RYGB did not change mRNA gene expressions. In the MO group, the LXRα pathway (LXRα/ABCA1/ABCG1) negatively correlated with obesity-related variables (weight, body mass index, and hip), inflammation (C-reactive protein), and liver function (alanine-aminotransferase, alkaline phosphatase, and fatty liver index), and positively with serum albumin. In the Ob-R pathway, Ob-Rb and Sam68 negatively correlated with alanine-aminotransferase and positively with albumin. The alteration of LXRα and Ob-R pathways may play an important role in NAFLD development in MO. It is possible that MO patients may require more than 6 months following RYBGB to normalize gene expression related to reverse cholesterol transport or leptin responsiveness.

Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

Metallocompounds as anticancer agents against osteosarcoma.

Metallocompounds are a class of anticancer compounds largely used in the treatment of several types of solid tumors, including bone cancer. Osteosarcoma (OS) is a primary malignant bone tumor that frequently affects children, adolescents and young adults. It is a very invasive type of tumor, so ∼40% of patients develop distant metastases, showing elevated mortality rates. In this review, we present an outline of the chemistry and antitumor properties of metal-based compounds in preclinical (in vitro and in vivo) and clinical OS models, focusing on the relationship between structure-activity, molecular targets and the study of the mechanism of action involved in metallocompound anticancer activity.

Lessons Learned from the COVID-19 Pandemic: Interpreting Vaccination Strategies in a Nationwide Demographic Study.

OBJECTIVE: Brazil was strongly affected by the COVID-19 pandemic. Its continental dimension and socio-demographic characteristics pose challenges to distribution and accessibility, making vaccination programs challenging. The objectives of the study were to describe the clinical and demographic characteristics of the general population vaccinated against COVID-19 by October 2021 and analyze the strategies implemented during the vaccination program. STUDY DESIGN AND SETTING: A retrospective nationwide study that analyzed data from the OpenDataSUS platform of the Informatics Department of the Brazilian Ministry of Health (DataSUS), which contains information from all individuals in Brazil who have received at least one dose of any vaccine against COVID-19 approved by the National Health Agency (ANVISA) from 17 January to 3 October 2021. RESULTS: Until 3 October, a total of 146,254,578 persons (68.6 per 100 inhabitants) received at least one dose of a vaccine in Brazil. The north and northeast regions had the lowest vaccination rates compared with the remaining regions (North: 56.8, Northeast: 62.0, South: 74.4, and Southeast: 73.2 per 100 inhabitants). Elderly individuals had the highest vaccination rates, particularly those above 70 years old. Heterologous dosing regimens were administered to 1,063,079 individuals (0.7% of those receiving the first dose). CONCLUSIONS: The COVID-19 vaccination program reached more than two-thirds of the population in Brazil by 9 months after its start, but the vaccination coverage was heterogeneous, reflecting the country's geographic and socio-demographic characteristics. Establishing priority groups for vaccination was a main characteristic of the vaccination strategy. In addition, technology transfer agreements have played an important role in increasing vaccine accessibility.

Epidemiology of Chronic Suppurative Otitis Media in the United States.

OBJECTIVE: This study aimed to evaluate the prevalence, incidence, and associated demographic factors of chronic suppurative otitis media (CSOM), utilizing a nationwide healthcare claims database. METHODS: This retrospective study utilized outpatient administrative claims data from the IBM MarketScan Research Database from 2007 to 2021. The database (11 246 909 584 claims with 148 147 615 unique patients) includes health data from the private-sector, Medicare/Medicaid, managed care providers, and EMR providers. Included patients had a diagnosis of CSOM based on ICD-9-CM and ICD-10-CM codes. Prevalence and health utilization were estimated by age, gender, and geographic region. RESULTS: In the United States, the estimated CSOM prevalence and incidence was 0.46% and 0.03%, respectively. Among CSOM patients (n = 679 906), mean age (SD) was 8.1 (15.4) years, and 52.8% were male. Most patients (81.1%) were aged 0 to 10 years. CSOM prevalence was lower in females (OR = 0.64, 95% CI 0.64-0.65, P < .001), less common in older age (OR = 0.94, 95% CI 0.94-0.94, P < .001), and highest in the South region (OR = 2.08, 95% CI 2.06-2.09, P < .001). CONCLUSION: Our results show CSOM prevalence (0.46%) is similar to other developed countries. CSOM prevalence was highest in those aged 0 to 10 years, in males and in the South region. Of note, prevalence and cost are likely significantly underestimated given limitations in accurate ICD-CM coding and the exclusion of uninsured patients. Further epidemiological studies are warranted to characterize the impact of CSOM on the US healthcare system.

OptimICE-RD: sacituzumab govitecan + pembrolizumab vs pembrolizumab (± capecitabine) for residual triple-negative breast cancer.

Patients with early-stage triple-negative breast cancer (TNBC) with residual invasive disease after neoadjuvant therapy have a high risk of recurrence even with neoadjuvant and adjuvant treatment with pembrolizumab. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload, improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with pre-treated metastatic TNBC. Moreover, preclinical data suggest that topoisomerase I inhibitors may enhance the effects of immune checkpoint inhibitors through activation of the cGAS-STING pathway. Here we describe the international randomized phase III AFT-65/ASCENT-05/OptimICE-RD trial, which evaluates the efficacy and safety of sacituzumab govitecan plus pembrolizumab versus treatment of physician's choice (pembrolizumab ± capecitabine) among patients with early-stage TNBC with residual invasive disease after neoadjuvant therapy.Clinical Trial Registration: NCT05633654 (ClinicalTrials.gov)Other Study ID Number(s): Gilead Study ID: GS-US-595-6184Registration date: 1 December 2022Study start date: 12 December 2022Recruitment status: Recruiting.

AFT-65/ASCENT-05/OptimICE-RD is an ongoing clinical trial that is testing a new treatment combination for patients with stage II or III triple-negative breast cancer (TNBC). Stage II­III means the cancer is confined to the breast and/or nearby lymph nodes and can be surgically removed. However, there remains a risk that the cancer could recur after surgery. To reduce this risk, patients with stage II­III TNBC receive anti-cancer medication before and after surgery. For some patients, receipt of anti-cancer medication before surgery produces a pathologic complete response (pCR), meaning there is no observable cancer left behind at surgery. Patients with a pCR have a lower risk of recurrence than patients with residual disease.The AFT-65/ASCENT-05/OptimICE-RD trial includes people with stage II-III TNBC who have residual cancer after completing their course of pre-surgery anti-cancer medication. All participants have any remaining cancer in their breast and/or lymph nodes removed surgically, after which they are randomly assigned to receive one of two treatments. The experimental therapy consists of pembrolizumab along with a medication called sacituzumab govitecan, which kills cancer cells directly and may strengthen the anti-cancer immune response. Pembrolizumab strengthens the anti-cancer immune response, so the hypothesis of this trial is that the two medications will be more effective together. The control therapy consists of pembrolizumab, alone or in combination with a chemotherapy medication called capecitabine, which is the current standard of care. To study the effectiveness of each treatment, the researchers are following up with all participants to learn if and when their breast cancer returns.

Impact of Obesity on Timing of Tracheotomy: A Multi-institutional Retrospective Study.

OBJECTIVE: To examine the impact of increased body mass index (BMI) on (1) tracheotomy timing and (2) short-term surgical complications requiring a return to the operating room and 30-day mortality utilizing data from the Multi-Institutional Study on Tracheotomy (MIST). METHODS: A retrospective analysis of patients from the MIST database who underwent surgical or percutaneous tracheotomy between 2013 and 2016 at eight institutions was completed. Unadjusted and adjusted logistic regression analyses were used to assess the impact of obesity on tracheotomy timing and complications. RESULTS: Among the 3369 patients who underwent tracheotomy, 41.0% were obese and 21.6% were morbidly obese. BMI was associated with higher rates of prolonged intubation prior to tracheotomy accounting for comorbidities, indication for tracheotomy, institution, and type of tracheostomy (p = 0.001). Morbidly obese patients (BMI ≥35 kg/m2) experienced a longer duration of intubation compared with patients with a normal BMI (median days intubated [IQR 25%-75%]: 11.0 days [7-17 days] versus 9.0 days [5-14 days]; p < 0.001) but did not have statistically higher rates of return to the operating room within 30 days (p = 0.12) or mortality (p = 0.90) on multivariable analysis. This same finding of prolonged intubation was not seen in overweight, nonobese patients when compared with normal BMI patients (median days intubated [IQR 25%-75%]: 10.0 days [6-15 days] versus 10.0 days [6-15 days]; p = 0.36). CONCLUSION: BMI was associated with increased duration of intubation prior to tracheotomy. Although morbidly obese patients had a longer duration of intubation, there were no differences in return to the operating room or mortality within 30 days. LEVEL OF EVIDENCE: III Laryngoscope, 2024.

Virtual patient analysis identifies strategies to improve the performance of predictive biomarkers for PD-1 blockade.

Patients with metastatic triple-negative breast cancer (TNBC) show variable responses to PD-1 inhibition. Efficient patient selection by predictive biomarkers would be desirable, but is hindered by the limited performance of existing biomarkers. Here, we leveraged in-silico patient cohorts generated using a quantitative systems pharmacology model of metastatic TNBC, informed by transcriptomic and clinical data, to explore potential ways to improve patient selection. We tested 90 biomarker candidates, including various cellular and molecular species, by a cutoff-based biomarker testing algorithm combined with machine learning-based feature selection. Combinations of pre-treatment biomarkers improved the specificity compared to single biomarkers at the cost of reduced sensitivity. On the other hand, early on-treatment biomarkers, such as the relative change in tumor diameter from baseline measured at two weeks after treatment initiation, achieved remarkably higher sensitivity and specificity. Further, blood-based biomarkers had a comparable ability to tumor- or lymph node-based biomarkers in identifying a subset of responders, potentially suggesting a less invasive way for patient selection.

Influence of the spaceflight environment on macrophage lineages.

Spaceflight and terrestrial spaceflight analogs can alter immune phenotypes. Macrophages are important immune cells that bridge the innate and adaptive immune systems and participate in immunoregulatory processes of homeostasis. Furthermore, macrophages are critically involved in initiating immunity, defending against injury and infection, and are also involved in immune resolution and wound healing. Heterogeneous populations of macrophage-type cells reside in many tissues and cause a variety of tissue-specific effects through direct or indirect interactions with other physiological systems, including the nervous and endocrine systems. It is vital to understand how macrophages respond to the unique environment of space to safeguard crew members with appropriate countermeasures for future missions in low Earth orbit and beyond. This review highlights current literature on macrophage responses to spaceflight and spaceflight analogs.

Bi-level Graph Learning Unveils Prognosis-Relevant Tumor Microenvironment Patterns from Breast Multiplexed Digital Pathology.

The tumor microenvironment is widely recognized for its central role in driving cancer progression and influencing prognostic outcomes. Despite extensive research efforts dedicated to characterizing this complex and heterogeneous environment, considerable challenges persist. In this study, we introduce a data-driven approach for identifying patterns of cell organizations in the tumor microenvironment that are associated with patient prognoses. Our methodology relies on the construction of a bi-level graph model: (i) a cellular graph, which models the intricate tumor microenvironment, and (ii) a population graph that captures inter-patient similarities, given their respective cellular graphs, by means of a soft Weisfeiler-Lehman subtree kernel. This systematic integration of information across different scales enables us to identify patient subgroups exhibiting unique prognoses while unveiling tumor microenvironment patterns that characterize them. We demonstrate our approach in a cohort of breast cancer patients, where the identified tumor microenvironment patterns result in a risk stratification system that provides complementary, new information with respect to alternative standards. Our results, which are validated in a completely independent cohort, allow for new insights into the prognostic implications of the breast tumor microenvironment, and this methodology could be applied to other cancer types more generally.