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Invasive lobular breast carcinoma (ILC), the most common special histological subtype of breast cancer, is characterized by nearly universal expression of estrogen receptor alpha (ER) and unique sites of metastases, neither of which is fully recapitulated by genetically engineered mouse models. Using reporter-labeled ILC mouse xenografts, herein we used mammary fat pad, tail vein and intracardiac orthotopic growth to analyze spontaneous and experimental metastasis and gene expression. We observed ER-positive primary tumors with single-file histology and collagen deposition, and spontaneous metastasis from the mammary fat pad to bones, ovaries, and brain including the leptomeninges, thereby closely mirroring the growth and metastatic spread of human ILC. Brain metastases showed strong ER staining, confirmed by sequencing analyses which identified estrogen signaling as top activated pathway, and the lesions exhibited robust response to endocrine therapy. In summary, we report endocrine responsive mammary fat pad, tail vein and intracardiac xenografts that faithfully demonstrate unique ILC features and can serve as invaluable pre-clinical translational platforms for validating candidate ILC genetic drivers and testing novel therapeutics.

OBJECTIVE To test the effect of physical activity on the gut microbiome and circulating short-chain fatty acids (SCFAs) among sedentary adults with prediabetes and overweight or obesity. RESEARCH DESIGN AND METHODS In a pilot and feasibility trial, we randomized 77 adults with prediabetes and a sedentary lifestyle into one of two groups: 1) intervention: invited to engage in home-based moderate-intensity walking 3×/week for 30 min/session in weeks 1–4 and for 45 min/session during weeks 5–8 of the 8-week intervention; or 2) control: maintained habitual physical activity levels. We performed metagenomic sequencing from stool collected at baseline, week 4, and week 8, with SCFAs measured from serum collected at baseline and week 8. Taxonomic and functional profiling was performed on the metagenomic reads; α-diversity metrics were subsequently derived. Linear regression assessed the difference in change between the intervention and control groups for α-diversity and SCFA levels. RESULTS We screened 1,533 participants for eligibility and consented 132. Of these, 87 entered the run-in phase, and 77 were randomized. Participants were mean (SD) 51.4 (8.9) years old, 87.7% female, and 74% non-Hispanic White. Mean fasting glucose was 103.3 (13.2) mg/dL, while mean BMI was 34.4 (5.7) kg/m2. Compared with the control group, the intervention group experienced decreased α-diversity as characterized by Shannon, Richness, and Faith diversity indices by intervention week 8 (P < 0.05). Changes in SCFA levels were not statistically significant different in intervention versus control. CONCLUSIONS Randomization to a walking intervention resulted in modest gut microbiome changes among adults with overweight or obesity and prediabetes.

ABSTRACT Background A randomized phase II screening trial of gemcitabine, nab‐paclitaxel, and cisplatin with a medically supervised ketogenic diet (MSKD) versus usual diet (non‐MSKD) was conducted in patients with treatment‐naive metastatic pancreatic ductal adenocarcinoma (PDAC). Methods Patients with untreated metastatic PDAC were randomized 1:1 to MSKD or non‐MSKD while receiving gemcitabine, nab‐paclitaxel, and cisplatin on days 1 and 8 of a 21‐day cycle. The MSKD was guided by a remote health care team and daily ketone (beta‐hydroxybutyrate) levels, with goal beta‐hydroxybutyrate of 0.5 to 3.0 mM. The primary endpoint was progression‐free survival (PFS) using a one‐sided alpha level of 0.20. Secondary endpoints included overall survival (OS), safety, and quality of life (QOL). Changes in microbiome were an exploratory endpoint. Findings Overall, there were 32 evaluable patients. In the MSKD arm, 15 of 16 patients achieved nutritional ketosis; the median proportion of days in ketosis was 39.4%. The median PFS was 8.5 months in MSKD patients and 6.2 months in non‐MSKD patients: hazard ratio, 0.53 (95% CI, 0.21–1.37); one‐sided p = .096. The median OS was 13.7 months with MSKD and 10.2 months in the non‐MSKD arm: hazard ratio, 0.58 (95% CI, 0.25–1.37); one‐sided p = .107). All MSKD‐related adverse events were grade 1‐2. There were no significant differences in grade ≥3 chemotherapy‐related adverse events between the arms. MSKD patients had no decline in QOL and had significant enrichment of beneficial taxa in the microbiome ( p < .05, log‐fold change ≥2). Conclusions The MSKD is feasible in patients with PDAC and, although not powered for definitive outcomes, shows trends in improved PFS and OS when combined with gemcitabine, nab‐paclitaxel, and cisplatin, without added toxicity or detriment to QOL. Larger studies are required to confirm these findings and establish the value of the MSKD in pancreatic cancer treatment.

Abstract Advances in biomarker technology, digital cognitive assessments, and amyloid‐targeting therapies have redefined the opportunities for accurate and early diagnosis and care of Alzheimer's disease (AD). These advances also create new possibilities for intervention before the onset of cognitive impairment. This paradigm shift has increased the focus on Stages 1 and 2 of AD, in which individuals are cognitively unimpaired but exhibit biological evidence of disease. While early identification of AD offers an opportunity to intervene early to delay progression and preserve quality of life, it also presents complex challenges related to communicating diagnostic results to patients and their families, contextualizing the cost effectiveness of early diagnosis and treatment, and implementation of and equitable access to treatments. Recent, successfully enrolled, preclinical AD trials highlight the complex strategies required to identify asymptomatic, biomarker‐positive individuals on a large scale, and demonstrate critical knowledge gaps in inclusion, follow‐up, and long‐term outcome measurement. The Spring 2025 Alzheimer's Association Research Roundtable (AARR) meeting brought together academics, clinicians, industry, and regulatory leaders to exchange perspectives on current challenges, key learnings, and potential strategies for identifying and treating individuals in very early stages of AD, effectively and safely. This paper presents key takeaways from the Spring 2025 AARR meeting. Highlights New criteria for Alzheimer's disease (AD) enable early identification of AD pathology. Blood tests and digital cognitive assessment tools may facilitate early and personalized care. Plasma biomarkers may be scalable in clinical settings but need confirmation or follow‐up assessments in those individuals with equivocal results. Early therapy shows best results in people with lower initial amyloid and tau burden.

Background: Sharing of family cancer history (FCH) in Black families has been documented as lower than in other populations. There has been limited exploration as to the factors and circumstances that facilitate or hinder FCH communication in these communities. Objective: To explore intersecting factors influencing FCH discussion in Black families with a breast or ovarian cancer diagnosis. Interventions/Methods: We conducted qualitative interviews with socioeconomically diverse breast and ovarian cancer patients or family members. Interviews were thematically analyzed for iterative themes on FCH. Results: A total of 107 participants completed an interview. Discussion of FCH was reported as being influenced by several factors, including relationship and family dynamics, personality of family members, involvement in caregiving and support, and perceived importance and responsibility of communicating FCH for cancer prevention. Participants also described how inequitable access to medical care influenced disclosure of a cancer diagnosis, and socioeconomic concerns can influence family communication and documentation of FCH in the medical record. Conclusion: Our analysis indicates that disclosure of FCH is improving over time as access to healthcare has increased for Black families. Implications for Oncology Nursing Practice: Strategies to collect FCH outside of clinic settings, such as digital tools or chatbots, should be considered for increased capture of cancer pedigrees in families where discussion is limited. Patient education on options for preventative care and communications tools may assist patients with family discussions, although patients with adverse social determinants of health are likely to experience additional barriers to genetic screening based on FCH alone.

Background: Functional hypothalamic amenorrhea (FHA) is a common form of secondary amenorrhea caused partly by undernutrition relative to demand. Objective: To compare the dietary nutritional intake between women with FHA and eumenorrheic controls and evaluate micronutrient profiles. Methods: This cross-sectional study included 30 women with FHA and 29 eumenorrheic controls not on hormones. FHA was defined as ≥3 consecutive months of amenorrhea, estradiol of <50 pg/mL, and FSH and LH of <10 mIU/L, excluding other etiologies. A 3-day food diary was collected for dietary analysis, excluding dietary supplements using ESHA Research Food Processor. Results: The mean age of women with FHA and controls was 26.4 years ± 6.2 versus 30.3 years ± 3.7 ( p = 0.002), with no differences in BMI ( p = 0.16) or the waist-to-hip ratio ( p = 0.71). Women with FHA and controls consumed comparable median calorie intake (1784 kcal [1465, 2011] vs. 1732 kcal [1578, 1982], p = 0.62), with no differences in self-reported exercise patterns. Women with FHA consumed more dietary protein (84.2g [74, 112] vs. 74 g [59, 92], p = 0.001) and dietary fiber (30.1 g [22, 43] vs. 17.3 g [15, 23], p = 0.02) versus controls, respectively. When expressed as a percentage of estimated average requirements (% estimated average requirement), women with FHA had higher intakes of vitamin A (105% [45, 219] vs. 43% [21, 86], p = 0.005), vitamin C (201% [139, 351] vs. 107% [75, 190], p = 0.004), and iron (169% [146, 220] vs. 120% [99, 192], p = 0.027) compared with controls. Conclusions: Women with FHA had similar caloric intake to eumenorrheic controls but consumed more dietary protein, fiber, vitamin A, vitamin C, and iron. Future studies should examine the nutritional profiles of women with FHA in relation to long-term health consequences such as bone and vascular health.

Extramedullary presentations of multiple myeloma (MM) involving the central nervous system (CNS) carry a dismal prognosis. Although historically rare, management of extramedullary disease—including CNS manifestations—has become increasingly clinically relevant as advances in systemic therapies have prolonged control of medullary disease. CNS manifestations may occur across a variety of clinical settings and at different time points throughout the disease course. Common symptoms include visual changes, headaches, loss of sensation, confusion, and seizures. MRI identifies leptomeningeal enhancement and/or parenchymal lesions in approximately 90% of cases, and lumbar puncture with cerebrospinal fluid testing for clonal plasma cell populations is confirmatory. Encouragingly, the incorporation of novel therapeutic agents has improved historically poor outcomes in CNS MM. Novel immunotherapeutic approaches using CAR T-cell therapy and bispecific T-cell–engaging antibodies have recently demonstrated significant efficacy in consolidating responses. Multimodality treatment strategies incorporating intrathecal chemotherapy, systemic novel agents, radiation therapy, and immunotherapy hold promise for achieving more durable responses in this devastating manifestation of MM.

Abstract Purpose: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34–mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis. Experimental Design: This retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34, and their association with progression-free survival (PFS) and overall survival (OS). Uni- and multivariable Cox proportional hazard models were applied with multiple imputed datasets. Results: A total of 153 patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. The median age at diagnosis was 17 years (range, 2–45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation), and initial chemotherapy was given in 87% [70% temozolomide-based (TMZ), 25% TMZ/lomustine, 5% non-TMZ]. Median OS was 24 months [interquartile range (IQR), 22–28] with a median PFS of 14 months (IQR, 12–19). Twelve patients (8%) were found to be long-term survivors (≥5 years). Exploratory multivariable analysis showed that adjuvant radiotherapy [HR, 0.076; 95% confidence interval (CI), 0.033–0.17] and achieving GTR/NTR compared with &lt; NTR (HR, 0.51; 95% CI, 0.33–0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR, 0.70; 95% CI, 0.57–0.87), initial radiotherapy (HR, 0.38; 95% CI, 0.15–0.96), and initial GTR/NTR compared with &lt; NTR (HR, 0.60; 95% CI, 0.37–0.97). Conclusions: This cohort highlights prognostic factors for patients with DHG, H3 G34, and describes relapse patterns and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.