PurposeLung and bronchus cancer (LBC) is the leading cause of cancer-related deaths. This study examines the relationship between exposure to industrial air pollution and lung and bronchus cancer survival (LBCS) in New Mexico, USA, from 1990 to 2019.MethodsThis retrospective cohort study included data from 18, 273 lung and bronchus cancer patients. Residential exposure to nine industrial air pollutants was estimated for each patient using the Emission Weighted Proximity Model (EWPM), which integrates industrial air emission data and air quality monitoring data form the U.S. Environmental Protection Agency's (EPA). Cox proportional hazards modeling was applied to identify industrial air pollutants as decreased LBCS risk factors, adjusting for age at diagnosis, gender, cancer stage, race/ethnicity, smoking prevalence, and urbanization of residential address.ResultsResults show that residential exposure to 1,1,1-trichloroethane and cobalt during the survival period was significantly associated with decreased LBCS (adjusted hazard ratio [adjHR] for 1,1,1-trichloroethane: 1.06, 95% CI: 1.04, 1.09 and adjHR for cobalt: 1.06, 95% CI: 1.03, 1.09) compared to those unexposed among all patients. When exposure levels were categorized into four groups (unexposed, low, medium, high) based on annual average exposure during the survival period, the associations remained consistent.ConclusionThis study underscores the negative influence of industrial air pollution on LBCS and emphasizes the need for targeted public health interventions in high-exposure areas.

Chemokine and chemokine receptors (CKRs) regulate cell growth, tumor immunity, migration, angiogenesis, and metastasis. We evaluated associations of inherited chemokine/CKR variants with subsequent primary melanomas among patients with a previous melanoma. Our population-based cohort included 2458 incident single primary and 1205 multiple primary melanoma (MPM) cases. We examined 215 a priori candidate polymorphisms selected based on prior evidence and predicted functional relevance, along with nine haplotype blocks. Logistic regression estimated odds ratios and 95% confidence intervals, adjusting for age at diagnosis, sex, age-by-sex interaction, and study center. Thirty variants across 14 genes were nominally associated with MPM ( P  < 0.05), with effect sizes ranging from 16 to 80%. Five haplotypes in CXCL12 , CCL18 , CXCR2 , and CCR9 were significantly associated with MPM ( Pglobal < 0.03) with stronger effects than individual-effect alleles. Functional annotation identified 160 associated index variants and linkage disequilibrium proxies acting as skin expression quantitative trait loci for CXCR2 , XCR1 , BCL9L , FYCO1 , PNKD , RUFY4 , and RP11-378A13.1 ( P < 1.06E-05 to 4.3E-34). These variants were classified functionally as candidate causal variants based on convergent regulatory annotation and skin‑specific expression quantitative trait locus evidence, linking chemokine/CKR variants and haplotypes to downstream genes involved in epithelial-mesenchymal-like transition, matrix remodeling, and other tumorigenic processes, thereby implicating immune regulatory mechanisms in melanoma development. To the best of our knowledge, this is the first study to demonstrate an association of a priori chemokine/CKR variants with subsequent melanoma risk. Validation and evaluation of associations with tumor characteristics and survival are warranted.

Female breast cancer (FBC) is the most commonly diagnosed malignant cancer and the second leading cancer cause of death among women in the United States. Environmental exposures, particularly PM2.5-bound metals, have been increasingly associated with breast cancer incidence. We evaluated associations between long-term residential exposure to PM2.5-bound metals and age-adjusted FBC incidence rate at the census tract level in New Mexico from 1997 to 2019. FBC records were obtained from the New Mexico Tumor Registry. Annual metal exposure intensities for chromium, cobalt, copper, manganese, and mercury were estimated using a calibrated Emission Weighted Proximity Model (EWPM) over a 10-year pre-diagnosis window. Generalized Estimating Equations (GEE) with Gaussian estimation was used to estimate rate ratio (RR) for the association between PM2.5-bound metal exposure and FBC incidence in New Mexico. Exposure to PM2.5-bound chromium (adjusted RR 1.07, 95

Digital AI systems spanning large language models, vision models, and generative architectures that operate primarily in symbolic, linguistic, or pixel domains. They have achieved striking progress, but almost all of this progress lives in virtual spaces. These systems transform embeddings and tokens, yet do not themselves touch the world and rarely admit a physical interpretation. In this work we propose a physical transformer that couples modern transformer style computation with geometric representation and physical dynamics. At the micro level, attention heads, and feed-forward blocks are modeled as interacting spins governed by effective Hamiltonians plus non-Hamiltonian bath terms. At the meso level, their aggregated state evolves on a learned Neural Differential Manifold (NDM) under Hamiltonian flows and Hamilton, Jacobi, Bellman (HJB) optimal control, discretized by symplectic layers that approximately preserve geometric and energetic invariants. At the macro level, the model maintains a generative semantic workspace and a two-dimensional information-phase portrait that tracks uncertainty and information gain over a reasoning trajectory. Within this hierarchy, reasoning tasks are formulated as controlled information flows on the manifold, with solutions corresponding to low cost trajectories that satisfy geometric, energetic, and workspace-consistency constraints. On simple toy problems involving numerical integration and dynamical systems, the physical transformer outperforms naive baselines in stability and long-horizon accuracy, highlighting the benefits of respecting underlying geometric and Hamiltonian structure. More broadly, the framework suggests a path toward physical AI that unify digital reasoning with physically grounded manifolds, opening a route to more interpretable and potentially unified models of reasoning, control, and interaction with the real world.

BACKGROUND:Recent genome-wide association studies (GWAS) have identified new susceptibility loci for melanoma, but their associations with multiple primary melanoma (MPM) are unclear. METHODS:We investigated the associations of 69 SNPs in 39 GWAS-identified loci with odds of MPM relative to single primary melanoma in the international, population-based Genes, Environment, and Melanoma study. Per-minor-allele ORs and 95% confidence intervals (CI) for individuals with MPM "cases" (n = 1,205) relative to single primary melanoma "controls" (n = 2,458) were estimated using multivariable logistic regression, and polygenic risk scores (PRS) were calculated and weighted based on a 2020 GWAS meta-analysis (57 of the 68 independent GWAS SNPs available). RESULTS:Thirteen SNPs in 11 gene regions (PARP1, CYP1B1/RMDN3, TERT, RAPGEF5, TYRP1, MTAP, CDKN2A/CDKN2B, KLF4, TYR, SOX6, and ASIP) were statistically significantly associated (P < 0.05) with MPM adjusting for age, sex, age-by-sex interaction, and study center. The highest versus lowest PRS quintile was associated with a 2.81-fold higher odds of MPM (95% CI, 2.10-3.78; P = 7.5 × 10-13); this association was attenuated but remained statistically significant after excluding SNPs individually associated with MPM (OR = 1.75, 95% CI, 1.32-2.31). CONCLUSIONS:Inherited genetic variants spanning 11 gene regions were independently associated with MPM. Nonsignificant SNPs were associated with MPM when aggregated into a PRS, indicating that their cumulative effect may influence MPM risk despite lacking individual statistical significance in our study population. IMPACT:Our findings provide additional evidence that these loci are associated with melanoma risk and estimate the magnitude of their genetic effect on subsequent (multiple) primary melanoma risk.

Rocky Mountain Spotted Fever (RMSF) is a potentially fatal tick-borne disease historically prevalent in the eastern and southeastern U.S. Since the early 2000s, there has been a notable rise in RMSF cases in the south-western U.S. Despite the documented role of dogs in tick-borne disease transmission, research on the influence of other factors, such as veterinary care access, climatic conditions and landscape characteristics on RMSF incidence is limited. This study investigated the combined impact of these factors on RMSF using county-level temperature, relative humidity, precipitation, land cover, dog populations and veterinary care access in Arizona from 2006 to 2021. Employing a spatial negative binomial regression model, the study revealed significant associations between veterinary care access, precipitation, relative humidity, shrubland, and RMSF incidence across three models incorporating lagged effects (0-month, 1-month, and 2-month) for climatic variables. A key finding was that counties experiencing higher veterinary care access were more likely to report lower RMSF case counts (incidence rate ratio (IRR): 0.9237). The mean precipitation consistently showed the highest positive IRR (1.8137) across all models, indicating its strong influence. In contrast, relative humidity (IRR: 0.9413) and shrubland presence (IRR: 0.9265) demonstrated significant negative associations with RMSF incidence. These findings underscore the importance of veterinary care access, climatic factors, and land cover in shaping RMSF dynamics, particularly in regions with increasing incidence rates.

Background: Malignant peritoneal mesothelioma (MPM) is a rare disease with a generally poor prognosis treated with systemic chemotherapy alone. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) can offer improved overall survival in select patients. This study examined the effect of travel distance on oncologic outcomes in patients with MPM undergoing CRS-HIPEC. Methods: The National Cancer Database (NCDB) was reviewed from 2006 to 2020. The primary variable was distance traveled to CRS-HIPEC facility (< 50 miles versus >= 50 miles). Primary outcome was overall survival. Secondary outcomes examined 30- and 90-day post-surgical outcomes. Results: Overall, 650 patients met inclusion criteria; 345 patients traveled < 50 miles and 305 patients traveled >= 50 miles. Rates of MPM were highest in the Northeast, Middle and South Atlantic regions. Patients traveling >= 50 miles were younger, had a lower median income, and were more likely to be privately insured and treated at an academic center. There was no difference in overall survival between groups (p=0.87). Secondary outcomes were comparable: 30-day survival was 98 % in both groups (p=0.9), 90-day survival was 93 % in both groups (p=0.9), 30-day readmission rate was 11 % in the shorter travel distance group versus 7 % (p=0.2). Hospital length of stay (LOS) was longer in the >= 50 miles group (9 vs 8 days; p=0.02). Conclusions: Outcomes following CRS-HIPEC for MPM did not differ based upon distance traveled for treatment, though patients who travel >= 50 miles have an increased LOS. Regionalization of CRS-HIPEC for MPM does not result in worse oncologic or surgical outcomes.

Hearing loss in newborns is a prevalent issue that can hinder the growth of language skills and cognitive development. Given that hearing loss often co-occurs with other adverse birth outcomes and the recognized role of metals in causing such outcomes, it is conceivable that metals may also serve as a risk factor of hearing loss. This study examined the associations between maternal residential exposure to thirteen PM2.5-bound metals and failure in Newborn Hearing Screening (NHS) in offspring in New Mexico from 2008 to 2017 to ascertain possible implications of these environmental exposures. This retrospective cohort study included 141,406 births (7670 births in disease group and 133,736 births in non-diseased group) in New Mexico during 2008-2017. Thirteen PM2.5-bound metals released from the U.S. Environmental Protection Agency (EPA) Toxic Release Inventory (TRI) facilities were investigated potentially as risk factors. The RSEI model estimated maternal residential exposure to PM2.5-bound metals during pregnancy, and spatial log-binomial regressions, adjusted for confounders, calculated adjusted relative risks (aRRs) for the association with NHS failure. Findings indicated that maternal residential exposure to PM2.5-bound metals - including antimony, barium, beryllium, chromium, cobalt, manganese, mercury, vanadium, and zinc - during pregnancy were positively associated with NHS failure in offspring, showing aRRs ranging from 1.07 to 2.18. A significant trend was observed when exposures were categorized as zero, low, medium, and high of these metals. Our findings indicate that maternal exposure to these PM2.5-bound metals may adversely affect newborn hearing, underscoring air pollution as a modifiable risk factor for improving hearing health outcomes.

PURPOSE:Patients with stage II and resected stage III melanomas have variable clinical outcomes, providing evidence of underlying biological differences in tumors and/or the patients themselves, beyond stage. The approval of adjuvant immunotherapy for stage IIB/C and resected stage III/IV disease (and adjuvant targeted therapy for resected stage III disease) has created a pressing need to develop biomarkers to accurately distinguish patients at low risk versus high risk for recurrence and death from melanoma. miRNAs are promising biomarkers because of their stability in tissues and fluids and their demonstrated functional and prognostic roles in melanoma. We hypothesized that miRNA expression could be integrated into prognostic models that would classify 5-year survival outcomes more accurately than clinical factors alone. EXPERIMENTAL DESIGN:Using a NanoString miRNA Expression Assay, we analyzed 715 primary melanomas from patients with stage II or stage III disease within the InterMEL consortium and examined associations between miRNA expression and melanoma-specific death. RESULTS:When integrated into clinical prognostic models for 5-year melanoma-specific survival, miRNA signatures improved the area under the receiver operating characteristic curve for patients in stage II from 0.71 for a "clinical factors-only" model to 0.81 for a "clinical plus miRNA" model in an independent test set, an improvement of 0.10 with a 95% confidence interval (0.03-0.19). The improvement was more modest for patients in stage III who were included in the analysis. CONCLUSIONS:Incorporating miRNA expression in primary melanomas may enhance the accuracy of clinical prognostic models and potentially aid in the selection of patients with melanoma for adjuvant treatment and clinical trials.

BACKGROUND:Chronic exposure to uranium (U) rich environments poses significant health risks, yet the molecular mechanisms underlying these effects remain poorly understood. Extracellular vesicles (EVs) are membrane-bound vesicles that transfer multiple biomolecules between cells and can regulate cellular function. OBJECTIVE:To determine whether U-mining tenure is associated with specific alterations in serum-derived EV proteomic and plasma cytokine profiles among former U-miners, and to assess the potential of EV-derived proteins as robust biomarkers of chronic U-exposure relative to canonical cytokines. METHODS:Serum and plasma samples were obtained from 39 former U-miners. Small and large EVs were isolated via differential ultracentrifugation and characterized by nanoparticle tracking and western blotting. EV proteomic profiles were analyzed using liquid chromatography-tandem mass spectrometry. Plasma cytokines were quantified using multiplex immunoassays. Age-adjusted linear regression was used to assess associations with mining tenure, and pathway enrichment analysis was performed on significant EV proteins. RESULTS:Eight small-EV and four large-EV proteins significantly correlated with mining tenure after age adjustment. Notably, Complement C1r subcomponent and Vitamin K-dependent protein S, and Fibrinogen alpha chain exhibited strong inverse correlations. Enrichment analyses highlighted immune-related and extracellular matrix pathways. Six cytokines were initially associated with mining tenure but lost significance after age adjustment. In contrast, EV protein associations appeared more robust for this confounding, underscoring their potential as exposure biomarkers. CONCLUSIONS:Serum EV-derived protein signatures were nominally associated with U-mining tenure independent of age, whereas cytokine profiles were confounded by age. These findings suggest that EV-derived proteins may provide sensitive biomarkers for monitoring long-term health effects of U-exposure, which warrants further investigation in larger cohorts.

Unobserved effect modifiers can induce bias when generalizing causal effect estimates to target populations. In this work, we extend a sensitivity analysis framework assessing the robustness of study results to unobserved effect modification that adapts to various generalizability scenarios, including multiple (conditionally) randomized trials, observational studies, or combinations thereof. This framework is interpretable and does not rely on distributional or functional assumptions about unknown parameters. We demonstrate how to leverage the multi-study setting to detect violation of the generalizability assumption through hypothesis testing, showing with simulations that the proposed test achieves high power under real-world sample sizes. Finally, we apply our sensitivity analysis framework to analyze the generalized effect estimate of secondhand smoke exposure on birth weight using cohort sites from the Environmental influences on Child Health Outcomes (ECHO) study.

AbstractBackground: Recent genome-wide association studies (GWAS) have identified new susceptibility loci for melanoma, but their associations with multiple primary melanoma (MPM) are unclear. Methods: We investigated the associations of 69 SNPs in 39 GWAS-identified loci with odds of MPM relative to single primary melanoma in the international, population-based Genes, Environment, and Melanoma study. Per-minor-allele ORs and 95% confidence intervals (CI) for individuals with MPM “cases” (n = 1,205) relative to single primary melanoma “controls” (n = 2,458) were estimated using multivariable logistic regression, and polygenic risk scores (PRS) were calculated and weighted based on a 2020 GWAS meta-analysis (57 of the 68 independent GWAS SNPs available). Results: Thirteen SNPs in 11 gene regions (PARP1, CYP1B1/RMDN3, TERT, RAPGEF5, TYRP1, MTAP, CDKN2A/CDKN2B, KLF4, TYR, SOX6, and ASIP) were statistically significantly associated (P < 0.05) with MPM adjusting for age, sex, age-by-sex interaction, and study center. The highest versus lowest PRS quintile was associated with a 2.81-fold higher odds of MPM (95% CI, 2.10–3.78; P = 7.5 × 10−13); this association was attenuated but remained statistically significant after excluding SNPs individually associated with MPM (OR = 1.75, 95% CI, 1.32–2.31). Conclusions: Inherited genetic variants spanning 11 gene regions were independently associated with MPM. Nonsignificant SNPs were associated with MPM when aggregated into a PRS, indicating that their cumulative effect may influence MPM risk despite lacking individual statistical significance in our study population. Impact: Our findings provide additional evidence that these loci are associated with melanoma risk and estimate the magnitude of their genetic effect on subsequent (multiple) primary melanoma risk.

Sex differences in melanoma are prominent, with female having a significant survival advantage. However, it is unclear why we see this survival advantage. Here, we investigate the relationship between sex, clinicopathologic variables, and melanoma specific survival in 1753 single primary melanomas from patients in the GEM (Genes, Environment, and Melanoma) study. Using Cox proportional hazard models and formal mediation analysis, the effect of sex on survival is explained largely by differences in the clinicopathologic features of tumors at diagnosis. Specifically, we find evidence that 86.5% of the effect of sex on melanoma survival is mediated by differences in age at diagnosis, Breslow thickness, ulceration, mitoses, and site (hazard ratio [HR] = 1.85, P < .001). This analysis indicates that the female survival advantage in melanoma is not primarily due to a direct effect of sex (HR = 1.19, P = .42) but is largely a result of an indirect effect of sex mediated by clinicopathologic features.

Introduction: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a potentially curative approach for appendiceal cancer (AC) with peritoneal dissemination and is most often employed at tertiary referral centers. Regionalization may provide geographic barriers to care for vulnerable patients. The aim of this study was to examine the effect of travel distance on oncologic outcomes of patients with AC treated with CRS-HIPEC. Methods: The National Cancer Database (NCDB) was reviewed from 2006 through 2020 for patients with AC who underwent CRS-HIPEC. The primary comparison variable was distance (<50 miles vs >= 50 miles from the CRS-HIPEC facility). Demographic and tumor characteristics were analyzed. Primary outcome was overall survival (OS). Secondary outcomes were 30-day and 90-day mortality, readmission, and length of stay (LOS). Results: During the study period, 1703 patients met inclusion criteria, with 1000 patients travelling < 50 miles for CRS-HIPEC (59 %) and 703 travelling >= 50 miles (41 %). Patients who traveled >= 50 miles were more likely to be non-Hispanic White (p < 0.001), have annual income less than $74,062, be treated at an academic center and live in the South-Atlantic region of the United States. There was no significant difference in OS between groups (Figure 1). There were no significant differences in 30-day postoperative survival, 90-day survival, or 30-day readmission. Post-operative LOS was 8.0 versus 9.0 days (p < 0.001). Conclusions: Travel distance >= 50 miles was not significantly associated with decreased OS or increased postoperative mortality, suggesting that regionalization of care does not worsen oncologic outcomes for patients with AC undergoing CRS-HIPEC.

Ideally, detection of somatic mutations in a tumor is accomplished using a patient-matched sample of normal cells as the benchmark. In this way somatic mutations can be distinguished from rare germline mutations. In large retrospective studies, archival tissue collection can pose challenges in obtaining samples of normal DNA. In this article we propose a protocol that improves somatic mutation analysis in the absence of a matched normal sample. The method was motivated by the InterMEL study, a large-scale epidemiologic investigation involving multiomic, multi-institutional genomic profiling of 1000 primary melanoma samples. The key insight for accomplishing improved mutation calling is the fact that germline mutations should produce a variant allele frequency (VAF) of around 50%. While a similar VAF of 50% would also be expected for somatic mutations in pure tumor samples, typically the tumor purity is much less than 50%, resulting in a considerably lower VAF. Making use of a technique that can simultaneously estimate both tumor purity and VAF from tumor-only samples we have developed a method for better distinguishing somatic versus germline variants. Based on 137 melanomas from the InterMEL Study with matched normal tissue to provide a gold standard we show that the conventional pipeline using a panel of (unmatched) normal samples has a false positive rate of 15.6% and a false negative rate of 3.5%. Our new technique improves these error rates to 6.4% and 2.1%, respectively.

Metals contaminants of the environment from mine waste have been implicated as contributing agents in autoimmune disease. The current study compares metals and autoimmunity in two Tribal communities residing in the Black Hills and the Bighorn Mountains geographical regions that are scattered with extant hard rock mines. With documented drinking water contamination in both communities, in vivo levels of more than half of the measured serum and urine metals differed between the two communities and were substantially different from their national median values. Serum autoantibodies associated with systemic autoimmune disease were rare or at low-level, but antibodies to denatured (single-stranded) DNA and thyroid-specific autoantibodies were commonly elevated, especially in women. A three-tier statistical modeling process was carried out to examine individual metals exposure as predictors of autoantibody levels. For the most part only weak positive associations between individual metals and systemic autoantibodies were found, although univariate quantile regression analysis showed positive statistical associations of serum lead and antimony with anti-chromatin and anti-histone autoantibodies. Using age and gender-adjusted multivariable statistical models, metals did not predict anti-thyroglobulin or -thyroid peroxidase significantly and metals were generally negative predictors of the other autoantibodies. Overall these results suggest that elevated levels of environmental metals and metalloids in these communities may result in suppression of autoantibodies associated with systemic autoimmune disease.

PURPOSE Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival. MATERIALS AND METHODS InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of melanoma recurrence or relapse. Methylation classes, distinguished by consensus clustering of 850K methylation data, were evaluated for their clinicopathologic characteristics, 5-year survival status, and differentially methylated gene sets. RESULTS Among 422 InterMEL melanomas, consensus clustering revealed three primary melanoma methylation classes (MethylClasses): a CpG island methylator phenotype (CIMP) class, an intermediate methylation (IM) class, and a low methylation (LM) class. CIMP and IM were associated with higher AJCC stage (both P = .002), Breslow thickness (CIMP P = .002; IM P = .006), and mitotic index (both P < .001) compared with LM, while IM had higher N stage than CIMP ( P = .01) and LM ( P = .007). CIMP and IM had a 2-fold higher likelihood of 5-year death from melanoma than LM (CIMP odds ratio [OR], 2.16 [95% CI, 1.18 to 3.96]; IM OR, 2.00 [95% CI, 1.12 to 3.58]) in a multivariable model adjusted for age, sex, log Breslow thickness, ulceration, mitotic index, and N stage. Despite more extensive CpG island hypermethylation in CIMP, CIMP and IM shared similar patterns of differential methylation and gene set enrichment compared with LM. CONCLUSION Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.

Objective:To evaluate the relation between solar elastosis and tumor mutation burden (TMB) in a large clinically annotated cohort of stage II and III melanoma patients. Methods:Primary cutaneous melanomas from 469 AJCC (8th edition) stage II and III patients with clinical annotation including outcome at 5 years of diagnosis were histopathologically evaluated for solar elastosis. Next-generation sequencing assay MSK-IMPACT™ was employed to determine TMB. Analysis by Fisher's exact test, chi-square, and Kruskal-Wallis were performed, as well as uni- and multivariate logistic regression. Results:Tumors stratified by low and high TMB showed marked and statistically significant differences in presence and extent of associated solar elastosis. Lower risk patient stage (II versus III by AJCC 8th edition) as well as better 5-year melanomaspecific survival (as binary variable of controls-survivors versus cases-dead of disease at 5 years of diagnosis) were associated with severe solar elastosis. On univariate and multivariate logistic regression models, severe solar elastosis predicted significantly decreased odds of dying of melanoma within 5 years of diagnosis (OR 0.60, 95 % CI 0.39-0.89; and OR 0.42, 95 % CI 0.20-0.83, respectively; both p<0.05). Conclusion:The association of solar elastosis to TMB and 5-year melanoma specific survival points to its potential as a biomarker of clinical relevance that can be assessed by routine histopathology.