Association Between Portal Vein Thrombosis and Pouchitis in Patients with Ulcerative Colitis.

BACKGROUND: Pouchitis is the most common long-term complication in patients requiring colectomy ileal pouch-anal anastomosis with medically refractory ulcerative colitis or colitis-associated neoplasia. A previous small case series suggests associated between portal vein thrombosis (PVT) and ischemic pouchitis. AIM: To evaluate the association between PVT and other demographic and clinical factors and pouchitis. METHODS: We used Explorys Inc., a population-based database, to search medical records between 1999 and 2020 with SNOMED-CT code criteria for "construction of pouch" and "ileal pouchitis." Patients with pouchitis were compared to those with previous pouch construction without pouchitis. Factors associated with pouchitis identified with univariable analysis were introduced into a multivariable model. A post hoc analysis further stratified demographical findings of the association between PVT and pouchitis. RESULTS: We identified 7900 patients with ileal pouchitis (7.5%) and 97,510 with pouch construction without pouchitis. In multivariate binary logistic regression, adjusted odds ratio (aOR) for the risk of pouchitis in patients with PVT was 10.78 (95% confidence interval [CI] 7.04-16.49, P < 0.001). Other significant factors associated with pouchitis included male gender (aOR 1.11, 95% CI 1.02-1.21, P = 0.018), deep vein thrombosis (aOR 1.46, 95% CI 1.23-1.72, P < 0.001), and the use of non-steroidal anti-inflammatory drugs (aOR 1.37, 95% CI 1.28-1.45, P < 0.001). Smoking was a protective factor (aOR 0.30, 95% CI 0.33-0.36, P < 0.001). Further sub-analysis showed a higher prevalence of younger patients with PVT and pouchitis. CONCLUSIONS: We report PVT as an independent risk factor associated with pouchitis. Our findings support that PVT is a potentially manageable perioperative complication, and intervention may reduce the risk of pouchitis.

High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer.

PURPOSE: The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts. METHODS: HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort. RESULTS: Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ2 = 12.07; P = 0.002) and advanced nuclear grade (χ2 = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes. CONCLUSIONS: Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.

Advances in the computational and molecular understanding of the prostate cancer cell nucleus.

Nuclear alterations are a hallmark of many types of cancers, including prostate cancer (PCa). Recent evidence shows that subvisual changes, ones that may not be visually perceptible to a pathologist, to the nucleus and its ultrastructural components can precede visual histopathological recognition of cancer. Alterations to nuclear features, such as nuclear size and shape, texture, and spatial architecture, reflect the complex molecular-level changes that occur during oncogenesis. Quantitative nuclear morphometry, a field that uses computational approaches to identify and quantify malignancy-induced nuclear changes, can enable a detailed and objective analysis of the PCa cell nucleus. Recent advances in machine learning-based approaches can now automatically mine data related to these changes to aid in the diagnosis, decision making, and prediction of PCa prognoses. In this review, we use PCa as a case study to connect the molecular-level mechanisms that underlie these nuclear changes to the machine learning computational approaches, bridging the gap between the clinical and computational understanding of PCa. First, we will discuss recent developments to our understanding of the molecular events that drive nuclear alterations in the context of PCa: the role of the nuclear matrix and lamina in size and shape changes, the role of 3-dimensional chromatin organization and epigenetic modifications in textural changes, and the role of the tumor microenvironment in altering nuclear spatial topology. We will then discuss the advances in the applications of machine learning algorithms to automatically segment nuclei in prostate histopathological images, extract nuclear features to aid in diagnostic decision making, and predict potential outcomes, such as biochemical recurrence and survival. Finally, we will discuss the challenges and opportunities associated with translation of the quantitative nuclear morphometry methodology into the clinical space. Ultimately, accurate identification and quantification of nuclear alterations can contribute to the field of nucleomics and has applications for computationally driven precision oncologic patient care.

PBOV1 as a potential biomarker for more advanced prostate cancer based on protein and digital histomorphometric analysis.

BACKGROUND: There are few tissue-based biomarkers that can accurately predict prostate cancer (PCa) progression and aggressiveness. We sought to evaluate the clinical utility of prostate and breast overexpressed 1 (PBOV1) as a potential PCa biomarker. METHODS: Patient tumor samples were designated by Grade Groups using the 2014 Gleason grading system. Primary radical prostatectomy tumors were obtained from 48 patients and evaluated for PBOV1 levels using Western blot analysis in matched cancer and benign cancer-adjacent regions. Immunohistochemical evaluation of PBOV1 was subsequently performed in 80 cancer and 80 benign cancer-adjacent patient samples across two tissue microarrays (TMAs) to verify protein levels in epithelial tissue and to assess correlation between PBOV1 proteins and nuclear architectural changes in PCa cells. Digital histomorphometric analysis was used to track 22 parameters that characterized nuclear changes in PBOV1-stained cells. Using a training and test set for validation, multivariate logistic regression (MLR) models were used to identify significant nuclear parameters that distinguish Grade Group 3 and above PCa from Grade Group 1 and 2 PCa regions. RESULTS: PBOV1 protein levels were increased in tumors from Grade Group 3 and above (GS 4 + 3 and ≥ 8) regions versus Grade Groups 1 and 2 (GS 3 + 3 and 3 + 4) regions (P = 0.005) as assessed by densitometry of immunoblots. Additionally, by immunoblotting, PBOV1 protein levels differed significantly between Grade Group 2 (GS 3 + 4) and Grade Group 3 (GS 4 + 3) PCa samples (P = 0.028). In the immunohistochemical analysis, measures of PBOV1 staining intensity strongly correlated with nuclear alterations in cancer cells. An MLR model retaining eight parameters describing PBOV1 staining intensity and nuclear architecture discriminated Grade Group 3 and above PCa from Grade Group 1 and 2 PCa and benign cancer-adjacent regions with a ROC-AUC of 0.90 and 0.80, respectively, in training and test sets. CONCLUSIONS: Our study demonstrates that the PBOV1 protein could be used to discriminate Grade Group 3 and above PCa. Additionally, the PBOV1 protein could be involved in modulating changes to the nuclear architecture of PCa cells. Confirmatory studies are warranted in an independent population for further validation.

Comparison of the outcomes of endoscopic ultrasound based on community hospital versus tertiary academic center settings.

OBJECTIVE: Endoscopic ultrasound (EUS) is an established tool in the management of gastrointestinal diseases. The majority of EUS procedures are performed in tertiary care hospitals but the technology has also disseminated to community hospitals. The data from community hospitals are limited and there are no published studies comparing EUS-fine needle aspiration (FNA) outcomes in community versus tertiary settings. Our objective is to compare EUS procedures performed in these two separate settings. METHODS: EUS procedures performed for pancreatobiliary indications in an academic tertiary care hospital and a community hospital were retrospectively reviewed and compared. The patient demographics, procedure time, procedure indications, FNA performed, pass counts, needle size, rapid onsite evaluation (ROSE) and final cytological diagnosis were compared between the two centers. Cytological diagnosis was categorized as satisfactory and unsatisfactory samples. RESULTS: There was no significant difference in patient age, gender, indications, procedure time, FNA performed, needle size, or pass counts between the tertiary hospital (n = 361) and community hospital (n = 119). ROSE was a significant determinant factor for adequacy of sample. There was a positive linear relationship between adequacy of the sample and number of pass counts. After performing a logistic regression and adjusting for target site, the overall odds of having an unsatisfactory specimen were not significantly different at the two centers (OR 0.51, CI 0.23-1.17, p = 0.11). Percentages of unsatisfactory samples were not significantly different at the two centers for solid lesions (7.4 vs. 3.1%, p = 0.33), cysts (33.3 vs. 23.8%, p = 0.31,) or lymph nodes (25.0 vs. 0%, p = 0.063). CONCLUSION: Cytological yield of EUS-FNA in a community hospital is similar to that of a tertiary hospital. Community hospitals can provide EUS services with reasonable success.

Mutual information for detecting multi-class biomarkers when integrating multiple bulk or single-cell transcriptomic studies.

Motivation: Biomarker detection plays a pivotal role in biomedical research. Integrating omics studies from multiple cohorts can enhance statistical power, accuracy and robustness of the detection results. However, existing methods for horizontally combining omics studies are mostly designed for two-class scenarios (e.g., cases versus controls) and are not directly applicable for studies with multi-class design (e.g., samples from multiple disease subtypes, treatments, tissues, or cell types). Results: We propose a statistical framework, namely Mutual Information Concordance Analysis (MICA), to detect biomarkers with concordant multi-class expression pattern across multiple omics studies from an information theoretic perspective. Our approach first detects biomarkers with concordant multi-class patterns across partial or all of the omics studies using a global test by mutual information. A post hoc analysis is then performed for each detected biomarkers and identify studies with concordant pattern. Extensive simulations demonstrate improved accuracy and successful false discovery rate control of MICA compared to an existing MCC method. The method is then applied to two practical scenarios: four tissues of mouse metabolism-related transcriptomic studies, and three sources of estrogen treatment expression profiles. Detected biomarkers by MICA show intriguing biological insights and functional annotations. Additionally, we implemented MICA for single-cell RNA-Seq data for tumor progression biomarkers, highlighting critical roles of ribosomal function in the tumor microenvironment of triple-negative breast cancer and underscoring the potential of MICA for detecting novel therapeutic targets. Availability: https://github.com/jianzou75/MICA.

Use of Natural Language Understanding to Facilitate Surgical De-Escalation of Axillary Staging in Patients With Breast Cancer.

PURPOSE: Natural language understanding (NLU) may be particularly well equipped for enhanced data capture from the electronic health record given its examination of both content-driven and context-driven extraction. METHODS: We developed and applied a NLU model to examine rates of pathological node positivity (pN+) and rates of lymphedema to determine whether omission of routine axillary staging could be extended to younger patients with estrogen receptor-positive (ER+)/cN0 disease. RESULTS: We found that rates of pN+ and arm lymphedema were similar between patients age 55-69 years and ≥70 years, with rates of lymphedema exceeding rates of pN+ for clinical stage T1c and smaller disease. CONCLUSION: Data from our NLU model suggest that omission of sentinel lymph node biopsy might be extended beyond Choosing Wisely recommendations, limited to those older than 70 years and to all postmenopausal women with early-stage ER+/cN0 disease. These data support the recently reported SOUND trial results and provide additional granularity to facilitate surgical de-escalation.

Use of natural language understanding to facilitate surgical de-escalation of axillary staging in patients with breast cancer.

Natural language understanding (NLU) may be particularly well-equipped for enhanced data capture from the electronic health record (EHR) given its examination of both content- and context-driven extraction. We developed and applied a NLU model to examine rates of pathological node positivity (pN+) and rates of lymphedema to determine if omission of routine axillary staging could be extended to younger patients with ER+/cN0 disease. We found that rates of pN+ and arm lymphedema were similar between patients 55-69yo and ≥70yo, with rates of lymphedema exceeding rates of pN+ for clinical stage T1c and smaller disease. Data from our NLU model suggest that omission of SLNB might be extended beyond Choosing Wisely recommendations, limited to those over 70 years old, to all postmenopausal women with early-stage ER+/cN0 disease. These data support the recently-reported SOUND trial results and provide additional granularity to facilitate surgical de-escalation.

Case report: abemaciclib-induced syndrome of inappropriate antidiuretic hormone (SIADH) without underlying kidney injury in a patient with early-stage estrogen receptor (ER)+ breast cancer.

The CDK4/6 inhibitor, abemaciclib, is now the standard of care adjuvant therapy for patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) tumors at high risk of recurrence. Real-world usage uncovers emerging side effects that may have been previously unreported in clinical trials. Here, we present the clinical course of a patient who developed a syndrome of inappropriate antidiuretic hormone (SIADH) without underlying kidney injury due to abemaciclib use.

The Great Immune Escape: Understanding the Divergent Immune Response in Breast Cancer Subtypes.

Breast cancer, the most common type of cancer affecting women, encompasses a collection of histologic (mainly ductal and lobular) and molecular subtypes exhibiting diverse clinical presentation, disease trajectories, treatment options, and outcomes. Immunotherapy has revolutionized treatment for some solid tumors but has shown limited promise for breast cancers. In this review, we summarize recent advances in our understanding of the complex interactions between tumor and immune cells in subtypes of breast cancer at the cellular and microenvironmental levels. We aim to provide a perspective on opportunities for future immunotherapy agents tailored to specific features of each subtype of breast cancer. SIGNIFICANCE: Although there are currently over 200 ongoing clinical trials testing immunotherapeutics, such as immune-checkpoint blockade agents, these are largely restricted to the triple-negative and HER2+ subtypes and primarily focus on T cells. With the rapid expansion of new in vitro, in vivo, and clinical data, it is critical to identify and highlight the challenges and opportunities unique for each breast cancer subtype to drive the next generation of treatments that harness the immune system.

Strategies for Achieving Gender Equity and Work-Life Integration in Physician-Scientist Training.

Substantial gender inequities persist across academic medicine. These issues are not new: Recent evidence still points to a chilly climate for women in academic medicine, including those in physician-scientist training. The discussion for how to address gender equity and issues of work-life integration typically centers around faculty and rarely includes trainees. The authors delineate specific strategies to address gender inequity in physician-scientist training by identifying key stakeholders for implementation and proposing areas to integrate these strategies with current training timelines. Strategies discussed include multiple-role mentoring, allyship training for trainees and faculty, early implementation of professional development sessions, incorporation of childcare and family-friendly policies, and additional policies for funding bodies to prioritize gender equity practices. The goal of this article is to equip trainees and the academic community with proactive strategies to create a more equitable environment for future generations of trainees in academic medicine.

Predoctoral MD-PhD grants as indicators of future NIH funding success.

MD-PhD trainees constitute an important source of physician-scientists. Persistence on this challenging path is facilitated by success in garnering independent (R grant) support from the NIH. Published research tracks academic appointments and global R01 success for MD-PhD trainees but has not included information on future funding success of individual MD-PhD predoctoral grant holders. Here, we used data from the NIH RePORTER database to identify and track the funding trajectory of physician-scientists who received predoctoral grant support through the F30 mechanism, which is specific for dual-degree candidates. Male and female F30 awardees did not differ in their success in garnering K (postdoctoral training) grants, but, among F30 grant awardees, men were 2.6 times more likely than women to receive R funding. These results underscore the need for analysis of factors that contribute to the disproportionate loss of NIH-supported female physician-scientists between the predoctoral F30 and the independent R grant-supported stages.

Clinicopathological Features and Outcomes Comparing Patients With Invasive Ductal and Lobular Breast Cancer.

BACKGROUND: There is increasing interest in better understanding the biology and clinical presentation of invasive lobular cancer (ILC), which is the most common special histological subtype of breast cancer. Limited large contemporary data sets are available allowing comparison of clinicopathologic features between ILC and invasive ductal cancer (IDC). METHODS: The Great Lakes Breast Cancer Consortium was formed to compare clinical behavior of ILC (n = 3617) and IDC (n = 30 045) from 33 662 patients treated between 1990 and 2017 at 3 large clinical centers. We used Kaplan-Meier analysis, Cox proportional hazards modeling, and propensity score matching to evaluate treatment differences and outcomes. All statistical testing used 2-sided P values. RESULTS: Compared with IDC, patients with ILC were more frequently diagnosed at later stages and with more lymph node involvement (corrected P < .001). Estrogen receptor-positive ILCs were of lower grade (grade 1 and 2: 90% in ILC vs 72% in IDC) but larger in size (T3 and 4: 14.3% in ILC vs 3.4% in IDC) (corrected P < .001), and since 1990, the mean ILC size detected at diagnosis increased yearly. Patients with estrogen receptor (ER)-positive ILC underwent statistically significantly more mastectomies compared with ER-positive IDC (57% vs 46%). Using Kaplan-Meier analysis, patients with ER-positive ILC had statistically significantly worse disease-free survival and overall survival than ER-positive IDC although 6 times more IDCs were classified as high risk by OncotypeDx Breast Recurrence Score assay. CONCLUSIONS: This large, retrospective, collaborative analysis with 3 clinical centers identified meaningful differences in clinicopathological features between ILC and IDC, providing further evidence that these are 2 different entities requiring different clinical management.

MALT1 Is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-Low, Triple-Negative Breast Cancer.

MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein-coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC). In concert, MALT1 was activated in these cells and contributed to the dramatic EMT phenotypic changes through regulation of master EMT transcription factors including Snail and ZEB1. Importantly, blocking MALT1 signaling, through either siRNA-mediated depletion of MALT1 protein or pharmacologic inhibition of its activity, was effective at partially reversing the molecular and phenotypic indicators of EMT. Treatment of mice with mepazine, a pharmacologic MALT1 inhibitor, reduced growth of PAR1+, MDA-MB-231 xenografts and had an even more dramatic effect in reducing the burden of metastatic disease. These findings highlight MALT1 as an attractive therapeutic target for claudin-low TNBCs harboring overexpression of one or more selected GPCRs. IMPLICATIONS: This study nominates a GPCR/MALT1 signaling axis as a pathway that can be pharmaceutically targeted to abrogate EMT and metastatic progression in TNBC, an aggressive form of breast cancer that currently lacks targeted therapies.