Improving Automating Quality Control in Radiology: Leveraging Large Language Models to Extract Correlative Findings in Radiology and Operative Reports.

Radiology Imaging plays a pivotal role in medical diagnostics, providing clinicians with insights into patient health and guiding the next steps in treatment. The true value of a radiological image lies in the accuracy of its accompanying report. To ensure the reliability of these reports, they are often cross-referenced with operative findings. The conventional method of manually comparing radiology and operative reports is labor-intensive and demands specialized knowledge. This study explores the potential of a Large Language Model (LLM) to simplify the radiology evaluation process by automatically extracting pertinent details from these reports, focusing especially on the shoulder's primary anatomical structures. A fine-tuned LLM identifies mentions of the supraspinatus tendon, infraspinatus tendon, subscapularis tendon, biceps tendon, and glenoid labrum in lengthy radiology and operative documents. Initial findings emphasize the model's capability to pinpoint relevant data, suggesting a transformative approach to the typical evaluation methods in radiology.

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a "gold-standard" as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance. METHODS: Using flow cytometry and immunohistochemistry, we characterized the immunological features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC (C57BL/6) models using two mouse cell lines, KPC-Luc and MT-5, isolated from C57BL/6 KPC-GEMM (KrasLSL-G12D/+p53-/- and KrasLSL-G12D/+p53LSL-R172H/+, respectively). RESULTS: The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate the KPC-Luc tumors, which have less stroma, although CD4+ and CD8+ T cells were similarly detected in the MT-5 tumors compared with KPC-GEMM in mice. Interestingly, we found that chimeric antigen receptor (CAR) T cells redirected to recognize mesothelin on these tumors that signal via CD3ζ and 41BB (Meso-41BBζ-CAR T cells) infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors. CONCLUSIONS: Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve an indepth study of how to overcome barriers that limit antitumor activity of adoptively transferred T cells.

Pancreatic ACTH Hypersecretion and Pituitary Macroadenoma.

A 55-year-old woman admitted for hypertensive emergency and myocardial infarction reported weight gain, muscle weakness, easy bruising, and recent-onset diabetes in the past 3 to 12 months. Urinary and salivary cortisol and adrenocorticotropin hormone (ACTH) levels were elevated. Pituitary imaging detected a macroadenoma. ACTH and cortisol did not increase after corticotropin-releasing hormone administration. Imaging revealed a large pancreatic mass. Pathology indicated a well-differentiated World Health Organization (WHO) grade 2 distal pancreatic neuroendocrine neoplasm which stained for ACTH by immunohistochemistry. Postoperatively, Cushing manifestations resolved, ACTH and cortisol levels became low, and patient required hydrocortisone replacement for 7 months. During the 3.5 years of follow-up, the pituitary macroadenoma size remained stable and pituitary hormone axes other than ACTH remained normal. This extremely rare case of ectopic ACTH-secreting pancreatic neuroendocrine tumor coexisting with a nonfunctioning pituitary macroadenoma illustrates the importance of dynamic endocrine testing in Cushing syndrome.

CHRONIC ETHANOL USE WORSENS GUT PERMEABILITY AND ALTERS TIGHT JUNCTION EXPRESSION IN A MURINE SEPSIS MODEL.

ABSTRACT: Alcohol use disorder is associated with increased mortality in septic patients. Murine studies demonstrate that ethanol/sepsis is associated with changes in gut integrity. This study examined intestinal permeability after ethanol/sepsis and investigated mechanisms responsible for alterations in barrier function. Mice were randomized to drink either 20% ethanol or water for 12 weeks and then were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability was disproportionately increased in ethanol/septic mice via the pore, leak, and unrestricted pathways. Consistent with increased permeability in the leak pathway, jejunal myosin light chain (MLC) kinase (MLCK) expression and the ratio of phospho-MLC to total MLC were both increased in ethanol/CLP. Gut permeability was altered in MLCK -/- mice in water/CLP; however, permeability was not different between WT and MLCK -/- mice in ethanol/CLP. Similarly, jejunal IL-1ß levels were decreased while systemic IL-6 levels were increased in MLCK -/- mice in water/CLP but no differences were identified in ethanol/CLP. While we have previously shown that mortality is improved in MLCK -/- mice after water/CLP, mortality was significantly worse in MLCK -/- mice after ethanol/CLP. Consistent with an increase in the pore pathway, claudin 4 levels were also selectively decreased in ethanol/CLP WT mice. Furthermore, mRNA expression of jejunal TNF and IFN-γ were both significantly increased in ethanol/CLP. The frequency of CD4 + cells expressing TNF and IL-17A and the frequency of CD8 + cells expressing IFN-γ in Peyer's Patches were also increased in ethanol/CLP. Thus, there is an ethanol-specific worsening of gut barrier function after CLP that impacts all pathways of intestinal permeability, mediated, in part, via changes to the tight junction. Differences in the host response in the setting of chronic alcohol use may play a role in future precision medicine approaches toward the treatment of sepsis.

Analysis of KRAS Mutations in Gastrointestinal Tract Adenocarcinomas Reveals Site-Specific Mutational Signatures.

Adenocarcinomas of the luminal gastrointestinal tract and pancreatobiliary system often show histologic and immunohistochemical overlap, making delineation of the primary site in a metastatic setting difficult. Previous studies have shown that site-specific missense mutations in the oncogene KRAS could be used in conjunction with immunohistochemistry to differentiate metastatic pancreatic adenocarcinoma from primary lung adenocarcinoma. In this study, we assessed the patterning of KRAS mutations across sites in the gastrointestinal and pancreatobiliary system. By integrating sequencing data from 44 separate studies, we assessed 2523 KRAS mutations in 7382 distinct cases of adenocarcinoma, including those from the esophagus, stomach, ampulla, biliary system, pancreas, and colon. We found that gastrointestinal adenocarcinomas demonstrate a marked regional variation in the frequency of KRAS mutations, with the most frequent KRAS mutation observed in pancreatic adenocarcinoma (up to 94.9%), whereas the frequency is much lower in adenocarcinomas from the esophagus and stomach (5.4% and 8.7%, respectively). Intriguingly, the pattern of missense mutations showed site specificity as well, with c.35G>T (p.G12V) and c.34G>C (p.G12R) mutations enriched in pancreatic primaries and codon 13 and non-codon 12/13 alterations enriched in gastric primaries (specificity of 98.9% and 93.2%, respectively, with a negative predictive value of 93.6% and 92.93% against pancreatic adenocarcinoma). Furthermore, we found that esophageal and gastric adenocarcinomas show an enrichment in transitional mutations, whereas other sites showed an equal distribution. Importantly, the examination of a validation cohort from our own institution revealed similar trends. These findings indicate that, in addition to providing therapeutic and diagnostic information, KRAS mutational analysis may also prove useful in delineating the site of origin in gastrointestinal adenocarcinomas that share morphologic and immunohistochemical overlap. Moreover, transitional mutations are more frequent in esophageal and gastric adenocarcinomas, reiterating the role of chronic inflammation in the pathogenesis of foregut adenocarcinomas.

Hepatocellular Carcinoma With Atypical Imaging Features: Review of the Morphologic Hepatocellular Carcinoma Subtypes With Radiology-Pathology Correlation.

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer death in the United States with the incidence rate more than doubling in 20 years. HCC is unique since a noninvasive diagnosis can be achieved with imaging alone when specific clinical criteria and imaging characteristics are met, obviating the need for tissue sampling. However, HCC is a highly heterogeneous neoplasm. Atypical HCC subtypes vary significantly in their morphology, which can be attributed to specific histologic and molecular features, and can cause deviations from the classic imaging characteristics. The different morphologic subtypes of HCC frequently present a diagnostic challenge for radiologists and pathologists since their imaging and pathologic features can overlap with those of non-HCC malignancies. Identifying an atypical subtype can have important clinical implications. Liver transplant, albeit a scarce and limited resource, is the optimal treatment for conventional HCC, potentially curing both the tumor and the underlying pre-malignant condition. Some HCC subtypes as well as mimickers are associated with unacceptably high recurrence and poor outcome after transplant, and there remains limited data on the role and prognosis of liver transplantation for treatment of rare HCC subtypes. Other subtypes tend to recur later than classic HCC, potentially requiring a different follow-up scheme. This review will discuss the appearance of different HCC subtypes in relation to their histopathologic features. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.

Metastases can occur in cirrhotic livers with patent portal veins.

OBJECTIVES: Metastases are common in non-cirrhotic livers but are considered unlikely in the setting of cirrhosis. However, the degree of fibrosis in cirrhosis may vary; thus metastases may still access the liver vasculature and present as a mass in cirrhotic livers. This possibility may affect pathologists' diagnostic algorithms when faced with a liver mass biopsy. METHODS: We hypothesized that metastases can occur in cirrhotic livers if fibrous remodeling is not severe or abnormal veno-arterial shunting exists to override an obstructed portal system. We searched departmental archives for cirrhotic livers with masses, categorizing fibrosis by Laennec staging: 4A = mild cirrhosis, 4B = moderate, 4 C = severe. RESULTS: Of 1453 cirrhotic livers with masses, 1429 were primary tumors and 24 were metastases (1.7 %). Of livers with metastases, most had 4A or 4B cirrhosis by Laennec staging (n = 17; 71 %). Eleven patients were evaluated by ultrasound Doppler; 2 of 5 with Laennec 4 C had reversal of portal vein flow, but all 4A & 4B patients had patent portal veins without reversed flow. Echocardiograms (13 patients) showed no ventricular or atrial septal defects or arteriovenous shunts. CONCLUSIONS: Metastases are uncommon in cirrhotic livers, accounting for 1.7 % of masses. Most involved livers had mild or moderate cirrhosis (Laennec 4A/4B) and patent portal veins; however, as some Laennec 4 C cases also contained metastases, obstructed portal access may not be enough to deter metastatic access.

Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer.

Gastric cancer remains an unmet clinical problem in urgent need of newer and effective treatments. Here we show that the nuclear export protein, Exportin 1 (XPO1, chromosome region maintenance 1 or CRM1), is a promising molecular target in gastric cancer. We demonstrate significant overexpression of XPO1 in a cohort of histologically diverse gastric cancer patients with primary and metastatic disease. XPO1 RNA interference suppressed gastric cancer cell growth. Anti-tumor activity was observed with specific inhibitor of nuclear export (SINE) compounds (selinexor/XPOVIO), second-generation compound KPT-8602/eltanexor, KPT-185 and +ve control Leptomycin B in three distinct gastric cancer cell lines. SINE compounds inhibited gastric cancer cell proliferation, disrupted spheroid formation, induced apoptosis and halted cell cycle progression at the G1/S phase. Anti-tumor activity was concurrent with nuclear retention of tumor suppressor proteins and inhibition of colony formation. In combination studies, SINE compounds enhanced the efficacy of nab-paclitaxel in vitro and in vivo. More significantly, using non-coding RNA sequencing studies, we demonstrate for the first time that SINE compounds can alter the expression of non-coding RNAs (microRNAs and piwiRNAs). SINE treatment caused statistically significant downregulation of oncogenic miR-33b-3p in two distinct cell lines. These studies demonstrate the therapeutic significance of XPO1 in gastric cancer that warrants further clinical investigation.

Maspin differential expression patterns as a potential marker for targeted screening of esophageal adenocarcinoma/gastroesophageal junction adenocarcinoma.

AIM: Barrett's esophagus (BE) is a predisposing factor of esophageal adenocarcinoma/gastroesophageal junction adenocarcinoma (ECA/GEJ Aca). BE patients are stratified and subsequently monitored according to the risk of malignant progression by the combination of endoscopy and biopsy. This study is to evaluate the maspin expression patterns as early diagnostic markers of malignancy in BE patients. MATERIALS AND METHODS: Immunohistochemistry (IHC) staining was performed on 62 archival core biopsies from 35 patients, including BE without dysplasia (intestinal metaplasia, IM), BE with low grade dysplasia, BE with high grade dysplasia, carcinoma in situ, and well to poorly differentiated ECA/GEJ Aca (PD-ECA/GEJ Aca). The intensity and the subcellular distribution of immunoreactivity were evaluated microscopically. Statistical analysis was performed using the χ2 and Fisher exact tests. RESULTS: The level of epithelial-specific tumor suppressor maspin protein inversely correlated with the progression from IM to PD-ECA/GEJ Aca. Lesions of each pathological grade could be divided into subtypes that exhibited distinct maspin subcellular distribution patterns, including nuclear only (Nuc), combined nuclear and cytoplasmic (Nuc+Cyt), cytoplasmic only (Cyt) and overall negligible (Neg). The Cyt subtype, which was minor in both IM and dysplasia (approximately 10%), was predominant in ECA/GEJ Aca as early as well-differentiated lesions (more than 50%: p = 0.0092). In comparison, nuclear staining of the tumor suppressor TP53 was heterogeneous in dysplasia, and did not correlate with the differentiation grades of ECA/GEJ Aca. CONCLUSION: The Cyt subtype of maspin expression pattern in core biopsies of BE patients may serve as a molecular marker for early diagnosis of ECA/GEJ Aca.

The Impact of Androgen Receptor Expression on Endometrial Carcinoma Recurrence and Survival.

Endometrial carcinomas (ECs) are the most common gynecologic cancers in the western world. The impact of androgen receptor (AR) on clinicopathologic parameters of EC is not well studied. The aim of our study is to assess the role of AR expression in ECs and correlate its expression with estrogen (ER) and progesterone (PR). A retrospective review of 261 EC was conducted. H&E slides were reviewed and clinicopathologic parameters were analyzed. Immunohistochemical stains for AR, ER, and PR were performed on a tissue microarray. The hormonal expression was evaluated and the data were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. Patients' age ranged from 31 to 91 (median=65 y). Type I EC included 202 endometrioid and 7 mucinous carcinoma, whereas type II included 34 serous, 16 carcinosarcoma, and 2 clear cell carcinoma. Although not significant, AR expression showed more frequent association with type I EC, early tumor stage (I-II), and low FIGO grade (1-2) EC. AR expression significantly correlated with absence of lymphovascular invasion (P=0.041) and decreased LN involvement (P=0.048). Patients with AR expression showed increased disease-free survival (208 vs. 165 mo, P=0.008) and late disease recurrence (P=0.009). AR expression had a positive significant correlation with PR (P<0.001) and ER (P=0.037) expression. AR might play a role as a prognostic marker for ECs.

Post-exposure therapeutic efficacy of COX-2 inhibition against Burkholderia pseudomallei.

Burkholderia pseudomallei is a Gram-negative, facultative intracellular bacillus and the etiologic agent of melioidosis, a severe disease in Southeast Asia and Northern Australia. Like other multidrug-resistant pathogens, the inherent antibiotic resistance of B. pseudomallei impedes treatment and highlights the need for alternative therapeutic strategies that can circumvent antimicrobial resistance mechanisms. In this work, we demonstrate that host prostaglandin E2 (PGE2) production plays a regulatory role in the pathogenesis of B. pseudomallei. PGE2 promotes B. pseudomallei intracellular survival within macrophages and bacterial virulence in a mouse model of pneumonic melioidosis. PGE2-mediated immunosuppression of macrophage bactericidal effector functions is associated with increased arginase 2 (Arg2) expression and decreased nitric oxide (NO) production. Treatment with a commercially-available COX-2 inhibitor suppresses the growth of B. pseudomallei in macrophages and affords significant protection against rapidly lethal pneumonic melioidosis when administered post-exposure to B. pseudomallei-infected mice. COX-2 inhibition may represent a novel immunotherapeutic strategy to control infection with B. pseudomallei and other intracellular pathogens.

The A subunit of Escherichia coli heat-labile enterotoxin functions as a mucosal adjuvant and promotes IgG2a, IgA, and Th17 responses to vaccine antigens.

Enterotoxigenic Escherichia coli (ETEC) produces both heat-labile (LT) and heat-stable (ST) enterotoxins and is a major cause of diarrhea in infants in developing countries and in travelers to those regions. In addition to inducing fluid secretion, LT is a powerful mucosal adjuvant capable of promoting immune responses to coadministered antigens. In this study, we examined purified A subunit to further understand the toxicity and adjuvanticity of LT. Purified A subunit was enzymatically active but sensitive to proteolytic degradation and unable to bind gangliosides, and even in the presence of admixed B subunit, it displayed low cyclic AMP (cAMP) induction and no enterotoxicity. Thus, the AB5 structure plays a key role in protecting the A subunit from proteolytic degradation and in delivering the enzymatic signals required for secretion. In contrast, the A subunit alone was capable of activating dendritic cells and enhanced immune responses to multiple antigens following intranasal immunization; therefore, unlike toxicity, LT adjuvanticity is not dependent on the AB5 holotoxin structure or the presence of the B subunit. However, immune responses were maximal when signals were received from both subunits either in an AB5 structure or with A and B admixed. Furthermore, the quality of the immune response (i.e., IgG1/IgG2 balance and mucosal IgA and IL-17 secretion) was determined by the presence of an A subunit, revealing for the first time induction of Th17 responses with the A subunit alone. These results have important implications for understanding ETEC pathogenesis, unraveling immunologic responses induced by LT-based adjuvants, and developing new mucosal vaccines.