Rotating shift and BMI increase among healthcare workers in a military hospital: pre- and post-pandemic analysis in Taiwan.

Background: The increasing prevalence of high body mass index (BMI) emphasizes the need for action. Understanding of BMI factors among military hospital healthcare workers remains limited. This study aims to address this gap by analyzing BMI risk factors and changes pre- and post-coronavirus 2019 pandemic among military hospital healthcare workers in central Taiwan from 2019 to 2021. Methods: Conducted at a military hospital in central Taiwan, this study analyzed anonymized health examination data from 2019 to 2021 for 483 healthcare workers. We performed generalized estimating equations to investigate trends in BMI and its association with various factors, including age, sex, job titles, military status, job tenure, work shifts, and lifestyle habits. Results: The risk of increased BMI was higher in 2021 compared to 2019 (risk ratio [RR]: 1.008, 95% confidence interval [CI]: 1.001-1.014). Individuals on rotating shifts had a higher risk of increased BMI compared to day shift workers (RR: 1.021; 95% CI: 1.008-1.035) and higher odds of obesity (odds ratio: 1.546; 95% CI: 1.099-2.175). Among obese individuals, BMI in soldiers was approximately 4.9% lower than in non-soldiers (RR: 0.951; 95% CI: 0.915-0.988). Conclusions: This study identified a significant post-pandemic increase in BMI among healthcare workers in a Taiwanese military hospital, with rotating shifts being a key risk factor for both increased BMI and obesity. Work-related factors influenced BMI changes among obese individuals, while non-work-related factors were significant for non-obese individuals. These findings highlight the broader effects of the pandemic and the specific impact of work-related factors on obese healthcare workers.

Morphological findings in different subtypes of hepatic amyloid.

The classic findings have been well described for light-chain amyloid involving the liver. In addition to light chain, however, many additional proteins are now known to be amyloidogenic and can involve the liver. A total of 58 surgical pathology specimens with amyloid deposits were analyzed for patterns of amyloid deposition, including amyloid from light chain lambda (N = 17), light chain kappa (N = 15), transthyretin (N = 15), serum amyloid A (N = 4), apolipoprotein A1 (N = 4), fibrinogen alpha (N = 2), LECT2 (N = 1). Amyloid deposits predominately targeted the liver vasculature, including the walls of the hepatic arteries, portal veins, and sinusoids. While there was overlap, light chain amyloid predominately involved the sinusoids, while transthyretin amyloid predominately targeted the hepatic arteries, especially the larger ones in the hilum and larger portal tracts. Serum amyloid A formed nodular deposits that started in the portal vasculature but then extended into the portal tract stroma, leading to large, bulbous, portal-based amyloid deposits. Apolipoprotein A amyloid also formed large portal-based nodules. Fibrinogen was mild and subtle on H&E and predominately affected portal veins. Amyloid deposits in hilar nerves were prominent with amyloid light chain, transthyretin, and apolipoprotein A1. In conclusion, the histology of hepatic amyloid is diverse and shows several distinct clusters of findings that can aide in recognition in surgical pathology specimens.

CRP Versus SAA for Identification of Inflammatory Hepatic Adenomas.

Subtyping hepatic adenomas is important for patient management due to differing complication risks. Immunohistochemical staining with C-reactive protein (CRP) and serum amyloid-A (SAA) is widely accepted as a surrogate for molecular classification to identify inflammatory hepatocellular adenomas. Limited data, however, has been published on how these 2 stains compare for sensitivity. We conducted a large, multicenter, retrospective study to examine the sensitivity and staining characteristics of CRP and SAA in inflammatory hepatic adenomas, with focal nodular hyperplasia (FNHs) as a control group. Inflammatory adenomas were identified in 133 patients (average age 37 years, 109 were female). In all, 69.9% of cases were resection specimens and 90.2% of all cases showed positive staining for both CRP and SAA; 10 (7.5%) were positive for CRP only and 3 (2.3%) were positive for SAA only. CRP was more sensitive than SAA (97.74% vs. 92.48%, P -value = 0.0961) and showed more extensive and intense staining, with a significantly higher modified H-score ( P <0.001). Focal nodular hyperplasia can also show positive CRP and SAA staining but with a lower modified H-score ( P <0.0001). Based on beta-catenin and glutamine synthetase staining, 26 of inflammatory adenomas also had beta-catenin activation (19.5%). All 3 cases with positive SAA and negative CRP staining were beta-catenin activated. In contrast, the proportion of cases that were CRP positive and SAA negative was similar regardless of beta-catenin activation. The data affirms the strategy of using both CRP and SAA immunostains for hepatic adenoma subtyping and raises the awareness of the highly variable nature of SAA staining characteristics.

Berberine oleanolic acid complex salt grafted hyaluronic acid/silk fibroin (BOA-g-HA/SF) composite scaffold promotes cartilage tissue regeneration under IL-1ß caused stress.

Since inflammatory cytokines cause stress to chondrocytes and the failure of cartilage defects repair with cartilage tissue engineering, it is necessary to develop a scaffold to maintain cartilage regeneration under inflammatory factors caused stress. Following a berberine-oleanolic acid (OA) complex salt (BOA) was grafted to hyaluronic acid (HA) to obtain water soluble BOA-g-HA, it mixed with silk fibroin (SF) to prepared 4 solutions, which contained 30 mg/mL SF and 0.75, 1.5, 2.25, and 3.0 mg/mL BOA-g-HA respectively. They were lyophilized to fabricate BOA-g-HA/SF-1, BOA-g-HA/SF-2, BOA-g-HA/SF-3, and BOA-g-HA/SF-4 composite scaffolds respectively. All prepared scaffolds displayed porous network structure and exhibited promising mechanical properties for tissue engineering applications. Among them, the BOA-g-HA/SF-3 composite scaffold showed the highest influence on maintaining chondrocytic phenotype of chondrocytes under IL-1ß induced stress. Following SF, HA/SF, and BOA-g-HA/SF-3 composite scaffolds with seeded chondrocytes were treated with IL-1ß induction for 1 week, specimens were incubated with cell culture medium for 3 week or were subcutaneously implanted into nude mice for 4 weeks. The results demonstrated that the BOA-g-HA/SF-3 composite scaffold promotes cartilage tissue regeneration in vitro and in vivo under IL-1ß caused stress, suggesting that it can be potential applied for repairing cartilage defects in osteoarthritis patients.

Time from immune checkpoint inhibitor to sotorasib use correlates with risk of hepatotoxicity in non-small cell lung cancer: A brief report.

INTRODUCTION: We evaluated the risk factors and outcomes for patients who experienced hepatotoxicity after use of sotorasib in KRAS G12C mutated NSCLC. METHODS: Retrospective review of medical records of patients with KRAS G12C mutated NSCLC who received sotorasib between May 28th, 2021, and December 31st, 2021 across all Mayo Clinic sites, with follow up until December 31st, 2022. RESULTS: Thirty-one patients received sotorasib as standard of care treatment. Grade 3 or higher hepatoxicity was seen in 32% (10/31) patients presenting at a median of 51 days (range, 27-123) of sotorasib initiation. Baseline demographics were comparable between patients with and without ≥grade 3 hepatotoxicity, except for presence of CNS metastases and time from prior immune checkpoint inhibitor (ICI) treatment. Improvement in liver tests was observed in all patients after stopping sotorasib, and it was restarted at a lower dose in 8 patients. Despite dose reduction, hepatotoxicity requiring sotorasib discontinuation occurred in 2 patients. Twenty-eight of 31 patients had received prior ICI. Median time from prior ICI therapy was 69 days (range, 4-542). Rates of ≥grade 3 hepatoxicity were 75% (3/4), 64% (7/11) and 0% (0/13) for patients who received ICI within 30 days, 31-90 days and >90 days. None of the 3 patients without prior ICI exposure developed hepatoxicity. The median PFS and OS were 3.9 months and 9.9 months respectively. CONCLUSION: One-third of patients developed grade 3 or higher sotorasib induced hepatotoxicity. Risk of hepatotoxicity was higher in patients who received sotorasib within 90 days of ICI treatment.

Hepatic Angiosarcomas With Sinusoidal Growth Patterns.

Hepatic angiosarcomas are aggressive malignant tumors of the liver with variable morphology. One of the rare morphologies is that of the sinusoidal growth pattern, which is challenging to diagnose because of its subtle imaging and morphologic findings. This retrospective study characterizes the clinical, histologic, and immunohistochemical features of sinusoidal hepatic angiosarcomas. Thirteen cases were included in the study, comprising 12 (92.3%) needle core biopsies and 1 wedge biopsy; one of the needle biopsies also had a subsequent resection specimen available for review. Multiple biopsies were needed to make the diagnosis in 4 cases. At least moderate sinusoidal dilatation was seen in 53.8% of cases. Increased cellularity within the sinusoids was seen at both low-power and high-power magnification (69.2% and 84.6%, respectively). Cytologic atypia ranged from mild to marked. Multinucleated tumor cells were present in most cases (10/13 cases) but were often sparse. Mitotic activity was identified in 5/13 cases. ERG immunostains were more reliable than CD31 and CD34 in identifying the tumor cells. Ki-67 proliferative index ranged from 5% to 30%. p53 immunostains were available in 9 cases and c-MYC in 7 cases; they were positive in 62.5% and 33.3% of cases, respectively and had a mutually exclusive staining pattern. In summary, this rare pattern of hepatic angiosarcoma is challenging to diagnose but has distinctive morphologic findings that can be supplemented with immunostains to establish the diagnosis.

Unique Morphologic Findings in the Liver After Stereotactic Radiation for Cholangiocarcinoma.

Newer radiotherapy techniques, such as stereotactic body radiation, have been increasingly used as part of the treatment of cholangiocarcinomas, particularly as a bridge to liver transplantation. Although conformal, these high-dose therapies result in tissue injury in the peritumoral liver tissue. This retrospective study characterized the morphologic changes in the liver after stereotactic body radiation in a series of liver explant specimens with perihilar cholangiocarcinoma. The morphologic changes in the irradiated zone were compared against the nonirradiated background liver parenchyma to control for chemotherapy-related changes. Of the 21 cases studied, 16 patients (76.2%) had underlying primary sclerosing cholangitis, and 13 patients (61.9%) had advanced liver fibrosis. The average duration between completion of radiotherapy and liver transplantation was 33.4 weeks (range: 6.29 to 67.7). Twelve patients (57.1%) had no residual tumor in the liver. The most frequent histologic changes in the peritumoral irradiated liver tissue were sinusoidal congestion (100%), sinusoidal edematous stroma (100%), and hepatocellular atrophy (100%), followed by partial/complete occlusion of central veins (76.2%), sinusoidal cellular infiltrates (76.2%), and hepatocyte dropout (66.7%). The findings in the radiated areas were more extensive than in the background liver ( P <0.01). Sinusoidal edematous stroma was striking and dominated the histologic findings in some cases. Over time, there was less sinusoidal congestion but more hepatocyte dropout (r s =-0.54, P =0.012 and r s =0.64, P =0.002, respectively). Uncommon findings, such as foam cell arteriopathy in the liver hilum, were also observed. In summary, postradiation liver specimens have distinctive morphologic findings.

The Characteristics of Isolated Bulb Celiac Disease in Children.

OBJECTIVES: Mucosal injury in celiac disease (CD) patients can be patchy, and up to 12% of CD patients can have mucosal changes limited to the duodenal bulb. Hence, recent guidelines recommend obtaining bulb biopsies in addition to distal duodenum. This study aimed to describe a cohort of children with isolated bulb CD and assess the benefit of separating bulb biopsies. METHODS: A retrospective chart review between January 2011 and January 2022 at 2 medical centers was conducted. We included children with CD who underwent endoscopy with separated biopsies from the bulb and distal duodenum. A blinded pathologist performed Marsh-Oberhuber grading on selected cases. RESULTS: We identified 224 CD patients, of which 33 (15%) had histologically confirmed isolated bulb CD. Patients with isolated bulb CD were older at diagnosis (10 vs 8 years; P = 0.03). Median anti-tissue transglutaminase immunoglobulin A (TTG IgA) level was lower in isolate bulb CD (2.8 vs 16.7 times the upper limit of normal [ULN], P < 0.001). Almost 88% (29/33) of isolated bulb CD patients had an anti-TTG IgA value of less than 10 times the ULN. Time to anti-TTG IgA normalization (mean 14 months) was similar between the 2 groups. A pathologist review of diagnostic biopsies could not distinguish between the bulb and distal duodenum biopsies in approximately one-third of the reviewed samples. CONCLUSIONS: Separating bulb from distal duodenum biopsies can be considered during CD diagnosis, particularly in children with anti-TTG IgA levels less than 10 times the ULN. Larger prospective cohorts are needed to decide whether isolated bulb CD is a unique cohort or an early stage of the conventional CD.

Multi-Institutional Study of Pathologist Reading of the Programmed Cell Death Ligand-1 Combined Positive Score Immunohistochemistry Assay for Gastric or Gastroesophageal Junction Cancer.

The assessment of the expression of programmed cell death ligand-1 (PD-L1) using immunohistochemistry (IHC) has been controversial since its introduction. The methods of assessment and the range of assays and platforms contribute to confusion. Perhaps the most challenging aspect of PD-L1 IHC is the combined positive score (CPS) method of interpretation of IHC results. Although the CPS method is prescribed for more indications than any other PD-L1 scoring system, its reproducibility has never been rigorously assessed. In this study, we collected a series of 108 gastric or gastroesophageal junction cancer cases, stained them using the Food and Drug Administration-approved 22C3 assay, scanned them, and then circulated them to 14 pathologists at 13 institutions for the assessment of interpretative concordance for the CPS system. We found that higher cut points (10 or 20) performed better than a CPS of <1 or >1. We used the Observers Needed to Evaluate Subjective Tests algorithm to assess how the CPS system might perform in the real-world setting and found that the cut points of <1 or >1 showed an overall percent agreement of only 30% among the pathologist raters, with a plateau occurring at 8 raters. The raters performed better at higher cut points. However, the best cut point of <20 versus that of >20 was still disappointing, with a plateau at an overall percent agreement of 70% (at 7 raters). Although there is no ground truth for CPS, we compared the score with quantitative messenger RNA measurement and showed no relationship between the score (at any cut point) and messenger RNA amount. In summary, we showed that CPS shows high subjective variability among pathologist readers and is likely to perform poorly in the real-world setting. This system may be the root cause of the poor specificity and relatively low predictive value of IHC companion diagnostic tests for PD-1 axis therapies that use the CPS system.

The interventional direct peroral cholangioscopy toolbox for endoscopic snare resection of a high-grade biliary intraductal neoplasia.

Video 1Demonstration of techniques for performing direct peroral cholangioscopy.

Histologic evaluation in the diagnosis and management of celiac disease: practical challenges, current best practice recommendations and beyond.

Celiac disease (CD) is an immunoallergic enteropathy affecting genetically susceptible individuals upon dietary exposure to gluten. In current clinical practice, the diagnosis of CD is based on a combination of clinical, serologic, and histologic factors with the possible exception of pediatric patients. Histopathologic evaluation of small intestinal tissue plays a critical role in the disease diagnosis and management, despite many practical challenges. Recently published best practice guidelines help to standardize biopsy sample procurement, tissue preparation, histology interpretation, and reporting, to optimize patient care. In addition, an increasing demand for monitoring the disease course, particularly demonstrating the efficacy of dietary and nondietary interventions for disease management, calls for the use of quantitative histology. With the advent of a gradual transition toward digital pathology in routine diagnostic practice, quantitative histopathologic evaluation in CD shows a promising future.

Artificial intelligence in anatomical pathology: building a strong foundation for precision medicine.

With the convergence of digital pathology (DP) and artificial intelligence (AI), anatomic pathology practice has been experiencing an exciting paradigm shifting. Pathologists will be provided with an augmented ability to improve diagnostic accuracy, efficiency, and consistency. There will be subvisual morphometric features discovered and multiomics data integrated to provide better prognostic and theragnostic information to guide individual patients' management. The perspective for future precision medicine is promising. However, there are many challenges before AI-assisted DP diagnostic workflows can be successfully implemented. Herein, we briefly review some examples of AI application in anatomic pathology with an emphasis on the subspecialty of gastrointestinal pathology and discuss potential challenges for clinical implementation.

Alternative lengthening of telomeres in primary hepatic neoplasms.

The alternative lengthening of telomeres (ALT) phenotype is characterized by ultra-bright telomeres on fluorescence in situ hybridization (FISH) and is a marker of a unique mechanism of telomere maintenance in tumors. ALT does not occur in normal tissues. ALT has been described in hepatocellular carcinoma (5-10%) and in primary hepatic angiosarcomas (75%). To study the frequency of ALT in other primary hepatic tumors, a wide range of primary hepatic neoplasms were retrieved. The tumors included the following: intrahepatic and hilar cholangiocarcinomas (N = 110), hepatic adenomas (N = 35), hepatocellular carcinomas (N = 30), fibrolamellar carcinomas (n = 11), combined cholangiocarcinoma-hepatocellular carcinomas (N = 8), carcinosarcoma (N = 10), hepatoblastomas (N = 5), hemangiomas (N = 4), angiosarcomas (N = 8), epithelioid hemangioendotheliomas (N = 10), calcified nested stromal epithelial tumor (N = 2), embryonal sarcoma (N = 2), rhabdoid tumor (N = 1), bile duct adenoma (N = 1), and angiomyolipoma (N = 1). For epithelial tumors, ALT-FISH was positive in one carcinosarcoma (10% of cases), one cholangiocarcinoma (1% of cases), and one combined hepatocellular carcinoma-cholangiocarcinoma (13% of cases). In the hepatocellular carcinoma component of both the carcinosarcoma and the combined hepatocellular carcinoma-cholangiocarcinoma, the tumor cells showed patchy marked nuclear pleomorphism akin to that described previously for chromophobe hepatocellular carcinoma, which are typically ALT FISH positive. The ALT-positive cholangiocarcinoma also showed patchy, striking nuclear pleomorphism. For soft tissue tumors, ALT was positive in two angiosarcomas (N = 2; 25% of cases). In summary, this study shows that ALT-FISH is positive in rare carcinosarcomas, cholangiocarcinomas, and combined cholangiocarcinoma-hepatocellular carcinoma. ALT is not a significant mechanism of telomere maintenance in hepatocellular adenomas or fibrolamellar carcinomas and was negative in all other tested primary hepatic neoplasms. ALT-FISH is also positive in a subset of primary hepatic angiosarcomas.

Histological assessment of new cholangioscopy-guided forceps in ERCP biliary stricture sampling: a blinded comparative study.

Background and study aims Obtaining quality tissue during ERCP biliary stricture sampling is of paramount importance for a timely diagnosis. While single-operator cholangioscopy (SOC)-guided biopsies have been suggested to be the superior biliary tissue acquisition modality given direct tissue visualization, less is known about the specimen histological quality. We aimed to analyze the specimen quality of SOC biopsies and compare the new generation forceps with prior "legacy" forceps. Patients and methods Patients who underwent SOC from January 2017-August 2021 for biliary sampling were reviewed. In February 2020, the SOC-guided biopsy forceps were changed from legacy SpyBite to the SpyBite Max forceps (max). Specimens were assessed by blinded pathologists for crush artifact (none, mild, or severe) and gross size (greatest dimension in mm). Crush artifact and gross size were compared between the two groups. The diagnostic performance characteristics for cholangiocarcinoma (CCA), were assessed in an exploratory fashion. Results Eighty-one patients (max = 27, legacy = 54) with similar baseline characteristics were included in this study. On blinded pathological assessment, 58 % had crush artifact, without significant differences between the two groups (Max 63 % vs. Legacy 56 %; P  = 0.64). A similar mean specimen size was found (max 3 mm vs. legacy 3.2 mm; P  = 0.24). The overall prevalence of CCA was 40 %. The sensitivity, specificity, positive predictive value, and negative predictive value of the entire cohort using a combination of cytology, fluorescence in situ hybridization, and SOC-guided biopsies were 78.1 %, 91.8 %, 86.2 %, and 86.5 %, respectively. No difference between legacy or max groups was found. Conclusions A high rate of crush artifact was found in SOC-guided biopsy specimens. Further investigation regarding proper biopsy technique and handling is necessary to increase the diagnostic yield with SOC-guided biopsies.

Hepatic Adenomas in Patients 60 and Older Are Enriched for HNF1A Inactivation and Malignant Transformation.

Hepatic adenomas occur most commonly in women between the ages of 20 and 40 years, but rarely they occur in older aged persons, including those 60 years of age or older. This group of adenomas, however, has not been systemically examined. Twenty-six hepatic adenomas in persons 60 years of age or older were studied, along with a control group of 50 hepatic adenomas in persons aged 30 to 39. Hepatic adenomas in persons 60 or more years of age were found in 21 women and 5 men, while the control group had 44 women and 6 men. Subtyping the adenomas in persons 60 years or older showed the following results: 18 HNF1A-inactivated adenomas (69%), 4 inflammatory adenomas (15%), and 4 unclassified adenomas (15%). In contrast, the control group showed a significantly different pattern (P=0.003), with a greater percentage of inflammatory adenomas (28, 56%), fewer HNF1A-inactivated adenomas (8, 16%), and more unclassified adenomas (14, 28%). Atypia and malignant transformation within the hepatic adenomas was studied next. Of the hepatic adenomas in persons age 60 or greater, 3 (12%) showed atypical histologic features, and 6 (23%) had a malignant transformation. In contrast, for hepatic adenomas in the control group, only 4 (8%) adenomas showed atypical histologic features, and 3 (6%) had undergone malignant transformation. In addition, the hepatic adenomas that were atypical or showed early malignant transformation were less likely to have beta-catenin activation in patients over 60 (2/9 cases) compared with those between 30 and 39 years (5/7 cases). Myxoid change and heavy lipofuscin deposition were also more common in adenomas in older aged persons. In conclusion, hepatic adenomas in persons 60 years of age or older are enriched for HNF1A-inactivated adenomas and have a higher frequency of malignant transformation. Malignant transformation, however, is less likely to develop through activation of the beta-catenin pathway.

Collagenous Gastritis: Characteristics and Response to Topical Budesonide.

BACKGROUND AND AIMS: Collagenous gastritis (CG) is a rare disorder characterized by subepithelial collagen deposition in the stomach. Standard medications have been only moderately successful in treating CG. We report results of a large, retrospective, open-label noncontrolled study of topical budesonide for CG, with an aim of establishing an alternative therapy for the disease. METHODS: We identified patients treated for CG at Mayo Clinic (2000-2017) with topically targeted budesonide (TTB) in 2 formulations: open-capsule budesonide or compounded immediate-release budesonide capsule. Demographic, clinical, biochemical, and histologic variables were assessed for all patients before and after treatment. RESULTS: We identified 64 patients with CG (50 adults, 14 children). Most were female (68%), mean age was 41 ± 22.8 years, and body mass index was 23.1 ± 5.9 kg/m2. In most pediatric patients, CG presented with abdominal pain and anemia; in adults, CG presented more often with weight loss (P < .001). Collagenous sprue or colitis were more common in patients >50 years of age (83%) vs those 19-50 years of age (27%) or <19 years of age (50%) (P < .001). Of the patients treated with TTB, 89% had a clinical response to TTB (42% complete, 46% partial), and 88% had a histologic response (53% complete, 33% partial). CONCLUSIONS: Adults and children with CG have a wide variety of symptoms, and notably, TTB therapy produced clinical and histologic improvement after other therapy had failed.

Morphological heterogeneity in beta-catenin-mutated hepatocellular carcinomas: implications for tumor molecular classification.

Beta-catenin (CTNNB1) is commonly mutated in hepatocellular carcinoma (HCC). CTNNB1-mutated HCC has important clinical correlates, such as being immune cold and less likely to respond to immune checkpoint inhibitor therapies. It remains unclear, however, if they are a morphologically homogenous group of tumors. To better understand the association between the morphology, CTNNB1 mutations, and other molecular features, a detailed study of 338 The Cancer Genome Atlas cases was performed. A characteristic histological morphology was strongly associated with CTNNB1 mutations but was present in only 58% of CTNNB1-mutated HCCs. Tumors with APC mutations tended to have the classic morphology; those with AXIN mutations did not. Pseudoglands are a key feature of the classic morphology, and they were associated with CTNNB1 mutations, male gender, specific CTNNB1 mutation site, and lack of TP53 mutations. Differential gene expression analysis stratified by the presence/absence of pseudoglands identified 60 differentially expressed genes (FDR <5%); clustering according to these differentially expressed genes revealed three groups of tumors, one with pseudoglands and a strong association with genes regulated by Wnt signaling; within this group, TP53 mutations were associated with a loss of the typical morphology of CTNNB1-mutated HCCs. When stratified by gender, further differential gene expression showed Wnt-regulated genes were associated with pseudoglands in men but not women. These findings indicate HCC with CTNNB1 mutations are morphologically heterogeneous, with gene penetrance for morphology dependent in part on gender, specific CTNNB1 mutations, and co-occurring TP53 mutations. This heterogeneity has important implications for the classification of HCC.

PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and 68 Ga-PSMA-11 PET Using Cyclotron-Produced 68 Ga.

Prostate-specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68 Ga-PSMA-11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68 Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced 68 Ga. Uptake was graded qualitatively and semi-quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor-associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10-5 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = -0.753; P = 1.58 × 10-6 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68 Ga-PSMA-11 standardized uptake value: SUVmax (median [range] 9.2 [4.9-28.4]), SUVmean 4.7 (2.4-12.7), and tumor-to-liver background ratio 2 (1.1-11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68 Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

Periaqueductal gray neurons encode the sequential motor program in hunting behavior of mice.

Sequential encoding of motor programs is essential for behavior generation. However, whether it is critical for instinctive behavior is still largely unknown. Mouse hunting behavior typically contains a sequential motor program, including the prey search, chase, attack, and consumption. Here, we reveal that the neuronal activity in the lateral periaqueductal gray (LPAG) follows a sequential pattern and is time-locked to different hunting actions. Optrode recordings and photoinhibition demonstrate that LPAGVgat neurons are required for the prey detection, chase and attack, while LPAGVglut2 neurons are selectively required for the attack. Ablation of inputs that could trigger hunting, including the central amygdala, the lateral hypothalamus, and the zona incerta, interrupts the activity sequence pattern and substantially impairs hunting actions. Therefore, our findings reveal that periaqueductal gray neuronal ensembles encode the sequential hunting motor program, which might provide a framework for decoding complex instinctive behaviors.