Discovery of Novel 2-Oxoacetamide Derivatives as B3GAT3 Inhibitors for the Treatment of Hepatocellular Carcinoma.

Beta-1,3-glucuronosyltransferase (B3GAT3), overexpressed in hepatocellular carcinoma (HCC) and negatively correlated to prognosis, is a promising target for cancer therapy. Currently, no studies have reported small molecule inhibitors of B3GAT3. In this study, we designed and synthesized a series of small-molecule inhibitors of B3GAT3 through virtual screening and structure optimization. The lead compound TMLB-C16 exhibited potent B3GAT3 inhibitory activity (KD = 3.962 µM) by effectively suppressing proliferation and migration, and inducing cell cycle arrest and apoptosis in MHCC-97H (IC50= 6.53 ± 0.18 µM) and HCCLM3 (IC50= 6.22 ± 0.23 µM) cells. Furthermore, compound TMLB-C16 demonstrated favorable pharmacokinetic properties with a relatively high bioavailability of 68.37%. It significantly inhibited tumor growth in both MHCC-97H and HCCLM3 xenograft tumor models without causing obvious toxicity. These results indicate that compound TMLB-C16 is an effective small molecule inhibitor of B3GAT3, providing a basis for the future development of B3GAT3-targeted drugs.

Multiparametric US for Identifying Metabolic Dysfunction-associated Steatohepatitis: A Prospective Multicenter Study.

Background Noninvasive evaluation of metabolic dysfunction-associated fatty liver disease (MAFLD) with multiparametric US is essential, but multicenter studies are lacking. Purpose To evaluate the ability of multiparametric US with attenuation imaging (ATI) and two-dimensional (2D) shear-wave elastography (SWE) for predicting metabolic dysfunction-associated steatohepatitis (MASH) in participants with MAFLD, regardless of hepatitis B virus infection status. Materials and Methods This prospective cross-sectional multicenter study of consecutive adults with MAFLD who underwent multiparametric US with ATI and 2D SWE, as well as liver biopsy, from September 2020 to June 2022 was conducted in 12 tertiary hospitals in China. Multivariable logistic regression was performed to assess risk factors associated with MASH. Area under the receiver operating characteristic curve (AUC) analysis was used to evaluate diagnostic performance in predicting MASH in training and validation groups (6:4 ratio of participants), and for a post hoc subgroup analysis of hepatitis B virus infection and diabetes. Results A total of 424 participants (median age, 47 years; IQR, 34-59 years; 244 male) were evaluated, including 332 participants (78%) with MASH and 92 (22%) without. Attenuation coefficient (AC) (odds ratio [OR], 3.32 [95% CI: 1.94, 5.71]; P < .001), alanine aminotransferase (ALT) level (OR, 4.42 [95% CI: 1.78, 10.94]; P = .001), and international normalized ratio (INR) (OR, 0.59 [95% CI: 0.37, 0.95]; P = .03) were independently associated with MASH. A combined model (AC, ALT, and INR) had AUCs of 0.85 (95% CI: 0.79, 0.91) and 0.77 (95% CI: 0.69, 0.85) for predicting MASH in the training and validation groups, respectively. AUC values for the subgroups with and without diabetes were 0.83 (95% CI: 0.72, 0.94) and 0.81 (95% CI: 0.75, 0.87) and for the subgroups with and without hepatitis B were 0.82 (95% CI: 0.74, 0.90) and 0.79 (95% CI: 0.71, 0.87), respectively. Conclusion A model combining AC, ALT level, and INR showed good discrimination ability for predicting MASH in participants with MAFLD. Clinical trial registration no. NCT04551716 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Reuter in this issue.

Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma.

Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure-activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5-2.5 µM for inhibiting sphere formation and 0.5-15 µM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood-brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.

Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial.

BACKGROUND: Over 70% of the patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage and lose the opportunity for radical surgery. Combination therapy of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein-1 (PD-1) antibodies has achieved a high tumor response rate in both the first-line and second-line treatment of advanced HCC. However, few studies have prospectively evaluated whether TKIs plus anti-PD-1 antibodies could convert unresectable intermediate-advanced HCC into resectable disease. METHODS: This single-arm, phase II study enrolled systemic therapy-naïve adult patients with unresectable Barcelona Clinic Liver Cancer stage B or C HCC. Patients received oral lenvatinib one time per day plus intravenous anti-PD-1 agents every 3 weeks (one cycle). Tumor response and resectability were evaluated before the fourth cycle, then every two cycles. The primary endpoint was conversion success rate by investigator assessment. Secondary endpoints included objective response rate (ORR) by independent imaging review (IIR) assessment per modified RECIST (mRECIST) and Response Evaluation Criteria in Solid Tumors, V.1.1 (RECIST 1.1), progression-free survival (PFS) and 12-month recurrence-free survival (RFS) rate by IIR per mRECIST, R0 resection rate, overall survival (OS), and safety. Biomarkers were assessed as exploratory objectives. RESULTS: Of the 56 eligible patients enrolled, 53 (94.6%) had macrovascular invasion, and 16 (28.6%) had extrahepatic metastasis. The median follow-up was 23.5 months. The primary endpoint showed a conversion success rate of 55.4% (31/56). ORR was 53.6% per mRECIST and 44.6% per RECIST 1.1. Median PFS was 8.9 months, and median OS was 23.9 months. Among the 31 successful conversion patients, 21 underwent surgery with an R0 resection rate of 85.7%, a pathological complete response rate of 38.1%, and a 12-month RFS rate of 47.6%. Grade ≥3 treatment-related adverse events were observed in 42.9% of patients. Tumor immune microenvironment analysis of pretreatment samples displayed significant enrichment of CD8+ T cells (p=0.03) in responders versus non-responders. CONCLUSION: Lenvatinib plus anti-PD-1 antibodies demonstrate promising efficacy and tolerable safety as conversion therapy in unresectable HCC. Pre-existing CD8+ cells are identified as a promising biomarker for response to this regimen. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR1900023914.

Clinicopathological features and differential diagnosis of gastric metastases.

OBJECTIVE: Due to the rarity and non-specificity of symptoms, gastric metastases are often misdiagnosed, and patients are not treated promptly. The aim of this study was to study the clinicopathological features and differential diagnosis of gastric metastases. METHODS: From 2004 to 2021, 14 patients were diagnosed with gastric metastases not resulting from direct invasion (GMNDI) in our hospital, and their imaging and clinicopathological features were analyzed. RESULTS: PET-CT examination showed hypermetabolic nodules in the stomach. Under gastroscopy, GMNDI showed eminence, nodular or vegetable pattern mass, and ulcer. Microscopically, GMNDI showed similar pathological features and immunophenotypes to the primary tumor. In our study, the most common primary tumors were malignant melanoma (4 cases), small cell lung cancer (3 cases), and hepatocellular carcinoma (3 cases). Immunohistochemistry contributed to the pathological diagnosis and differential diagnosis of gastric metastases. Malignant melanoma expressed HMB45, MelanA, and S-100; small cell lung cancer expressed TTF-1, CD56, and CgA; hepatocellular carcinoma expressed GPC-3, hepatocyte, and Sall4. In a few cases, tumor cells may lose immune markers during metastasis. Therefore, it is necessary to combine medical history, imaging examination, and other clinical diagnosis methods in the pathological diagnosis. CONCLUSION: An in-depth understanding of GMNDI is conducive to better diagnosis and treatment planning for gastric metastases and subsequent improvement in patient prognosis.

Corrigendum: The role of 18F-FDG PET in predicting the pathological response and prognosis to unresectable HCC patients treated with lenvatinib and PD-1 inhibitors as a conversion therapy.

[This corrects the article DOI: 10.3389/fimmu.2023.1151967.].

The role of 18F-FDG PET in predicting the pathological response and prognosis to unresectable HCC patients treated with lenvatinib and PD-1 inhibitors as a conversion therapy.

Purpose: To investigate the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), as an imaging biomarker, for predicting pathological response and prognosis of unresectable hepatocellular carcinoma (HCC) patients treated with Lenvatinib and programmed cell death protein 1 (PD-1) inhibitors as a conversion therapy. Methods: A total of 28 unresectable HCC patients with BCLC stage B or C were treated with Lenvatinib and PD-1 inhibitors before surgery. The 18F-FDG PET/CT scans were acquired before pre- (scan-1) and post-conversion therapy (scan-2). The maximum standardized uptake value (SUVmax), TLR (tumor-to-normal liver standardized uptake value ratio), and the percentages of post-treatment changes in metabolic parameters (ΔSUVmax [%] and ΔTLR [%]) were calculated. Major pathological response (MPR) was identified based on the residual viable tumor in the resected primary tumor specimen (≤10%). Differences in the progression-free survival (PFS) and overall survival (OS) stratified by ΔTLR were examined by the Kaplan-Meier method. Results: 11 (11/28, 39.3%) patients were considered as MPR responders and 17 (17/28, 60.7%) patients as non-MPR responders after conversion therapy. ΔSUVmax (-70.0 [-78.8, -48.8] vs. -21.7 [-38.8, 5.7], respectively; P<0.001) and ΔTLR (-67.6 [-78.1, -56.8] vs. -18.6 [-27.9, 4.0], respectively; P<0.001) were reduced in the responder group than those in the non-responder group. According to the results of the receiver operating characteristic curve analysis, ΔTLR showed an excellent predictive value for the MPR of primary HCC lesions (area under curve=0.989, with the optimal diagnostic threshold of -46.15). When using ΔTLR of -21.36% as a threshold, patients with ΔTLR-based metabolic response had superior PFS (log-rank test, P=0.001) and OS (log-rank test, P=0.016) compared with those without ΔTLR-based metabolic response. Conclusion: 18F-FDG PET is a valuable tool for predicting pathological response and prognosis of unresectable HCC patients treated by Lenvatinib combined with PD-1 as a conversion therapy.

A meta-analysis of circulating tumor DNA as a survival indicator in small cell lung cancer patients.

A high level of circulating tumor DNA (ctDNA) has been linked to poor survival in patients with certain solid tumors. In spite of this, it is still unclear whether ctDNA is associated with poor survival in small cell lung cancer (SCLC). To investigate the above association, we conducted a systematic review and meta-analysis. PubMed, Web of Science, Cochrane's Library, and Embase were searched for relevant cohort studies from the inception of the databases to November 28, 2022. Data collection, literature search, and statistical analysis were carried out independently by two authors. To account for heterogeneity, we used a random-effects model. In this meta-analysis, 391 patients with SCLC were identified, and the data were pooled from nine observational studies and followed for 11.4 to 25.0 months. A high ctDNA was associated with worse overall survival (OS, risk ratio [RR] 2.50, 95% confidence interval [CI]1.85 to 3.38, p < 0.001; I2 = 25%) and progression-free survival (PFS, RR 2.33, 95% CI 1.48 to 3.64, p < 0.001, I2 = 42%). Subgroup analyses retrieved consistent results in prospective and retrospective studies, in studies with ctDNA measured with polymerase chain reaction or next-generation sequencing, and in studies analyzed with univariate or multivariate regression models. Studies suggest that ctDNA may be an important factor in predicting poor OS and PFS in SCLC patients.

Local injection of adipose-derived mesenchymal stem cells in silk fibroin solution on the regeneration of lower esophageal sphincter in an animal model of GERD.

Presently, various tissue engineering methods using adult stem cells and biomaterials are being confirmed to regenerate vessels, cardiac muscle, bladder, and intestines. However, there are few studies about the repair of the lower esophageal sphincter (LES) may help alleviate the symptoms of gastroesophageal reflux disease (GERD). This study aims to determine whether Adipose-Derived Stem Cells (ADSCs) combined with regenerated silk fibroin (RSF) solution could regenerate the LES. In vitro, the ADSCs were isolated, identified, and then cultured with an established smooth muscular induction system. In vivo, in the experimental groups, CM-Dil labeled ADSCs or induced ADSCs mixed with RSF solution were injected into the LES of rats after the development of the animal model of GERD respectively. The results showed that ADSCs could be induced into smooth muscular-like cells with the expression of h-caldesmon, calponin, α-smooth muscle actin, and a smooth muscle-myosin heavy chain in vitro. In vivo, the thickness of LES in the experiment rats was much thicker than those in the controlled groups. This result indicated that ADSCs mixed with RSF solution might contribute to the regeneration of the LES, thus reducing the occurrence of GERD.

Primary hepatic myopericytoma coexisting with multiple cystic hepatic lesions: a case report.

BACKGROUND: Hepatic myopericytoma (MPC) is an extremely rare pathological entity in the liver. Conversely, cystic hepatic lesions are a group of heterogeneous lesions encountered commonly in daily practice. Here, we report a unique case of the coexistence of primary hepatic MPC and multiple cystic hepatic lesions along with our perceptions on its diagnosis and treatment. CASE PRESENTATION: A 56-year-old female patient was found to have a left liver mass during a routine physical examination. Computer tomography (CT) and magnetic resonance imaging (MRI) confirmed the existence of a left hepatic neoplasm along with multiple hepatic cysts but could not exclude the possible malignant nature of the neoplasm. Computer tomography (CT) also identified an enlarged mediastinal lymph node with a maximum diameter of 4.3 cm, which further underwent core needle biopsy under CT guidance. A histopathological examination was performed to rule out malignancy. Afterwards, the patient underwent left hemihepatectomy to resect a solid tumor of 5.5 cm × 5 cm × 4.7 cm with multiple cystic lesions which were histopathologically examined to establish the diagnosis of myopericytoma with hepatic cysts. Postoperatively, the patient recovered from the surgery quickly without significant adverse events and was not found to have a reoccurrence of the primary pathological entity. CONCLUSIONS: This is the first reported case of a patient with the co-existence of primary hepatic myopericytoma and multiple cystic hepatic lesions undergoing surgical treatment with eventual recovery.

Expert Consensus on Pathological Diagnosis of Intrahepatic Cholangiocarcinoma (2022 version).

Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.

Case report: Ectopic thyroid tissue found in a liver with hepatocellular carcinoma.

Background: Concomitant intrahepatic ectopic thyroid is rare in patients with hepatocellular carcinoma. Thyroid follicular structures outside the hepatocellular carcinoma lesions are regarded as satellite nodules or intrahepatic metastases of hepatocellular carcinoma, which often leads to misdiagnosis and overtreatment of hepatocellular carcinoma patients. Case presentation: We report the case of an 83-year-old man with moderately differentiated hepatocellular carcinoma (2.5 cm) whose liver contained ectopic thyroid tissue. An encapsulated, multinodular grayish-yellow mass and multiple satellite nodules were detected and removed by right hepatic lobectomy. Microscopically, the main tumor displayed a predominant trabecular, cord-like structure. Liver tissue 0.5 cm from the tumor had a benign-appearing follicular thyroid structure. The follicles contained colloid tissue and were lined with low cuboidal cells with scant cytoplasm; lymphatic tissue was also present in the area. The hepatocellular carcinoma cells were positive for hepatocyte antigen and glypican-3 and negative for cytokeratin 19. The follicular thyroid cells expressed thyroglobulin, PAX8, and thyroid transcription factor-1. A metastatic thyroid neoplasm was excluded clinically and by ultrasound and computed tomography. One month after surgery, all of the patient's serological markers were normal; no tumor recurrence or metastasis has been detected for 7 postoperative months. Conclusions: The finding of ectopic thyroid tissue in the liver of a patient with hepatocellular carcinoma is very rare. The possibility of hepatocellular carcinoma forming satellite nodules and intrahepatic metastasis should be ruled out first and immunohistochemistry may be definitive in making the diagnosis. Further examination is needed to exclude thyroid cancer liver metastases.

Pretreatment Metabolic Parameters Measured by 18F-FDG PET to Predict the Pathological Treatment Response of HCC Patients Treated With PD-1 Inhibitors and Lenvatinib as a Conversion Therapy in BCLC Stage C.

Objectives: This study aimed to assess the pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) as a predictor of the pathological treatment response (PTR) of hepatocellular carcinoma (HCC) patients treated with PD-1 inhibitors and lenvatinib as a conversion therapy in BCLC stage C. Methods: All patients (n=20) underwent pretreatment 18F-FDG PET/CT and were treated with conversion therapy and surgery. Patients were categorized into responders (n=9) and non-responders (n=11) according to PTR. The parameters of PET/CT, including lesion size, SUVmean (mean standard uptake value), MTV (metabolic tumor volume), TLG (total lesion glycolysis), SUVpeak (peak standard uptake value), and TLR (tumor-to-normal liver standardized uptake value ratio), were calculated. The diagnostic efficacy was evaluated by receiver operating characteristic analysis (ROC). PTR was compared with pretreatment PET/CT parameters by using Spearman correlation analysis. The patients were followed up. Results: There was significant difference in TLR (5.59 ± 1.90 vs. 2.84 ± 1.70, respectively; P=0.003) between responders and non-responders, with the largest area under the curve (sensitivity=100%, specificity=72.7%, AUC=0.899, 95%CI: 0.759-1.000, optimal diagnostic threshold of 3.09). The relationship between 18F-FDG PET/CT parameters and PTR indicated TLR was moderately and positively correlated with pathological treatment response, with correlation coefficients (rs) of 0.69 (P<0.01). During the follow-up, no patients died, and tumor recurrence was found in one of the responders (11.1%). In all 11 non-responders, tumor recurrence was found in six patients (54.5%) and four patients (36.4%) died. Conclusions: TLR may be a powerful marker to predict PTR of HCC patients with BCLC stage C who were treated with conversion therapy.

Amelanotic metastatic gastric malignant melanoma: a case report.

Melanoma is a malignant form of cutaneous cancer with an increasing incidence since 1970s, accounting for nearly 75% of the death related to skin cancer especially in western countries. Highest recurrence and mortality were observed for the subtype with distal metastasis, demonstrating poor outcomes. However, high incidence of gastrointestinal metastasis of malignant melanoma is frequently misdiagnosed due to lack of specific clinical manifestations, especially for the rare observed cases presented amelanotic appearance, accounting for about 2% of all metastatic cases. In the present study, we reported a 36-year-old male patient, who was firstly diagnosed as gastric cancer, and then was confirmed as amelanotic melanoma metastasis by pathological examination, demonstrating positive for melanoma markers including Melan A, S-100, Hmb45 and CD79a. In conclusion, for the amelanotic neoplasm observed during gastroscopy in patients with melanoma history, pathological examination should be carried out to confirm the possibility of melanoma metastasis, providing evidences for the following treatment.

Clinical characteristics of patients with chronic eosinophilic pneumonia in a Chinese tertiary-care hospital: A 6-year retrospective study.

INTRODUCTION: Chronic eosinophilic pneumonia (CEP) is a rare disease with unknown etiology. Due to lack of specificity of CEP symptoms, clinicians are not experienced in establishing its diagnosis. OBJECTIVES: To summarize the clinical data of CEP patients to improve the understanding of CEP and reduce misdiagnosis. METHODS: Data of patients pathologically diagnosed with CEP in the PLA General Hospital between May 2013 and May 2019 were collected, and clinical manifestations, imaging characteristics, pathological features, and treatment were retrospectively analyzed. RESULTS: Twenty patients, including 6 males and 14 females, were diagnosed with CEP. The average age was 47.0 ± 10.2 years. The main clinical manifestations were cough and dyspnea. The average duration of CEP was 15.5 ± 11.5 months. The average proportion of eosinophils in the peripheral blood was 18.9 ± 17.8%, and the average proportion of eosinophils in the bronchoalveolar lavage fluid was 41.5 ± 19.4%. The main imaging features were patchy shadows and consolidation shadows. The most common manifestations on bronchoscopic examination were congestion and edema of the bronchial mucosa. Two patients had granular protrusions of the endotracheal membrane. Histological examination indicated infiltration of numerous eosinophils. All patients improved after prednisone therapy. CONCLUSION: CEP onset is insidious, and clinical manifestations lack specificity. Typical imaging features are peripheral and subpleural distribution of lung infiltrates. Some patients have a normal proportion of eosinophils in the peripheral blood, but most have an increased number of eosinophils in the BALF, which contributes to CEP diagnosis. A biopsy is necessary when differential diagnosis is difficult. A systemic glucocorticoid is effective.

Surgery After Conversion Therapy With PD-1 Inhibitors Plus Tyrosine Kinase Inhibitors Are Effective and Safe for Advanced Hepatocellular Carcinoma: A Pilot Study of Ten Patients.

BACKGROUND AND AIMS: Immunotherapy with PD-1 inhibitors combined with tyrosine kinase inhibitors (TKIs) has been proven to be effective against advanced hepatocellular carcinoma (HCC). The aim of this study was to identify the feasibility and safety of subsequent salvage surgery after this combination therapy. METHODS AND PATIENTS: A retrospective analysis was performed on patients with primary HCC with major vascular invasion between 2018 and 2019. All cases were treated with a combination of a PD-1 inhibitor and TKI agents and subsequent surgery. RESULTS: A total of 10 HCC cases with major vascular invasion met the successful conversion criteria after the combination therapy, and eight patients underwent subsequent salvage surgery after both radiology and 3D quantitative oncological assessment. Partial response (PR) was recorded in 7 of 10 patients and complete response (CR) in 3 of 10 patients before salvage surgery. Salvage surgery included right hepatectomy, left hepatectomy, and anatomic segmental hepatectomy. The mean intraoperative blood loss was 1,650 ml (50-3,000 ml). No complications beyond Clavien-Dindo level III or postoperative mortality were observed. The viable tumor cell rate of the PR cases (modified response evaluation criteria in solid tumors, mRECIST) varied from 1.5% to 100%, and only one patient had pathology-proven pathological complete response (pCR). The postoperative median follow-up time was 19.7 months (9.1-24.9 months). The 12-month recurrence-free survival rate of all cases who underwent salvage surgery was 75%. CONCLUSION: Salvage surgery was effective and safe after conversion therapy with PD-1 inhibitors plus TKIs and may increase the long-term oncological benefit for patients with unresectable HCC.

Successful Treatment of Advanced Intrahepatic Cholangiocarcinoma With a High Tumor Mutational Burden and PD-L1 Expression by PD-1 Blockade Combined With Tyrosine Kinase Inhibitors: A Case Report.

Advanced intrahepatic cholangiocarcinoma (iCCA) is not suitable for surgical treatment. Guided by the concept of precision medicine, preoperative systematic treatment may reshape the clinical outcomes of advanced intrahepatic cholangiocarcinoma patients. We describe the case of a 38-year-old female who has been diagnosed with stage IV intrahepatic cholangiocarcinoma with a high tumor mutational burden and positively programmed death-ligand 1 (PD-L1) expression. The patient was treated with programmed cell death 1 (PD-1) inhibitors combined with tyrosine kinase inhibitors (TKIs). After 7 cycles of combination therapy, she underwent radical resection and no tumor cells were found in the postoperative histopathological examination. In addition, the patient's survival time had reached 25 months, as of August 2021. To date, this is the first case of successful radical resection after combined immunotherapy with TKIs for advanced PD-L1-positive intrahepatic cholangiocarcinoma with a high tumor mutational burden (TMB). The case provides a new approach to the treatment of advanced intrahepatic cholangiocarcinoma.

CT and MRI features of sclerosing angiomatoid nodular transformation of the spleen: A report of 18 patients with pathologic correlation.

PURPOSE: The purpose of this study was to describe the computed tomography (CT) and magnetic resonance imaging (MRI) features of sclerosing angiomatoid nodular transformation (SANT) of the spleen and correlate imaging features with those obtained at histopathologic analysis. MATERIALS AND METHODS: A total of 18 patients (9 men, 9 women; mean age, 42.2±10.7 [standard deviation (SD)] years; range, 23-59 years) with histopathologically confirmed SANT were retrospectively evaluated. The presenting symptoms, gross pathologic changes, and histopathologic and correlative immunohistochemical results were recorded. CT (n=8) and MRI (n=12) features were analyzed by two radiologists and included number, size, shape, boundary, attenuation, signal intensity, and enhancement patterns. RESULTS: Seventeen patients (17/18; 94%) had a single SANT without specific clinical symptoms and one patient (1/18; 6%) had multiple SANTs with left-upper-quadrant bloating and pain. The largest lesion diameter exceeded 3cm. On plain CT images, SANTs were slightly hypoattenuating in seven patients (7/8; 88%), isoattenuating in one patient (1/8; 13%), and contained calcification in two patients (2/8; 25%). On T2-weighted MR images, SANTs displayed hypointensity in ten patients (10/12; 83.3%), isointensity in one patient (1/12; 8%) and hyperintensity in one patient (1/12; 8%). On T2-weighted images, stellate or scattered fibrous scars were observed in all patients (12/12; 100%). On diffusion-weighted images, SANTs appeared as heterogenous or homogeneous hypointense in 12 patients (12/12; 100%). Compared to out-of-phase images, SANTs displayed decreased local signal intensity on in-phase images in 12 patients (12/12; 100%). On enhanced CT and MRI images, SANTs had clear boundaries (17/18; 94%), oval (7/18; 39%) or lobular (7/18; 39%) shape, displayed progressive centripetal enhancement (18/18; 100%), spoke-wheel pattern (14/18; 78%), nodular enhancement (11/18; 61%), or delayed enhancement of central fibrous scar (9/18; 50%). CONCLUSIONS: SANT of the spleen predominantly manifests as a solid, single, oval or lobular, and well-defined lesion with a fibrous scar and occasional calcification. Typical enhancement characteristics include progressive and centripetal enhancement, spoke-wheel pattern, nodular enhancement, and delayed enhancement of central fibrous scar. Hypointensity on T2- and diffusion-weighted images are due to hemosiderin deposition and fibrous tissue.

A standardized pathological proposal for evaluating microvascular invasion of hepatocellular carcinoma: a multicenter study by LCPGC.

BACKGROUND AND AIMS: Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present. METHODS: 119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG. RESULTS: The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p < 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (p < 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS. CONCLUSIONS: SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.

Automatic deep learning-based colorectal adenoma detection system and its similarities with pathologists.

OBJECTIVES: The microscopic evaluation of slides has been gradually moving towards all digital in recent years, leading to the possibility for computer-aided diagnosis. It is worthwhile to know the similarities between deep learning models and pathologists before we put them into practical scenarios. The simple criteria of colorectal adenoma diagnosis make it to be a perfect testbed for this study. DESIGN: The deep learning model was trained by 177 accurately labelled training slides (156 with adenoma). The detailed labelling was performed on a self-developed annotation system based on iPad. We built the model based on DeepLab v2 with ResNet-34. The model performance was tested on 194 test slides and compared with five pathologists. Furthermore, the generalisation ability of the learning model was tested by extra 168 slides (111 with adenoma) collected from two other hospitals. RESULTS: The deep learning model achieved an area under the curve of 0.92 and obtained a slide-level accuracy of over 90% on slides from two other hospitals. The performance was on par with the performance of experienced pathologists, exceeding the average pathologist. By investigating the feature maps and cases misdiagnosed by the model, we found the concordance of thinking process in diagnosis between the deep learning model and pathologists. CONCLUSIONS: The deep learning model for colorectal adenoma diagnosis is quite similar to pathologists. It is on-par with pathologists' performance, makes similar mistakes and learns rational reasoning logics. Meanwhile, it obtains high accuracy on slides collected from different hospitals with significant staining configuration variations.