Three-Dimensional Structure of Novel Liver Cancer Biomarker Liver Cancer-Specific Serine Protease Inhibitor Kazal (LC-SPIK) and Its Performance in Clinical Diagnosis of Hepatocellular Carcinoma (HCC).

LC-SPIK is a liver cancer-specific isoform of Serine Protease Inhibitor Kazal and has been proposed as a new biomarker for the detection of HCC given its unique 3D structure, which differs from normal pancreatic SPIK. An ELISA technology based on its unique structure was developed to use LC-SPIK as an effective biomarker for the clinical diagnosis of HCC. AFP, the most widely used biomarker for HCC surveillance currently, suffers from poor clinical performance, especially in the detection of early-stage HCC. In one case-control study, which included 164 HCC patients and 324 controls, LC-SPIK had an AUC of 0.87 compared to only 0.70 for AFP in distinguishing HCC from liver disease controls (cirrhosis, HBV/HCV). LC-SPIK also performed significantly better than AFP for the 81 patients with early-stage HCC (BCLC stage 0 and A), with an AUC of 0.85 compared to only 0.61 for AFP. Cirrhosis is the major risk factor for HCC; about 80% of patients with newly diagnosed HCC have preexisting cirrhosis. LC-SPIK's clinical performance was also studied in HCC patients with viral and non-viral cirrhosis, including cirrhosis caused by metabolic dysfunction-associated steatotic liver disease (MASLD) and alcoholic liver disease (ALD). In a total of 163 viral cirrhosis patients with 93 HCC patients (50 early-stage), LC-SPIK had an AUC of 0.85, while AFP had an AUC of 0.70. For patients with early-stage HCC, LC-SPIK had a similar AUC of 0.83, while AFP had an AUC of only 0.60. For 120 patients with nonviral cirrhosis, including 62 HCC (23 early-stage) patients, LC-SPIK had an AUC of 0.84, while AFP had an AUC of only 0.72. For the 23 patients with early-stage HCC, LC-SPIK had a similar AUC of 0.83, while the AUC for AFP decreased to 0.65. All these results suggest that LC-SPIK exhibits significantly better performance in the detection of HCC than AFP in all etiologies of liver diseases. In addition, LC-SPIK accurately detected the presence of HCC in 71-91% of HCC patients with false-negative AFP test results in viral-associated HCC and non-viral-associated HCC.

Role of CA 19.9 and CEA in predicting diagnosis in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is responsible for 90% of cases of primary liver cancer and is also responsible for the fourth most common cause of cancer death worldwide. To improve the current scenario for the early diagnosis and management of HCC patients, a better understanding of HCC is required. Hence, serum tumor biomarkers such as CA 19-9 (cancer antigen), CEA (carcinoembryonic antigen), and AFP (alpha-fetoprotein) show promising future, when it comes to early diagnosis of primary liver cancer (PHC), liver cirrhosis, and metastasis. Methods: It was a retrospective cross-sectional analysis of patients diagnosed with primary hepatocellular carcinoma, data were collected from the hospital database and included a total of 245 patients of HCC attending the out-patient department and some were admitted for treatment at our institution. Out of 245 patients, 68 patients were selected for the study. We have collected information related to the patient's demographic profile, pathological diagnosis, biochemical profile, and even radiological diagnosis. The sensitivity and specificity of CA 19-9 and CEA were also done. Results: Adenocarcinoma is the most common type of liver cancer followed by HCC. We have shown a weak correlation between tumor markers CA 19-9 and CEA for the diagnosis of liver carcinoma. Further our study shows that the sensitivity of tumor marker CA 19-9 for the diagnosis of liver carcinoma is 64.28% and that of CEA is 83.67%. Conclusion: The search for a novel biomarker of early liver carcinoma requires further research. Competing Interests: The authors declare that they have no competing interests.

Imaging features of primary hepatic sarcomatoid carcinoma: Differentiation from hepatocellular carcinoma and intrahepatic cholangiocarcinoma on CT: A preliminary study.

Purpose: Primary hepatic sarcomatoid carcinoma (PHSC) is a rare type of malignant tumor in the liver. Nevertheless, few studies have focused on the imaging diagnosis of PHSC. In this study, we collected clinical and computed tomography (CT) imaging data of PHSC from two institutions, aiming to investigate the clinical and radiological characteristics of PHSC. Methods: We retrospectively investigated the clinical characteristics and CT features of 22 PHSC patients (19 males and 3 females; mean age, 63.4 years; range, 49 to 76 years), 95 hepatocellular carcinoma (HCC) patients and 50 intrahepatic cholangiocarcinoma (ICC) patients. Two radiologists independently evaluated the CT features of the three groups. Subsequently, we analyzed the differences in the clinical characteristics and CT features between the PHSC and control groups. Results: Most PHSCs were larger than 5 cm (72.7%). PHSC mainly showed irregular (81.8%), heterogeneous (100%) masses with ill-defined (72.7%) borders with necrosis (86.4%) on CT, which are more common CT features versus HCC (p < 0.001). In the arterial phase, PHSC always showed noticeable heterogeneous enhancement (100.0%), mainly manifesting as partial arterial phase hyperenhancement (APHE) (86.4%). The enhancement patterns of PHSC mainly included delayed progressive enhancement (72.7%), nonperipheral washout (22.7%), and unclassified enhancement (4.5%), which were significantly different from the HCC enhancement pattern but similar to the enhancement pattern of ICC. In addition, vein tumor thrombus (18.2%), intrahepatic metastasis (27.3%), and lymphadenopathy (27.3%) were relatively common in PHSC. Furthermore, most PHSC tumors classified as LR-M (66.7%) were similar to ICC. Conclusions: PHSC generally presents as irregularly large masses with necrosis, intrahepatic metastasis, and lymphadenopathy. The CT enhancement of PHSC is mainly part of APHE and delayed progressive enhancement.

Development of a tongue image-based machine learning tool for the diagnosis of gastric cancer: a prospective multicentre clinical cohort study.

Background: Tongue images (the colour, size and shape of the tongue and the colour, thickness and moisture content of the tongue coating), reflecting the health state of the whole body according to the theory of traditional Chinese medicine (TCM), have been widely used in China for thousands of years. Herein, we investigated the value of tongue images and the tongue coating microbiome in the diagnosis of gastric cancer (GC). Methods: From May 2020 to January 2021, we simultaneously collected tongue images and tongue coating samples from 328 patients with GC (all newly diagnosed with GC) and 304 non-gastric cancer (NGC) participants in China, and 16 S rDNA was used to characterize the microbiome of the tongue coating samples. Then, artificial intelligence (AI) deep learning models were established to evaluate the value of tongue images and the tongue coating microbiome in the diagnosis of GC. Considering that tongue imaging is more convenient and economical as a diagnostic tool, we further conducted a prospective multicentre clinical study from May 2020 to March 2022 in China and recruited 937 patients with GC and 1911 participants with NGC from 10 centres across China to further evaluate the role of tongue images in the diagnosis of GC. Moreover, we verified this approach in another independent external validation cohort that included 294 patients with GC and 521 participants with NGC from 7 centres. This study is registered at ClinicalTrials.gov, NCT01090362. Findings: For the first time, we found that both tongue images and the tongue coating microbiome can be used as tools for the diagnosis of GC, and the area under the curve (AUC) value of the tongue image-based diagnostic model was 0.89. The AUC values of the tongue coating microbiome-based model reached 0.94 using genus data and 0.95 using species data. The results of the prospective multicentre clinical study showed that the AUC values of the three tongue image-based models for GCs reached 0.88-0.92 in the internal verification and 0.83-0.88 in the independent external verification, which were significantly superior to the combination of eight blood biomarkers. Interpretation: Our results suggest that tongue images can be used as a stable method for GC diagnosis and are significantly superior to conventional blood biomarkers. The three kinds of tongue image-based AI deep learning diagnostic models that we developed can be used to adequately distinguish patients with GC from participants with NGC, even early GC and precancerous lesions, such as atrophic gastritis (AG). Funding: The National Key R&D Program of China (2021YFA0910100), Program of Zhejiang Provincial TCM Sci-tech Plan (2018ZY006), Medical Science and Technology Project of Zhejiang Province (2022KY114, WKJ-ZJ-2104), Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer (JBZX-202006), Natural Science Foundation of Zhejiang Province (HDMY22H160008), Science and Technology Projects of Zhejiang Province (2019C03049), National Natural Science Foundation of China (82074245, 81973634, 82204828), and Chinese Postdoctoral Science Foundation (2022M713203).

Mortality risk and years of life lost for people with reduced renal function detected from regular health checkup: A matched cohort study.

With the increasing threat of metabolic syndromes, a focus on maintaining kidney health from early- to mid-adulthood is necessary. This study elucidates mortality risk and years of life lost (YLLs) due to abnormal renal function. This was a retrospective, matched cohort study from health checkup data from 2000 to 2015. We identified 12,774 participants with abnormal renal function (eGFR < 60 mL/min/1.73 m2) and used propensity score matching to identify 25,548 participants with normal renal function (eGFR ≥ 60). YLLs were estimated using the life expectancy differences between the abnormal and matched normal cohorts. Cox models were used to estimate the adjusted mortality risk. The estimated life expectancy of participants with proteinuria and eGFR < 60 was 26.24 years, with a 95 % confidence interval of (23.96, 29.36), 17.62 (16.37, 18.78), and 11.70 (11.02, 12.46) for age groups of 30 - 54, 55 - 64, and 65 - 79 years, respectively. The estimated YLLs of participants with proteinuria and eGFR < 60, as compared with the matched normal cohort, were 17.86 (13.41, 20.36), 12.55 (11.41, 13.78), and 8.31 (7.47, 9.13) years for the three age groups, respectively. The Cox model estimates of mortality hazard ratios of participants having proteinuria and eGFR < 60 against matched referents were 5.29 (3.97, 7.05), 3.99 (3.34, 4.75), and 3.05 (2.62, 3.55) for the three age groups, respectively. Abnormal renal function shortens life expectancy, particularly in patients with proteinuria and in younger adults. Active health management of renal function can reduce the disease burden.

AFP score and metroticket 2.0 perform similarly and could be used in a "within-ALL" clinical decision tool.

Background & Aims: Two recently developed composite models, the alpha-fetoprotein (AFP) score and Metroticket 2.0, could be used to select patients with hepatocellular carcinoma (HCC) who are candidates for liver transplantation (LT). The aim of this study was to compare the predictive performance of both models and to evaluate the net risk reclassification of post-LT recurrence between them using each model's original thresholds. Methods: This multicenter cohort study included 2,444 adult patients who underwent LT for HCC in 47 centers from Europe and Latin America. A competing risk regression analysis estimating sub-distribution hazard ratios (SHRs) and 95% CIs for recurrence was used (Fine and Gray method). Harrell's adapted c-statistics were estimated. The net reclassification index for recurrence was compared based on each model's original thresholds. Results: During a median follow-up of 3.8 years, there were 310 recurrences and 496 competing events (20.3%). Both models predicted recurrence, HCC survival and survival better than Milan criteria (p <0.0001). At last tumor reassessment before LT, c-statistics did not significantly differ between the two composite models, either as original or threshold versions, for recurrence (0.72 vs. 0.68; p = 0.06), HCC survival, and overall survival after LT. We observed predictive gaps and overlaps between the model's thresholds, and no significant gain on reclassification. Patients meeting both models ("within-ALL") at last tumor reassessment presented the lowest 5-year cumulative incidence of HCC recurrence (7.7%; 95% CI 5.1-11.5) and higher 5-year post-LT survival (70.0%; 95% CI 64.9-74.6). Conclusions: In this multicenter cohort, Metroticket 2.0 and the AFP score demonstrated a similar ability to predict HCC recurrence post-LT. The combination of these composite models might be a promising clinical approach. Impact and implications: Composite models were recently proposed for the selection of liver transplant (LT) candidates among individuals with hepatocellular carcinoma (HCC). We found that both the AFP score and Metroticket 2.0 predicted post-LT HCC recurrence and survival better than Milan criteria; the Metroticket 2.0 did not result in better reclassification for transplant selection compared to the AFP score, with predictive gaps and overlaps between the two models; patients who met low-risk thresholds for both models had the lowest 5-year recurrence rate. We propose prospectively testing the combination of both models, to further optimize the LT selection process for candidates with HCC.

Impact of waiting time on post-transplant survival for recipients with hepatocellular carcinoma: A natural experiment randomized by blood group.

Background & Aims: When listing for liver transplantation, one can transplant as soon as possible or introduce a test-of-time to better select patients, as the tumor's biological behavior is observed. Knowing the degree of harm caused by time itself is essential to advise patients and decide on the maximum duration of the test-of-time. Therefore, we investigated the causal effect of waiting time on post-transplant survival for patients with hepatocellular carcinoma. Methods: We analyzed the UNOS-OPTN dataset and exploited a natural experiment created by blood groups. Relations between variables and assumptions were described in a causal graph. Selection bias was addressed by inverse probability weighting. Confounding was avoided using instrumental variable analysis, with an additive hazards model in the second stage. The causal effect was evaluated by estimating the difference in 5-year overall survival if all patients waited 2 months instead of 12 months. Upper bounds of the test-of-time were evaluated for probable scenarios by means of simulation. Results: The F-statistic of the first stage was 86.3. The effect of waiting 12 months vs. 2 months corresponded with a drop in overall survival rate of 5.07% (95% CI 0.277-9.69) and 8.33% (95% CI 0.47-15.60) at 5- and 10-years post-transplant, respectively. The median survival dropped by 3.41 years from 16.21 years (95% CI 15.98-16.60) for those waiting 2 months to 12.80 years (95% CI 10.72-15.90) for those waiting 12 months. Conclusions: From a patient's perspective, the choice between ablate-and-wait vs. immediate transplantation is in favor of immediate transplantation. From a policy perspective, the extra waiting time can be used to increase the utility of scarce donor livers. However, the duration of the test-of-time is bounded, and it likely should not exceed 8 months. Impact and implications: When listing patients with liver cancer for transplantation, it is unclear whether a test-of-time or immediate transplantation offer better outcomes at the population level. In this study, we found that increased liver transplant waiting times are detrimental in patients with liver cancer. Furthermore, our simulation showed that a pre-operative observational period can be useful to ensure good donor liver allocation, but that its duration should not exceed 8 months.

What to do about hepatocellular carcinoma: Recommendations for health authorities from the International Liver Cancer Association.

Hepatocellular carcinoma (HCC) is a major public health problem worldwide for which the incidence and mortality are similar, pointing to the lack of effective treatment options. Knowing the different issues involved in the management of HCC, from risk factors to screening and management, is essential to improve the prognosis and quality of life of affected individuals. This document summarises the current state of knowledge and the unmet needs for all the different stakeholders in the care of liver cancer, meaning patients, relatives, physicians, regulatory agencies and health authorities so that optimal care can be delivered to patients. The document was commissioned by the International Liver Cancer Association and was reviewed by senior members, including two ex-presidents of the Association. This document lays out the recommended approaches to the societal management of HCC based on the economic status of a given region.

Clinical Profile, Patterns of Care & adherence to Guidelines in Patients with Hepatocellular Carcinoma: Prospective multi-center Study.

Background and aims: Increasing incidence of hepatocellular carcinoma (HCC) in India is a matter of concern and need for adequate profiling and streamlining management strategies cannot be over-emphasized. Methods: This is a prospective multi-centric observational cohort study comprising of an oncology center, one university tertiary hospital with specialized hepatology service, one public hospital with gastroenterology service, and a private liver transplant center located within a 3-km radius. The demographic and clinical parameters were recorded on a prospectively maintained database. The clinical profile, demographics, characteristics of HCC and the allocated treatment were noted and compared among the four centers. Results: In total, 672 patients were enrolled from June 2016 till January 2020. Abdominal pain (64.3%) and weight loss (47.3%) were the most common symptoms. Most common identified etiology was hepatitis B (39%). The cancer center received lesser patients with hepatitis C and those with advanced stage of HCC. The private transplant center reported the highest proportion of NASH, which was also significantly higher in those belonging to higher socioeconomic strata, and lowest proportion of alcoholic cirrhosis. Metastasis was seen in almost one-fifth (19%) cases at diagnosis. Portal vein thrombosis was evident in 40%. Adherence to treatment guidelines was seen in three-fourth cases (76%). Conclusions: Hepatitis B is the most common underlying cause for HCC, whereas other causes like NASH are on the rise. Etiologic profile may vary with selective specialization of centers catering to patients with HCC. Adherence to guideline while allocating treatment was high among all centers with highest non-adherence in BCLC A.

Downregulation of SOCS1 increases interferon-induced ISGylation during differentiation of induced-pluripotent stem cells to hepatocytes.

Background & Aims: Increased expression of IFN-stimulated gene 15 (ISG15) and subsequently increased ISGylation are key factors in the host response to viral infection. In this study, we sought to characterize the expression of ISG15, ISGylation, and associated enzymes at each stage of differentiation from induced pluripotent stem cells (iPSCs) to hepatocytes. Methods: To study the regulation of ISGylation, we utilized patient samples and in vitro cell culture models including iPSCs, hepatocytes-like cells, immortalized cell lines, and primary human hepatocytes. Protein/mRNA expression were measured following treatment with poly(I:C), IFNα and HCV infection. Results: When compared to HLCs, we observed several novel aspects of the ISGylation pathway in iPSCs. These include a lower baseline expression of the ISGylation-activating enzyme, UBE1L, a lack of IFN-induced expression of the ISGylation-conjugation enzyme UBE2L6, an attenuated activation of the transcription factor STAT1 and constitutive expression of SOCS1. ISGylation was observed in iPSCs following downregulation of SOCS1, which facilitated STAT1 activation and subsequently increased expression of UBE2L6. Intriguingly, HCV permissive transformed hepatoma cell lines demonstrated higher intrinsic expression of SOCS1 and weaker ISGylation following IFN treatment. SOCS1 downregulation in HCV-infected Huh 7.5.1 cells led to increased ISGylation. Conclusions: Herein, we show that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Furthermore, as iPSCs differentiate into hepatocytes, epigenetic mechanisms regulate ISGylation by modifying UBE1L and SOCS1 expression levels. Overall, this study demonstrates that the development of cell-intrinsic innate immunity during the differentiation of iPSCs to hepatocytes provides insight into cell type-specific regulation of host defense responses and related oncogenic processes. Impact and implications: To elucidate the mechanism underlying regulation of ISGylation, a key process in the innate immune response, we studied changes in ISGylation-associated genes at the different stages of differentiation from iPSCs to hepatocytes. We found that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Importantly, epigenetic regulation of SOCS1 and subsequently ISGylation may be important factors in the development of cell type-specific host defense responses in hepatocytes that should be considered when studying chronic infections and oncogenic processes in the liver.

An extensive surgical resection in stage T4 small cell lung cancer with cardiac invasion: A case report and literature review.

Introduction and importance: We report a rare case of a patient with a mass involving both the hilum and the heart, but its specific nature could not be determined. SCLC was confirmed by postoperative pathology. It revealed that radical surgical resection for T4 SCLC should be considered an important part of multimodality treatment. Case presentation: A 49-year-old gentleman complained of mild chest tightness for a week. Two large mass lesions were detected on CECT in the left atrium and left hilum. After an MDT discussion, an extended resection was recommended. Postoperative pathology denoted a complete excision with no residuals and negative lymph nodes. Clinical discussion: Due to the rarity of lung metastases to the heart, it is vital to determine the homology between the hilar mass and the cardiac mass. Based on this, simultaneous surgical treatment is done and it is very beneficial for patients by eliminating those hazards, such as acute mechanical cardiac obstruction, and cardiac embolism. Our literature review demonstrates that the SCLC tumour progresses rapidly after cardiac metastasis, limiting the chance of a complete resection. Furthermore, complete resection of T4 tumours in NSCLC has been attempted many times, so it should also be tried on SCLC. Conclusion: It is common for SCLC tumours to progress rapidly once they havemetastasized to the heart. An aggressive operation such as radical resection can reduce tumor burdens, minimize the risk of sudden acute death and improve patient follow-up treatment, all of which may prolong the survival of patients.

Rapidly Progressive Precocious Puberty With an Elevated Testosterone Level in a 5-Year-Old Boy With a ß-Human Chorionic Gonadotropin-Secreting Intracranial Germ Cell Tumor in the Pineal Gland.

Objective: Peripheral precocious puberty (PP) is an infrequent etiology for early sexual development. Intracranial germ cell tumors (GCTs) are rare but can present infrequently with PP with the rate of development affected by the degree of tumor hormone production. Our objective was to describe a young boy with a ß-human chorionic gonadotropin (hCG)-secreting intracranial GCT with an extremely elevated testosterone level, who presented with rapidly progressive PP. Case Report: A 5-year-old boy presented with penile growth plus pubic hair, deepening voice, and body odor for 3 months. Physical examination revealed a height velocity of 16.25 cm/year, Tanner stage 3 pubic hair, and enlarged penis for age. Laboratory results revealed elevated serum and cerebrospinal fluid ß-hCG and 17-hydroxyprogesterone progesterone levels. The testosterone level was above the initial detection range at 2700 ng/dL. Follicle-stimulating hormone and luteinizing hormone were prepubertal with normal serum and cerebrospinal fluid alpha-fetoprotein levels. Imaging showed a pineal mass diagnosed as a ß-hCG-secreting GCT. During chemotherapy, the physical signs of PP remitted and laboratory values normalized. Discussion: Intracranial tumors can cause peripheral PP in boys. If the tumor produces high ß-hCG levels, this could cause severe hyperandrogenemia resulting in the rapid development of secondary sexual signs. GCTs should be considered in male patients with rapidly progressive PP, even in those lacking other signs of a brain tumor. Conclusion: When presented with a boy with PP, a GCT should be considered if workup shows an elevated testosterone level in conjunction with an elevated ß-hCG level, especially if with rapid development.

Clear cell carcinoma palisading in a focus of endometriosis on the uterine serosa - A case report and review of the literature.

Background: Clear cell carcinoma arising from the malignant transformation of endometriosis is a rare but aggressive cancer often diagnosed in perimenopausal women. Malignant transformation constitutes a rare complication of endometriosis, with only a few cases reported in the medical literature. Clear cell carcinoma and endometrioid carcinoma are the two most common histological subtypes associated with malignant endometriosis. Case Presentation: A 61-year-old Afro-Trinidadian woman underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for a degenerated uterine leiomyoma. Histopathology demonstrated an isolated finding of clear cell carcinoma occurring within an endometriotic cyst on the uterine serosa. Subsequent surgical staging demonstrated early-stage disease associated with a high-risk histological subtype and the patient was referred for adjuvant chemoradiotherapy. Conclusion: This case highlights the clinical manifestations and treatment modalities employed for an early-stage high-risk subtype of endometriosis-associated cancer. In light of the few publications on this clinical entity, we hope to raise awareness of this unique complication of endometriosis and contribute evidence to the development of standardized treatment protocols.

The Course of LIRADS 3 and 4 Hepatic Abnormalities as Correlated With Explant Pathology: A Single Center Experience.

Background and aims: The Liver Reporting and Data System (LI-RADS) is the standard classification of imaging findings of hepatic abnormalities for hepatocellular carcinoma (HCC) surveillance. We aimed to study the course of LI-RADS 3 and 4 (LR-3 and LR-4) abnormalities through correlations with explant pathology. Methods: A single center retrospective study of liver transplant recipients between January 2016 and September 2019 with HCC on explant pathology was conducted. Eligible patients were divided into three subgroups based on their LI-RADS classification: LR-3/4, LR-5 only, and combination of LR-3/4/5. Results: There were 116 eligible patients with 99 LR-3/4 observations (60 LR-3 and 39 LR-4); the rest had LR-5 lesions. LR-4 more often than LR-3 observations progressed to LR-5 (36% vs 12%) and with shorter duration during follow-up (median 175 days and 196 days). Mean size growth of LR-3 and LR-4 abnormalities were 2.6 and 3.8 mm; median growth rates were 0.2 and 0.4 mm/month, respectively. Numbers of HCC lesions per explant, largest HCC lesion size, and cumulative size were higher in LR-3/4/5 subgroup than LR-5 subgroup (P = 0.007, 0.007 and 0.006, respectively); 68% of LR-3 and 82% of LR-4 abnormalities were confirmed HCC on explant (P = 0.09). Conclusion: Compared to LR-3, more LR-4 abnormalities progressed to LR-5 (12% and 36%, respectively) in a shorter time and with faster growth rate. A high proportion of LR-3 and LR-4 lesions (68% and 82%, respectively) were confirmed HCC on explant, raising the question of whether excluding HCC based on radiologic criteria alone is adequate in those with LR-3/4 abnormalities.

Aristolochic acids exposure was not the main cause of liver tumorigenesis in adulthood.

Aristolochic acids (AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I (AAI) reacts with DNA to form covalent aristolactam (AL)-DNA adducts, leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in mainland China. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI-DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA-DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood.

SQSTM1 Expression in Hepatocellular Carcinoma and Relation to Tumor Recurrence After Radiofrequency Ablation.

Background/Aims: Autophagy is a process that allows the degradation of detrimental components through the lysosome to maintain cellular homeostasis under variable stimuli. SQSTM1 is a key molecule involved in functional autophagy and is linked to different signaling pathways, oxidative responses, and inflammation. Dysregulation of autophagy is reported in a broad spectrum of diseases. Accumulation of SQSTM1 reflects impaired autophagy, which is related to carcinogenesis and progression of various tumors, including hepatocellular carcinoma (HCC). This study investigated SQSTM1 protein expression in HCC and its relation to the clinicopathological features and the likelihood of tumor recurrence after radiofrequency ablation (RFA). Methods: This study included 50 patients with cirrhotic HCC of Barcelona Clinic Liver Cancer stages 0/A-B eligible for RFA. Tumor and peritumor biopsies were obtained just prior to local ablation and assessed for tumor pathological grade and SQSTM1 expression by immunohistochemistry. Patients were followed for one year after achieving complete ablation to detect any tumor recurrence. Results: Serum alpha-fetoprotein level (U = 149.50, P = 0.027∗) and pathological grade of the tumor (χ2 = 12.702, P = 0.002∗) associated significantly with the tumor response to RFA. SQSTM1 expression level was significantly increased in HCC compared to the adjacent peritumor cirrhotic liver tissues (Z = 5.927, P < 0.001∗). Significant direct relation was found between SQSTM1 expression level in HCC and the pathological grade of the tumor (H = 33.789, P < 0.001∗). On follow-up, tumor and peritumor SQSTM1 expression levels performed significantly as a potential predictor of the overall survival, but not the disease recurrence. Conclusions: SQSTM1 expression could determine aggressive HCC, even with reasonable tumor size and number, and identify the subset of HCC patients with short overall survival and unfavorable prognosis. SQSTM1 expression could not predict post-RFA intrahepatic HCC recurrence. SQSTM1 may be a potential biomarker and target for the selection of HCC patients for future therapies.

First Report of a Paediatric Collision Tumour in the Liver Recognised After Liver Transplantation: Blissful Ignorance Has Benefits!

Liver tumours are uncommon in the paediatric population, constituting 1-2 % of all paediatric tumours and 4% of all paediatric liver tumours. Hepatoblastoma followed by hepatocellular carcinoma is the most common tumours in this age group. Simultaneous development of two discrete liver tumours of distinct histologies (collision tumour) has been occasionally reported in adults but never in children. We hereby present the first reported case of hepatic collision tumours (hepatocellular carcinoma and cholangiocarcinoma) in the explant liver of a child who underwent living donor liver transplantation for end-stage liver disease and severe hepatopulmonary syndrome. The manuscript describes the clinical, radiological and histopathological findings of this case and also highlights the dilemma associated with management of this case had the diagnosis been made in the preoperative setting and also about the proposed management plan for this case in the postoperative period.

Spontaneous Rupture of Hepatocellular Carcinoma: New Insights.

Background: Spontaneous rupture of hepatocellular carcinoma (HCC) is a potentially fatal complication and the third leading cause of death in patients with HCC after tumor progression and liver failure. Previous studies suggested that improved HCC surveillance has decreased the incidence of rupture. This study aims to characterize patients with ruptured HCC over time and identify predictors of rupture. Methods: We retrospectively reviewed a prospectively collected database of 1451 HCC patients to identify cases with rupture and predictors of rupture. Data were divided into three 9-year eras to compare and trend patient/tumor characteristics and rupture. Results: Fifty-seven patients (3.9%) presented with spontaneous HCC rupture and the following characteristics: mean age 62.6 years, 73.7% males, 41% cirrhosis, and mean tumor size of 8.0 cm. On multivariate analyses, predictors of rupture included obesity, tumor >5 cm, and single tumors, whereas the presence of cirrhosis was a negative predictor for rupture.Across three eras, there were changes in disease etiology and decreases in tumor size, and more HCCs were found with surveillance. However, more patients were noncirrhotic, and the incidence of spontaneous rupture was unchanged over time. Conclusion: Despite improved early detection of HCC over time, the incidence of rupture has been unchanged. The persistent incidence of rupture may possibly be attributed to increasing proportion of fatty liver-related HCC patients who lack traditional risk factors for surveillance and may not have cirrhosis. Better identification of fatty liver disease and determining which patients need HCC surveillance may be needed in the future to prevent spontaneous rupture.

Adapting the Utility of Lipiodol CT in Treating Small Hepatocellular Carcinoma.

Introduction: Multiphase MRI liver is the gold-standard imaging modality for staging hepatocellular carcinoma (HCC) in patients with cirrhosis. Often, small HCCs diagnosed on multiphase MRI are occult on B-mode ultrasound and multiphase CT (MPCT) and thus pose a challenge for loco-regional therapy. We adapted the technique of lipiodol CT in treating two such patients of small HCC. Methods: Lipiodol-CT involved an intra-arterial lipiodol injection through the hepatic artery followed by a noncontrast CT liver. CT delineated small, hyperdense, lipiodol-laden hepatic nodules, which served as a target for executing ablation of the nodule and also revealed the true disease stage by depicting the additional number of tumors in the liver. Results: Case one was a 51-year female, known case of chronic hepatitis C who presented with ascites for two months. She was diagnosed with a small HCC (LI-RADS-4) in a cirrhotic liver on multiphase MRI. Percutaneous radiofrequency ablation was planned, but the mass was not located on ultrasound or multiphase CT. Lipiodol-CT was undertaken, which delineated the lipiodol-laden small HCC, which served as a target for executing ablation. Case 2 was a 55-year male, Child-Pugh A cirrhotic, who had undergone right extended hepatectomy for hepatitis B-related HCC. Follow-up MRI revealed a 5 mm segment III nodule, which had increased in size on repeat MRI at 3 months (LI-RADS-4). This nodule, too, was occult on both ultrasound and MPCT. Lipiodol CT revealed additional multiple, variable-sized lipiodol-laden nodules in the liver remnant. Treatment of trans-arterial chemoembolization was performed at one month. Both patients showed complete response to treatment. Conclusion: Lipiodol CT can be safely used in a new role of facilitating treatment of small HCCs diagnosed on MRI but occult on ultrasonography and MPCT.

Hepatic Follicular Dendritic Cell Sarcoma with Epithelioid Morphology: Histopathologist's Perspective.

Follicular dendritic cell (FDC) sarcoma is an uncommon tumor of the liver with only 30 previous cases reported in the English literature. Histopathological examination is the gold standard for the diagnosis of FDC sarcoma although the diagnosis is often missed because of its rarity. It usually presents with spindle-cell morphology although epithelioid/biphasic morphology is also well-known. This morphological variation can also pose a diagnostic challenge. We discuss a case of unresectable hepatic FDC sarcoma in an adult male who was diagnosed in core biopsy. We highlight the relevant histomorphological differentials and diagnostic approaches to FDC sarcoma in this anecdote.