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.

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.

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.

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.

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.

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.

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).

Xanthogranulomatous orchitis: A rare case of testicular mass.

Xanthogranulomatous orchitis is a rare non-malignant condition. This study reports a new case of xanthogranulomatous orchitis in a 77-year-old male, who presented with acute right scrotal mass. Ultrasound and computed tomography showed a heterogenous lesion involving the testis, with a loculated collection in the overlying scrotal wall. Scrotal exploration revealed an abscess involving the scrotal skin, with hard mass involving the testis, with histological evidence of infiltration and replacement of most testicular parenchyma. This case highlights this important consideration for xanthogranulomatous orchitis in the differential of testicular mass, particularly when associated with a purulent collection. Section headings: •Inflammation and Infection•General Urology.

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.

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.

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.

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.

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.

Clinical and genetic characteristics of two patients with tyrosinemia type 1 in Slovenia - A novel fumarylacetoacetate hydrolase (FAH) intronic disease-causing variant.

Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism that leads to severe liver, kidney, and neurological dysfunction. Newborn screening (NBS) can enable a timely diagnosis and early initiation of treatment. We presented the follow up of the only two Slovenian patients diagnosed with HT1. Metabolic control was monitored by measuring tyrosine, phenylalanine and succinylacetone from dried blood spots (DBSs). Retrograde screening of HT1 was performed from DBSs taken at birth using tandem mass spectrometry. First patient was diagnosed at the age of 6 months in the asymptomatic phase due to an abnormal liver echogenicity, the other presented at 2.5 months with an acute liver failure and needed a liver transplantation. The first was a compound heterozygote for a novel FAH intronic variant c.607-21A>G and c.192G>T whereas the second was homozygous for c.192G>T. At the non-transplanted patient, 66% of tyrosine and 79% of phenylalanine measurements were in strict reference ranges of 200-400 µmol/L and >30 µmol/L, respectively, which resulted in a favorable cognitive outcome at 3.6 years. On retrograde screening, both patients had elevated SA levels; on the other hand, tyrosine was elevated only at one. We showed that non-coding regions should be analyzed when clinical and biochemical markers are characteristic of HT1. DBSs represent a convenient sample type for frequent amino acid monitoring. Retrograde diagnosis of HT1 was possible after more than three years of birth with SA as a primary marker, complemented by tyrosine.

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.

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.

CRISPR-targeted genome editing of human induced pluripotent stem cell-derived hepatocytes for the treatment of Wilson's disease.

BACKGROUND & AIMS: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by loss-of-function mutations in ATP7B, which encodes a copper-transporting protein. It is characterized by excessive copper deposition in tissues, predominantly in the liver and brain. We sought to investigate whether gene-corrected patient-specific induced pluripotent stem cell (iPSC)-derived hepatocytes (iHeps) could serve as an autologous cell source for cellular transplantation therapy in WD. METHODS: We first compared the in vitro phenotype and cellular function of ATP7B before and after gene correction using CRISPR/Cas9 and single-stranded oligodeoxynucleotides (ssODNs) in iHeps (derived from patients with WD) which were homozygous for the ATP7B R778L mutation (ATP7BR778L/R778L). Next, we evaluated the in vivo therapeutic potential of cellular transplantation of WD gene-corrected iHeps in an immunodeficient WD mouse model (Atp7b -/- / Rag2 -/- / Il2rg -/- ; ARG). RESULTS: We successfully created iPSCs with heterozygous gene correction carrying 1 allele of the wild-type ATP7B gene (ATP7BWT/-) using CRISPR/Cas9 and ssODNs. Compared with ATP7BR778L/R778L iHeps, gene-corrected ATP7BWT/- iHeps restored i n vitro ATP7B subcellular localization, its subcellular trafficking in response to copper overload and its copper exportation function. Moreover, in vivo cellular transplantation of ATP7BWT/- iHeps into ARG mice via intra-splenic injection significantly attenuated the hepatic manifestations of WD. Liver function improved and liver fibrosis decreased due to reductions in hepatic copper accumulation and consequently copper-induced hepatocyte toxicity. CONCLUSIONS: Our findings demonstrate that gene-corrected patient-specific iPSC-derived iHeps can rescue the in vitro and in vivo disease phenotypes of WD. These proof-of-principle data suggest that iHeps derived from gene-corrected WD iPSCs have potential use as an autologous ex vivo cell source for in vivo therapy of WD as well as other inherited liver disorders. LAY SUMMARY: Gene correction restored ATP7B function in hepatocytes derived from induced pluripotent stem cells that originated from a patient with Wilson's disease. These gene-corrected hepatocytes are potential cell sources for autologous cell therapy in patients with Wilson's disease.

Early hepatocellular carcinoma detection using magnetic resonance imaging is cost-effective in high-risk patients with cirrhosis.

BACKGROUND & AIMS: Reinforced hepatocellular carcinoma (HCC) surveillance using magnetic resonance imaging (MRI) could increase early tumour detection but faces cost-effectiveness issues. In this study, we aimed to evaluate the cost-effectiveness of MRI for the detection of very early HCC (Barcelona Clinic Liver Cancer [BCLC] 0) in patients with an annual HCC risk >3%. METHODS: French patients with compensated cirrhosis included in 4 multicentre prospective cohorts were considered. A scoring system was constructed to identify patients with an annual risk >3%. Using a Markov model, the economic evaluation estimated the costs and life years (LYs) gained with MRI vs. ultrasound (US) monitoring over a 20-year period. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental costs by the incremental LYs. RESULTS: Among 2,513 patients with non-viral causes of cirrhosis (n = 840) and/or cured HCV (n = 1,489)/controlled HBV infection (n = 184), 206 cases of HCC were detected after a 37-month follow-up. When applied to training (n = 1,658) and validation (n = 855) sets, the construction of a scoring system identified 33.4% and 37.5% of patients with an annual HCC risk >3% (3-year C-Indexes 75 and 76, respectively). In patients with a 3% annual risk, the incremental LY gained with MRI was 0.4 for an additional cost of €6,134, resulting in an ICER of €15,447 per LY. Compared to US monitoring, MRI detected 5x more BCLC 0 HCC. The deterministic sensitivity analysis confirmed the impact of HCC incidence. At a willingness to pay of €50,000/LY, MRI screening had a 100% probability of being cost-effective. CONCLUSIONS: In the era of HCV eradication/HBV control, patients with annual HCC risk >3% represent one-third of French patients with cirrhosis. MRI is cost-effective in this population and could favour early HCC detection. LAY SUMMARY: The early identification of hepatocellular carcinoma in patients with cirrhosis is important to improve patient outcomes. Magnetic resonance imaging could increase early tumour detection but is more expensive and less accessible than ultrasound (the standard modality for surveillance). Herein, using a simple score, we identified a subgroup of patients with cirrhosis (accounting for >one-third), who were at increased risk of hepatocellular carcinoma and for whom the increased expense of magnetic resonance imaging would be justified by the potential improvement in outcomes.

Safety Assessment of Autologous Stem Cell Combination Therapy in Patients With Decompensated Liver Cirrhosis: A Pilot Study.

BACKGROUND: Haematopoietic stem cell (HSC) infusion has demonstrated short-term improvement in liver functions in patients with chronic liver disease. The combination of HSC with mesenchymal stem cells (MSCs), which has an immunomodulatory effect, may augment the effects and enhance the duration of improvements on liver functions. The aim of the present study was to assess the safety of infusing the combination of autologous HSCs and MSCs in decompensated liver cirrhosis. METHODS: In phase I of the study, in vitro assessment was performed to observe the effect of coculturing MSCs with HSCs on their viability and cytokine profiles. Phase II of the study was to assess the safety of combination of stem cell infusions. Bone marrow (50 ml) was aspirated for MSC isolation and expansion using standard protocol. Patients received subcutaneous doses (n = 5) of granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization followed by leukapheresis for harvesting HSCs using CliniMacs. HSCs and MSCs were infused through the hepatic artery under fluoroscopic guidance and were monitored for any adverse effects. RESULTS: In vitro studies revealed 94% viable HSCs in coculture similar to monoculture. HSCs released only interleukin (IL)-8, whereas MSCs secreted IL-8 and IL-6 in monocultures, and both IL-8 and IL-6 were secreted in coculture. G-CSF administration- and bone marrow aspiration-related complications were not observed. Infusion of the cells through the hepatic artery was safe, and no postprocedural complications were noted. CONCLUSION: The combination of autologous HSC and MSC infusion is a safe procedure in patients with decompensated liver cirrhosis, and the outcomes needed to be assessed in larger studies. TRIAL NUMBER: NCT04243681.