Elevated Alpha-fetoprotein Research Articles

Diagnostic features of pediatric testicular yolk sac tumors: a 13-year retrospective analysis

BackgroundTesticular yolk sac tumor (YST) is a rare neoplasm with limited practical guidance for preoperative diagnostic assessment. This study aims to conduct a retrospective analysis of the value of clinical profiles and MRI parameters in accurately diagnosing pediatric testicular YST while exploring characteristic indicators for these patients.MethodsThis retrospective study analyzed eighty patients with a testicular mass who underwent surgical treatment and preoperative MRI. Clinical characters (age, preoperative serum alpha-fetoprotein (AFP) levels), and radiology features were recorded and compared. Subsequently, patients were categorized into YST and non-YST groups based on histology. Comparative statistical analyses were then used to compare factors between the two groups. The receiver operating characteristic curve (ROC) analysis was conducted to evaluate the diagnostic performance of the indicators for pediatric testicular YST.ResultsForty patients (50%) were diagnosed with YST. In comparison to the non-YST group, patients with testicular YST were younger and had larger tumor sizes, accompanied by significantly elevated AFP levels. On MRI, most YST cases (n = 38) exhibited predominantly solid lesions, whereas non-YST tumors were more likely to contain cystic components. The bright dot sign and thickened spermatic cord might also be helpful in differentiating YST (p < 0.05). The optimal factor for diagnosing testicular YST was signal intensity, with an AUC value of 0.936 (95%CI: 0.877 ~ 0.995).ConclusionsA predominantly solid testicular mass with a bright dot sign, thickened spermatic cord ipsilaterally, and elevated AFP levels should raise suspicion for YST.

Risk assessment of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis and hypertension: a propensity score matching-based retrospective cohort study

To analyze the factors affecting the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B-associated cirrhosis (CHB-Cir) complicated by essential hypertension (EH) and explore the impact of EH on HCC risk in patients with CHB-Cir. This study was conducted among the patients with CHB-Cir with or without EH received antiviral therapy in the Infectious Disease Department, Third Affiliated Hospital of Xinxiang Medical University from January, 2017 to January, 2024. The cases with insufficient follow-up time or missing data were excluded. The patients were subjected to propensity score matching in a 1:1 ratio to form an EH group and a non-EH group. The Kaplan-Meier method was used to compare the cumulative incidence of HCC between the two groups, and the Cox proportional hazards regression model was used to analyze the risk of HCC and the factors affecting HCC risk. A total of 390 CHB-Cir patients (274 male and 116 female patients) were enrolled in this study, including 195 with EH and 195 without EH. In these patients, EH was significantly correlated with the occurrence of HCC (HR=1.69, P=0.002). Multivariate analysis suggested that the male gender (HR=1.73, P=0.005), a family history of liver cancer (HR=2.23, P < 0.001), elevated alpha-fetoprotein (HR=2.83, P=0.001), elevated glutathione reductase (HR=1.53, P=0.046), reduced high-density lipoprotein (HR=1.46, P=0.027), and elevated low-density lipoprotein (HR=2.29, P=0.003) were all significantly correlated with HCC occurrence, while elevated triglycerides (HR= 0.37, P < 0.001) was a protective factor against HCC. In the EH group, treatment with non-RASIs drugs (HR=2.77, P=0.021) and no treatment/diuretic treatment (HR=7.18, P < 0.001) were significantly correlated with HCC occurrence. Hypertension increases the risk of HCC in patients with CHB-Cir, suggesting the importance of controlling hypertension in these patients.

Nomogram for predicting testicular yolk sac tumor in children based on age, alpha-fetoprotein, and ultrasonography.

To establish a predictive model for distinguishing testicular benign or yolk sac tumors in children. We retrospectively analyzed data for 119 consecutive patients with unilateral testicular tumors treated at a single institution from June 2014 to July 2020. The patients were divided into the benign (n = 90) and yolk sac (n = 29) tumor groups based on the pathological diagnosis. We recorded patient age, serum markers [serum alpha-fetoprotein (AFP), human chorionic gonadotropin], and tumor ultrasonic findings (maximum diameter, ultrasonic echo, blood flow signal). Predictive factors were identified using descriptive statistical methods. A nomogram was established for preoperative prediction. An additional 46 patients were used as a validation cohort to verify the model. Patients with testicular yolk sac tumors were younger (median age: 14.0 vs. 34.0 months, P = 0.001) and had a higher incidence of elevated AFP levels (93.1% vs. 2.2%, P < 0.001). Ultrasonography indicated that testicular yolk sac tumors tended to have larger maximum diameters (26.5 ± 11.3 vs. 16.6 ± 9.2 cm, P < 0.001), a higher proportion of hypoechoic masses (44.8% vs. 8.9%, P < 0.001), and a higher incidence of masses with strong blood flow signals (93.1% vs. 5.6%, P < 0.001). A nomogram based on age, AFP levels, and ultrasound blood flow signals effectively predicted the probability of yolk sac tumor in children, with an accuracy of 0.98 (95% confidence interval: 0.984-1.003). The Brier score of the nomogram was 0.0002. A nomogram based on age, AFP levels, and ultrasound blood flow signals can effectively predict the probability of testicular yolk sac tumor preoperatively, aiding in clinical decision-making and patient counseling.

A rat model of cirrhosis with well-differentiated hepatocellular carcinoma induced by thioacetamide

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, and commonly associated with hepatic fibrosis or cirrhosis. This study aims to establish a rat model mimicking the progression from liver fibrosis to cirrhosis and subsequently to HCC using thioacetamide (TAA). We utilized male Lewis rats, treating them with intra-peritoneal injections of TAA. These rats received bi-weekly injections of either 200 mg/kg TAA or saline (as a control) over a period of 34 weeks. The development of cirrhosis and hepatocarcinogenesis was monitored through histopathological examinations, biochemical markers, and immunohistochemical analyses. Our results demonstrated that chronic TAA administration induced cirrhosis aggressive cholangiocarcinoma in addition to well-differentiated HCC, providing a model for early-stage, stage and a mixed liver cancer phenotype. This model is characterized by increased fibrosis, altered liver architecture, and increased hepatocyte proliferation. Biochemical analyses revealed significant alterations in liver function markers, including elevated alpha-fetoprotein (AFP) levels, without affecting kidney function or causing significant weight loss or mortality in rats. This TAA-induced cirrhosis and mixed HCC rat model successfully replicates the clinical progression of human HCC, particularly in terms of liver function impairment and early-stage liver cancer characteristics. It serves as a valuable tool for future research on the mechanisms of antitumor drugs in tumor initiation and development.

Outcomes of Pediatric Hepatocellular Carcinoma: A Single-Center Experience With Resection Versus Transplantation.

Pediatric hepatocellular carcinoma (HCC) presents significant challenges due to its aggressive nature, with survival depending on complete resection. We aimed to assess outcomes between liver resection (LR) and liver transplantation (LT). A total of 25 patients were retrieved, four of whom were classified as palliative at diagnosis. A subanalysis comparing cirrhotic liver (n = 14) versus de novo (n = 11) HCC was performed to identify confounding variables. Further evaluation focused on the 21 children with histologically confirmed HCC who underwent LR (n = 7) versus LT (n = 14). Kaplan-Meier survival curves were constructed. The mean age was 7.8 ± 6.1 years for patients with cirrhotic liver and 12.1 ± 3.5 years for de novo HCC. Our group observed overall total survival rates of 100%, 85%, and 77% at 12, 36, and 60 months, respectively. De novo tumors had a higher recurrence rate and a poorer prognosis (p = 0.039 and p = 0.045). The disease-free survival at 60 months in our cohort was significantly lower among the LR group compared to the LT group (14% vs. 82%; p = 0.0081). Recurrence after initial management (n = 8) showed location differences between LR and LT. Preoperative alpha-fetoprotein (AFP) was elevated in 71% of children, but did not correlate with recurrence or compromised survival. Elevated AFP 3 months post-operation affected the course negatively (p = 0.044). Tumor number and diameter exhibited a trend towards poorer outcomes. These findings emphasize the need for comprehensive pediatric surgical guidelines for HCC. We recommend LT over LR in pediatric cases. Extrahepatic disease post-neoadjuvant chemotherapy remains the only absolute contraindication.

The Neoangiogenic Transcriptomic Signature Impacts Hepatocellular Carcinoma Prognosis and Can Be Triggered by Transarterial Chemoembolization Treatment.

Background/Objectives: We evaluated the relationship between the neoangiogenic transcriptomic signature (nTS) and clinical symptoms, treatment outcomes, and survival in hepatocellular carcinoma (HCC) patients. Methods: This study prospectively followed 328 patients in the derivation and 256 in the validation cohort (with a median follow-up of 31 and 22 months, respectively). The nTS was associated with disease presentation, treatments administered, and overall survival rates. Additionally, this study investigated how multiple treatments influenced changes in nTS status and alterations in microRNA expression. Results: The nTS was identified in 27.4% of patients, linked to aggressive features like multifocality and elevated alpha-fetoprotein (AFP), a pattern consistent with that of the validation cohort. Most patients in both cohorts received treatment for HCC. nTS+ patients had limited access to, and benefited less from, liver transplantation or radiofrequency ablation (RFA) compared to nTS- patients. By the end, 78.9% had died, with nTS- patients showing better median survival and response to treatments than their nTS+ counterparts, who had lower survival across all treatment types. Among those who received transarterial chemoembolization (TACE), 31.2% (21/80 patients after the initial treatment and another four following a second TACE) transitioned from an nTS- to an nTS+ status. This shift was associated with lower survival and alterations in microRNA expressions related to oncogenic pathways. Conclusions: The nTS markedly influences treatment eligibility and survival in patients with HCC. Notably, the nTS can develop after repeated TACE procedures, significantly impacting patient survival and altering oncogenic microRNA expression patterns. These findings highlight the critical role of the nTS in guiding treatment decisions and prognostication in HCC management.

TRIM55 restricts the progression of hepatocellular carcinoma through ubiquitin-proteasome-mediated degradation of NF90

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide. Tripartite motif containing 55 (TRIM55), also known as muscle-specific ring finger 2 (Murf2), belongs to the TRIM protein family and serves as an E3 ligase. Recently, the function and mechanism of TRIM55 in the advancement of solid tumors have been elucidated. However, the role of TRIM55 and its corresponding protein substrates in HCC remains incompletely explored. In this study, we observed a significant reduction in TRIM55 expression in HCC tissues. The downregulation of TRIM55 expression correlated with larger tumor size and elevated serum alpha-fetoprotein (AFP), and predicted unfavorable overall and tumor-free survival. Functional experiments demonstrated that TRIM55 suppressed the proliferation, migration, and invasion of HCC cells in vitro, as well as hindered HCC growth and metastasis in vivo. Additionally, TRIM55 exhibited a suppressive effect on HCC angiogenesis. Mechanistically, TRIM55 interacted with nuclear factor 90 (NF90), a double-stranded RNA-binding protein responsible for regulating mRNA stability and gene transcription, thereby facilitating its degradation via the ubiquitin-proteasome pathway. Furthermore, TRIM55 attenuated the association between NF90 and the mRNA of HIF1α and TGF-β2, consequently reducing their stability and inactivating the HIF1α/VEGF and TGFβ/Smad signaling pathways. In conclusion, our findings unveil the important roles of TRIM55 in suppressing the progression of HCC partly by promoting the degradation of NF90 and subsequently modulating its downstream pathways, including HIF1α/VEGF and TGFβ/Smad signaling.

Clinical Rarity Unveiled: Adenocarcinoma with Enteroblastic Differentiation at the Gastroesophageal Junction in a Young Patient - A Diagnostic Challenge Shaping Therapeutic Paradigms

Abstract Introduction/Objective This report details a case of a young patient diagnosed with an adenocarcinoma with enteroblastic differentiation at the gastroesophageal junction (GEJ), characterized by Alpha-Fetoprotein (AFP) production. This manifestation previously rarely documented in young patients (25-44 years old), underscores the critical role of precise pathology diagnosis in guiding effective patient management. Methods/Case Report The patient’s clinical presentation included chest pain, abdominal pain, and weight loss, prompting imaging studies revealing liver masses, lesions in the lung and adrenal gland, and retroperitoneal adenopathy with unremarkable testicular findings. Rapidly progressing dysphagia led to a liver biopsy and esophagogastroduodenoscopy (EGD), where a fungating mass extending from the distal esophagus into the stomach was biopsied. A subsequent serologic test unveiled an elevated serum AFP level (approximally 31, 000 ng/ml). Results (if a Case Study enter NA) Histological examination revealed similarities between the liver and distal esophageal tumors, characterized by moderately differentiated carcinoma with solid and glandular growth patterns. The tumor cells, resembling fetal gut epithelium, exhibited positive immunostaining for SALL4, AFP, CK8-18, CK19, and CDX2. A diagnosis of adenocarcinoma with enteroblastic differentiation at the GEJ was determined, correlating with clinical and radiological assessments. Despite initiating one cycle of gastrointestinal related chemotherapy, the patient succumbed to tumor lysis syndrome within a month of diagnosis. Conclusion This case highlights the critical need for a comprehensive differential diagnosis when encountering young patients with AFP-producing malignancies. Although metastatic non-seminomatous germ cell cancer is a primary consideration, upper gastrointestinal adenocarcinoma with unique characteristics, as demonstrated in this case, requires distinct therapeutic approaches, emphasizing the importance of accurate and timely diagnosis.

The umblicus says it all

Abstract Introduction/Objective Umbilical nodules can be divided into benign and malignant. Malignant lesions of the umbilicus are very rare. They can arise from primary tumors or secondary to abdominal and pelvic malignancies. Literature review suggests that these umbilical lesions can present as primary tumor in 38% of the cases, endometriosis in 32%, and metastatic lesions in 30%. Umbilical metastasis is one of the main characteristic signs of extensive neoplastic disease and is known as Sister Mary Joseph’s nodule (SMJN). It is a very rare finding and the incidence of SMJN is 1- 3% in people diagnosed with intra-abdominal or pelvic malignancies. Methods/Case Report A 31-year-old male with no past medical history presented to the emergency room with 3 months history of umbilical nodule and 60 pounds weight loss. He experienced early satiety, abdominal pain, nausea and generalized fatigue. CT abdomen showed hepatomegaly with numerous hypoattenuating lesions throughout the liver with peripheral enhancement, and hypoattenuating mass within the pancreatic tail and body measuring approximately 2.1 x 5.8 cm that appears contiguous with hilar splenic lesion. CT chest showed multiple pulmonary metastases with prominent precarinal and subcarinal lymph nodes. Serologic tests revealed elevated Alpha fetoprotein, ALP, ALT, and CA19-9. Patient underwent umbilical nodule core biopsy and right liver core biopsy. Microscopic evaluation of the specimens revealed pancreatic acinic cell carcinoma with two different morphological variants. Umbilical nodule with glandular pattern and liver lesion with trabecular pattern. Immunohistochemical stains were performed with tumor cells positive for CK 7, Trypsin and BCL-10 and negative for Glypican 3, CK 20, AFP and CD56. The prognosis is poor, with an average survival time of about 19 months. After the diagnosis patient underwent chemotherapy. Results (if a Case Study enter NA) NA Conclusion Umbilical nodules can be diagnosed with careful clinical and histopathological evaluation. The prognosis of patients presenting with SMJN is generally poor as it is a sign of advanced malignancy. Sometimes it may be the first and only sign of an internal neoplasm. Therefore, this is an important differential diagnosis to consider.

Prognostic Impact of the Cholangiolar Component in Combined Hepatocellular-Cholangiocarcinoma: Insights From a Western Single-Center Study.

Primary liver malignancies, such as hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA), represent significant contributors to global cancer-related mortality. The diagnostic challenges associated with distinguishing cHCC-CCA from HCC and ICC stem from their rarity and overlapping histological features. This study aimed to reclassify primary liver tumors resected at a Western center and to compare clinicopathological features and prognosis among patients with HCC, ICC, and cHCC-CCA. A retrospective analysis was conducted on patients undergoing resection for HCC, ICC, or cHCC-CCA between 2007 and 2017. Clinical and perioperative data were collected, and pathological specimens were reclassified by a specialized pathologist. Statistical analysis was employed to compare clinical features and survival outcomes among the different tumor types. Out of the initially identified 192 patients, 140 were included in the analysis. Following reclassification, 71.42% were diagnosed with HCC, 12.14% with ICC, and 16.42% with cHCC-CCA. Patients with HCC were predominantly male and exhibited a higher incidence of isolated liver recurrence. ICC patients more frequently underwent open procedures. Additionally, patients with HCC and cHCC-CCA showed higher rates of cirrhosis, elevated alpha-fetoprotein levels, and extrahepatic recurrence, while those with ICC and cHCC-CCA demonstrated elevated CA 19-9 levels. Overall survival and disease-free survival were longer for HCC compared to cases with a cholangiolar component (ICC and cHCC-CCA). Histological evaluation should actively incorporate the search for a cholangiolar component in primary liver tumors to prevent misdiagnosis, as its presence indicates a poorer prognosis.

B-149 Diverse glycosylation of circulating alpha fetoprotein in chronic liver diseases profiled by intact mass high resolution mass spectrometry

Abstract Background Alpha fetoprotein (AFP) is a circulating tumor marker utilized clinically to detect liver cirrhosis, liver cancer and testicular seminomas. AFP molecule contains one single N-glycosylation site, with highly variable glycan structures, resulting in diverse AFP glycoforms in circulating blood. The core fucosylation of AFP (AFP-L3) is a clinical biomarker to monitor and predict risks of liver cancer progression and recurrence. Clinical testing for AFP-L3 utilizes lectin-binding and gel-shift electrophoresis. We developed a novel method to measure AFP glycoforms, based on immune-enrichment and liquid chromatography with high resolution mass spectrometry (LC-HRMS). Methods Immune enrichment of AFP was achieved by anti-AFP antibody, immobilized to magnetic beads. After binding and enrichment, the magnetic beads were washed, AFP was eluted, and the samples were analyzed by LC-HRMS (Exploris 480 MS and Vanquish UHPLC, Thermo Fisher Scientific), using full scan, positive polarity acquisition mode. Chromatographic separation was performed on PLRP column (Agilent); flow rate 200 µL/min. The HRMS data were processed and deconvoluted with intact mass analysis workflow in Biopharma Finder 5.1 (Thermo Fisher Scientific) to derive the intact AFP masses. The method’s sensitivity and imprecision were assessed by replicate analysis of serial diluted patient serum samples. AFP and its associated glycoforms were matched and identified with an in-house developed bioinformatics workflow. The deconvoluted intact masses and the sum intensity of detected charged species for each AFP glycoform were used to quantify relative abundance of AFP glycoforms. Results The method specificity for AFP was confirmed by bottom-up analysis after immune-enrichment with observed peptide sequence coverage over 35%. The recovery of the immune enrichment was shown to be independent of the AFP glycoform compositions. The identified AFP glycoforms and their relative abundance were consistent among replicates between AFP concentration 100 ng/mL and 5000 ng/mL. Analysis of authentic serum specimens from patients with different chronic liver diseases and liver cancer (n=102), revealed multiple complex biantennary branched AFP glycan modifications, with different numbers of terminal sialic acid and core fucose. Four AFP glycoforms were identified in over 60% patient samples with elevated AFP concentrations. Although occurring consistently, relative abundance of these AFP glycoforms varied significantly among patients. Assessment of the AFP fucosylation and sialylation features suggested that the two are orthogonal processes. Clinical correlations suggested that fewer terminal sialic acids were associated with impaired liver functions, while the fucosylation was linked to inflammatory responses and presence of liver malignancy. Strong linear correlation (Spearman’s rs=0.952, N=35) was observed between AFP-L3% quantitated by the LC-HRMS method, and AFP-L3% determined by the lectin-binding based isotachophoresis assay (Wako Diagnostics). Discrepancies between the two methods were observed in specimens containing &amp;lt; 400 ng/mL of AFP, in which the LC-HRMS method detected only a single predominant glycoform. Conclusions We developed and evaluated the LC-HRMS method for profiling circulating AFP glycoforms in patients with chronic liver diseases and liver cancer. The detected AFP glycoforms and their relative abundance were used to establish glycan features, which can be further linked to cancer development, impaired liver function, and inflammation.

Growth differentiation factor 7 alleviates the proliferation and metastasis of hepatocellular carcinoma

Background and aimInflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma (HCC). However, the tumor-protective functions of growth differentiation factors (GDFs) in HCC are yet to be clarified. In this study, we aimed to evaluate the expression levels of 10 GDFs in tumor and paratumor tissues from patients with HCC and perform in vitro and in vivo experiments to elucidate the role of GDF7 in regulating the proliferation and metastasis of HCC. MethodsThe gene expression of 10 GDFs was compared between HCC and paratumors using The Cancer Genome Atlas dataset and patient-derived tissues. A tumor microarray containing 108 HCC tissue samples was used to explore the prognostic value of GDF7 expression. Loss-of-function experiments were also performed in vitro and in vivo to investigate the role of GDF7 in HCC. ResultsThe mRNA and protein levels of GDF7 were significantly lower in HCC tumors than in paratumors (P < 0.001). Kaplan–Meier analysis showed that decreased GDF7 expression in HCC was associated with worse overall survival (5-year rate: 61.8% vs. 27.5%, P < 0.001) and increased recurrence risk (P < 0.001). Multivariate Cox regression analysis demonstrated that low GDF7 expression, the presence of microvascular invasion, and elevated alpha-fetoprotein (AFP) levels were independent risk factors for tumor recurrence and poor survival. Downregulation of GDF7 also increased the tumor growth in HCC cells and in an HCC xenograft model. GDF7 knockdown promoted migration and invasion via epithelial–mesenchymal transition. Meanwhile, a negative correlation between JunB proto-oncogene (JUNB) and GDF7 was observed in HCC tissues. Modulating JUNB levels altered GDF7 protein expression. ConclusionGDF7 is a potential biomarker for predicting superior outcomes in patients with HCC. GDF7 amplification is a potential therapeutic option for HCC.

S4348 Elevated Alpha Fetoprotein of Unclear Origin: A New Subtype?

S4348 Elevated Alpha Fetoprotein of Unclear Origin: A New Subtype?

Vaginal Bleeding in an Infant due to Extragonadal Germ Cell Tumor: A Case Report with Review of Literature

Abstract Background: The occurrence of germ cell tumors (GCTs) in the vagina is uncommon in children, with yolk sac tumors being the most commonly identified histological subtype in young female infants. Clinical Description: A 7-month-old baby girl was presented with gradually progressive painless vaginal bleeding for 2 weeks. The infant was otherwise thriving well with no evidence of any local or systemic abnormality or constitutional symptoms. Management and Outcome: The child’s initial laboratory investigations were normal except for mild anemia. Further tests revealed elevated alpha-fetoprotein levels. Magnetic resonance imaging showed a mass in the vagina, which on cystovaginoscopic biopsy showed vaginal GCT. The patient was treated as per carboplatin (JM8), etoposide, and bleomycin (JEB) protocol. After the completion of the first cycle of chemotherapy, the infant responded well and was symptom-free. Conclusion: Vaginal bleeding in an otherwise healthy infant should raise suspicion of malignancy with GCT being a rare occurrence in this location. The present case highlights the success of the JEB protocol which is well tolerated by an infant.

Unusual presentation of fetal ventriculomegaly: a case report

Fetal ventriculomegaly (VM) is a relatively common finding during prenatal examinations and occurs in approximately 0.2% of live births. Although there are various causes, obstructive VM due to cerebellar hemorrhage is exceedingly rare. A 33-year-old primigravida presented at 32 weeks of gestation with VM. At 36 weeks of age, a male infant was delivered via cesarean section. Postnatal imaging revealed severe bilateral hydrocephalus and space-occupying lesions in the cerebellum. Initial concerns about a potential germ cell tumor were raised due to elevated alpha-fetoprotein levels in both serum and cerebrospinal fluid. An external ventricular drain was placed to manage obstructive hydrocephalus. When the baby was 1 month old, surgical exploration revealed an old blood clot without any evidence of a tumor. Histopathological examination confirmed an old hemorrhage with no malignant cells. This case underscores the diagnostic challenges in distinguishing between hemorrhages and tumors in the context of fetal VM. Despite elevated alpha-fetoprotein levels, no tumors were identified. The underlying cause of cerebellar hemorrhage remains unclear despite extensive workups. Nevertheless, this case report details multifaceted diagnostic efforts to address the rare occurrence of cerebellar hemorrhage related to fetal VM, leading to a comprehensive case presentation.

De Novo GRID2 Variant as a Cause of Ataxia with Oculomotor Apraxia and Alpha-Fetoprotein Elevation.

Bi-allelic pathogenic variants in GRID2 have been initially associated to an autosomal recessive form of spinocerebellar ataxia, namely SCAR18. Subsequently, few monoallelic cases have been described. Here we present a new subject harboring a novel de novo heterozygous GRID2 missense variant presenting with progressive ataxia together with cerebellar atrophy and, for the first time, alpha-fetoprotein (AFP) elevation. We retrospectively collected data of the patient followed at our clinic. Genetic analysis was performed through clinical exome sequencing with an in-house in-silico ataxia-related genes panel. Variant effect prediction was performed through in silico modeling. The patient had normal psychomotor development except for mild fine and gross motor impairment. In adolescence, he started presenting dysarthria and progressive ataxia. Blood tests showed significant AFP elevation. Brain MRI showed cerebellar atrophy mainly involving the vermis. The novel de novo heterozygous GRID2 (c.1954C>A; p.Leu652Ile) missense variant was disclosed. This variant is located within a highly conserved site with low tolerance to variation and it is predicted to cause protein structure destabilization. GRID2 expression appears to be influenced by other genes related with ataxia and AFP elevation, like ATM and APTX, suggesting a possible shared mechanism. This additional patient increases the scarce literature and genotypic spectrum of the GRID2-related ataxia and evidences a fairly homogeneous phenotype of ataxia with oculomotor abnormalities for the autosomal-dominant form. Alfa-fetoprotein elevation is a novel finding in this condition and this data must be confirmed in larger case-series to definitively state that GRID2-related ataxia can be included among ataxias with AFP increase.

Obsessive-compulsive disorder as a first manifestation of Ataxia with Oculomotor Apraxia type 2 due to a novel mutation of SETX gene.

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disorder presenting with cerebellar ataxia, sensory-motor axonal neuropathy, oculomotor apraxia, cerebellar atrophy and high alpha-fetoprotein (AFP) serum level. AOA2 is due to coding mutations of the SETX gene, mapped to chromosome 9q34. Seldom noncoding mutations affecting RNA processing have been reported too. To date psychiatric symptoms have never been reported in AOA2. A 19 years-old man came to our attention for progressive gait ataxia debuted five years earlier. His past medical history was unremarkable, while his parents were consanguineous. On neurological examination, he had bilateral horizontal gaze-evoked nystagmus with hypometric saccades and saccadic horizontal smooth pursuit, appendicular ataxia, limbs and trunk myoclonic involuntary movements with hands' dystonic postures and dance of the tendons. Psychological evaluation described intrusive and obsessive thoughts experienced by the patient, then diagnosed as obsessive-compulsive disorder. Blood tests detected an elevated AFP level. Brain MRI showed cerebellar atrophy, while electroneuromyography revealed an axonal sensory-motor polyneuropathy. In the suspicion of a pathology belonging to the autosomal recessive cerebellar ataxias (ARCA) spectrum disorder, a direct search of point mutations by whole-exome sequencing was performed revealing a novel biallelic variant in SETX gene (c.6208+2dupT), which was classified as likely pathogenic. The present case expands the genotypic and phenotypic spectrum of AOA2, reporting a novel likely pathogenic SETX mutation (c.6208+2dupT) and highlighting an early psychiatric involvement in AOA2, suggesting the need for psychiatric assessment in these neurologic patients.

Adult Uterine Wilm’s Tumor Miss-interpreted as Carcinosarcoma: A Case Report

Introduction: Wilm’s tumor (WT) is a common renal malignancy in children. Adult extrarenal WT involving the uterus is extremely rare. Herein, we reported a case of uterine WT in an old woman who was primarily diagnosed with carcinosarcoma. Case Presentation: A 63-year-old woman presented with abdominal pain and radiologic evidence of pelvic mass originating from the uterus, which was suggestive of sarcoma. Her Serum levels of Cancer Antigen 125 (CA125), Human Epididymis protein 4 (HE4), Cancer Antigen 19-9 (CA19-9), and Alpha Fetoprotein (AFP) were found to be elevated. She underwent total hysterectomy, bilateral salpingo-oophrectomy, and omentectomy. Pathologic examination of the specimens revealed a large uterine mass with serosal surface and omental invasion. The initial diagnosis was carcinosarcoma based on the mixed epithelial and mesenchymal components observed on microscopic examination. Triphasic components of papillary, primitive tubules, and glomeruloid structures, along with mesenchymal and blastemal elements were identified upon second opinion. An immunohistochemistry (IHC) study revealed positive reactions for WT1, CKAE1 /AE3, EMA, Glypican-3, and CD56 in all components of the tumor cells. P53 expression was normal. GATA3, ER, PR, and CD10 were negative. The final diagnosis was changed to WT. Conclusions: Uterine WT is an extremely rare malignancy, which could be associated with elevated serum AFP. Diagnosis and treatment of these rare tumors pose challenges for both pathologists and clinicians.

Challenges related to clinical decision-making in hepatocellular carcinoma recurrence post-liver transplantation: Is there a hope?

Hepatocellular carcinoma (HCC) is a common liver malignancy and represents a serious cause of cancer-related mortality and morbidity. One of the favourable curative surgical therapeutic options for HCC is liver transplantation (LT) in selected patients fulfilling the known standard Milan/University of California San Francisco criteria which have shown better outcomes and longer-term survival. Despite careful adherence to the strict HCC selection criteria for LT in different transplant centres, the recurrence rate still occurs which could negatively affect HCC patients' survival. Hence HCC recurrence post-LT could predict patients' survival and prognosis, depending on the exact timing of recurrence after LT (early or late), and whether intra/extrahepatic HCC recurrence. Several factors may aid in such a complication, particularly tumour-related criteria including larger sizes, higher grades or poor tumour differentiation, microvascular invasion, and elevated serum alpha-fetoprotein. Therefore, managing such cases is challenging, different therapeutic options have been proposed, including curative surgical and ablative treatments that have shown better outcomes, compared to the palliative locoregional and systemic therapies, which may be helpful in those with unresectable tumour burden. To handle all these issues in our review.

Identification of novel M2 macrophage-related molecule ATP6V1E1 and its biological role in hepatocellular carcinoma based on machine learning algorithms.

Hepatocellular carcinoma (HCC) remains the most prevalent form of primary liver cancer, characterized by late detection and suboptimal response to current therapies. The tumour microenvironment, especially the role of M2 macrophages, is pivotal in the progression and prognosis of HCC. We applied the machine learning algorithm-CIBERSORT, to quantify cellular compositions within the HCC TME, focusing on M2 macrophages. Gene expression profiles were analysed to identify key molecules, with ATP6V1E1 as a primary focus. We employed Gene Set Enrichment Analysis (GSEA) and Kaplan-Meier survival analysis to investigate the molecular pathways and prognostic significance of ATP6V1E1. A prognostic model was developed using multivariate Cox regression analysis based on ATP6V1E1-related molecules, and functional impacts were assessed through cell proliferation assays. M2 macrophages were the dominant cell type in the HCC TME, significantly correlating with adverse survival outcomes. ATP6V1E1 was robustly associated with advanced disease stages and poor prognostic features such as vascular invasion and elevated alpha-fetoprotein levels. GSEA linked high ATP6V1E1 expression to critical oncogenic pathways, including immunosuppression and angiogenesis, and reduced activity in metabolic processes like bile acid and fatty acid metabolism. The prognostic model stratified HCC patients into distinct risk categories, showing high predictive accuracy (1-year AUC = 0.775, 3-year AUC = 0.709 and 5-year AUC = 0.791). Invitro assays demonstrated that ATP6V1E1 knockdown markedly inhibited the proliferation of HCC cells. The study underscores the significance of M2 macrophages and ATP6V1E1 in HCC, highlighting their potential as therapeutic and prognostic targets.