Increased Alpha-fetoprotein Levels Research Articles

Alpha-fetoprotein level in fetuses, infants, and children with ovarian masses: a literature review.

Alpha-fetoprotein (AFP) is a serum protein highly produced during the fetal period. It is also known as a biomarker of various pathologies. Commonly, tumors requiring diagnosis and monitoring through AFP determination appear during the first year of life, with poorer outcomes when presenting in fetal life. Due to advancements in imaging technology, the detectability of ovarian masses in infants is higher. However, the use of AFP as a biomarker could improve diagnosis in cases when imaging and histological examinations are not sensitive enough to detect tumors. From the outcome of our investigation, it is possible to conclude that there is evidence of an association between increased AFP levels and ovarian masses. However, previous studies have presented contradictory and unverified results, with the authors emphasizing that future research is needed. In this article, an analysis of the available literature on AFP as a biomarker of ovarian masses in children was performed. Two types of literature were reviewed: guidance and published studies (clinical trials, reviews, and systematic reviews). We searched the Embase, PubMed, ScienceDirect, and Web of Science databases to collect essential data.

Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, a substantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlying mechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96 promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, and its stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular docking showed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. The binding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCC patients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered a novel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination. These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.

Salvage Liver Transplant in the Treatment of a Child With Local Recurrence of Hepatoblastoma

Hepatoblastoma is the most common primary liver cancer of childhood, accounting for two-thirds of primary malignant hepatic neoplasms. Radical surgical removal combined with efficient chemotherapy is essential for cure. Despite a complete tumor resection, hepatoblastoma may recur as isolated local disease. Intrahepatic recurrence of hepatoblastoma after liver resection is among the indications for liver transplant. Here, we present a patient who underwent salvage liver transplant for the treatment of local recurrence of hepatoblastoma. A 13-year-old boy who was diagnosed with hepatocellular carcinoma arising from the left liver lobe and who had been treated with surgical resection was admitted to our outpatient oncology clinic for further evaluation because alpha-fetoprotein levels had started to increase after surgery. Histopathological reexamination of hemihepatectomy material showed a histological aspect of an epithelial hepatoblastoma. Magnetic resonance imaging revealed multifocal lesions in the right liver lobe compatible with local recurrence. Despite a favorable initial response to chemotherapy, the tumor showed progression with increased alpha-fetoprotein levels. The patient was deemed a viable candidate for an urgent liver transplant and underwent right lobe living donor liver transplant. He had excellent graft function without any complications or signs of malignancy in the last follow-up visit at 7 months posttransplant. Salvage liver transplant is a lifesaving and sometimes the only treatment option for patients with local recurrence of hepatoblastoma. Although transplant in the salvage setting has been associated with worse outcomes than primary transplant, recent data have indicated more favorable and acceptable outcomes. Further studies are warranted to better understand the role of salvage liver transplant in the treatment of hepatoblastoma. Early consultation with the liver transplant team is critical in children who are most likely to need extreme resection or liver transplant.

Update on the applications and limitations of alpha-fetoprotein for hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is an oncofetal glycoprotein that has been used as a tumor marker for hepatocellular carcinoma (HCC) in combination with ultrasound and other imaging modalities. Its utility is limited because of both low sensitivity and specificity, and discrepancies among the different methods of measurements. Moreover, its accuracy varies according to patient characteristics and the AFP cut-off values used. Combination of AFP with novel biomarkers such as AFP-L3, Golgi specific membrane protein (GP73) and des-gamma-carboxyprothrombin significantly improved its accuracy in detecting HCC. Increased AFP level could also signify severity of hepatic destruction and subsequent regeneration and is commonly observed in patients with acute and chronic liver conditions and cirrhosis. Hereditary and other non-hepatic disorders can also cause AFP elevation.

Validation of ZMYND8 as a new treatment target in hepatocellular carcinoma.

ZMYND8 (Zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8) has been known to play an important role in tumor regulation in various types of cancer. However, the results of ZMYND8 expression and their clinical significance in hepatocellular carcinoma (HCC) have not yet been published. In the present study, we investigate the expression of ZMYND8 protein and mRNA in HCC and elucidate its prognostic significance. ZMYND8 protein and mRNA expression in 283 and 234 HCCs were investigated using immunohistochemistry and microarraygene expression profiling data. The relationships between ZMYND8 expression with clinicopathologic features and prognosis of HCC patients were evaluated. Furthermore, we performed the invasion, migration, apoptosis, soft agar formation assay and sphere formation assay in HCC cell lines, and evaluated tumorigenicity in a nude mouse model, after ZMYND8 knockdown. Overexpression of ZMYND8 protein and mRNA was observed in 20.5% and 26.9% of HCC cases, respectively. High ZMYND8 expression showed significant correlations with microvascular invasion, high Edmondson grade, advanced American Joint Committee on Cancer, and increased alpha-fetoprotein level. ZMYND8 mRNA overexpression was an independent prognostic factor for predicting early recurrence as well as short recurrence-free survival (RFS). Downregulation of ZMYND8 reduced migration and invasion of HCC cells, and promoted apoptosis of HCC cells in an in vitro model. In a xenograft nude mouse model, knockdown of ZMYND8 significantly reduced tumor growth. ZMYND8 mRNA overexpression could be a prognostic marker of shorter RFS in HCC patients after curative resection. ZMYND8 might play an important role in the proliferation and progression of HCC and could be a promising candidate for targeted therapy.

Role of the alpha-fetoprotein response in immune checkpoint inhibitor-based treatment of patients with hepatocellular carcinoma.

The dynamics of serum alpha-fetoprotein (AFP) level have been found to be a useful predictor of therapeutic responsiveness in patients with hepatocellular carcinoma (HCC). We evaluated whether AFP changes were able to accurately reflect imaging-based responses and predict prognosis in patients receiving therapies including immune-checkpoint inhibitors (ICIs). A total of 108 HCC patients with baseline serum AFP ≥ 20ng/mL who received ICI-based treatment were included. We evaluated AFP-based responses, coupled with radiographic responses by RECIST, at 6-10 (time-point 1, TP1) and 14-18weeks (time-point 2, TP2) of therapy in terms of the change of AFP from baseline, with a > 20% decrease or increase in level corresponding to the AFP response and progression, respectively. We examined the correlations between AFP and imaging-based responses, and the prognostic implications of the AFP-based measure. Based on AFP change, there were 24 and 20 responders and 74 and 24 progressors at TP1 and TP2, respectively. The AFP responders yielded radiological objective responses in 90.9% (10/11) and 93.8% (15/16) of the cases at TP1 and TP2, respectively, compared with only 1.4% and none, respectively, of the AFP progressors at the corresponding times. The agreement between progression by RECIST and increased AFP level at the two time-points was 93.8% and 95.0%, respectively. The accuracy of the AFP-based criterion for predicting radiologic response/progression was comparable at TP1 and TP2. Both "AFP responder" and "AFP progressor" at TP1 or TP2 independently predicted the overall survival of patients (adjusted hazard ratios [95% confidence intervals], 0.360 [0.174-0.743] and 0.315 [0.117-0.850]; and 2.525 [1.362-4.679] and 3.908 [1.563-9.769], respectively). Our study suggests that on-treatment AFP changes can complement imaging findings and provide prognostic information for evaluating patients with AFP-producing HCC treated with ICI-based regimens.

Sorafenib and hepatocellular carcinoma: is alpha-fetoprotein a biomarker predictive of tumor biology and primary resistance?

Background: Alpha-fetoprotein (AFP) is the only biomarker with proven prognostic value in advanced hepatocellular carcinoma. Preliminary data indicate crosstalk between AFP and VEGF signaling. Methods: The authors looked at 69 patients with advanced hepatocellular carcinoma who were previously tested for VEGFR2 expression, had available baseline AFP serum concentrations and were treated with sorafenib within clinical trials. Results: Shorter progression-free survival and overall survival were associated with increased AFP level and elevated VEGFR2 staining. At multivariate analysis of AFP level was the only independent prognostic factor for progression-free survival and overall survival. Conclusion:The authors' study confirms the adverse prognostic role of elevated baseline AFP and also suggests a possible role of AFP in primary resistance to sorafenib therapy.

87. Small Case Series of Neonatal Autoamputated Ovary Presenting as Enlarging Complex Ovarian Mass with Increasingly Elevated AFP

<h3>Background</h3> We present a case series of two girls with enlarging complex ovarian masses associated with increasing levels of alpha-fetoprotein (AFP). Both girls were found to have an autoamputated ovary. Tumor markers associated with benign ovarian masses are usually within the normal range. Abnormally elevated AFP levels in the neonates with large complex ovarian masses should be surgically evaluated. This case series could suggest an association between elevated AFP and ovarian autoamputation. <h3>Case</h3> The first patient was a term female baby delivered without complications and known to have a complex cyst in utero. She was a thriving baby girl and her physical exam was unremarkable. Post-natal pelvic ultrasound revealed a 62 × 40 mm enlarging right ovarian cyst with a vascularized nodule. Imaging was suggestive of a mature teratoma or a germinal tumor. Tumor markers were significant for elevated levels of AFP up to 373 mcg/L. Repeat ultrasound showed a persistent ovarian cyst. The second patient was a 7-month-old female with a known history of a right neonatal ovarian cyst followed with serial ultrasounds. She appeared healthy and her exam was unremarkable. A pelvic ultrasound revealed a 44 × 53 mm ovarian cyst with echogenic debris. Tumor markers were significant for an elevated AFP level of 695 mcg/L. Given the elevated AFP and persistence of the cysts, surgical excision were performed. Both diagnostic laparoscopies revealed autoamputated right ovary and fallopian tube and right salpingoophorectomies were performed. Surgeries were uneventful. The pathology exam of the first specimen showed necrotic ovarian tissue with benign cystic lesion of unknown origin, without neoplasia. The second pathology specimen analysis showed a torsed hemorrhagic cyst with no evidence of malignancy. The AFP levels normalized subsequently. <h3>Comments</h3> Prenatal ovarian cysts are frequent and tend to regress in the first months of life. Complex cysts require follow-up with serial ultrasounds and tumor marker measurements. Large or complex cysts may require surgical intervention due to suspicion of ovarian torsion or malignancy. Perinatally, increased AFP levels are associated with hepatic or germ cell tumors. Suggested reference level of AFP is 15.7 to 146.5 mcg/L. Although autoamputated ovaries are thought to be normal, on pathology, it is difficult to identify ovarian tissue. Elevated AFP levels found in this case series are somewhat difficult to interpret since pathology analysis was limited by necrosis. Nonetheless, abnormally elevated AFP levels in the neonates with large complex ovarian masses should be surgically evaluated. Further research is needed to investigate the possible association of elevated AFP levels and ovarian autoamputation.

Changes in hepatocellular carcinoma aggressiveness characteristics with an increase in tumor diameter.

Hepatocellular carcinoma prognosis depends on both liver and tumor determinants, especially on maximum tumor diameter, multifocality, and presence of portal vein thrombosis, despite apparently complete tumor removal by resection or liver transplantation. To examine parameters of hepatocellular carcinoma aggressiveness as tumor size increases. A large hepatocellular carcinoma database was examined for trends in serum alpha-fetoprotein and the percentage of patients with macroscopic portal vein thrombosis or tumor multifocality. A total of 13,016 hepatocellular carcinoma patients were identified having full tumor and survival data. Of these, 76.56% were male and 23.44% were female, with a median age of 64.4 years. We found that as the maximum tumor diameter increased, there was a significant trend for increased alpha-fetoprotein levels (P<0.001) and an increased percentage of patients with either portal vein thrombosis or tumor multifocality, each P<0.0001. Furthermore, the increases of both alpha-fetoprotein and portal vein thrombosis were proportionately greater than the related maximum tumor diameter increases. These trends of increased alpha-fetoprotein, portal vein thrombosis, and multifocality with increasing maximum tumor diameter had non-linear patterns. Within alpha-fetoprotein and multifocality trends, there were identifiable sub-trends associated with specific maximum tumor diameter ranges. The greater fold-increases in alpha-fetoprotein and portal vein thrombosis compared with increases in maximum tumor diameter imply that hepatocellular carcinoma characteristics may change with increasing size to a more aggressive phenotype, suggesting that follow-up tumor sampling might be useful, in addition to baseline tumor sampling, for optimal therapeutic choices to be made.

Role of Alpha-Fetoprotein in Hepatocellular Carcinoma Drug Resistance.

Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and a major cause of cancer-related deaths worldwide because of its high recurrence rate and poor prognosis. Surgical resection is currently the major treatment measure for patients in the early and middle stages of the disease. Because due to late diagnosis, most patients already miss the opportunity for surgery upon disease confirmation, conservative chemotherapy (drug treatment) remains an important method of comprehensive treatment for patients with middle- and late-stage liver cancer. However, multidrug resistance (MDR) in patients with HCC severely reduces the treatment effect and is an important obstacle to chemotherapeutic success. Alpha-fetoprotein (AFP) is an important biomarker for the diagnosis of HCC. The serum expression levels of AFP in many patients with HCC are increased, and a persistently increased AFP level is a risk factor for HCC progression. Many studies have indicated that AFP functions as an immune suppressor, and AFP can promote malignant transformation during HCC development and might be involved in the process of MDR in patients with liver cancer. This review describes drug resistance mechanisms during HCC drug treatment and reviews the relationship between the mechanism of AFP in HCC development and progression and HCC drug resistance.

Primrose syndrome: Characterization of the phenotype in 42 patients.

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down‐slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha‐fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype‐phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.

Ataxia-telangiectasia: A new remitting form with a peculiar transcriptome signature.

ObjectiveAtaxia-telangiectasia (AT) is a rare, severe, and ineluctably progressive multisystemic neurodegenerative disease. Variant AT phenotypes have been described in patients with mild- and late-onset neurologic deterioration and atypical features (dystonia and myoclonus). We report on the clinical characteristics and transcriptome profile of patients with a typical AT presentation and genotype who experienced an unexpected favorable course.MethodsA 24-year-old woman developed, by the age of 3 years, all the classic symptoms of AT associated with increased alpha-fetoprotein levels, a compound AT-mutated (ATM) genotype with an inframe deletion c.2250G>A (p.Glu709_Lys750del42) and a missense mutation c.8122G>A (p.Asp2708Gln), and no residual ATM protein expression. By the age of 12 years, ataxia slowly disappeared, and a very mild choreic disorder was the only neurologic feature in adulthood. Brain MRI was normal. The blood transcriptome profile was assessed and compared with that of healthy controls and patients with the classic AT phenotype.ResultsThe atypical clinical course of the patient was associated with a transitional transcriptome profile: while 90% of transcripts were expressed as in patients with the classic AT presentation, 10% of transcripts were expressed as in healthy controls.ConclusionsThe unexpected mild clinical outcome and transcriptome profile of this patient with AT suggest the existence of individual resilience to the altered ATM synthesis. Because of their possible prognostic and therapeutic implications, the identification of modifier factors affecting the phenotype would deserve further studies.

Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings.

Germline mutations in the RING finger protein gene RNF168 have been identified in a combined immunodeficiency disorder called RIDDLE syndrome. Since only two patients have been described with somewhat different phenotypes, there is need to identify further patients. Here, we report on two Polish siblings with RNF168 deficiency due to homozygosity for a novel frameshift mutation, c.295delG, that was identified through exome sequencing. Both patients presented with immunoglobulin deficiency, telangiectasia, cellular radiosensitivity, and increased alpha-fetoprotein (AFP) levels. The younger sibling had a more pronounced neurological and morphological phenotype, and she also carried an ATM gene mutation in the heterozygous state. Immunoblot analyses showed absence of RNF168 protein, whereas ATM levels and function were proficient in lymphoblastoid cells from both patients. Consistent with the absence of RNF168 protein, 53BP1 recruitment to DNA double-strand breaks (DSBs) after irradiation was undetectable in lymphoblasts or primary fibroblasts from either of the two patients. γH2AX foci accumulated normally but they disappeared with significant delay, indicating a severe defect in DSB repair. A comparison with the two previously identified patients indicates immunoglobulin deficiency, cellular radiosensitivity, and increased AFP levels as hallmarks of RNF168 deficiency. The variability in its clinical expression despite similar cellular phenotypes suggests that some manifestations of RNF168 deficiency may be modified by additional genetic or epidemiological factors.

Efficacy of regorafenib (REG) in patients with hepatocellular carcinoma (HCC) in the phase III RESORCE trial according to alpha-fetoprotein (AFP) and c-Met levels as predictors of poor prognosis.

4078 Background: REG is a multikinase inhibitor which improved overall survival (OS; HR 0.63, 95% CI 0.50, 0.79; P&lt;0.0001) and time to progression (TTP; HR 0.44, 95% CI 0.36, 0.55; P&lt;0.0001) compared with placebo in patients with HCC who progressed during prior sorafenib treatment in the RESORCE trial. This exploratory analysis evaluated the impact of baseline AFP and c-Met on REG treatment benefit (OS and TTP) in the RESORCE trial. Methods: Circulating AFP and c-Met protein (shed ectodomain) levels were quantified by a Luminex assay (Myriad RBM) in plasma samples collected at baseline from patients enrolled in the RESORCE trial. Valid biomarker data were available from 497 (AFP) and 499 (c-Met) out of 573 patients. Patients were subgrouped according to the median protein concentration (high vs low), and the treatment effect HR and its 95% CI were evaluated using a Cox proportional hazards model. The predictive effect was modeledas a protein–treatment interaction effect and subjected to Akaike information criterion (AIC)-based selection to assess its association with OS and TTP. Results: Baseline characteristics of patients were balanced across protein subgroups. While increased levels of both AFP (HR 1.09, 95% CI 1.07, 1.12; P&lt;0.001) and c-Met (HR 1.32, CI 95% 1.06, 1.63; P=0.011) were associated with a worse prognosis for OS, increased AFP levels were also associated with poor prognosis for TTP (HR 1.05, 95% CI 1.03, 1.07; P&lt;0.001). REG treatment benefit for both OS and TTP was independent of AFP and c-Met protein expression (Table). The protein–treatment interaction effect was not statistically significant. Conclusions: The treatment benefit of REG in patients with HCC was independent of AFP and c-MET protein expression at baseline. So far, no single protein has been associated with REG clinical benefit. Clinical trial information: NCT01774344. [Table: see text]

Ataxia telangiectasia: a review.

Definition of the diseaseAtaxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.EpidemiologyThe world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.Clinical descriptionA-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations.EtiologyA-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.DiagnosisThe diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.Differential diagnosisThere are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing.Antenatal diagnosisAntenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis.Genetic counselingGenetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted.Management and prognosisTreatment of the neurologic problems associated with A-T is symptomatic and supportive, as there are no treatments known to slow or stop the neurodegeneration. However, other manifestations of A-T, e.g. immunodeficiency, pulmonary disease, failure to thrive and diabetes can be treated effectively.

The Degree of Lipiodol Accumulation Can Be an Indicator of Successful Treatment for Unresectable Hepatocellular Carcinoma (HCC) Patients - in the Case of Transcatheter Arterial Chemoembolization (TACE) and External Beam Radiotherapy (EBRT).

Purpose: Transcatheter arterial chemoembolization (TACE) in combination with external beam radiotherapy (EBRT) results in improved survival due to better local control in patients with unresectable hepatocellular carcinoma (HCC). The purpose of this study was to investigate lipiodol accumulation, as it reflects tumor burden and is a potential prognostic factor, in HCC patients treated with TACE/EBRT.Methods and Materials: We retrospectively studied 147 patients with unresectable HCC treated with TACE and EBRT. Clinical features, adverse reactions, and prognostic factors were analyzed. All patients were treated with TACE 1-6 times in combination with EBRT (44-66 Gy) in dose of 2 Gy/fraction given once a day five times a week. Tumor status and laboratory findings were followed. The degree of lipiodol accumulation was assessed by computed tomography before EBRT, and was categorized as either complete/intense or low/moderate.Results: The response rate of tumor size after EBRT was 68.2%, median survival was 23.1 months, and overall survival rates were 86.6%, 49.2%, and 28.2% at 1, 2, and 3 years, respectively. Univariate analysis showed that lower hemoglobin levels, higher alkaline phosphatase levels, Child-Pugh B, negative alpha-fetoprotein (AFP) response after EBRT, poor treatment response after EBRT, tumor diameter >10 cm, and poor lipiodol accumulation were unfavorable prognostic factors. On multivariate analysis, higher hemoglobin levels, Child-Pugh A, decreased AFP levels after treatment, Helical Tomotherapy (HT) and intense lipiodol accumulation after TACE were significant favorable predictors.Conclusions: The degree of lipiodol accumulation before EBRT is a prognostic factor in patients with unresectable HCC. Increased AFP levels after EBRT are always associated with poor survival. HT is recommended as a potentially better EBRT modality than three-dimensional conformal radiation therapy (3D-CRT).

Evaluation of alpha‐fetoprotein in detecting hepatocellular carcinoma recurrence after radiofrequency ablation

The performance of alpha-fetoprotein (AFP) in the detection of hepatocellular carcinoma (HCC) recurrence after radiofrequency ablation was analyzed. One hundred and forty-six solitary HCC lesions treated by radiofrequency ablation were evaluated. Using the AFP cutoff level at ≥ 20 ng/mL, tumors were categorized into AFP or non-AFP-producing HCC. Factors associated with true and false interpretations for cancer recurrence including analysis of elevated alanine aminotransferase (ALT) were evaluated. The performance of AFP using different cutoff levels adjusted for abnormal ALT was compared. Of 146 HCCs, 103 demonstrated no HCC recurrence while 43 had local recurrence. In non-recurrence HCC cases, increased AFP levels (false positive) were associated with concomitant ALT elevations, while those with normal AFP (true negative) had correspondingly normal ALT values (P < 0.001). The AFP false positive rate in cases of elevated ALT was significantly higher than those with normal ALT levels (31.9% vs 5.4%, P = 0.001). Among all positive AFP tests, those with false positive values (non-recurrence) had a significantly lower AFP level than the true positive (recurrence) HCC cases (39.8 ng/mL vs 372 ng/mL, P < 0.001). At the 20 ng/mL cutoff level, the sensitivities of AFP for detecting recurrence in non-AFP-producing HCC and AFP-producing HCC were 12.0%, and 72.2%, respectively. Using a modified AFP criteria of ≥ 100 ng/mL for cases where ALT ≥ 40 U/L, the sensitivity and specificity in AFP-producing tumors increased from 72.2% and 56% to 100% and 85%, respectively. Serum AFP is a useful test in the detection of HCC recurrence in AFP-producing HCC. The performance in AFP-producing HCC was significantly improved after adjusting for elevation of serum ALT.

Poor Lipiodol Accumulation is an Unfavorable Predictor in Hepatocellular Carcinoma Patients Treated with Transcatheter Arterial Chemoembolization Combined with External Beam Radiation Therapy

Transcatheter arterial chemoembolization (TACE) is the first consideration for patients with ≥5 cm in diameter and unresectable hepatocellular carcinoma (HCC), while combined with external beam radiation (EBRT), a better survival is observed due to better local control. But it is lack of the information about relation between the patterns of lipiodol accumulation and the prognosis in those patients treated with EBRT. The purpose of this study is to identify prognostic factors, especially the pattern of lipiodol accumulation in patients treated with TACE combined with EBRT. We retrospectively studied 98 patients with intrahepatic unresectable HCC treated with TACE combined with EBRT, their clinical features, adverse reactions and prognostic factors were analyzed. All patients were treated with TACE 1-11 (median 3) times combined with EBRT 34Gy-66Gy (median 50Gy). The tumor status, laboratory parameters including tumor marker, blood routine and blood biochemistry were followed up. Lipiodol accumulation were assessed on CT scan 4 weeks after the last course of TACE before EBRT and divided them into two types: intense (>3/4 of the tumor volume) or not. All analyses were performed with SPSS. The response rate (CR+PR) after EBRT were 68.2%, 71 patients with positive pretreatment alpha-fetoprotein (AFP), 45 of them had AFP decreased more than 50% after EBRT, the biochemical response rate were 63.3%. The median survival were 23.1 months, overall survival rates were 86.6%, 49.2%, and 28.2% at 1, 2, and 3 years, respectively. Univariate analysis showed that lower serum levels of hemoglobulin and albumin, higher serum levels of bilirubin and alkaline phosphatase, increased AFP after treatment, tumors with diameter over 10cm and poor lipiodol accumulation after TACE were unfavorable prognostic factors. While in multivariate analysis, increased AFP after treatment, tumors with diameter over 10cm and poor lipiodol accumulation after TACE were still significant unfavorable predictors. The tumor burden including larger tumor and poor intrahepatic tumor lipiodol deposit before EBRT are poorer prognostic factors for patients with unresectable intrahepatic HCC, increased AFP level after EBRT is always associated with poorer survival.

Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

UTILITÉ DE L’ALFAFOETOPROTÉINE DANS LES HÉPATITES VIRALES SANS HÉPATOCARCINOME

Introduction : It is often measured in subjects with viral hepatitis for diagnosing hepatocellular carcinoma. However, its prevalence and clinical significance remain inconclusive in subjects without hepatocellular carcinoma. The aim of this work is to evaluate the clinical, virological and histopathological significance of elevated alpha-fetoprotein in patients with uncomplicated hepatitis B and C. Materials and methods : Alpha-fetoprotein is measured by radioimmunoassay in addition to other biological and virological parameters in 60 patients with viral hepatitis. Results : 50% of patients have an increased alpha-fetoprotein with high levels of transaminases, bilirubin and a significant viral load. Discussion - conclusion : In Viral hepatitis, increased alpha-fetoprotein level is associated with the increase transaminases levels that reflects the degree of the hepatocellular destruction and the importance of viral load. This may be related to the post necrotic regeneration in patients with viral hepatitis B or C. Serial alpha-fetoprotein measurements appear to be useful in identifying persons with advanced fibrosis and help to determine who needs periodic screening with liver ultrasound examination to detect hepatocellular carcinoma.