Emerging biomolecules for practical theranostics of liver hepatocellular carcinoma.

Most cases of hepatocellular carcinoma (HCC) are able to be diagnosed through regular surveillance in an identifiable patient population with chronic hepatitis B or cirrhosis. Nevertheless, 50% of global cases might present incidentally owing to symptomatic advanced-stage HCC after worsening of liver dysfunction. A systematic search based on PUBMED was performed to identify relevant outcomes, covering newer surveillance modalities including secretory proteins, DNA methylation, miRNAs, and genome sequencing analysis which proposed molecular expression signatures as ideal tools in the early-stage HCC detection. In the face of low accuracy without harmonization on the analytical approaches and data interpretation for liquid biopsy, a more accurate incidence of HCC will be unveiled by using deep machine learning system and multiplex immunohistochemistry analysis. A combination of molecular-secretory biomarkers, high-definition imaging and bedside clinical indexes in a surveillance setting offers a comprehensive range of HCC potential indicators. In addition, the sequential use of numerous lines of systemic anti-HCC therapies will simultaneously benefit more patients in survival. This review provides an overview on the most recent developments in HCC theranostic platform.

Factors associated with the inconsistent diagnosis between frozen section and permanent pathologic examination in borderline ovarian tumors.

AIM: The predictive accuracy of frozen sections for borderline ovarian tumors (BOTs) is suboptimal. The aim of this study was to determine the diagnostic accuracy of BOTs and factors associated with an upgrade to a permanent pathological diagnosis of invasive carcinoma in patients diagnosed with BOTs by frozen section. METHODS: We conducted a retrospective study between 2011 and 2018 at Kaohsiung Chang Gung Memorial Hospital (KCGMH). Two hundred and twenty-five records of eligible patients with a diagnosis of BOT by frozen section or permanent diagnosis were reviewed. Positive predictive value and the diagnostic accuracy of frozen sections were calculated. Univariate and multivariate analyses were used to determine the clinicopathological factors associated with an upgrade of the diagnosis from a borderline tumor to malignancy. RESULTS: The agreement between frozen section and permanent pathological diagnoses was 63.1%, and the positive predictive value was 72.1%. The multivariate analysis revealed that CA-125 level > 136 U/mL (odds ratio [OR] = 2.96, 95% confidence interval [CI] = 1.3-6.9; p = 0.012), and tumor histologic type (clear cell/endometrioid vs. mucinous; OR:32.8, 95% CI = 6.9-154.8, p < 0.001; clear cell/endometrioid vs. serous: OR 48.1, 95% CI = 8.8-261.8, p < 0.001) were independent risk factors for an upgrade of the permanent diagnosis from a BOT to ovarian carcinoma. CONCLUSION: An elevated CA-125 level (over 136 U/mL) and tumor histologic type (clear cell and endometrioid subtypes) were associated with an upgrade in the diagnosis of ovarian tumor from a BOT on frozen section to a permanent diagnosis of malignancy.

Point of care optical diagnostic technologies for the detection of oral and oropharyngeal squamous cell carcinoma.

BACKGROUND: Despite significant advances in treatment modalities, the 5 year survival rate in oral and oropharyngeal squamous cell carcinoma (SCC) is less than 60%. Clinical examination, white light endoscopy followed by blind biopsies and histopathological analysis remains the gold standard for diagnosis and surveillance. These modalities continue to have a limited diagnostic accuracy of less than 55%. METHODS: Novel optical-based diagnostic methods are promising new technologies for improving both screening and detection of cancer. This review will discuss their role in oral and oropharyngeal cancer detection with particular emphasis on optical imaging in oral and oropharyngeal cancer diagnosis, including the use of surface enhanced Raman spectroscopy, optical coherence tomography, fluorescence diagnosis, confocal laser endomicroscopy, confocal reflectance microscopy and narrow band imaging. RESULTS: Aided by the use of differing wavelengths of light, these methods are capable of detecting physical and biochemical changes that precede and mirror malignant change within tissue. CONCLUSION: Our review of the currently utilized optical diagnostic modalities suggests the possibility of a cost effective, point of care diagnosis that could facilitate early detection, reduce healthcare costs and improve patient survival and quality of life.

Construction of an immunosensor based on Cys/Au@TiO2 modification for the detection of liver cancer marker PIVKA-II.

An ultrasensitive immunosensor of Cys/Au@TiO2 based on disposable screen-printed electrodes (SPE) for PIVKA-II detection for hepatocellular carcinoma (HCC) diagnosis was developed by utilizing Cystine (Cys) and nanocomposite Au@TiO2. Firstly, HAuCl4 underwent a reduction reaction with NaBH4, then Au nanoparticles were coated onto TiO2 nanoparticles. Followed, Cys/Au@TiO2 was formed through self-assembly of cysteine to allow the monoclonal antibody of abnormal thrombospondin to bound to the amino group on the surface of the composite by covalent bonding. The mechanism is to determine the changes in the current of the sensor caused by the specific binding of the abnormal prothrombin monoclonal antibody adsorbed by the complex with its antigen. The Cys/Au@TiO2 immunosensor was fully characterized by various analytical approaches and it showed a wide linear testing range of 1-10000 pg mL-1 (R2 = 0.991) and the limit of detection down to 0.77 pg ml-1, with highly sensitivity and specificity. The results showed that the developed immunosensor platform can effectively detect trace amounts of PIVKA-II protein and has potent clinical application for HCC diagnosis.

Annular Basal Cell Carcinoma Expanding Around Central Hypertrophic Scarring: A Case Report.

A case of annular basal cell carcinoma (BCC) with central atrophic scarring that developed secondary to spontaneous regression has been reported. We present a novel case of a large, expanding nodular and micronodular BCC with annular morphology with central hypertrophic scarring. A 61-year-old woman presented with a two-year history of a mildly itchy lesion on the right breast. Previously diagnosed as an infection, the lesion persisted after treatment with topical antifungal agents and oral antibiotics. Physical examination revealed a 5x6 cm plaque consisting of a pink-red arciform/annular edge with an overlying scale crust and a large, centrally positioned, firm, alabaster-colored portion. A punch biopsy of the pink-red rim revealed nodular and micronodular BCC features. A deep shave biopsy of the central bound-down plaque showed histopathology of scarring fibrosis with no findings of BCC regression. The malignancy was treated with two sessions of radiofrequency destruction, which led to the resolution of the tumor with no recurrence to date. Contrary to the previously reported case, BCC in our case was expanding, associated with hypertrophic scarring, and showed no signs of regression. We discuss several possible etiologies of the scarring centrally. With further awareness of this presentation, more such tumors can be detected at early stages to facilitate prompt treatment and prevent local morbidity.

Primary Basal Cell Carcinoma Masquerading as Metastatic Basal Cell Carcinoma in the Left Axilla.

Basal cell carcinoma (BCC) is considered the most common malignancy in Caucasians. Despite its high prevalence, BCC has extremely low rates of metastasis. The patient was a 71-year-old male with extensive BCC and squamous cell carcinoma (SCC) skin cancer history who had an extensive, palpable left axillary mass concerning enlarged lymph nodes. No skin lesions were visualized. A lymph node biopsy revealed a sclerosing/infiltrative BCC with perineural invasion extending to the inked margins of the excision and one of four lymph nodes involved by BCC through direct extension. Sectioning revealed a 3.0 x 2.8 x 2.9 cm, ill-defined, fibrotic pink-white mass within the soft tissue. Two tan to pink possible lymph nodes were also identified within the soft tissue, measuring 0.7cm and 0.9cm. There was no definite direct invasion noted, making metastatic BCC suspicious. A left axillary lymph node dissection was performed. In short, he had a nonmobile tumor that showed evidence of invasion of the adjacent pectoralis muscle near the chest wall, abutting the left axillary vein, with extension. In July 2022, approximately one year after diagnosis, the patient received a PET scan and had no remote sites of disease. Every follow-up PET scan since has shown stable disease, most recently in May 2023. The patient continues dermatology follow-ups every three months for clinical surveillance. This case is unique because metastatic disease was never confirmed, though it is still a possibility. The affected lymph nodes were in the regional basin, where the patient had had extensive skin cancers in the past. Their involvement could have been secondary to direct invasion, though this could not be confirmed histologically, making the definitive characterization of this particular tumor difficult. As the PET CT scans have remained stable without evidence of distant disease, we favor that this is a recurrent primary tumor with direct extension to the underlying pectoralis and axillary lymph nodes. As common as BCCs are, this case highlights the importance of diligent treatment and follow-up to avoid the potential for tumor-related morbidity and, rarely, mortality.

Circulating tumour DNA methylation in hepatocellular carcinoma diagnosis using digital droplet PCR.

OBJECTIVE: To evaluate the performance of a DNA methylation-based digital droplet polymerase chain reaction (ddPCR) assay to detect aberrant DNA methylation in cell-free DNA (cfDNA) and to determine its application in the detection of hepatocellular carcinoma (HCC). METHODS: The present study recruited patients with liver-related diseases and healthy control subjects. Blood samples were used for the extraction of cfDNA, which was then bisulfite converted and the extent of DNA methylation quantified using a ddPCR platform. RESULTS: A total of 97 patients with HCC, 80 healthy control subjects and 46 patients with chronic hepatitis B/C virus infection were enrolled in the study. The level of cfDNA in the HCC group was significantly higher than that in the healthy control group. For the detection of HCC, based on a cut-off value of 15.7% for the cfDNA methylation ratio, the sensitivity and specificity were 78.57% and 89.38%, respectively. The diagnostic accuracy was 85.27%, the positive predictive value was 81.91% and the negative predictive value was 87.20%. The positive likelihood ratio of 15.7% in HCC diagnosis was 7.40, while the negative likelihood ratio was 0.24. CONCLUSIONS: A sensitive methylation-based assay might serve as a liquid biopsy test for diagnosing HCC.

Diagnosing Basal Cell Carcinoma of the Vulva: A Case Report and Review of the Literature.

Basal cell carcinoma (BCC) is a highly prevalent epidermal neoplasm that most commonly occurs in regions of sun-exposed skin, though rare cases arise in sun-protected areas. BCCs of the vulva account for a small fraction of cases and can be mistaken for other cutaneous genital pathologies on clinical examination. Here we report a case of vulvar BCC that presented as a firm, tender bilateral lesion of the mons pubis and was diagnosed by histopathology and immunostaining for classical BCC markers.

Multi-marker diagnosis method for early Hepatocellular Carcinoma based on surface plasmon resonance.

Early diagnosis of Hepatocellular Carcinoma (HCC) is an important means to raise the survival rate of patients. Multi-marker combined detection is a powerful tool of early HCC diagnosis. Traditional detection methods are not effective and accurate because it is difficult to achieve combined detection of multiple markers. In this paper, we selected Alpha Fetoprotein (AFP) and miRNA-125b as the combined detection markers to improve the simultaneously diagnostic sensitivity and specificity. The anti-AFP monoclonal antibody and the DNA probes paired with the miRNA-125b were modified on the surface of surface plasmon resonance (SPR) sensor respectively to specifically recognize AFP and miRNA-125b in serum. In order to enhance the SPR response signal and detection sensitivity, Double Antibody Sandwich Method (DASM) and S9.6 antibody enhanced method were applied to achieve low detection limit of the two markers. Experimental results showed that AFP (25-400 ng/mL) was accurately detected by DASM and the detection limit of miRNA-125b by S9.6 antibody enhanced method reached 123.044 pM. These results verified the feasibility of the multi-marker detection method in early diagnosis of HCC.

Combination of serum matrix metalloproteinase-3 activity and EBV antibodies improves the diagnostic performance of nasopharyngeal carcinoma.

Objective: Nasopharyngeal carcinoma (NPC) is a malignant head and neck tumor that is highly prevalent in Southeast Asia. The two traditional NPC markers VCA-IgA (EBV viral capsid antigen) and EA-IgA (EBV early antigen) are limited in the screening and diagnosis of NPC. The purpose of present study is to evaluate the diagnostic value of matrix metalloproteinase-3 (MMP3) in NPC. Methods: The levels of 23 secretory MMPs in serum samples from 15 healthy controls and 26 NPC patients were detected by Cytokine Antibody Array 2000. Immunohistochemistry, Real-time PCR and western bolt were used to detect MMP3 mRNA and protein levels in NPC tissues and cell lines. The serum protein levels of MMP3 were further measured by ELISA in healthy control individuals (n = 200) and NPC patients (n = 206). Results: MMP3 can be expressed and secreted by both NPC and fibroblast cell lines, suggesting that the higher expression of MMP3 protein in both tumor nests and stromal of NPC tissues may be the source of circulating MMP3 in NPC patients. Furthermore, we found out both MMP3 concentration and enzymatic activity were significantly increased in the NPC group (n = 206) than the healthy control group (n = 200) (P < 0.001). However, serum MMP3 enzymatic activity, but not MMP3 concentration, was significantly associated with the progression of NPC. In addition, serum MMP3 activity was more valuable in diagnosis of NPC than its concentration (0.86 vs. 0.78, AUC), and MMP3 activity can improve the diagnosis of NPC by combining with EBV-infection biomarkers VCA-IgA and EA-IgA with a sensitivity of 91.5% and a specificity of 92.3%. Conclusions: This study suggested the combination of MMP3 activity and EBV antibodies may be a useful biomarker for screening and diagnosis of NPC.

Association of Serum Ferritin with Diabetes and Alcohol in Patients with Non-Viral Liver Disease-Related Hepatocellular Carcinoma.

INTRODUCTION: Non-alcoholic fatty liver disease is a leading cause for hepatocellular carcinoma (HCC) in Sri Lanka. Diabetes mellitus, alcohol abuse, and liver inflammation are known to increase the risk of HCC. The present study evaluates serum ferritin levels in a cohort of patients with non-viral HCC (nvHCC). METHODOLOGY: Consecutive patients with nvHCC presenting to the Colombo North Liver transplant Service, Ragama, from January 2012 to July 2013 were investigated. All were negative for hepatitis B and C. At registration, 5 mL of serum was separated into plain tubes, stored at -80°C and analysed for ferritin using an enzyme-linked immunosorbent assay. Correlation between the serum ferritin and patient risk factors, liver status, and tumour characteristics were analysed. RESULTS: There were 93 patients with nvHCC (median age 65 [12-82] years; 82 [88.2%] males). The median ferritin level was 246.2 µg/L, and 38 (40.86%) patients had elevated ferritin. Non-diabetics (median 363.5 mg/L, p = 0.003) and alcohol abusers (median 261.2 mg/L, p = 0.018) had higher ferritin levels. On multiple-variable analysis, being non-diabetic (p = 0.013) and alcoholic (p = 0.046) was significantly associated with high serum ferritin. No association was found with body mass index, tumour stage, size, macrovascular invasion, number of nodules, alpha-fetoprotein, bilirubin, international normalized ratio, and survival. CONCLUSION: In patients with nvHCC, serum ferritin levels are higher in non-diabetics and alcoholics.

Atualização das recomendações da Sociedade Brasileira de Hepatologia para o diagnóstico e tratamento do carcinoma hepatocellular / Brazilian society of hepatology updated recommendations for diagnosis and treatment of hepatocellular carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2015 its first recommendations about the management of HCC. Since then, new data have emerged in the literature, prompting the governing board of SBH to sponsor a single-topic meeting in August 2018 in São Paulo. All the invited experts were asked to make a systematic review of the literature reviewing the management of HCC in subjects with cirrhosis. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of updated recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present manuscript is the final version of the reviewed manuscript containing the recommendations of SBH.

RESUMO O carcinoma hepatocelular (CHC) é uma das principais causas de mortalidade relacionada a câncer no Brasil e no mundo. A Sociedade Brasileira de Hepatologia (SBH) publicou em 2015 suas primeiras recomendações sobre a abordagem do CHC. Desde então, novas evidências sobre o diagnóstico e tratamento do CHC foram relatadas na literatura médica, levando a diretoria da SBH a promover uma reunião monotemática sobre câncer primário de fígado em agosto de 2018 com o intuito de atualizar as recomendações sobre o manejo da neoplasia. Um grupo de experts foi convidado para realizar uma revisão sistemática da literatura e apresentar uma atualização baseada em evidências científicas visando que pudesse nortear a prática clínica multidisciplinar do CHC. O texto resultante foi submetido a avaliação e aprovação de todos membros da SBH através de sua homepage. O documento atual é a versão final que contêm as recomendações atualizadas e revisadas da SBH.

Screening for hepatocellular carcinoma by Egyptian physicians.

AIM: To assess the practice of Egyptian physicians in screening patients for hepatocellular carcinoma (HCC). METHODS: The study included 154 physicians from all over Egypt caring for patients at risk for HCC. The study was based on a questionnaire with 20 items. Each questionnaire consisted of two parts: (1) personal information regarding the physician (name, age, specialty and type of health care setting); and (2) professional experience in the care of patients at risk for HCC development (screening, knowledge about the cause and natural course of liver diseases and HCC risk). RESULTS: Sixty-eight percent of doctors with an MD degree, 48% of doctors with a master degree or a diploma and 40% of doctors with a Bachelor of Medicine, Bachelor of Surgery certificate considered the hepatitis C virus (HCV) genotype as risk factor for HCC development (P < 0.05). Ninety percent of physicians specialized in tropical medicine, internal medicine or gastroenterology and 67% of physicians in other specialties advise patients to undergo screening for HCV and hepatitis B virus infection as well as liver cirrhosis (P < 0.05). Eighty-six percent of doctors in University Hospitals and 69% of Ministry of Health (MOH) doctors consider HCV infection as the leading cause of HCC in Egypt (P < 0.05). Seventy-two percent of doctors with an MD degree, 55% of doctors with a master degree or a diploma, 56% of doctors with an MBBCH certificate, 74% of doctors in University Hospitals and 46% of MOH hospital doctors consider abdominal ultrasonography as the most important investigation in HCC screening (P < 0.05). Sixty-five percent of physicians in tropical medicine, internal medicine or gastroenterology and 37% of physicians in other specialties recommend as HCC screening interval of 3 mo (P < 0.05). Seventy-one percent of doctors with an MD degree, 50% of doctors with a master degree or diploma and 60% of doctors with an MBBCH certificate follow the same recommendation. CONCLUSION: In Egypt, physicians specialized in tropical medicine, internal medicine or gastroenterology with an MD degree and working in a University Hospital are best informed about HCC.

Intrapericardial primary thymic carcinoma in a 73-year-old man.

Thymic carcinoma is a rare, highly aggressive type of tumor that typically occurs in the anterior mediastinum. We describe the case of a 73-year-old man who presented with weakness, cough, dyspnea, anorexia, and weight loss. An echocardiogram showed an intrapericardial mass that occupied the space around the lateral walls of the left ventricle and distally compressed the right ventricle. Magnetic resonance imaging and a biopsy confirmed the presence of intrapericardial primary thymic carcinoma. The patient underwent surgical excision of the tumor and died of right ventricular rupture during the procedure. This case highlights the importance of considering thymic carcinoma whenever an otherwise unexplained intrapericardial mass is encountered.