Unique situation of hepatocellular carcinoma in Egypt: A review of epidemiology and control measures

Hepatocellular carcinoma (HCC) is the sixth most common primary malignancy worldwide, and the third most common cause of death among cancers worldwide. HCC occurs in several pre-existing conditions, including hepatitis C, hepatitis B virus, and non-alcoholic cirrhosis. Egypt used to be the country with the heaviest hepatitis C virus (HCV) burden. The relationship between HCV and HCC is an important research area. In Egypt, HCC is a significant public health problem. A possible cause for the increasing rates of detection of HCC in Egypt is the mass screening program that was carried by the government for detecting and treating HCV. A multidisciplinary approach is now widely applied to HCC management in health centers all over Egypt. Different treatment modalities are available in Egypt, with success rates comparable to global rates. The Egyptian health authorities have made the elimination of HCV from Egypt a special priority, and this approach should lead to a decrease in number of HCC cases in the near future. In this article we review the current situation of HCC in Egypt, including epidemiological aspects, relevant risk factors for HCC development, strategies, and efforts established by health authorities for the screening and prevention of both HCV and HCC in Egypt. We highlight the different modalities for HCC treatment.     

Fatal unexpected death due to X-linked lymphoproliferative disease

X-linked lymphoproliferative disease (XLP) is a rare immunodeficiency disease characterized by severe immune disorder and extreme vulnerability to Epstein-Barr virus (EBV) infections. Here we report a 14-month-old Chinese boy presenting with fulminant infectious mononucleosis (FIM) following EBV infection, and died of hepatic failure within one week of disease progression. Postmortem examination revealed icterus, ascites, extensive enlarged mesenteric lymph nodes and hepatosplenomegaly. Histopathological examination showed diffuse proliferation of cytotoxic T lymphoid cells and hemophagocytosis in multiple organs. The family history revealed his brother had died under similar circumstances at 5 five years of age. The cause of death of the boy was ascribed to XLP. To the best of our knowledge, there is few autopsy-confirmed XLP case in the forensic practice. The complicated manifestations and systemic pathological changes should be well recognized by clinicians and forensic pathologists.     

A truncated glycoprotein G vaccine formulated with Advax-CpG adjuvant provides protection of mice against genital herpes simplex virus 2 infection

Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted disease that affects approximately 500 million individuals globally. There is currently no approved vaccine to prevent HSV-2 infection. EXCT4 is a truncated form of the mature glycoprotein G-2 (mgG-2) that unlike full mature form is secreted by expressing cells enabling it to be rapidly scaled up for production. The current study examined whether EXCT4 immunity in mice could be further enhanced through use of adjuvants. EXCT4 formulated with Advax-CpG adjuvant induced a strong Th1-type immune response characterized by interferon gamma (IFN-γ) and protected animals against a lethal genital challenge with HSV-2. This response was associated with reduced viral load in vaginal washes, spinal cord, and dorsal root ganglia. Together the results provide proof of concept that EXCT4 formulated with Advax-CpG adjuvant is a promising HSV-2 vaccine candidate warranting further investigation.     

Systematic comparison of plasma EBV DNA,anti-EBV antibodies and miRNA levels for early detection and prognosis of nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is originated from the epithelial cells of nasopharynx, Epstein–Barr virus (EBV)-associated and has the highest incidence and mortality rates in Southeast Asia. Late presentation is a common issue and early detection could be the key to reduce the disease burden. Sensitivity of plasma EBV DNA, an established NPC biomarker, for Stage I NPC is controversial. Most newly reported NPC biomarkers have neither been externally validated nor compared to the established ones. This causes difficulty in planning for cost-effective early detection strategies. Our study systematically evaluated six established and four new biomarkers in NPC cases, population controls and hospital controls. We showed that BamHI-W 76 bp remains the most sensitive plasma biomarker, with 96.7% (29/30), 96.7% (58/60) and 97.4% (226/232) sensitivity to detect Stage I, early stage and all NPC, respectively. Its specificity was 94.2% (113/120) against population controls and 90.4% (113/125) against hospital controls. Diagnostic accuracy of BamHI-W 121 bp and ebv-miR-BART7-3p were validated. Hsa-miR-29a-3p and hsa-miR-103a-3p were not, possibly due to lower number of advanced stage NPC cases included in this subset. Decision tree modeling suggested that combination of BamHI-W 76 bp and VCA IgA or EA IgG may increase the specificity or sensitivity to detect NPC. EBNA1 99 bp could identify NPC patients with poor prognosis in early and advanced stage NPC. Our findings provided evidence for improvement in NPC screening strategies, covering considerations of opportunistic screening, combining biomarkers to increase sensitivity or specificity and testing biomarkers from single sampled specimen to avoid logistic problems of resampling.     

Characterization of hepatitis B virus infection and viral DNA integration in non-Hodgkin lymphoma

Hepatitis B virus (HBV) infection has been reported to be associated with non-Hodgkin lymphoma (NHL). However, the evidence is limited to the seroepidemiological study. There is a lack of evidence showing the HBV infection and integration in NHL cells. Here, we reported that in the Shanghai area, the positive rates of serum HBsAg (OR: 3.11; 95% CI: 2.20-4.41) and HBeAg (OR: 3.99; 95% CI: 1.73-9.91) were significantly higher in patients with NHL. HBsAg, HBcAg and HBV DNA were detected in 34.4%, 45.2% and 47.0% of the NHL tissues, respectively. Furthermore, by using a high-throughput viral integration detection approach (HIVID), integrated HBV DNA was identified from 50% (6/12) HBV-related NHL tissues. There were a total of 313 HBV integration sites isolated from the NHL tissues, among which four protein-coding genes (FAT2, SETX, ITGA10 and CD63) were interrupted by HBV DNA in their exons. Seven HBV preferential target genes (ANKS1B, HDAC4, EGFLAM, MAN1C1, XKR6, ZBTB38 and CCDC91) showed significantly altered expression levels in NHL, suggesting a potential role of these genes in NHL development. Taken together, HBV integration is a common phenomenon in NHL. This finding opens up a new direction of research into the mechanistic link between HBV infection and NHL.     

直接抗病毒药物治疗丙型肝炎合并透析患者的临床应用

丙型肝炎病毒（HCV）感染在慢性肾功能不全患者中较常见，尤其是在进行透析的患者中，HCV感染较普通患者的风险极大增加，同时还会导致肝细胞癌及肝硬化的发病率明显升高。近年来直接抗病毒药物（DAAs）在慢性丙型肝炎的治疗中取得了较好的疗效及安全性，本文通过总结DAAs在丙型肝炎合并透析患者中的应用进展，发现对于基因1~6型HCV合并透析患者，推荐使用G/P方案；由于索磷布韦（SOF）经肾脏代谢，在重度肾损害人群中的血药浓度较高，因此SOF组合方案并不推荐用于丙型肝炎合并透析患者的治疗。     

Directly observed hepatitis C treatment with opioid substitution therapy in community pharmacies: A qualitative study

BackgroundThe hepatitis C virus (HCV) will only be eliminated through successful engagement with people who inject drugs (PWID), however some of this population experience socioeconomic and individual issues that can lead to poor HCV treatment adherence. A key sub-group of (PWID) are those who receive opioid substitution therapy (OST). In Australia, OST is most often delivered under direct supervision by a community pharmacist every day or multiple times a week. This regular interaction could be an ideal opportunity to enhance direct-acting antiviral (DAA) treatment adherence under directly observed therapy (DOT) by the pharmacist.AimThe aim of this study was to explore the perspectives of OST patients with a lived experience of HCV to understand whether or not dispensing DAAs in the same way as, or simultaneously with OST would benefit HCV treatment.MethodsData collection occurred from June to August 2017. Semi-structured interviews were conducted with a sample of PWID living with HCV and on OST programs (n = 12) in Melbourne, Australia. Interviews were voice recorded and transcribed in verbatim. Interpretive phenomenology guided analysis of the data.ResultsThemes reported by participants that provide insight into the suitability of DOT of DAAs include: Adherence and non-adherence to DAA treatment; Mixed views towards DOT of DAAs; Experiences and perceptions of OST providers; and Perceived stigma in the pharmacy.ConclusionsCommunity pharmacies offering OST may be an effective place for DOT of HCV treatment, but is likely only to benefit people who face significant challenges to adherence. We suggest that a positive pharmacist-patient relationship, high OST adherence, and commitment to reducing stigma in the pharmacy would be necessary for the intervention to be effective. Further research is needed to evaluate the expanded-role of community pharmacies in improving DAA adherence and eliminating HCV.     

从免疫炎性损伤角度探讨5种清热解毒药物抗流感的机制及其临床意义

目的探讨黄芩、板蓝根、白头翁、虎杖、白花蛇舌草5种清热解毒代表药物抗流感病毒感染所致免疫炎性损伤的作用机制。方法在流感病毒亚洲甲型鼠肺适应株FM1感染小鼠后的不同时相(初期、极期、后期),采用ELISA法,动态观察清热解毒代表药物对小鼠血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1(IL-1)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)、γ干扰素(IFN-γ)5种炎性细胞因子含量的影响。结果黄芩在感染后第3日可显著降低血清TNF-α、IL-1、IL-6含量,并于感染后各时相均可增加IFN-γ含量,感染后第1~5日增加IL-10含量。板蓝根在感染后第3日能显著降低血清TNF-α含量,第3~5日降低IL-6含量,并在感染后第1天升高IL-10含量,在感染后第3~5日能升高IFN-γ含量。白头翁在感染后第3日能明显降低血清TNF-α、IL-1、IL-6含量,同时显著升高IL-10含量。虎杖在感染后第1日可显著升高血清IL-10含量,在感染后第5日升高IFN-γ含量。白花蛇舌草在感染后第3日降低血清IL-6含量,在感染后第5日升高IFN-γ含量。结论黄芩的抗流感作用主要表现在流感病毒感染引起的急性外感热病的极期;板蓝根在流感病毒感染的各个时相均有一定的治疗作用;白头翁在流感病毒感染的极期可抑制炎性损伤;虎杖在感染流感病毒的初期与后期均可减少促炎性细胞因子的分泌;白花蛇舌草在流感病毒感染的极期及后期均可起到一定的抗免疫炎性损伤。各药物均具有抑制炎性损伤、防止多脏器功能衰竭、防止休克、退热和抑制促炎性细胞因子的分泌,调节机体免疫,从而减轻炎症反应的作用。     

Clinicopathologic characteristics of follicular lymphoma in hepatitis C virus-infected patients

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. It has been hypothesized that chronic hepatitis C virus (HCV) infection stimulates IGH-BCL2 clone proliferation, leading to development of FL. Furthermore, regression of FL after antiviral treatment without chemotherapy has been reported in HCV-infected patients. To clarify the relationship between HCV and FL, we compared the prevalence of IGH-BCL2 translocation and other clinicopathologic characteristics between HCV-infected and HCV-uninfected FL patients and determined the impact of HCV eradication on the oncologic outcomes of HCV-infected FL patients. The study included HCV-infected patients (cases) with FL seen at our institution during 2004-2018. Cases were matched with HCV-uninfected FL patients (controls) according to year of lymphoma diagnosis, sex, and hepatitis B serology. We studied 19 cases and 57 controls. More cases than controls had splenic involvement of FL (26% vs 5%, P = 0.02), higher histologic grade (grade 3 in 56% vs 24%, P = 0.01), absent or weak CD10 expression (42% vs 11%, P = 0.005), and absent BCL2 expression (33% vs 4%, P = 0.004). Compared to controls, cases had a lower rate of detection of IGH-BCL2 translocation (31% vs 68%, P = 0.02). Finally, cases with a sustained virologic response (virologic cure of HCV) had a better 10-year overall survival rate than did cases not treated with antivirals or controls (P = 0.001). In conclusion, HCV-infected patients with FL have unique clinicopathologic characteristics including improved overall survival with HCV eradication. The pathogenesis of FL in HCV-infected patients seems unrelated to antiapoptotic effect of IGH-BCL2 rearrangement.