Molecular targeted therapy for hepatocellular carcinoma:Current and future

Hepatocellular carcinoma(HCC)is one of the most frequent tumors worldwide.The majority of HCC cases occur in patients with chronic liver disease.Despite regular surveillance to detect small HCC in these patients,HCC is often diagnosed at an advanced stage.Because HCC is highly resistant to conventional systemic therapies,the prognosis for advanced HCC patients remains poor.The introduction of sorafenib as the standard systemic therapy has unveiled a new direction for future research regarding HCC treatment.However,given the limited efficacy of the drug,a need exists to look beyond sorafenib.Many molecular targeted agents that inhibit different pathways involved in hepatocarcinogenesis are under various phases of clinical development,and novel targets are being assessed in HCC.This review aims to summarize the efforts to target molecular components of the signaling pathways that are responsible for the development and progression of HCC and to discuss perspectives on the future direction of research.

Clinical significance of hepatitis B e antigen level measurement during long-term lamivudine therapy in chronic hepatitis B patients with e antigen positive

AIM: To determine the changes of quantitative hepatitis B e antigen (HBeAg) that predicts early detection of non- response or breakthrough to long-term lamivudine (LAM) therapy.METHODS: Among HBeAg positive chronic hepatitis B patients who failed to achieve HBeAg seroconversion within 12 mo, we retrospectively analyzed 220 patients who had received LAM more than 24 mo. RESULTS: The mean duration of LAM therapy was 36 (range, 24-72) mo. HBeAg seroconversion after the first 12 mo of LAM therapy was achieved in 53 (24.1%) patients. Viral breakthrough was observed in 105 (47.7%) patients. To find out whether the changing patterns of HBeAg levels can predict the outcome of LAM therapy, we analyzed the reduction rates of HBeAg levels during LAM therapy. Using the decrease more than 90% of pretreatment HBeAg levels, the sensitivity and specificity of response were 96.2% and 70.1%, respectively. Patients were divided into 3 groups according to the reduction patterns of the decrease of quantitative HBeAg: decrescendo, decrescendo-crescendo, no change or fluctuating groups. The optimal time to predict non- response or breakthrough was the first 9 mo of therapy. At 9 mo of therapy, 49 (92.5%) of 53 patients who had achieved HBeAg seroconversion were included in the decrescendo group. On the contrary, in the no change or fluctuating group, only four (7.5%) had achieved HBeAg seroconversion. Among patients who did not show the continuous decrease of HBeAg levels at 9 mo, 95.2% (negative predictive value) failed to achieve HBeAg seroconversion.CONCLUSION: Almost all patients who failed to showa continuous decrease of HBeAg levels at 9 mo of LAM therapy were non-response or breakthrough. Therefore, monitoring changes of HBeAg levels during LAM therapy in HBeAg positive chronic hepatitis B may be valuable for identifying patients who are at high risk of non-response or breakthrough.

A gastrointestinal stromal tumor of the duodenum masquerading as a pancreatic head tumor

Gastrointestinal stromal tumor (GIST) represents the most common kind of mesenchymal tumor that arises from the alimentary tract. GIST is currently defined as a gastrointestinal tract mesenchymal tumor showing CD117 (c-kit protein) positivity at immunohistochemistry. Throughout the whole length of the gastrointestinal tract, GIST arises most commonly from the stomach followed by the small intestine, the colorectum, and the esophagus. Only 3%-5% of GISTs occur in the duodenum, and especially, if GIST arises from the C loop of the duodenum, it can be difficult to differentiate from the pancreas head mass because of its anatomical proximity. Here, we report a case of duodenal GIST, which was assessed as a pancreatic head tumor preoperatively.

Fragile histidine triad gene alterations are not essential for hepatocellular carcinoma development in South Korea

AIM: To establish the role of FHIT in the pathogenesis hepatocellular carcinoma (HCC). METHODS: We examined genomic alterations, as well as, mRNA and protein expression patterns from the FHIT gene, in 48 surgically resected hepatocellular carcinoma (HCC) tissues. Additionally, p53 mutations were analyzed. RESULTS: Aberrant FHIT transcripts were detected in 11 of 48 surrounding non-tumor liver tissues and 27 of 48 HCC samples (22.9% vs 56.3%, P = 0.002). No point mutations were identified within the open reading frame region of FHIT. Loss of heterozygosity (LOH) of the FHIT locus was detected in 4 of 42 informative cases for D3S1300, and 3 of 29 informative cases for D3S1313. Reduced expression of FHIT protein (Fhit) was observed in 8 (16.7%) of 48 HCC samples, with complete loss of Fhit in only 1 case. There were no associations with abnormal transcripts, LOH, and Fhit expression. p53 mutations were identified in 9 of the 48 HCC cases. However, none of the cases displayed a G to T transversion at p53 codon 249. CONCLUSION: Aberrant FHIT transcripts were more common in HCC tissues as compared to non-cancerous liver tissues. However, Fhit expression was lost or reduced in a minor fraction of HCC tissues, while it was strongly expressed in non-cancerous liver tissues.Therefore, our study suggests that FHIT plays a role in relatively few HCC cases in South Korea.