Background/Aim: Additional primary malignancy (APM) risk is increasing with improved prognosis of cancer survivors. In order to clarify risk factors and patients susceptible to develop APMs, we investigated the clinical features, prognosis, and approaches for diagnosis and treatment in these patients. Patients and Methods: Among 874 patients newly diagnosed with gastrointestinal tract (GIT) or hepato-biliary-pancreatic (HBP) cancers between 2011 and 2014, 124 with a synchronous and/or metachronous APM were identified. Patient characteristics, time interval between the malignancies, clue to detect APMs, treatment approaches, and prognosis were investigated. Results: Patients with APMs were older and predominantly male. Half of the metachronous APMs were detected within 3 years after the first primary malignancy (PM). The main clue to detect synchronous and metachronous APMs was preoperative screening for current PM, and follow-up of prior PM, respectively. There was no significant difference in the overall survival between colon cancer patients with or without APMs. Conclusion: Multiple PMs were present in 14.2% of patients. Male and old age were identified to be risk factors for APM. Pre-operative screening and post-operative regular follow-ups are important for detecting synchronous or metachronous APMs.

Farnesyltransferase inhibitors (FTIs) suppress tumor aggressiveness in several malignancies by inhibiting Ras signaling. However, treatment of cells with a low dose of the FTI tipifarnib suppresses the expression of hypoxia‐inducible factor‐1α (HIF‐1α) and results in antitumor effects without inhibiting the Ras pathway. Although we previously reported that elevated HIF‐1α expression is associated with an aggressive phenotype in gastric cancer (GC), little is known about the antitumor effects of FTIs on GC. In this study, we examined the relationship between the antitumor effects of low‐dose tipifarnib and HIF‐1α expression in GC cells. Under normoxic conditions, HIF‐1α was expressed only in MKN45 and KATOIII cells. The inhibitory effect of tipifarnib on HIF‐1α was observed in HIF‐1α‐positive cells. Low‐dose tipifarnib had antitumor effects only on HIF‐1α‐positive cells both in vitro and in vivo . Furthermore, low‐dose tipifarnib inactivated ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) signaling and decreased intracellular reactive oxygen species (ROS) levels in HIF‐1α‐positive GC cells. Our results that the antitumor effects of low‐dose tipifarnib are at least partially mediated through suppression of mTOR signaling and HIF‐1α expression via inhibition of Rheb farnesylation and reduction in ROS levels. These findings suggest that low‐dose tipifarnib may be capable of exerting an antitumor effect that is dependent on HIF‐1α expression in GC cells. Tipifarnib may have potential as a novel therapeutic agent for HIF‐1α‐expressing GC exhibiting an aggressive phenotype.

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Inflammatory processes play major roles in carcinogenesis and progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But there are no therapies for NASH related HCC, especially focusing on these critical steps. Previous studies reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed expression of phosphorylated nuclear factor-κB and transforming growth factor-β. Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.

Inflammatory processes play major roles in carcinogenesis and the progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But, there are no therapies for NASH-related HCC, especially focusing on these critical steps. Previous studies have reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In hepatoblastoma and HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed the expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed the expression of phosphorylated nuclear factor-κB and transforming growth factor-β. Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high-fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.