DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling.

Epigenetic alterations play an important role in the pathogenesis in multiple myeloma, but their biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for myeloma cell survival. DOT1L expression levels were higher in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in normal plasma cells. Treatment with a DOT1L inhibitor induced cell cycle arrest and apoptosis in myeloma cells, and strongly suppressed cell proliferation in vitro The anti-myeloma effect of DOT1L inhibition was confirmed in a mouse xenograft model. Chromatin immunoprecipitation-sequencing and microarray analysis revealed that DOT1L inhibition downregulated histone H3 lysine 79 dimethylation and expression of IRF4-MYC signaling genes in myeloma cells. In addition, DOT1L inhibition upregulated genes associated with immune responses and interferon signaling. Myeloma cells with histone modifier mutations or lower IRF4/MYC expression were less sensitive to DOT1L inhibition, but with prolonged treatment, anti-proliferative effects were achieved in these cells. Our data suggest that DOT1L plays an essential role in the development of multiple myeloma and that DOT1L inhibition may provide new therapies for myeloma treatment.

Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment.

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.

Development of hypertension within 2 weeks of initiation of sorafenib for advanced hepatocellular carcinoma is a predictor of efficacy.

BACKGROUND: Sorafenib is an agent that inhibits vascular endothelial growth factor and is associated with onset or worsening of hypertension in some patients. We conducted a retrospective analysis of whether the development of hypertension during sorafenib treatment of advanced hepatocellular carcinoma could be a predictor of anti-cancer efficacy. METHODS: The study included 38 patients with advanced hepatocellular carcinoma who had received sorafenib for at least 1 month between January 2010 and December 2012. A retrospective analysis of the efficacy of sorafenib was conducted by dividing the patients into two groups-a hypertension group, presenting with grade 2 or higher hypertension according to the Common Terminology Criteria for Adverse Events (CTCTE) version 4.0; and a non-hypertension group, which included all other patients. This study evaluated the occurrence of hypertension within 2 weeks of initiation of therapy in order to avoid any treatment duration bias. Images were evaluated using the modified Response Evaluation Criteria in Solid Tumors. The response rate, time to progression, and overall survival were assessed. RESULTS: Twenty-two patients (58 %) developed grade 2 or higher hypertension within 2 weeks of initiation of therapy. The response rate was significantly higher in the hypertension group. Median time to progression was 153 days in the hypertension group versus 50.5 days in the non-hypertension group, which was significantly longer in the hypertension group. Moreover, median overall survival was 1,329 days in the hypertension group versus 302 days in the non-hypertension group, which was significantly longer in the hypertension group. CONCLUSIONS: Hypertension within 2 weeks of initiation of therapy may be a predictor of the anti-cancer efficacy of sorafenib when used for the treatment of advanced hepatocellular carcinoma.

[A case of recurrent gastric cancer showing partial response to capecitabine/CDDP after treatment with S-1/CDDP].

S-1 and capecitabine are orally administered fluoropyridines reported to be effective in the treatment of advanced gastric cancer(AGC). In fact, both S-1/CDDP and capecitabine/CDDP are considered to be the standard first-line treatments for AGC.However, no information concerning on the activity of capecitabine in S-1-pretreated patients with AGC has been reported. Here, we present a case of recurrent gastric cancer that showed a partial response resulting in 6 months of progres-sion-free survival, thanks to capecitabine/CDDP after the failure of multiple anticancer drugs such as S-1/CDDP. S -1 and capecitabine may exhibit cross-resistance because they both have the same final active metabolite: 5-fluorouracil(5-FU). Dihydropyrimidine dehydrogenase(DPD)is the rate-limiting enzyme in the degradation of 5-FU, and S-1 contains the inhibitor of DPD. Thus, S-1, but not capecitabine, is active against tumors with high DPD expression. On the other hand, capecitabine is activated to 5-FU by thymidine phosphorylase(TP)within the tumor tissue and is more effective against tumors with high TP expression. The present case suggests that S-1 and capecitabine do not always exhibit cross-resistance, and that capecitabine may be effective in S-1-pretreated patients with AGC.

Extensive portal and mesenteric vein thrombosis in a young man with Klinefelter's syndrome.

Klinefelter's syndrome (KS) is a unique physical condition characterized by tall stature, eunuchoid body proportions, gynecomastia, and azoospermia, in addition to an extra X chromosome. In contrast to the original description, symptoms or physical findings can be extremely varied. KS is the most common chromosomal disorder, with an incidence of 1 in 500 males and is also the most commonly undiagnosed chromosomal disorder. Here, we present the case of a 26-year-old man with KS, who visited our hospital with complaints of abdominal pain and fever. On a routine physical examination, he did not differ from a normal karyotype male. Computed tomography showed extensive portal and mesenteric vein thrombosis (PMVT). It is well known that KS is frequently associated with venous thrombosis, but KS with PMVT has rarely been reported. Approximately one-third of PMVT is idiopathic, but this case suggests the possibility that undiagnosed KS is one of the causes of PMVT, as some individuals with KS are not easily distinguishable from those with the normal karyotype.

Irinotecan as the key chemotherapeutic agent in second-line treatment of metastatic gastric cancer after failure of first-line S-1 or S-1/CDDP therapy.

BACKGROUND: S-1, an oral fluoropyrimidine, is one of the standard chemotherapeutic agents for the treatment of metastatic gastric cancer(MGC). However, the most effective second-line regimen after failure of treatment with first-line agents such as S-1 is yet to be determined. The aim of this study was to investigate the various second-line chemotherapy regimens in MGC patients. METHODS: We retrospectively studied patients with MGC who received second-line treatment after failure of the first-line S-1 or S-1/cisplatin treatment. The overall survival times with each second-line regimen were determined using the Kaplan-Meier method, and the effect on overall survival was analyzed using Cox regression analysis. RESULTS: The median survival time for all patients was 14. 2 months(95% confidence interval(CI): 12. 88-15. 43 months)with a 1-year survival rate of 60. 4%. Kaplan-Meier analysis revealed that the second-line regimens containing irinotecan significantly improved the median survival time as compared to regimens without irinotecan(median survival time: 16. 5 and 13. 8 months, respectively). Cox regression analysis showed that irinotecan-containing regimens were associated with improved overall survival(hazard ratio: 0. 165; 95% CI: 0. 041-0. 665). CONCLUSION: The use of irinotecan-containing regimens as second-line chemotherapy after failure of first-line S-1 therapy may be beneficial for MGC patients.

[A case of hepatocellular carcinoma diagnosed based on the result of a bone biopsy, in which the primary hepatocellular carcinoma was identified in the liver 14 months after the initial diagnosis].

A 64-year-old man complained of pain in his left humerus. A histopathological examination of biopsy specimens taken from the lesion revealed a hepatocellular carcinoma. No primary hepatic lesion was revealed in a subsequent examination performed at this time. Enhanced computed tomography examination of the abdomen 14 months later, showed a nodular lesion, approximately 15 mm in diameter, therefore a partial hepatectomy was performed. The lesion was histopathologically diagnosed as a moderately-poorly differentiated hepatocellular carcinoma. The inability to identify the primary hepatocellular carcinoma is quite rare, and the present case may be the first report of the discovery of the primary hepatocellular cancer after the diagnosis of a secondary lesion.

Anorectal melanoma with a KIT-activating mutation, which is a target for tyrosine kinase inhibitor.

Recent advances in our understanding of the genetic mutations associated with melanoma have led to the classification of distinct melanoma subtypes. A number of reports have consistently demonstrated that mucosal and acral melanomas more commonly harbor KIT-activating mutations than do other subtypes. Success in treating gastrointestinal stromal tumors with imatinib has led to speculation that KIT-mutated melanoma might also be effectively managed using this approach. A 78-year-old woman presented with a 4-month history of rectal bleeding. A colonoscopy revealed a black polypoid mass, 30 mm in diameter, originating near the dentate line, and a biopsy revealed malignant melanoma. Computed tomography showed multiple liver and lung metastases. A KIT mutation analysis showed the L576P mutation in exon 11. The patient did not want to undergo chemotherapy including a tyrosine-kinase inhibitor, so palliative radiotherapy for rectal symptoms was performed, but the patient died 4 months later due to disease progression. We describe the first case of anorectal melanoma with a KIT-activating mutation in Japan and summarize findings from the literature regarding the efficacy of KIT kinase inhibitors on this melanoma subtype.

[Effectiveness and safety of chemoradiation in a community-based population of patients with esophageal cancer].

BACKGROUND: In Japan, esophagectomy with three-field lymphadenectomy is the standard therapy for resectable esophageal cancer. However, its outcome is considered unsatisfactory because the 5-year survival rate is less than 50%. Chemoradiotherapy (CRT) is the standard therapy for unresectable esophageal cancer and could also be considered as an option for resectable esophageal cancer. We retrospectively determined the efficacy and safety of CRT for patients with esophageal cancer. METHODS: The study population comprised patients with esophageal cancer who had been treated with CRT between April 2004 and October 2009 in our institute. Acute and late toxicity was assessed with NCI-CTC and RTOG/EORTC late radiation morbidity scoring scheme, respectively. Survival time was calculated using Kaplan-Meier methods. RESULTS: We enrolled 29 consecutive patients and classified them on the basis of clinical staging: stage I, 4 patients; stage II/III, 11 patients; and stage IV, 14 patients. Complete response was achieved in 37.9% and 45.5% of the total study population and the stage II/III group, respectively. The median survival time in these groups was 12.1 months and 15 months, respectively. Grade 3/4 acute toxicities were observed in 62.1% of the patients. Grade 3/4 late toxicities were observed in 12% of the patients. The first failure after CRT was almost locoregional. CONCLUSION: CRT appears to be an effective therapy for esophageal cancer; however, its outcome is not satisfactory. Therefore, it is necessary to evaluate the role of salvage surgery after CRT and new chemotherapeutic agents.

[Hyperplastic hepatic nodules in a case of idiopathic portal hypertension: changes in imaging findings during a 6-year follow-up].

A 22-year-old man had been given a diagnosis of idiopathic portal hypertension in childhood. In June 2001, a hepatic nodule which gradually increased in size over the next 2 years, was detected in the left hepatic lobe. In February 2003, a left lateral segmentectomy was performed. Histological examination of the nodules suggested focal nodular hyperplasia (FNH)-like hyperplasia. Computerized tomography performed 2 years later showed other hepatic nodules, and a liver biopsy was performed. Histopathological examination conducted at this time also suggested FNH-like hyperplasia. Owing to the substantial enlargement of the nodules and frequent recurrence, it can be difficult to distinguish between benign and malignant lesions.

Leukoencephalopathy during administration of etanercept for refractory rheumatoid arthritis.

A 74-year-old Japanese woman was diagnosed with rheumatoid arthritis due to polyarthralgia. She was prescribed various disease-modifying anti-rheumatic drugs, but most of them were discontinued because of side effects or poor effectiveness. She was referred to our hospital in 2004, and etanercept was administered from June 2005. This resulted in rapid improvement of polyarthritis; however, she developed disorientation from February 2006. She was admitted to our hospital because of convulsions and loss of consciousness. She was diagnosed with progressive multifocal leukoencephalopathy on the basis of clinical symptoms and magnetic resonance imaging of the brain. In this significant and important case, leukoencephalopathy occurred during etanercept administration, and we refer to the risk of anti-TNFalpha drugs.