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High-dose methotrexate therapy(HDMTX)is effective against lymphoid malignancies. However, delayed elimination of methotrexate(MTX)after HDMTX administration may lead to severe adverse drug reactions. We surveyed the drugs coadministered with MTX and the incidence of delayed MTX elimination in patients treated with HDMTX in a clinical setting. We analyzed the plasma MTX concentration in 110 samples after 55 cycles of HDMTX in 33 patients. Delayed MTX elimination was defined as a plasma MTX concentration ≥1.0 mmol/L at 48 h after the start of HDMTX administration or ≥0.1 mmol/L at 72 h after the start of HDMTX administration. The incidence of the combined use of drugs affecting MTX excretion and drugs that exhibited typical renal excretion was 84.8%(n=28). The incidence of delayed MTX elimination was 39.4%(n=13). MTX-induced acute kidney injury occurred in 9 patients, all of whom also exhibited delayed MTX elimination. Therefore, when prescribing HDMTX, it is important to monitor adverse events, including acute kidney injury, which may be induced by prolonged MTX blood concentrations.

We analyzed 95 cases of MDS (n=78), CMML (n=8) and AML (n=9) with blast counts of <30%, treated by AZA since March 2011, for a possible association of hematological improvement (HI) and overall survival duration (OS). We defined four categories as follows: stable disease (SD): no exacerbation of disease even if HI was not achieved after nine cycles of AZA treatment; early and late response (ER, LR): achievement of HI within and beyond three cycles, respectively; and drop out (DO): termination of treatment within nine cycles due to disease progression or complication without obtaining HI. OS was significantly longer in the LR than in the ER. The OS of ER was significantly shorter than that of the SD group. Patients in ER group who relapsed had significantly shorter survival than those who were able to maintain HI. Additionally, 3 out of 11 SD cases achieved HI after 10 cycles. We conclude that AZA should be continued until disease progression besides an achievement of HI.

Azacitidine (AZA), a hypomethylating agent, is widely used in patients with high-risk (HR) myelodysplastic syndromes (MDS). AZA is also believed to aid in the treatment of acute myeloid leukemia (AML). In randomized clinical trials for MDS, major and overall response rates for AZA alone were 16-33% and 38-60%, respectively. In the AZA-001 trial, the median overall survival (OS) for the AZA group was >24 months compared to 15 months for the control. However, other clinical trials have reported OS periods of 15-21 months, while population-based studies have reported OS rates much shorter than 20 months. Only a fraction of HR-MDS patients appears to benefit from AZA treatment. Furthermore, despite its low-intensity nature, the risk may outweigh the benefit in a significant proportion of patients; therefore, the indication of AZA should be reconsidered if good biomarkers that predict its efficacy are discovered. The response rate to AZA was moderately higher in MDS patients with TET2 mutations than in those without the mutations. Recently, increasing attention has been paid to a report, according to which, majority of the patients with TP53 mutations showed good response to a higher dose of decitabine. The use of AZA and the biomarkers predicting its efficacy is discussed.

A 67-year-old man was admitted to our hospital with a complaint of epigastric discomfort. A 29-mm hypovascular tumor was detected in the head of the pancreas by abdominal computed tomography imaging. As the superior mesenteric artery (SMA) was also involved, we diagnosed the tumor as unresectable pancreatic cancer. With S-1 chemotherapy, a radiological partial response was seen. After 4 courses of chemotherapy, a subtotal-stomach-preserving-pancreatoduodenectomy with dissection of the nerve plexus surrounding the SMA was performed. Although the tissue surrounding the SMA was hard, invasion of the SMA was not detected. Microscopic investigation revealed a few moderately differentiated adenocarcinoma cells in the fibrous tissue and the nerve fibers of pancreas. No cancer cells were found at the edges of the surgical specimen. The patient underwent R0 resection and a pathological evaluation showed Grade III tumor according to the Evans classification. After surgery, S-1 was interrupted because of diarrhea and local recurrence appeared 4 months postoperatively. For improving the prognosis of patients with pancreatic cancers, surgical intervention is often performed in patients with initially unresectable pancreatic cancers who have "long-term" favorable responses to chemotherapy or chemoradiotherapy. However, because of the possibility of relatively good prognosis with nonsurgical treatment for such patients and also the demerits of surgical stress, it is important to carefully consider the adjuvant surgery option.

TS-1 (S-1), developed by the scientific theory of both potentiating antitumor activity of 5-fluorouracil (5-FU) and reducing gastrointestinal toxicity induced by 5-FU, is a new oral formulation consisting of 1 M tegafur, 0.4 M gimeracil and 1 M oteracil potassium. We investigated the antitumor efficacy of S-1 alone and in combination with other cytotoxic anticancer drugs using subcutaneously or orthotopically implanted murine and human tumors in rodents. As a single agent, S-1 showed higher antitumor activity with its low intestinal toxicity compared to continuous venous infusion 5-FU, the most effective dosing method of 5-FU, and/or to clinically available oral fluoropyrimidines such as UFT, doxyfluridine and capecitabine on various murine tumors and human tumor xenografts. Especially, it was noteworthy that S-1 as a DPD-inhibitory fluoropyrimidine markedly affected human tumor xenografts with high expression levels of DPD on which other fluoropyrimidines showed a low antitumor activity. In combination with other anticancer drugs such as CPT-11 and taxanes, S-1 exercised synergistic antitumor efficacy not only on 5-FU-sensitive tumors with low expression levels of thymidylate synthase (TS) but also on 5-FU-resistant tumors with originally higher and/or elevated levels of TS expression. As one of the reasonable mechanism of antitumor synergism by the combination, CPT-11 and taxanes were found to reduce the expression of TS in human tumor resistant to 5-FU with high expression TS levels. Throughout our preclinical antitumor studies of S-1, alone and/or in combination with other anticancer drugs, it would be expected to contribute greatly to the treatment of cancer patients.