Impact of chronological age on efficacy and safety of fluoropyrimidine plus bevacizumab in older non-frail patients with metastatic colorectal cancer: a combined analysis of individual data from two phase II studies of patients aged >75 years.

OBJECTIVE: Many clinical trials for older patients with metastatic colorectal cancer have been conducted, and fluoropyrimidine and bevacizumab are standard treatments. However, the relationship between age and the efficacy and safety of this treatment is unclear in older metastatic colorectal cancer patients. METHODS: Individual data from two phase II studies on older (≥75 years), non-frail patients with metastatic colorectal cancer treated with uracil-tegafur/leucovorin or S-1 combined with bevacizumab were collected. Patient characteristics were evaluated with multiple regression analyses for survival outcomes, using the Cox proportional hazard model and linear regression analyses for the worst grade of adverse events. RESULTS: We enrolled 102 patients with a median age of 80 years (range, 75-88 years). Of the 70 patients who died, seven (10%) died of causes unrelated to disease or treatment. The study treatment was discontinued due to adverse events in 19 patients (18.6%), with 63% aged ≥85 years. The adverse event that most commonly resulted in treatment discontinuation was grade 2 fatigue (21%). Chronological age was not associated with progression-free survival (Hazard ratio, 1.03; P = 0.40) or overall survival (Hazard ratio, 1.02; P = 0.65). Age was weakly associated with non-hematologic adverse events (regression coefficient [R], 0.27; P = 0.007), especially fatigue (R, 0.23; P = 0.02) and nausea (R, 0.19; P = 0.06), but not with hematologic (R, 0.05; P = 0.43) or bevacizumab-related (R, -0.06; P = 0.56) adverse events. CONCLUSIONS: The efficacy of fluoropyrimidine plus bevacizumab was age-independent in patients with metastatic colorectal cancer aged ≥75 years, and attention should be paid to non-hematologic adverse events as age increases.

[A Case of Abdominal Fullness Caused by a Retroperitoneal Bulky Tumor Treated with Epidural Analgesia].

We presented the case of a 63-year-old woman with severe abdominal distention due to recurrent retroperitoneal sarcoma. Further, the rapid progression of the tumor made it difficult to relieve the abdominal distention. Titrated intravenous morphine was administered. Although the dose of morphine was escalated and the patient was sedated, she continued to experience pain. The addition of a continuous epidural analgesic lidocaine to manage the abdominal distention was effective. This case report describes a stepwise approach with continuous epidural analgesia of lidocaine for a bulky tumor- related abdominal distention.

Simple index for validity of the evaluation point for dosimetric verification results of intensity-modulated radiation therapy using a Farmer-type ionization chamber.

PURPOSE: Based on a retrospective analysis, this study aims to develop a simple index for validity of the evaluation point for the dosimetric verification of intensity-modulated radiation therapy (IMRT). METHODS: The results for the dosimetric verifications of a total of 69 IMRT plans were analyzed in this study. A Farmer-type ion chamber was used as a dose detector, and a solid water-equivalent phantom was used. Index values were obtained by dividing the difference between the maximum and minimum dosages by the mean dosage of the 69 plans, and the values were classified into five groups with index value <4, 4-8, 8-12, 12-16, and >16. A t-test was used to assess the statistical significance of the mean differences of the absolute values of the relative errors among these groups. RESULTS: We found that there was no significant difference between the groups with index value <4 and 4-8 (p = 0.152); however, there were significant differences between the other groups (p < 0.01). In addition, when the index values were smaller than 8, the pass ratio of 3% tolerance was 96.2% and the pass ratio of 5% tolerance was 99.9%. We observed that the smaller the index value, the smaller the uncertainty of the dose measurement. CONCLUSIONS: The results obtained in this study may prove to be useful for accurate dosimetric verifications of IMRTs when ion chambers are used.

PTEN mRNA expression is less pronounced in left- than right-sided colon cancer: a retrospective observational study.

BACKGROUND: Several recent studies have reported that patients with metastatic colorectal cancer (CRC) whose primary tumor is located in left side of the colon have more favorable responses to anti-epidermal growth factor receptor (EGFR) antibody therapy than those with right-sided tumors. However, the mechanism for this phenomenon is unknown. METHODS: Fifty-two cases of primary CRC with liver metastases were analyzed in this retrospective study. The mRNA levels of 19 signal transduction genes in both primary tumor and liver metastases were measured by real-time reverse transcription polymerase chain reaction. The purposes of this study were (1) to determine the correspondence between signal transduction gene expressions in primary tumors and corresponding liver metastases, and (2) to determine whether expression levels of these genes differ by primary tumor location. RESULTS: mRNA expression levels of 14 of 19 signal transduction genes, including PTEN, ERBB2, MET, HGF, AREG, and EREG, showed significant correlations between the primary tumor and corresponding liver metastases. When the mRNA levels of the primary tumors were compared by tumor location, only PTEN mRNA expression differed significantly between left and right-sided CRC (median PTEN expression: left 1.00 vs. right 1.68; p = 0.017). When rectal cancers were separated from left-sided colon cancers, PTEN mRNA levels increased progressively from rectum to right-sided colon (median; rectum 0.84, left colon 1.23, right colon 1.68, p = 0.013). PTEN mRNA expression in liver metastases also differed significantly according to primary tumor location (median; left 0.92 vs. right 1.27, p = 0.048). There was no difference in overall survival between patients with high versus low levels of PTEN mRNA (p = 0.59). CONCLUSIONS: Our data suggest that the PIK3/AKT/mTOR pathway is more active in left- than right-sided CRC, which provides a possible explanation for the fact that efficacy of anti-EGFR therapy differs by location of primary tumor.

ERCC1 mRNA expression as a postoperative prognostic marker in extrahepatic bile duct cancer.

BACKGROUND: No reliable biomarker for biliary tract cancer has yet been identified because of the varying composition of the cancer type, differences in tumor location, a mixture of curative and non-curative operations, and differences in operative methods. METHODS: Fifty extrahepatic bile duct cancer patients, pathologically diagnosed with papillary or tubular adenocarcinoma who underwent a pancreatoduodenectomy with R0 resection, were included in the study. Messenger RNA (mRNA) expression levels were measured from formalin-fixed, paraffin-embedded samples by real-time reverse-transcription polymerase chain reaction. RESULTS: The preliminary analysis selected ten patients who have survived more than 5 years (LS group) and ten who had a relapse within 2 years (SS group). mRNA expression of seven target genes was examined, but only excision repair cross-complementing 1 (ERCC1) mRNA levels showed a significant difference between the LS and SS groups (median ERCC1: LS 26.5 vs. SS 9.7; p = 0.0073). The median survival time of patients with high ERCC1 levels was significantly longer than in patients with low ERCC1 levels (p = 0.0105). Thirty more patients with identical backgrounds were added to the study, and ERCC1 mRNA levels were measured in all 50 patients. Those with high ERCC1 mRNA levels had a significantly greater overall survival (OS) time compared with those with low ERCC1 levels (MST: 174 vs. 86 M; p = 0.048). Multivariate analysis found that an absence of lymph node metastases and high ERCC1 expression were significantly associated with improved OS. CONCLUSION: ERCC1 mRNA expression appears to be a useful prognostic biomarker for extrahepatic bile duct cancer with R0 resection.

Enhancement of 5-fluorouracil-induced cytotoxicity by leucovorin in 5-fluorouracil-resistant gastric cancer cells with upregulated expression of thymidylate synthase.

BACKGROUND: Elucidation of the mechanisms by which gastric cancer cells acquire resistance to 5-fluorouracil (5FU) may provide important clues to the development of effective chemotherapy for 5FU-resistant gastric cancer METHODS: Four 5FU-resistant cell lines (MKN45/5FU, MKN74/5FU, NCI-N87/5FU, and KATOIII/5FU) were established by continuous exposure of the cells to progressively increasing concentrations of 5FU for about 1 year. Then, mRNA expression levels of four genes associated with 5FU metabolism, i.e., thymidylate synthase (TS), dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase, were quantitatively evaluated by real-time reverse transcriptase-polymerase chain reaction. In addition, TS protein expression was measured by Western blot analysis. RESULTS: As compared with the parent cell lines, the 5FU-resistant cell lines showed 3.8- to 11.6-fold higher resistance to 5FU, as well as 1.9- to 3.5-fold higher TS mRNA expression and 1.6- to 7.1-fold higher TS protein expression. In contrast, the expressions of other genes did not differ significantly among the cell lines. The cytotoxicity of 5FU was enhanced 2.3- to 2.8 fold by leucovorin (LV) against three of the four 5FU-resistant cell lines. CONCLUSIONS: Collectively, LV enhanced the cytotoxicity of 5FU not only against the parent gastric cancer cell lines, but also against the 5FU-resistant cell lines, even those with elevated TS expression levels. These results suggest that clinical studies of a combination of 5FU and LV are warranted in patients who have recurrent gastric cancer after 5FU-based therapy.

Degraded DNA may induce discordance of KRAS status between primary colorectal cancer and corresponding liver metastases.

BACKGROUND: KRAS mutation is widely accepted as a strong, negative predictive marker for anti-epidermal growth factor receptor antibodies, including cetuximab and panitumumab. Previous reports demonstrated approximately 100 % concordance of KRAS status between primary colorectal cancer and liver metastases; however, mismatched KRAS status still occurs. METHODS: KRAS status was evaluated in 105 pairs of formalin-fixed primary colorectal cancer and corresponding liver metastases specimens by direct sequencing. DNA quality of patients displaying mismatched KRAS status between primary tumors and metastases was assessed using a Bioanalyzer. RESULTS: KRAS status was successfully analyzed in 90/105 patients (85.7 %). The concordance rate between primary tumors and metastases was 88.2 % in synchronous metastases (n = 76) and 100 % in metachronous metastases (n = 14). Discordance in KRAS status was observed in nine patients. Independent method validation revealed only five samples showed the same KRAS status between the two methods. DNA quality assessment by a Bioanalyzer revealed that the median length of DNA samples in the peak concentration of the mismatched group was significantly shorter than those in the control group (153.5 vs 276.5 bp, P = 0.0059). In addition, the median value of the percentage of degraded DNA (0-200 bp) in each sample in the mismatched group was significantly higher than the control group (35.5 vs 22 %, P = 0.020). These data suggest that the discordant results for these nine patients (18 samples) were due to low quality DNA, which may obscure polymerase chain reaction analysis, affecting sequencing reliability. CONCLUSION: Quality control and assurance of KRAS genotyping is critical, and standardization of the methodology is warranted.

A Case of Pathologically Complete Response After Nivolumab Combined with Chemotherapy in a Gastric Cancer Patient with Virchow's Lymph Node Metastasis.

Gastric cancer with Virchow's lymph node metastasis (LNM) is not indicated for initial curative surgery. Although there have been some case reports of curative resections after pre-operative treatment, including immune checkpoint inhibitors (ICIs), there is no consensus regarding the optimal timing of surgery. We describe a rare case of initially unresectable gastric cancer treated preoperatively with nivolumab combined chemotherapy, which achieved a pathologically complete response. An 82-year-old man was referred for gastric cancer treatment. Contrast-enhanced computed tomography revealed stomach wall thickening and swollen left supraclavicular LN. This gastric cancer was assessed as unresectable due to the presence of Virchow's LNM; therefore, chemotherapy and ICI using S-1 plus oxaliplatin plus nivolumab were administered. After three courses of treatment, the primary tumor and Virchow's LN showed a marked reduction in size. The patient underwent Virchow's LNM resection as a preliminary step to determine indications for curative surgery. A pathological examination revealed no viable cancer cells were found inside the resected LN. The patient underwent distal gastrectomy. Pathological examination revealed complete degeneration of the primary tumor and regional LN without residual carcinoma. The patient did not receive adjuvant chemotherapy and survived with no evidence of recurrence for one year after the initial treatment.

Amphiregulin and Epiregulin mRNA expression in primary colorectal cancer and corresponding liver metastases.

BACKGROUND: Amphiregulin (AREG) and Epiregulin (EREG), ligands of EGFR, are reported to be predictive biomarkers of colorectal cancer patients treated with Cetuximab, an anti-EGFR antibody. The purpose of this study is to determine the correlation of AREG and EREG expression between primary colorectal cancer and corresponding liver metastases. METHODS: One hundred twenty colorectal cancer patients with liver metastases (100 with synchronous metastases, 20 with metachronous) were evaluated. No patients had ever received anti-EGFR antibody agents. AREG and EREG mRNA expression from both the primary tumor and liver metastases were measured using real-time RT-PCR. KRAS codon 12, 13 mutation status was analyzed by direct sequencing. RESULTS: Modest, but significant, correlations were observed between primary tumor and corresponding liver metastases in both AREG mRNA expression (Rs = 0.54, p < 0.0001) and EREG mRNA expression (Rs = 0.58, p < 0.0001). AREG and EREG mRNA expression was strongly correlated in both the primary tumor (Rs = 0.81, p < 0.0001) and the liver metastases (Rs = 0.87, p < 0.0001). No significant survival difference was observed between low and high AREG or EREG patients when all 120 patients were analyzed. However, when divided by KRAS status, KRAS wild-type patients with low EREG mRNA levels in the primary site showed significantly better overall survival rates than those with high levels (p = 0.018). In multivariate analysis, low EREG expression was significantly associated with better overall survival (p = 0.006). CONCLUSIONS: AREG and EREG expression showed a modest correlation between primary tumor and liver metastases. As EREG mRNA expression was associated with decreased survival, it is appeared to be a useful prognostic marker in KRAS wild-type patients who never received anti-EGFR therapy.

Drug monitoring during FOLFOX6 therapy in a rectal cancer patient on chronic hemodialysis.

Long-term hemodialysis is considered to be a significant risk factor for cancer, but little is known about the use of oxaliplatin in patients on chronic hemodialysis. A 58-year-old man on chronic hemodialysis was treated for unresectable rectal cancer with synchronous hepatic metastasis by FOLFOX6 therapy with therapeutic drug monitoring. Plasma levels of total platinum, ultrafiltrate (free) platinum and 5-fluorouracil were monitored from the start of oxaliplatin administration to 120 h after the end of oxaliplatin infusion. Pharmacokinetic data of free platinum showed a bimodal pattern, decreased rapidly during the first dialysis and subsequently rose until 48 h after oxaliplatin infusion. The free platinum area under the curve was 15.7-18.9 microg h/ml when 40 mg/m(2) of oxaliplatin was administered, which was comparable to the area under the curve at 85 mg/m(2) in patient with normal renal function. The total platinum level reached a peak immediately before dialysis and gradually decreased. The 5-fluorouracil level decreased rapidly after the start of dialysis and remained constant during the continuous infusion of 5-fluorouracil. Tumor response was judged to be stable disease for >6 months, and no peripheral neuropathy or other toxicity was observed even after 11 courses. FOLFOX6 therapy with reduced dose of oxaliplatin had been safely performed for >6 months without any severe toxicity. The serum levels of free platinum showed bimodal pattern, and this second peak increased the area under the curve of free platinum. This pattern seems to be unique in patients on hemodialysis.

ERCC1 codon 118 polymorphism is a useful prognostic marker in patients with pancreatic cancer treated with platinum-based chemotherapy.

Excision repair cross-complementation 1 (ERCC1) has been reported to play a major role in the response to platinum-based therapies. It has recently been proposed that a synonymous polymorphism at codon 118 converting a common codon usage (AAC) to an infrequent one (AAT) may impair ERCC1 translation and to affect the response to cisplatin chemotherapy. We analyzed the association between this polymorphism and clinical outcome in 67 pancreatic cancer patients treated with cisplatin and S-1 or with S-1 alone. ERCC1 codon 118 polymorphism was analyzed using PCR-RFLP. Thirty-nine of the patients (58.2%) were homozygous for AAC codon, 7 (10.4%) were homozygous for AAT codon, and 21 (31.3%) were heterozygous. Among those treated with cisplatin and S-1, no significant difference in objective response rate was observed between genotypes. However, the patients with one or two AAT codons had a significantly longer progression-free survival (PFS) and overall survival (OS) than those homozygous for AAC allele (PFS: 338 days vs 106 days, p=0.006, OS: 763 days vs 415 days, p=0.030). In contrast, no significant difference in PFS or OS was observed between genotypes among the patients treated with S-1 alone. ERCC1 polymorphism may be a useful prognostic marker in patients with pancreatic cancer treated with platinum-based chemotherapy.

Validation of biomarkers associated with 5-fluorouracil and thymidylate synthase in colorectal cancer.

Previous studies from our laboratory have identified a number of genes associated with chemosensitivity to 5-fluorouracil (5-FU) using an in vitro colon cancer cell line model. In this study, the in vivo significance of several marker genes in terms of prognostic potential was evaluated using colorectal cancer patient samples. Eight marker genes were selected based on their functional roles and significant fold changes in expression. They are SERTA domain containing 1 (SEI1), ribonucleotide reductase M2 polypeptide (RRM2), origin recognition complex, subunit 6 homolog-like (ORC6L), eukaryotic translation initiation factor 4E (EIF4E), thymidylate synthase (TS), SET and MYND domain containing 3 (SMYD3), Dickkopf homolog 4, and methyl-CpG binding domain protein 4 (MBD4). Forty-eight snap frozen clinical colorectal samples (24 normal and 24 paired colorectal cancer patient samples) were selected with detailed clinical follow-up information. cDNAs were synthesized and the expression levels of marker genes were quantified via qRT-PCR analysis. The statistical significance of these markers for disease prognosis was evaluated using the two-tailed paired Wilcoxon test. Survival curves were plotted according to the method of Kaplan-Meier and compared using the log-rank test. Based on the quantitative expression analysis, RRM2 (p=0.0001; 95% CI, 2.0-4.5), ORC6L (p=0.0001; 95% CI, 1.8-4.6), EIF4E (p=0.0002; 95% CI, 0.3-0.9), TS (p=0.0005; 95% CI, 0.7-2.2) and SMYD3 (p=0.0001; 95% CI, 0.8-1.5) were overexpressed in tumor tissues. However, the expression of SEI1 was decreased in tumors (p=0.02; 95% CI, 0.1-1.3), consistent with the function of SEI1 as a potential tumor suppressor. Kaplan-Meier survival analysis indicated that MBD4 is a significant prognostic factor for patient survival (p=0.03). MBD4 was a key protein involved in DNA methylation. The expression of TS was associated with tumor stage as it had a significantly higher expression level in UICC stage I and II compared to stage IV patients (p=0.03). MBD4 may be a potential novel prognostic marker for predicting patient survival for colorectal cancer.

CDH11 expression is associated with survival in patients with osteosarcoma.

Previous studies have shown that cadherin-11 (CDH11) may be involved in the metastatic process of osteosarcoma. The correlation of the expression levels of CDH11 in osteosarcoma samples with the risk of disease progression and metastasis was examined. Real time qRT-PCR was used to quantify CDH11 expression in a set of newly established osteosarcoma cell lines, 11 primaries and five metastases, compared to the levels in 12 normal osteoblast cell lines established from healthy bone, and also in a set of 10 snap-frozen osteosarcoma samples. In all cases long term clinical follow-up data was available. The CDH11 expression level decreased gradually from the osteoblast to the primary cell lines (p=0.2184) and further to those established from the tumor metastases (p=0.0275). Importantly, the level of CDH11 expression correlated significantly (p=0.01) with patient survival (Kaplan-Meier survival analysis) in both sample sets (p=0.0128 for the cell lines, p=0.0492 for the biopsies). In conclusion, the results indicate that CDH11 may be useful as a prognostic marker of disease progression and survival in osteosarcoma.

[Three cases of stomatitis caused by chemotherapy for gastrointestinal cancer that responded well to lafutidine].

We described 3 cases of stomatitis caused by chemotherapy with the fluoropyrimidine preparation S-1, alone or combined with other anticancer drugs. The stomatitis did not respond to conventional oral mucosal treatment such as triamcinolone acetonide(Kenalog)or allopurinol, but improved after treatment with the histamine H2-receptor antagonist lafutidine. The concurrent use of lafutidine allowed these 3 patients to continue chemotherapy with no recurrence of stomatitis. We concluded that lafutidine may be a viable treatment option for chemotherapy-induced stomatitis, allowing treatment to be continued.

Retrospective analysis of multi-institutional, patient-specific treatment planning results of high-dose-rate intracavitary brachytherapy for gynecological cancer using V100.

The objective of this study was to clarify the usefuleness of the K parameters of the independent verification method using V100% (the volume of water receiving 100% of the prescription dose) for institutions implementing the high-dose-rate (HDR) intracavitary brachytherapy for gynecological cancer. The data of 249 plans of 11 institutions in Japan were used, and the constant K value obtained by a parameter fit for single-192Ir, two-192Ir, and three-192Ir systems was calculated. The predicted total dwell time calculated using the constant K value was defined as Tpr, and the total dwell time calculated using a radiation treatment planning system was defined as TRTP. The ratio of Tpr and TRTP for each plan was calculated. The constant K values (95% CI) obtained for each system outlined above were 1233 (1227-1240), 1205 (1199-1211), and 1171 (1167-1175), respectively. Regarding the Tpr/TRTP, the entire data were within 0.9-1.1. For accurate verification, it was clarified that constant K values should be calculated for each system. The Nuclear Regulatory Commission considers a difference of 20% between the prescribed total dose and the administered total dose as a reportable medical event. There is a need for a quick method to verify the accuracy with a minimum of 10% threshold of a plan. The constant K values in this study were obtained from multiple institutions, and the variation in the values among these institutions was small. The data obtained by this study may be used as a parameter of this verification method employed by numerous institutions, particularly those who have recently initiated HDR brachytherapy. In addition, for institutions already using this method, this data might be useful for the validation of the parameters which were used in such institutions.

Combination therapy of S-1 and CDDP for patients with colorectal cancer.

PURPOSE: We evaluate the feasibility and efficacy of S-1 in combination with cisplatin (CDDP) for patients with colorectal cancer. METHODS: A total of 52 patients with advanced or recurrent colorectal cancer were included. S-1 was given orally twice daily for 21 days and CDDP 30 mg/m(2) on day 1 and 8, followed by a 2-week period of no treatment. RESULTS: Tumor responses among patients included 18 PR, 12 SD, and 16 PD (n = 46). The overall response rate was 36.4% (18/46). The response rate of the patients with prior chemotherapy was 22.2% (4/18) and 50.0% (12/24) among the patients who had no prior therapy. The median survival periods were 555 days and the median progression free survival periods were 183 days, respectively. S-1 in combination with CDDP shows promising activity with acceptable toxicities against colorectal cancer. CONCLUSIONS: A combination of S-1 and CDDP could be a standard therapy for treating colorectal carcinoma.

Association of insulin-like growth factor binding protein-3 expression with melanoma progression.

Previous studies from our laboratory have identified several endothelial cell-associated marker genes implicated in human melanoma metastasis via tumor vasculogenic mimicry. In this study, we used dual model systems composed of melanoma cell lines and clinical melanoma samples to validate the importance of insulin-like growth factor binding protein-3 (IGFBP-3) as a marker involved in disease progression. Gene expression analysis was done using a microarray approach for both primary and metastatic melanoma samples. The expression of IGFBP-3 was decreased using a small interfering RNA (siRNA) knockdown approach and quantified with real-time quantitative reverse transcription-PCR analysis. The expression of insulin-like growth factor binding protein 3 (IGFBP-3) was up-regulated by nearly 16-fold in WM266-4 compared with WM35 cells. A subsequent parallel analysis using freshly isolated primary and metastatic melanoma cell samples and melanoma tissue array confirmed the previous findings. The functional significance of IGFBP-3 in melanoma invasion was further investigated using a siRNA gene knockdown approach, with the expression of IGFBP-3 markedly reduced. Additionally, siRNA knockdown resulted in a significant reduction in cell motility, migration, and invasive capacity of WM266-4 cells in vitro. These results strongly suggest that IGFBP-3 expression may be a vital cell motility, migration, and proliferation factor necessary for melanoma metastasis and is an important biomarker in human melanoma.

Elevated levels of mRNAs encoding dihydropyrimidine dehydrogenase and thymidylate synthase are associated with improved survival of patients with hepatocellular carcinoma treated with S-1.

Thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPYD) are associated with the response of tumors to fluoropyrimidines. The aim of the present study was to investigate the association between the levels of TYMS and DPYD mRNAs and the efficacy of S-1 for treating patients with HCC. A total of 35 patients with HCC who received S-1 upon recurrence (S-1 group) and 20 patients who never received a fluoropyrimidine (control group) were studied. The levels of TYMS and DPYD mRNA in surgically resected specimens were determined using reverse transcription-polymerase chain reaction assays. Overall survival (OS) time of S-1 group patients with high levels of DPYD mRNA was significantly longer compared with that of patients with low levels (median 501 days vs. 225 days; P=0.016). Similarly, the OS time of those patients with high levels of TYMS mRNA was significantly longer compared with those with low levels (median 503 days vs. 239 days; P=0.0076). By contrast, there was no difference in OS time of the control group between patients with high and low levels of DPYD and TYMS mRNAs. The levels of TYMS and DPYD mRNAs may serve as predictive markers for patients with HCC who receive S-1 chemotherapy.

Phase II study of bevacizumab and irinotecan as second-line therapy for patients with metastatic colorectal cancer previously treated with fluoropyrimidines, oxaliplatin, and bevacizumab.

PURPOSE: Fluorouracil and folinic acid with irinotecan (FOLFIRI) plus bevacizumab (BV) is widely used as second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, oxaliplatin, and BV. FOLFIRI requires a CV catheter and an infusion pump, which are inconvenient for patients. Sufficient data are not available for characterizing the effectiveness of fluoropyrimidines beyond first disease progression. In this study, we evaluated the efficacy and safety of irinotecan (CPT-11) plus BV as second-line therapy. METHODS: Patients with mCRC previously treated with at least four courses of a fluoropyrimidine, oxaliplatin, and BV were designated to receive 150 mg/m2 of CPT-11 and 10 mg/kg of BV every 2 weeks as second-line therapy. The primary endpoint was progression-free survival (PFS), and secondary endpoints included response rate (RR), overall survival (OS), and adverse events. RESULTS: Thirty patients from six institutes were enrolled from March 2011 to January 2014. The median PFS was 5.7 months (95% CI 4.2-7.3 months), and the RR was 6.7% (range 0.8-22.1%). Grades 3-4 adverse events included leucopenia (36.7%), neutropenia (50%), thrombocytopenia (26.7%), anemia (30%), diarrhea (3.3%), anorexia (6.7%), and hypertension (3.3%). Relative dose intensities were 94.5 and 96.3% for CPT-11 and BV, respectively. The median OS was 11.8 months (6.3 months-not reached). CONCLUSIONS: Administration of CPT-11 plus BV to patients with mCRC achieved comparable efficacies with relatively lower toxicities compared with the results of previous studies using FOLFIRI plus BV as second-line therapy. The dose intensity of CPT-11 was judged as satisfactory. CLINICAL TRIAL INFORMATION: UMIN000005228.

Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer.

BACKGROUND: Thymidylate synthase (TS) is a critical target for cancer chemotherapy and is one of the most extensively studied biomarkers for fluoropyrimidine-based chemotherapy. In addition to its critical role in enzyme catalysis, TS functions as an RNA binding protein to regulate the expression of its own mRNA translation and other cellular mRNAs, such as p53, at the translational level. In this study, a comprehensive gene expression analysis at the levels of both transcriptional and post-transcriptional regulation was conducted to identify response markers using human genome array with TS-depleted human colon cancer HCT-C18 (TS-) cells and HCT-C18 (TS+) cells stably transfected with the human TS cDNA expression plasmid. RESULTS: A total of 38 genes were found to be significantly affected by TS based on the expression profiles of steady state mRNA transcripts. However, based on the expression profiles of polysome associated mRNA transcripts, over 149 genes were affected by TS overexpression. This indicates that additional post-transcriptionally controlled genes can be captured with profiling polysome associated mRNA population. This unique approach provides a comprehensive overview of genes affected by TS. Additional novel post-transcriptionally regulated genes affected by 5-fluorouracil (5-FU) treatment were also discovered via similar approach. CONCLUSION: To our knowledge, this is the first time that a comprehensive gene expression profile regulated by TS and 5-FU was analyzed at the multiple steps of gene regulation. This study will provide candidate markers that can be potentially used for predicting therapeutic outcomes for fluoropyrimidine-based cancer chemotherapy.