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.

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.

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.

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.

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.

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.

Uracil-Tegafur and Oral Leucovorin Combined With Bevacizumab in Elderly Patients (Aged ≥ 75 Years) With Metastatic Colorectal Cancer: A Multicenter, Phase II Trial (Joint Study of Bevacizumab, Oral Leucovorin, and Uracil-Tegafur in Elderly Patients [J-BLUE] Study).

BACKGROUND: We previously reported that uracil-tegafur with oral leucovorin (UFT/LV) treatment for elderly patients (aged ≥ 75 years) was well-tolerated in a phase II study. In the present study, the efficacy and safety of a modified (1-week shorter administration period) UFT/LV schedule combined with bevacizumab for a similar population are reported. PATIENTS AND METHODS: The present study was a single-arm, open-label, multicenter, cooperative group clinical trial. The key eligibility criteria included age ≥ 75 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, first-line chemotherapy, measurable lesions, and preserved organ function. Patients received UFT 300 mg/m(2)/d and LV 75 mg/d on days 1 to 21 and intravenous bevacizumab 5 mg/kg on days 1 and 15. Treatment was repeated every 28 days. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR), overall survival (OS), and safety. RESULTS: Of the 55 patients enrolled from 15 Japanese institutions, 52 eligible patients were evaluated. Their median age was 80 years (range, 75-87 years), and 73% had an ECOG performance status of 0. The median PFS was 8.2 months (95% confidence interval [CI], 6.2-10 months). The ORR was 40% (95% CI, 27%-55%). The median OS was 23 months (95% CI, 12-33 months). The most common grade 3 and 4 treatment-related adverse events were hypertension (12%), fatigue (8%), anemia (8%), nausea (6%), and diarrhea (6%). Treatment-related death occurred in 2 patients. CONCLUSION: UFT/LV (3 weeks of therapy and 1 week without) combined with biweekly bevacizumab is a tolerable and effective treatment option for elderly patients (aged ≥ 75 years) with metastatic colorectal cancer.

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.

HER2-positive gastric cancer with paraaortic nodal metastasis successfully resected after chemotherapy with trastuzumab: a case report.

We report on a case of human epidermal growth factor receptor-2 (HER2)-positive gastric cancer with paraaortic lymph node metastasis. The patient (a 49-year-old female) received chemotherapy (capecitabine and cisplatin) plus molecular-targeted therapy (trastuzumab), followed by curative resection. Interestingly, the resected residual cancer was HER2-negative. Intra-tumor heterogeneity hinders molecular-targeted therapy for gastric cancer. In our case, continued trastuzumab administration presented few benefits since the residual cancer cells were HER2-negative. No consensus exists regarding the appropriate therapy for unresectable gastric cancers whose non-curative factors disappear following trastuzumab chemotherapy. The principal options are treatment with surgery or continued chemotherapy with trastuzumab. In our case, resection treated the HER2-negative residual cancer effectively, resulting in curative therapy. This is the first case of positive-to-negative change in the HER2 expression of residual tumor cells following trastuzumab therapy. It suggests that, due to intra-tumor heterogeneity, the risks presented by remnant HER2-negative cancer cells persist despite trastuzumab therapy.

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.

Lymphatic vessel endothelial hyaluronan receptor-1 is a novel prognostic indicator for human hepatocellular carcinoma.

Angiogenesis is an important mechanism of tumor development, growth and metastasis in hepatocellular carcinoma (HCC). The poor prognosis of HCC patients has been associated with a failure to detect recurrences following surgery. In the present study, we investigated the association between the patient characteristics and the expression of angiogenic genes to identify early biomarkers of HCC. A comprehensive angiogenic gene expression profile was obtained by paired TaqMan gene array analysis of primary HCC nodules and adjacent non-HCC liver tissue from 12 patients. A total of 14 genes were found to be differentially expressed in HCC liver nodules (>2-fold change); the genes encoding collagen type XVα1, IVα1 and IVα2 were upregulated and the genes associated with vessel growth, neuropilin 2 (NRP2) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) were downregulated. The histopathological analysis revealed that the evolution of HCC nodules from well to poorly differentiated was associated with a 5-fold decrease in LYVE-1 expression, reaching its lowest level early during the transition. The significance of this gene as a biomarker of postoperative survival was demonstrated by a 2-fold decrease in overall survival (OS) rates in the low expression group compared to the high expression group. The multivariate and univariate Cox regression analyses identified LYVE-1 expression as a significant independent prognostic parameter of OS [hazard ratio (HR)=3.067; 95% confidence interval (CI): 1.507-6.273; P=0.0021]. Thus, the results of this study suggested that LYVE-1 expression may constitute a novel early biomarker of postoperative survival in HCC patients.

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.

Impact of dihydropyrimidine dehydrogenase and γ-glutamyl hydrolase on the outcomes of patients treated with gemcitabine or S-1 as adjuvant chemotherapy for advanced pancreatic cancer.

Gene expression analyses may play useful roles in determining the prognosis of cancer patients and in selecting antitumor drugs. This retrospective study examined potential prognostic factors in patients with pancreatic cancer who received adjuvant chemotherapy after surgery. The study group consisted of 79 patients who had received gemcitabine or S-1 as adjuvant chemotherapy for advanced pancreatic cancer. Using laser-captured microdissection and real-time RT-PCR assay, we quantitatively evaluated the mRNA levels of 10 genes associated with patient prognosis and sensitivity to chemotherapy using paraffin-embedded specimens of the primary tumors resected before the start of adjuvant chemotherapy. In univariate analyses, a low gene expression level of γ-glutamyl hydrolase (GGH) and a high gene expression level of folylpolyglutamate synthase correlated with a favorable outcome. In a multivariate analysis, a low gene expression level of dihydropyrimidine dehydrogenase (DPD) and GGH significantly correlated with outcome (hazard ratio of the high DPD group to the low DPD group: 5.55; 95% confidence interval (CI) 1.27-24.05; P=0.022; the high GGH group to the low GGH group: 3.77; 95% CI 1.04-13.79, P=0.043). For adjuvant chemotherapy of patients with pancreatic cancer, the mRNA level of DPD and GGH may affect the prognosis of these patients.

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.

Epidermal growth factor receptor (EGFR) mRNA levels and protein expression levels in primary colorectal cancer and corresponding liver metastases.

PURPOSE: High expression levels of EGFR mRNA are reported to be associated with a higher response probability in epidermal growth factor receptor (EGFR) targeted drugs. Our aim was to determine how EGFR gene expression levels in primary colorectal cancer (CRC) were related to those in liver metastases. METHODS: 31 pairs of primary CRC and corresponding liver metastases were analyzed. Gene expression level was measured using real-time RT-PCR. RESULTS: No significant difference was observed between median mRNA expression levels of EGFR in primary cancer and those in corresponding liver metastases (P = 0.99). When matched tissue sets were compared on an individual basis, there was a significant correlation for EGFR mRNA expression between primary cancer and corresponding liver metastases (rs = 0.78, P < 0.0001). CONCLUSIONS: A good prediction of EGFR mRNA levels in liver metastases can be obtained by measuring those in the primary CRC.

[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.

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.