Effects of 137Cs contamination after the TEPCO Fukushima Dai-ichi Nuclear Power Station accident on food and habitat of wild boar in Fukushima Prefecture.

After the Tokyo Electric Power Company Fukushima Dai-ichi Nuclear Power Station accident, wild boar was found to have greater radiocesium (137Cs) activity concentrations in their bodies than other wild animals in Japan; however, the reason for this remains unknown. To understand the mechanism of 137Cs transfer from the environment to wild boar, and the factors that affect variation in 137Cs contamination in wild boar, we sampled muscle and stomach contents from wild boar captured in Fukushima Prefecture and analyzed the relationships among 137Cs concentrations in muscle tissue and in the stomach contents, 137Cs ground deposition at capture sites, and wild boar food habits. Significant positive relationships were observed among 137Cs activity concentrations in muscle and stomach contents, as well as 137Cs deposition density at capture sites. These results suggest that 137Cs is transferred from the environment to plant and animal materials consumed by wild boar, and then from these foods to the bodies of wild boar through digestion. However, no correlation was observed between 137Cs concentrations in stomach contents and the presence of any particular food item in stomachs of wild boar, including mushrooms. These findings suggest mushrooms and underground food items, which were found to affect 137Cs concentrations in wild animals in Europe, were not important contributors to high levels of 137Cs contamination in Japanese wild animals.

[Selection of Chemotherapy Regimen on the Basis of Monitoring NLR and Soluble PD-L1 during CRC Chemotherapy].

AIM: It is known that the neutrophil-to-lymphocyte ratio(NLR)is associated with outcomes in patients with cancer. In this study, changes in the NLR and soluble programmed death-1 ligand-1(sPD-L1)levels were assessed in patients with metastatic colorectal cancer treated with chemotherapy. METHODOLOGY: Ten patients with unresectable metastatic colorectal cancer were administered chemotherapy from January 2005 to April 2017 at the Niitsu Medical Center Hospital. The NLR was calculated based on complete blood counts obtained prior to the administration of chemotherapy. Serum sPD-L1 levels were measured by enzyme-linked immunosorbent assay. NLR and sPD-L1 level changes from baseline were compared with tumor response and tumor markers. RESULTS: A relationship was found between sPD-L1 levels and NLR after the treatment of metastatic colorectal cancer(r=0.241, p=0.0459). Decreased sPD-L1 levels were associated with reduced NLR and tumor marker levels. Increased sPD-L1 levels were not related to elevated tumor marker levels. CONCLUSION: Changes in the NLR and sPD-L1 levels during chemotherapy may have a uniquely predictive value in patients with CRC treated with chemotherapy.

[The Changes in the Neutrophil-to-Lymphocyte Ratio Can Predict the Timing of Chemotherapeutic Regimen Alteration in Patients with Metastatic Colorectal Cancer].

AIM: In order to determine if the changes in the neutrophil-to-lymphocyte ratio(NLR)can predict the timingof regimen alteration, the outcome of chemotherapy for metastatic colorectal cancer was analyzed retrospectively. METHODOLOGY: Thirty patients with unresectable metastatic colorectal cancer were administered chemotherapy from January 2005 to December 2015 at the Niitsu Medical Center Hospital. The NLR was calculated from complete blood counts obtained prior to administration of chemotherapy and at the time of the best response. We defined the period with an NLR≤2.5 as the total interval of an NLR≤2.5. The role of the NLR in overall survival was determined by univariate and multivariate Cox regression models. RESULTS: The median overall survival was 27 months in patients with an NLR≤2.5(n=22)and 11 months in those with an NLR>2.5 (n=8)at the best response(p<0.001). The period with an NLR≤2.5 was found to correlate with overall survival(p<0.001). The patients who survived for more than 3 years were introduced to a second-line treatment prior to achievingan NLR>2.5. The period with an NLR≤2.5(p=0.001)and prechemotherapy CA19-9(p<0.0001)were independent, significant predictors of better survival in multivariate analysis. CONCLUSION: The introduction of a new chemotherapeutic regimen prior to achievingan NLR>2.5 predicted better survival in patients with mCRC.

[Change of Blood Neutrophil-to-Lymphocyte Ratio Predicts Survival in Patients with Metastatic Colorectal Cancer].

AIM: The impact of neutrophil-to-lymphocyte ratio(NLR)changes on the outcome of chemotherapy for metastatic colorectalcancer (mCRC)was analyzed retrospectively. METHODOLOGY: Twenty seven patients with unresectable mCRC were administered chemotherapy from January 2005 to December 2014 at the Niitsu Medical Center Hospital. The NLR was calculated from complete blood counts obtained prior to the administration of chemotherapy and at the best response. We defined the period with NLR≤2.5 as the totalintervalof NLR≤2.5. The impact of NLR on overallsurvivalwas determined using univariate and multivariate Cox regression models. RESULTS: The median overall survival was 26 months in patients with an NLR≤5(n= 22), and 11 months in those with an NLR>5(n=5)before chemotherapy(p=0.03). The median overall survival was 31 months in patients with an NLR≤2.5(n=19), and 11 months in those with an NLR>2.5(n=8)at the best response(p< 0.001). The period with an NLR≤2.5 was found to correlate with overall survival(p<0.001). The period with an NLR≤2.5 was the only independent, statistically significant predictor of better survival in multivariate analysis(p=0.001). CONCLUSION: The change of NLR may be a dynamic predictor of better survivalin patients with mCRC.

[Individual Dose Adjustment of 5-Fluorouracil Based on Pharmacokinetic Monitoring May Improve the Outcome of FOLFOX for Metastatic Colorectal Cancer].

AIM: The effect of individual dose adjustment of 5-fluorouracil (5-FU) based on pharmacokinetic monitoring on the outcome of FOLFOX for metastatic colorectal cancer was analyzed retrospectively. METHODOLOGY: Twenty patients with metastatic colorectal cancer underwent FOLFOX chemotherapy from January 2005 to December 2013 at the Niitsu Medical Center Hospital. The sample group included 11 patients in whom 5-FU doses were adjusted individually based on pharmacokinetic monitoring according to an algorithm to maintain the area under the curve (AUC) in the range of 20-25 mg·h/L (Group A) and 9 patients in whom 5-FU doses were adjusted conventionally based on body surface area (Group B). RESULTS: The objective response rate was 63% and 33% in Group A and Group B, respectively (p=0.174). The median overall survival was 34 months and 14 months in Group A and Group B, respectively (p=0.036). There were 4 cases of Grade 3 toxicity (2 in Group A, 2 in Group B; p=0.636) and no cases of Grade 4 toxicity or treatment-related death. CONCLUSION: Pharmacokinetically guided dose adjustment of 5-FU may improve the outcome of FOLFOX for metastatic colorectal cancer.

[Improved Response to 5-FU Using Dose Adjustment and Elastomeric Pump Selection Based on Monitoring of the 5-FU Level--A Case Report].

A 6 1-year-old man with unresectable multiple hepatic metastases after resection of sigmoid colon carcinoma was treated with irinotecan and infused 5-fluorouracil (5-FU) plus Leucovorin (FOLFIRI). Since the levels of tumor markers increased, the 5-FU dose was increased from 2,700 to 3,000 mg/m2 using a Jackson-type pump and an extended infusion time of 53 hours. The blood level of 5-FU was 507 ng/mL 16 hours after starting the infusion. The pump was then changed to a bottle-type pump with the same dose of 3,000 mg/m2. At 16 hours, the 5-FU level was 964.5 ng/mL. The areas under the concentration vs. time curve (AUC mg・h/L)were 21 and 44 mg・h/L for the Jackson- and bottle-type pumps, respectively. Owing to the development of Grade 3 stomatitis and hand-foot syndrome, 5-FU was reduced to 2,700 mg/m2 with a bottle-type pump. The AUC decreased to 27 mg・h/L, but the liver metastases were reduced and the adverse effects subsided to Grade 1. This case shows that individual dose adjustment of 5-FU to the appropriate AUC based on pharmacokinetic monitoring of the blood 5-FU level can improve the response, reduce adverse effects, and have a clinical benefit.

Ribonucleotide reductase M1 expression in intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Ribonucleotide reductase M1 (RRM1) is a key molecule for gemcitabine resistance. This study evaluated the immunohistochemical expression of RRM1 in resected specimens of intrahepatic cholangiocarcinoma (ICC) and investigated the efficacy of gemcitabine-based neoadjuvant chemotherapy in relation to RRM1 expression in tumors. METHODOLOGY: A retrospective analysis was conducted on 34 consecutive Japanese patients who underwent resection of ICC. Of the 34 patients, 2 were treated with neoadjuvant chemotherapy consisting of gemcitabine 800mg/m2 every 2 weeks to address extrahepatic tumor extension. Expression of RRM1 in tumor specimens was assessed using immunohistochemistry and was classified as either positive or negative. RESULTS: RRM1-positive expression was detected in 19/34 (56%) tumor specimens. Two patients were treated with gemcitabine-based neoadjuvant chemotherapy; one had a tumor specimen showing RRM1-positive expression and showed a 14% tumor reduction rate (stable disease); another patient had a tumor showing RRM1-negative expression and showed a 68% tumor reduction rate (partial response). Surgical procedures planned before administration of neoadjuvant chemotherapy were performed in both patients. CONCLUSIONS: Neoadjuvant chemotherapy with gemcitabine for locally advanced ICC was well tolerated and did not impair planned surgical resections. Tumor expression of RRM1 may determine the efficacy of gemcitabine-based chemotherapy for patients with ICC.

[Effect of pylorus-preserving pancreaticoduodenectomy on serum levels of 5-fluorouracil during S-1 treatment for pancreaticobiliary malignancy].

AIMS: The aim of this study was to evaluate the effect of surgical procedures on the serum levels of 5-fluorouracil (5-FU) in patients undergoing S-1 treatment for pancreaticobiliary malignancy. METHODOLOGY: From January 2003 through December 2008, 27 chemotherapy-naive patients who underwent a surgical procedure for pancreaticobiliary malignancy received S-1 chemotherapy for unresectable or recurrent disease. The primary site of disease was: the extra hepatic bile duct (n=10); gallbladder (n=8); pancreas (n=6); or ampulla of Vater (n=3). The surgical procedure was: pylorus-preserving pancreaticoduodenectomy (PPPD) (n=6); combined major hepatic and bile duct resection (n=6); bilioenteric anastomosis (n=4); or exploratory laparotomy (n=11). S-1 (80-120 mg/day) was administered orally twice daily for 28 days, followed by 14 days without therapy. Subsequently, the serum levels of 5-FU were measured using the HPLC-UV method. RESULTS: The median number of cycles administered per patient was 6 (range, 2-13). Although grade 3 watery eye developed in one patient, neither grade 4 toxicities nor treatment-related deaths were observed. The overall response rate was 19%, the median overall survival time was 9 months, and the 1-year cumulative survival rate was 11%. The maximum levels of 5-FU in the sera of individual patients differed significantly according to the surgical procedure (Kruskal-Wallis test; p=0. 0049); the patients who underwent PPPD had the highest 5-FU levels, as compared with the other patients (Mann-Whitney test; p= 0.003). CONCLUSIONS: The type of operative procedure appears to influence the serum levels of 5-FU in S-1-treated surgical patients with pancreaticobiliary malignancy. Given the possibility of elevated levels of 5-FU in the sera of patients who are treated with S-1 after PPPD, adverse events must be monitored carefully in this cohort.

Interstitial pneumonia arising in a patient treated with oxaliplatin, 5-fluorouracil, and, leucovorin (FOLFOX).

Information concerning the pulmonary toxicity of oxaliplatin with infusional 5-fluorouracil plus leucovorin (FOLFOX) is very limited. We herein report the case of a patient with FOLFOX-induced interstitial pneumonia. An 82-year-old man with unresectable colon cancer liver metastases was referred to our department for chemotherapy with the FOLFOX protocol. After the administration of ten cycles, he visited our outpatient clinic with a 2-week history of coughing and shortness of breath; he was afebrile. A chest radiograph showed reticular shadows with ground-glass opacities mainly involving the middle and lower zones of the right lung. Computed tomography depicted ground-glass opacities with superimposed reticulation in the right lung. A diagnosis of FOLFOX-induced interstitial pneumonia was made based on the clinical course and imaging findings. The symptoms disappeared within 3 days after the cessation of the FOLFOX regimen and the initiation of high-dose corticosteroid treatment. Two months after the initiation of the corticosteroid treatment, complete remission of the radiological abnormalities was confirmed; thereafter, interstitial pneumonia did not recur despite the reintroduction of 5-fluorouracil/leucovorin alone, suggesting that 5-fluorouracil/leucovorin alone was not responsible for the development of the interstitial pneumonia. Thus, oxaliplatin, alone or in combination with 5-fluorouracil/leucovorin, may have caused the interstitial pneumonia in this patient. Once interstitial pneumonia has occurred, cessation of the regimen is mandatory, and high-dose corticosteroid treatment is commonly given to rescue patients from this potentially lethal complication.

Induction of oncogene addiction shift to NF-kappaB by camptothecin in solid tumor cells.

The biological basis of the resistance of solid tumor cells to chemotherapy is not well understood. While addressing this problem, we found that gastric cancer cell line St-4/CPT, lung cancer cell line A549/CPT, and colon cancer cell line HT-29/CPT, all of which are resistant to camptothecin (CPT), showed strong and constitutive nuclear factor (NF)-kappaB activity driven by IkappaB kinase compared with their parental cell lines St-4, A549, and HT-29. A new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced viability and induced apoptosis in St-4/CPT, A549/CPT, and HT-29/CPT cell lines, while their parental cell lines were resistant to DHMEQ. The results in this study present an example of the shift in signals that support the survival of solid tumor cells to NF-kappaB during the acquisition of resistance to CPT. The results also indicate that solid tumor cells that become resistant to chemotherapy may be more easily treated by NF-kappaB inhibitors.

[Pharmacokinetic monitoring of 5-fluorouracil may improve the clinical benefit with an individualized regimen-a case report].

Serum levels of 5-fluorouracil(5-FU)were measured in a patient receiving pharmacokinetic modulation chemotherapy( PMC), with 5-FU, as well as a combination of oxaliplatin and infusional 5-FU plus leucovorin(FOLFOX). A 77- year-old man presented with unresectable multiple hepatic metastases after abdominoperineal resection of rectal / carcinoma, and was successfully treated by PMC. The patient initially received infusional 5-FU at 750 mg/m(2) once a week, and showed a partial response. Serum 5-FU levels were higher at night, and the peak concentration of 5-FU was / 398 ng/mL. After 13 months of PMC, second-line chemotherapy with FOLFOX was initiated because new liver metastases had appeared. After 4 cycles of FOLFOX4, progression was observed, and the concentration profile of 5-FU / was measured. The area under the concentration vs. time curve(AUC ngxh/mL)was smaller with FOLFOX4 than with PMC, so the FOLFOX6 regimen was tried instead. The AUC increased and disease progression was suppressed. This case shows that individual adjustment of the dose and regimen based on pharmacokinetic monitoring can increase the clinical benefit of fluorouracil.

[Team-based medical care can improve tailor made chemotherapy for colorectal cancer].

We report that team-based medical care has an important role in tailor made chemotherapy for colorectal cancer. We organized a chemotherapy support team to facilitate the early detection of toxicity and to get hold of therapeutic needs in individual patients. We also measured the circadian variation of 5-fluorouracil plasma concentrations to permit tailor dosed chemotherapy. To date, the chemotherapy support team has managed the performance of pharmacokinetic modulating chemotherapy in 30 patients with unresectable or recurrent colorectal cancer. The median survival time was 19 months after the first-line chemotherapy and 14 months after the second-line treatment. Our results suggest that team-based medical care is practically useful for tailor made chemotherapy in patients with colorectal cancer.

[Irinotecan plus gemcitabine(IRINOGEM)in the treatment of biliary malignancies].

AIMS: The present study was conducted to evaluate the effects of irinotecan plus gemcitabine(IRINOGEM)on biliary malignancies. METHODOLOGY: From January 2005 through January 2007, 15 consecutive patients with chemotherapy- naive, locally advanced or metastatic biliary malignancies were enrolled. The primary affected sites were the gallbladder( n=7), extrahepatic bile ducts(n=5), and intrahepatic bile ducts(n=3). All the patients received starting doses of gemcitabine at 250 mg/m /(2) and irinotecan at 25 mg/m(2) given once per 2-week cycle. In the event of progressive disease, the dosage was increased for subsequent cycles. RESULTS: The median number of cycles administered was 16(range, 4-24 cycles)per patient. Although one case of grade 3 neutropenia was noted, neither grade 4 toxicities nor treatment-related deaths were observed. The overall response rate was 40% and the median overall survival time was 8 months, with a 1-year cumulative survival rate of 28%. CONCLUSIONS: IRINOGEM shows promising antitumor activity, and may be a worthwhile treatment option for locally advanced or metastatic biliary malignancies.

JunB induced by constitutive CD30-extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling activates the CD30 promoter in anaplastic large cell lymphoma and reed-sternberg cells of Hodgkin lymphoma.

High expression of CD30 and JunB is characteristic of tumor cells in anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL). Possible interactions of CD30 and JunB were examined in this study. We found that the CD30 promoter in tumor cells of both nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK)-positive and NPM-ALK-negative ALCL and HL is regulated by a constitutively active CD30-extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK). Phosphorylation of ERK1/2 MAPK was confirmed in nuclei of tumor cells in both ALCL and HL. CD30-ERK1/2 MAPK signals induce JunB expression, which maintains high activity of the CD30 promoter. JunB induction seems to be largely independent of nuclear factor kappaB in ALCL and HL. These results show a common mechanism of CD30 overexpression in ALCL and HL, although the outcome of CD30 signaling differs between NPM-ALK-positive ALCL and NPM-ALK-negative ALCL, cutaneous ALCL, and HL as we recently reported.

A novel NF-kappaB inhibitor DHMEQ selectively targets constitutive NF-kappaB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo.

Multiple myeloma (MM) is a fatal lymphoid malignancy that is incurable with conventional modalities of chemotherapy. Strong and constitutive activation of nuclear factor kappa B (NF-kappaB) is a common characteristic of MM cells. In our study we successfully target NF-kappaB with a novel NF-kappaB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ). DHMEQ completely abrogates constitutive NF-kappaB activity and induces apoptosis of MM cells, whereas control peripheral blood mononuclear cells (PBMC) are resistant to NF-kappaB inhibition and apoptosis by DHMEQ treatment. DHMEQ inhibition of NF-kappaB triggers activation of caspases 8 and 9, as well as G0/G1 cell cycle arrest accompanied by downregulation of antiapoptotic genes Bcl-XL and c-FLIP and cell cycle progression gene cyclins D1 and D2. DHMEQ-mediated inhibition of vascular endothelial growth factor (VEGF) production in MM cells raises the possibility that DHMEQ abrogates the autocrine VEGF loop and enhances its antitumor effects by inhibiting neovascularization in the bone marrow. Using an in vivo NOD/SCID/gammac(null) (NOG) mice model, we show that DHMEQ has a potent inhibitory effect on the growth of MM cells. Compared to other compounds having the potential to inhibit NF-kappaB, DHMEQ is a unique compound that blocks the translocation of NF-kappaB p65 into the nucleus and selectively targets NF-kappaB activated in tumor cells. Therefore, our study presents a new molecular target therapy in MM.

Primary jejunal malignant melanoma first noticed because of the presence of parotid lymph node metastasis.

The case of a 71-year-old Japanese man with primary jejunal melanoma with an unusual clinical course is reported. Several cases of primary malignant melanoma of the small intestine have been reported, but in most cases no clear evidence has shown whether the lesions were primary or metastatic. We discuss why the tumor in our case was considered primary, and we review similar cases of primary melanoma of the small intestine.