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Kazuyoshi Kawakami,1 Takeru Wakatsuki,2 Azusa Soejima,1 Kazuo Kobayashi,1 Takashi Yokokawa,1 Takeshi Aoyama,1 Kenichi Suzuki,1 Mitsukuni Suenaga,2 Kensei Yamaguchi,2 Ayaka Inoue,3 Yoshiaki Machida,3 Toshihiro Hama1 1Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-Ku, Tokyo 135-8550, Japan; 2Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-Ku, Tokyo 135-8550, Japan; 3Section for Practical Education, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-Ku, Tokyo 142-8501, JapanCorrespondence: Kazuyoshi KawakamiThe Japanese Foundation for Cancer Research, Cancer Institute Hospital, Depatment of Pharmacy, 3-8-31 Ariake Koto-ku, Tokyo 135-8550, JapanEmail kazu.kawakami@jfcr.or.jpIntroduction: Regorafenib is an oral multikinase inhibitor for the treatment of metastatic colorectal cancer (mCRC). The clinical factors that may affect adherence to regorafenib remain unclear. The aim of this study was to evaluate adherence to regorafenib with mCRC and to identify factors that might affect adherence to regorafenib.Methods: A total of 108 consecutively enrolled Japanese patients with mCRC received regorafenib. Adherence was measured by pharmacists using pill counts and a self-reported treatment diary for patients at a pharmaceutical outpatient clinic. The median relative dose intensities of regorafenib and the factors adversely affecting adherence were retrospectively surveyed. Logistic regression analysis was then performed using patient socio-demographic factors and clinical factors.Results: A total of 96 patients were included in the analysis. The median adherence rate was 61.7% in the first cycle. The median relative dose intensity was 57.1%. The most common reason for non-adherence was a hand-foot-skin reaction (35.6%). On multivariate analysis, increased non-adherence to regorafenib was significantly associated with sex (female) [odds ratio (OR) = 4.36; 95% confidence interval (CI): 1.43–13.22, p = 0.01].Discussion: Hand-foot-skin reactions and female sex were associated with lower adherence to regorafenib. Since these factors could be associated with lower adherence to regorafenib, it would be useful to consider these factors when assessing adherence.Keywords: adherence, regorafenib, colorectal cancer, hand-foot-skin reactions

Yusuke Kitagawa, Hiroki Osumi, Eiji Shinozaki, Yumiko Ota, Izuma Nakayama, Takeshi Suzuki, Takeru Wakatsuki, Takashi Ichimura, Mariko Ogura, Akira Ooki, Daisuke Takahari, Mitsukuni Suenaga, Keisho Chin, Kensei YamaguchiDepartment of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JapanPurpose: Patients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have poor prognoses. Although platinum-based combination chemotherapy is commonly used as first-line treatment, the benefit of amrubicin (AMR) and salvage chemotherapy in those who develop platinum-refractory GI-NEC remains unknown. This study aimed to evaluate the efficacy and safety of AMR monotherapy in patients with platinum-refractory GI-NEC.Patients and methods: Platinum-refractory GI-NEC patients who received AMR monotherapy between April 2012 and September 2017 were retrospectively analyzed. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. PFS and OS were estimated using Kaplan-Meier methods and compared using log-rank tests.Results: In total, 16 patients were enrolled. Of them, 13 (81.3%), 1 (6.2%), and 2 (12.5%) received cisplatin plus irinotecan, cisplatin plus etoposide, and fluoropyrimidine plus platinum, respectively, before AMR monotherapy. The primary sites of NEC included the esophagus (N=3, 18.8%), stomach (N=10, 62.5%), duodenum (N=1, 6.2%) and colorectum (N=2, 12.5%). Patients were administered a median of 3 (range, 1–15) cycles of AMR. The ORR was 6.3%, and the median PFS and OS were 2.9 months (95% CI: 1.7–7.4) and 13.8 months (95% CI: 7.9–23.5), respectively. Neutropenia was the most serious adverse event. Grade 3 or higher neutropenia and febrile neutropenia occurred in 50.0% and 6.2% of patients, respectively. Other nonhematological toxicities were not severe, and no treatment-related deaths occurred. The 10 patients who received subsequent chemotherapy after AMR had significantly longer OS than those who did not (17.3 months vs 8.9 months; p=0.018). The median PFS of those who received organ-specific subsequent chemotherapy after AMR was 3.8 months, which was longer than that of those who received prior AMR.Conclusion: AMR is feasible with minimal side effects for platinum-refractory GI-NEC. Organ-specific subsequent chemotherapy after AMR may improve patient survival.Keywords: amrubicin monotherapy, platinum refractory, gastrointestinal neuroendocrine carcinoma

Izuma Nakayama, Keisho Chin, Daisuke Takahari, Mariko Ogura, Takashi Ichimura, Takeru Wakatsuki, Hiroki Osumi, Yumiko Ota, Takeshi Suzuki, Mitsukuni Suenaga, Eiji Shinozaki, Kensei Yamaguchi Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Purpose: Gastric cancer in young adults (GCYA) is known to have distinct clinicopathological features, including a female predominance and diffuse-type histology. Previous reports have focused on patients who had undergone gastrectomy with curative intent. Information concerning the treatment of unresectable advanced- or recurrent-stage GCYA is lacking. Therefore, we aimed to investigate whether the distinct clinicopathological features of GCYA affect the outcome of systemic chemotherapy.Patients and methods: We conducted a retrospective cohort study at a single institution in Japan. GCYA was classified as a disease in individuals who were

Mitsukuni Suenaga,1 Nobuyuki Mizunuma,1 Satoshi Matsusaka,1 Eiji Shinozaki,1 Masato Ozaka,1 Mariko Ogura,1 Toshiharu Yamaguchi21Department of Gastroenterology, 2Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanBackground: The effectiveness of reintroducing oxaliplatin in patients with metastatic colorectal cancer refractory to standard chemotherapy has not been verified. We performed a single-arm, open-label, Phase II study to evaluate the safety and efficacy of reintroducing oxaliplatin. Methods: Eligible patients had received prior chemotherapy including oxaliplatin and irinotecan that achieved a response or stable disease followed by confirmed disease progression ≥6 months previously during prior oxaliplatin-based therapy. The primary endpoint was the disease control rate (DCR) after 12 weeks of treatment starting. The DCR was defined as the sum of patients with complete response, partial response, and stable disease. Results: Thirty-three patients were enrolled. The median age was 62 (range: 35–77) years and the male/female ratio was 19/14. Eastern Cooperative Oncology Group performance status was 0 in 84.8%. Fourteen primary tumors were in the colon and 19 were in the rectum. All patients received modified FOLFOX6 as the protocol treatment. After 12 weeks of treatment starting, the DCR was 39.4% (95% confidence interval 21.8–57.0) and the response rate (complete response and partial response) was 6.1%. The median number of chemotherapy cycles was five and the median total dose of oxaliplatin was 425 mg/m2. Median progression-free survival time was 98 days and median overall survival was 300 days. The incidence of grade ≥1 and grade ≥3 allergic reactions was 28.1% and 3.1%, respectively. The incidence of grade ≥1 and grade ≥3 peripheral sensory neuropathy was 53.1% and 0%, respectively. There were no other severe adverse events and no treatment-related deaths.Conclusion: Reintroducing oxaliplatin can be both safe and effective. This may be a salvage option for patients with metastatic colorectal cancer who achieved a response or stable disease with prior oxaliplatin-based therapy followed by disease progression ≥6 months previously during prior oxaliplatin-based therapy.Keywords: reintroduction, oxaliplatin, FOLFOX, advanced colorectal cancer, salvage-line

Kazuyoshi Kawakami,1 Eri Nakamoto,1 Takashi Yokokawa,1 Kazuo Sugita,1 Yutarou Mae,1 Akane Hagino,1 Mitsukuni Suenaga,2 Nobuyuki Mizunuma,2 Sayaka Oniyama,3 Yoshiaki Machida,3 Toshiharu Yamaguchi,2 Toshihiro Hama1 1Department of Pharmacy, 2Gastroenterology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3Section for Practical Education, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan Background: Capecitabine plus oxaliplatin (XELOX) has been established as a first-line treatment for metastatic colorectal cancer. Adherence is particularly important with capecitabine to maintain appropriate curative effect. In this study, we monitored the adherence to capecitabine on XELOX treatment and investigated which factors might decrease compliance.Methods: The study included 242 consecutive patients who received XELOX treatment for metastatic colorectal cancer between October 2009 and March 2012. Adherence to capecitabine was checked by pharmacists with a patient-reported treatment diary at a pharmaceutical outpatient clinic. Adherence rate was defined as the number of times that a patient took capecitabine in a 14-day cycle/28 prescribed doses. We retrospectively surveyed median relative dose intensities of capecitabine and the factors deteriorating adherence across eight cycles from electronic patient records and examined differences in compliance rates according to age. Results: The study included 144 male and 98 female patients. The overadherence rate was 1.5% (n=23). The median adherence rate was 93.5% (n=242) in the first cycle of XELOX treatment, which gradually rose to 96.1% (n=148) in the eighth cycle. The median relative dose intensity of capecitabine was 79.2%. The main factors contributing to decreased adherence to capecitabine were diarrhea (22.5%, 352 instances) and nausea/vomiting (13.8%, 215 instances). The rate of missed dose was 12.1%. Analysis of adherence issues in relation to patient age showed a trend toward worse adherence to capecitabine therapy in the group of patients aged ≥80 years (hazard ratio =3.83; 95% confidence interval 2.48–5.91, P

Mitsukuni Suenaga,1 Nobuyuki Mizunuma,1 Satoshi Matsusaka,1 Eiji Shinozaki,1 Masato Ozaka,1 Mariko Ogura,1 Keisho Chin,1 Toshiharu Yamaguchi2 1Department of Gastroenterology, 2Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake, Koto-ku, Tokyo, Japan Background: Triweekly capecitabine plus irinotecan (XELIRI) is not completely regarded as a valid substitute for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. We conducted a phase I/II study to assess the efficacy and safety of biweekly XELIRI plus bevacizumab (BV) as second-line chemotherapy for mCRC.Methods: Patients with mCRC who had received prior chemotherapy including oxaliplatin and BV and had a UGT1A1 genotype of wild-type or heterozygous for UGT1A1*6 or *28 were eligible for this study. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan on day 1, and BV 5 mg/kg on day 1 every 2 weeks. The phase I study consisted of two steps (irinotecan 150 and 180 mg/m2), and dose-limiting toxicity was assessed during the first treatment cycle. The primary endpoint of the phase II study was progression-free survival (PFS). Results: The recommended dose of irinotecan was determined to be 180 mg/m2 in the phase I study. Between November 2010 and August 2013, 44 patients were enrolled in phase II. The patients’ characteristics were as follows (N=44): median age, 60 years (range 32–80); male/female, 21/23; and UGT1A1 wild-type/heterozygous, 29/15. The median PFS was 6.8 months (95% confidence interval, 5.3–8.2 months), and the primary endpoint was met. Median overall survival was 18.3 months. The response rate was 22.7%. There was no significant difference in PFS or overall survival according to UGT1A1 status. Grade 3 or higher adverse events were mainly neutropenia in six patients and diarrhea in five patients. There were no other severe adverse events or treatment-related deaths.Conclusion: In mCRC patients with wild-type or heterozygous UGT1A1*6 or *28 genotype, biweekly XELIRI + BV is effective and feasible as second-line chemotherapy. Biweekly XELIRI + BV is considered a valid substitute for FOLFIRI + BV in mCRC. Keywords: XELIRI, bevacizumab, metastatic colorectal cancer, UGT1A1

Investigating a comparative study of superconducting and microstructural properties of the bulk MgB2/Mg nano-composites and the press-sintered MgB2, in order to reveal the controlling factors for the critical current of MgB2 superconductors is discussed. It is found that the nano-composites are extremely dense and carries more than four times J(sub c), as compared to the press-sintered pellet.

A local calorimetric method was used to measure ac losses in structures of hight temperature superconductors.

YBa2Cu3O7-delta thick film grain boundaries on SrTiO3 bicrystal substrates were studied to determine their superconducting and microstructural properties.

A technique for measuring alternating current losses (AC) in a superconductor that is subjected to a transport current and an applied field is presented. The results of simultaneous measurements of the AC losses of both power supplies to a high temperature superconducting tape show magnetic losses of field applied perpendicularly to the tape face to be very much higher compared to losses in field applied parallel to the tape face.

Alternating current (ac) losses for a stack of Bi2223/Ag were found to be a function of the angular difference between the tape face and the applied ac magnetic field. The results were compared against the values derived by using the Bean critical-state model. The subsequent analysis revealed that, despite the seeming agreement of the Bean model with the general qualitative behavior of the calculated loss, the model failed substantially in its predictions.

Analytical studies of the effects of 2.2 GeV Au-ions irradiation on the transport properties of the bicrystals of Bi2Sr2CaCu2O8+delta bicrystals with (001) twist grain boundaries were conducted. The studies involved measuring the critical current and irreversibility line within the single crystals and across the twin grain boundaries prior to and after irradiation. The results indicate that the columnar defects from the irradiation increased the irreversible temperatures by a large factor.

The study of the transport properties of the grain boundary was undertaken using more than a dozen successfully isolated, naturally-grown (100) tilt Bi2Sr2CaCu2O8+delta bicrystals. The bicrystals are characterized by a single clean (100) non-basal-plane-faced tilt grain boundary with various degrees of misorientation. The results showed that almost all the (100) non-basal-plane-faced tilt grain boundary had a T(sub c) depression as compared to the constituent single crystals. However, these grain boundaries did not behave like weak-links at low temperatures.

A study was conducted on the electromagnetic properties of high angle twist grain boundaries in Bi2Sr2CaCu2O8+delta bicrystals. Electrical resistivity and V-I curves were measured as a function of temperature and magnetic field up to 9 T. Results reveal that the resistive onset temperature and field for all high angle twist grain boundaries were like those of their constituent single crystals.

A study was conducted on the influence of direct current transport currents on alternating current losses by the magnetically induced currents in silver-sheathed Bi(2223) tapes. Results were in agreement with a theory based on the the bean critical state model. Quantitative inconsistencies between the measurements and the theory were discussed and their sources analyzed.

The vortex solid-liquid phase transformation phenomenon was used as the magnetic field scaling factor to investigate the field-dependence of the flux pinning force in tapes silver-sheathed Bi2Sr2Ca2Cu3O10 tapes at temperatures above 27 K. To this end, transport measurements were performed on tapes immersed in liquid neon and in liquid oxygen. Consequently, it was shown that the vortex solid-liquid transition is the key parameter that limits the critical current density of such tapes in magnetic fields at temperatures above 27 K.

An experiment to study the impact of gold and silver ion irradiation on the superconducting properties of epitaxial YBa2Cu3O7 thin films is described. The experiment measured resistivity and transport critical current density as quantitative metrics of the mixed-state samples. It found the existence of a global linear scaling between the fractional regional damage versus the superconducting transition temperature and normal state resistivity.