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GaN-on-Diamond high electron mobility transistors were successfully fabricated by surface-activated room-temperature bonding technique. Various diamond substrates were finely polished and bonded to GaN-HEMTs by surface-activated room-temperature bonding. Fabricated devices showed superior characteristics in thermal dissipation compared to the device with conventional structure.

Although dose reduction of S-1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5-fluorouracil, 5-chloro-2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S-1 in patients with renal impairment. We classified patients receiving S-1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S-1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m(2)), 10 patients in cohort 2 (eGFR = 50-79 mL/min/1.73 m(2)), 10 patients in cohort 3 (eGFR = 30-49 mL/min/1.73 m(2)), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m(2)). Those in cohorts 3 and 4 treated with an adjusted dose of S-1 showed a similar area under the curve for 5-fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S-1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S-1 in patients with impaired renal function using eGFR is appropriate and safe.

Background Although rare, cytomegalovirus (CMV) reactivation can be lethal in patients with cancer. However, the criteria for the prevention of cytomegalovirus reactivation during cancer treatment are unclear. This study aimed to identify factors associated with CMV reactivation in patients with esophageal cancer who were receiving chemoradiotherapy. Methods This retrospective study included esophageal cancer patients receiving definitive or palliative chemoradiotherapy during April 2013–March 2020. Patients with fever during chemoradiotherapy underwent a systemic work‐up to detect the primary focus of infection, and CMV antigenemia was assessed in cases of unidentifiable infection. Results Among 132 patients (80.3% male, median age 69 years [range, 39–86 years]), 124 received 5‐fluorouracil plus cisplatin and 8 received oxaliplatin–5‐fluorouracil–levofolinate chemotherapy. Overall, 19 patients had CMV reactivation, 37 had other infections, and 76 had no identified infection (groups 1, 2, and 3, respectively). Median minimum lymphocyte counts were 81.0/µl (interquartile range: 52.0–144.0/µl), 120.0/µl (81.0–162.5/µl), and 185.5/µl (120.5–328.0/µl) in groups 1, 2, and 3, respectively, with counts being significantly lower in groups 1 and 2 than in group 3 (p, CMV reactivation is not rare in esophageal cancer patients receiving chemoradiotherapy and is associated with minimum lymphocyte counts. CMV reactivation should be considered in differential diagnosis when a patient receiving chemoradiotherapy presents with a marked decrease in the lymphocyte count.

BackgroundWe previously reported that a high tumor burden is a prognostic factor based on an analysis of 26 patients with radioactive iodine-refractory differentiated thyroid cancer (RR-DTC) who were treated with lenvatinib. However, the optimal tumor burden for starting lenvatinib still remains to be defined. The aim of this retrospective study was to further explore in the same patient cohort the optimal timing for the start of lenvatinib by focusing on the pre- and post-treatment tumor burden.MethodsThe 26 patients were treated with lenvatinib from 2012 to 2017. We explored the optimal timing for the start of lenvatinib by comparing the characteristics of long-term responders who were defined as patients with progression-free survival ≥ 30 months and non-long-term responders.ResultsLong-term responders had a smaller post-treatment tumor burden at maximum shrinkage than non-long-term responders. Further, post-treatment tumor burden had a strong linear correlation with baseline tumor burden. We created an estimation formula for baseline tumor burden related to prognosis, using these regression lines. Patients with a sum of diameters of target lesions < 60 mm or maximum tumor diameter < 34 mm at baseline were estimated to have significantly better survival outcomes.ConclusionsWe found a strong linear correlation between pre- and post-treatment tumor burden. Our results suggested a cut-off value for baseline tumor burden for long-term prognosis among patients treated with lenvatinib.

Sorafenib and lenvatinib showed efficacy for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) in pivotal phase 3 clinical trials. Although the efficacy of lenvatinib in patients who received previous treatment with multi-target kinase inhibitors (m-TKIs), including sorafenib, was reported, the efficacy of sorafenib in patients who previously received lenvatinib remains unknown. A 75-year-old woman diagnosed as RAI-refractory poorly differentiated carcinoma with multiple lung metastases and started treatment with lenvatinib. She continued to receive lenvatinib but with repeated dose interruptions and reductions due to continuous proteinuria. Because of severe and persistent proteinuria as well as newly developed renal impairment, lenvatinib was suspended after two years of treatment. After the 7-month suspension, her proteinuria and renal impairment were partially improved, but her lung metastases progressed. Because she was unable to tolerate previous treatment with lenvatinib, sorafenib was started. At 7 months of treatment with sorafenib, her lung metastases shrank and she could continue sorafenib without exacerbation of proteinuria or renal impairment. This case may suggest that sorafenib does not exacerbate the proteinuria or renal impairment induced by lenvatinib, and may be an effective treatment option for RAI-refractory DTC patients who are unable to tolerate lenvatinib.

Standard therapy for radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) is multi-targeted kinase inhibitors (m-TKIs), represented by sorafenib and lenvatinib. One of the main target molecules of m-TKIs is vascular endothelial growth factor receptor (VEGF-R). m-TKIs are known to cause adverse reactions such as hypertension and proteinuria as a class effect. In particular, proteinuria is thought to result from vascular endothelial damage and podocytopathy in glomeruli, and the development of thrombotic microangiopathy (TMA) has been reported for VEGF inhibitors. We encountered a patient with RAI-refractory (RR) papillary thyroid carcinoma (PTC) who developed proteinuria and renal dysfunction due to lenvatinib. Renal biopsy demonstrated that these changes were caused by TMA. To our knowledge, this is the first reported case of TMA due to lenvatinib in a Japanese patient with RR-PTC. A 70-year-old woman developed proteinuria, renal impairment and hypertension while receiving lenvatinib for RR-PTC. Her proteinuria and renal damage continued to worsen despite dose reductions and dose interruptions. Renal biopsy was consistent with the chronic type of TMA. These findings indicate that TMA is a possible cause of proteinuria due to lenvatinib, as has been reported for the VEGF inhibitors. (C) 2018 The Author(s) Published by S. Karger AG, Basel

// Meiko Nishimura 1, * , Mitsuhiro Hayashi 2, 3, * , Yu Mizutani 1 , Kei Takenaka 1 , Yoshinori Imamura 1 , Naoko Chayahara 1, 4 , Masanori Toyoda 1 , Naomi Kiyota 1 , Toru Mukohara 1, 5 , Hiroaki Aikawa 3 , Yasuhiro Fujiwara 6 , Akinobu Hamada 2, 3, 7 and Hironobu Minami 1, 5 1 Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan 2 Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan 3 Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan 4 Present Address: Department of Medical Oncology, Kobe Minimally invasive Cancer Center, Kobe, Hyogo, Japan 5 Cancer Center, Kobe University Hospital, Kobe, Hyogo, Japan 6 Department of Breast and Medical Oncology, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan 7 Department of Medical Oncology and Translational Research, Graduate school of Medical Sciences, Kumamoto University, Kumamoto, Japan * These authors contributed equally to this work Correspondence to: Hironobu Minami, email: hminami@med.kobe-u.ac.jp Akinobu Hamada, email: akhamad@ncc.go.jp Keywords: erlotinib; rash; mass spectrometry imaging; drug distribution; liquid chromatography-tandem mass spectrometry Abbreviations: EGFR-TKI: epidermal growth factor receptortyrosine kinase inhibitor; LC-MS/MS: liquid chromatography-tandem mass spectrometry; MSI: mass spectrometry imaging; MALDI: matrix-assisted laser desorption/ionization; LMD: laser microdissection Received: August 23, 2017 Accepted: March 08, 2018 Published: April 06, 2018 ABSTRACT Background: The development of skin rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-tyrosine kinase inhibitors such as erlotinib. However, the pharmacological evidence has not been fully revealed. Results: Erlotinib distribution in the rashes was more heterogeneous than that in the normal skin, and the rashes contained statistically higher concentrations of erlotinib than adjacent normal skin in the superficial skin layer (229 ± 192 vs. 120 ± 103 ions/mm 2 ; P = 0.009 in paired t -test). LC-MS/MS confirmed that the concentration of erlotinib in the skin rashes was higher than that in normal skin in the superficial skin layer (1946 ± 1258 vs. 1174 ± 662 ng/cm 3 ; P = 0.028 in paired t -test). The results of MALDI-MSI and LC-MS/MS were well correlated (coefficient of correlation 0.879, P < 0.0001). Conclusions: Focal distribution of erlotinib in the skin tissue was visualized using non-labeled MALDI-MSI. Erlotinib concentration in the superficial layer of the skin rashes was higher than that in the adjacent normal skin. Methods: We examined patients with advanced pancreatic cancer who developed skin rashes after treatment with erlotinib and gemcitabine. We biopsied both the rash and adjacent normal skin tissues, and visualized and compared the distribution of erlotinib within the skin using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The tissue concentration of erlotinib was also measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS) with laser microdissection.