Peripheral neuropathy and nerve electrophysiological changes with enfortumab vedotin in patients with advanced urothelial carcinoma: a prospective multicenter cohort study.

BACKGROUND: Enfortumab vedotin is a novel antibody-drug conjugate used as a third-line therapy for the treatment of urothelial cancer. We aimed to elucidate the effect of enfortumab vedotin-related peripheral neuropathy on its efficacy and whether enfortumab vedotin-induced early electrophysiological changes could be associated with peripheral neuropathy onset. METHODS: Our prospective multicenter cohort study enrolled 34 patients with prior platinum-containing chemotherapy and programmed cell death protein 1/ligand 1 inhibitor-resistant advanced urothelial carcinoma and received enfortumab vedotin. The best overall response, progression-free survival, overall survival, and safety were assessed. Nerve conduction studies were also performed in 11 patients. RESULTS: The confirmed overall response rate and disease control rate were 52.9% and 73.5%, respectively. The median overall progression-free survival and overall survival were 6.9 and 13.5 months, respectively, during a median follow-up of 8.6 months. The patients with disease control had significantly longer treatment continuation and overall survival than did those with uncontrolled disease. Peripheral neuropathy occurred in 12.5% of the patients. The overall response and disease control rates were 83.3% and 100%, respectively: higher than those in patients without peripheral neuropathy (p = 0.028 and p = 0.029, respectively). Nerve conduction studies indicated that enfortumab vedotin reduced nerve conduction velocity more markedly in sensory nerves than in motor nerves and the lower limbs than in the upper limbs, with the sural nerve being the most affected in the patients who developed peripheral neuropathy (p = 0.011). CONCLUSION: Our results indicated the importance of focusing on enfortumab vedotin-induced neuropathy of the sural nerve to maximize efficacy and improve safety.

Effects of acute strawberry consumption on serum levels of vitamin C and folic acid, the antioxidant potential of LDL and blood glucose response: a randomised cross-over controlled trial.

Strawberry contains many bioactive compounds such as vitamin C and polyphenols as well as folate, a vitamin that is especially important for women of childbearing age. We investigated the effects of the acute consumption of strawberry on the serum levels of vitamin C and folate, and on the antioxidant potential of low-density lipoprotein (LDL). In a randomised, placebo-controlled, double-blind, crossover study, twenty-three healthy female volunteers (age 22⋅5 ± 1⋅4 years) ingested 500 g of a strawberry purée beverage or a sugar content-matched placebo beverage. Blood samples were collected at fasting and at 0⋅5, 1, 2 and 4 h post-ingestion. The serum concentrations of vitamin C and folate were significantly elevated from 0⋅5 to 4 h after the strawberry beverage ingestion (P < 0⋅001); the levels peaked at 2 h, with peak levels of 15⋅0 ± 2⋅5 µg/ml for vitamin C and 14⋅4 ± 7⋅0 ng/ml for folate. Notably, at 1 h after the strawberry beverage ingestion, the LDL oxidation lag time was significantly prolonged (P < 0⋅05), suggesting that the antioxidant potential of LDL was increased. After the ingestion of either beverage, the serum levels of glucose and insulin reached a peak at 0⋅5 h and then quickly returned to baseline levels. These results suggest that strawberries are a useful source of vitamin C and folate and may help enhance the antioxidant potential of LDL in healthy young women.

Generation of Tfap2c-T2A-tdTomato knock-in reporter rats via adeno-associated virus-mediated efficient gene targeting.

Gene editing in mammalian zygotes enables us to generate genetically modified animals rapidly and efficiently. In this study, we compare multiple gene targeting strategies in rat zygotes by generating a novel knock-in reporter rat line to visualize the expression pattern of transcription factor AP-2 gamma (Tfap2c). The targeting vector is designed to replace the stop codon of Tfap2c with T2A-tdTomato sequence. We show that the combination of electroporation-mediated transduction of CRISPR/Cas9 components with adeno-associated virus-mediated transduction of the targeting vector is the most efficient in generating the targeted rat line. The Tfap2c-T2A-tdTomato fluorescence reflects the endogenous expression pattern of Tfap2c in preimplantation embryo, germline, placenta, and forebrain during rat embryo development. The reporter line generated here will be a reliable resource for identifying and purifying Tfap2c expressing cells in rats, and the gene targeting strategy we used can be widely applied for generating desired animals.

Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells.

ATP-binding cassette transporter A1 (ABCA1) is a key regulator of lipid efflux, and the absence of ABCA1 induces hepatic lipid accumulation, which is one of the major causes of fatty liver. 2-Methoxyestradiol (2-ME2) has been demonstrated to protect against fatty liver. In this study, we investigated the effects of 2-ME2 on the hepatic lipid content and ABCA1 expression. We found that 2-ME2 dose-dependently increased ABCA1 expression, and therefore, the lipid content was significantly decreased in HepG2 cells. 2-ME2 enhanced the ABCA1 promoter activity; however, this effect was reduced after the inhibition of the PI3K pathway. The overexpression of Akt or p110 induced ABCA1 promoter activity, while dominant-negative Akt diminished the ability of 2-ME2 on ABCA1 promoter activity. Further, 2-ME2 stimulated the rapid phosphorylation of Akt and FoxO1 and reduced the nuclear accumulation of FoxO1. Chromatin immunoprecipitation confirmed that FoxO1 bonded to the ABCA1 promoter region. The binding was reduced by 2-ME2, which facilitated ABCA1 gene transcription. Furthermore, mutating FoxO1-binding sites in the ABCA1 promoter region or treatment with FoxO1-specific siRNA disrupted the effect of 2-ME2 on ABCA1 expression. All of our results demonstrated that 2-ME2 might upregulate ABCA1 expression via the PI3K/Akt/FoxO1 pathway, which thus reduces the lipid content in hepatocytes.

Pluripotent stem cells related to embryonic disc exhibit common self-renewal requirements in diverse livestock species.

Despite four decades of effort, robust propagation of pluripotent stem cells from livestock animals remains challenging. The requirements for self-renewal are unclear and the relationship of cultured stem cells to pluripotent cells resident in the embryo uncertain. Here, we avoided using feeder cells or serum factors to provide a defined culture microenvironment. We show that the combination of activin A, fibroblast growth factor and the Wnt inhibitor XAV939 (AFX) supports establishment and continuous expansion of pluripotent stem cell lines from porcine, ovine and bovine embryos. Germ layer differentiation was evident in teratomas and readily induced in vitro. Global transcriptome analyses highlighted commonality in transcription factor expression across the three species, while global comparison with porcine embryo stages showed proximity to bilaminar disc epiblast. Clonal genetic manipulation and gene targeting were exemplified in porcine stem cells. We further demonstrated that genetically modified AFX stem cells gave rise to cloned porcine foetuses by nuclear transfer. In summary, for major livestock mammals, pluripotent stem cells related to the formative embryonic disc are reliably established using a common and defined signalling environment. This article has an associated 'The people behind the papers' interview.

Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells.

Impaired insulin secretion is one of the main causes of type 2 diabetes. Cholesterol accumulation-induced lipotoxicity contributes to impaired insulin secretion in pancreatic beta cells. However, the detailed mechanism in this process remains unclear. In this study, we proved that oxidized low-density lipoprotein (OxLDL) reduced insulin content, decreased PDX-1 expression, and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells, which were rescued by addition of high-density lipoprotein (HDL). OxLDL receptors and cholesterol content were increased by OxLDL. Consistently, OxLDL suppressed cholesterol transporter ABCA1 expression and transcription in a dose-dependent and time-dependent manner. Inhibition of MEK by its specific inhibitor, PD98059, altered the effect of OxLDL on ABCA1 transcription and activation of ERK. Next, chromatin immunoprecipitation assay demonstrated that liver X receptor (LXR) could directly bind to ABCA1 promoter and this binding was inhibited by OxLDL. Furthermore, OxLDL decreased the nuclear LXR expression, which was prevented by HDL. LXR-enhanced ABCA1 transcription was suppressed by OxLDL, and the effect was cancelled by mutation of the LXR-binding sites. In summary, our study shows that OxLDL down-regulates ABCA1 expression by MEK/ERK/LXR pathway, leading to cholesterol accumulation in INS-1 cells, which may result in impaired insulin synthesis and GSIS.

Nivolumab-induced hypophysitis followed by acute-onset type 1 diabetes with renal cell carcinoma: a case report.

BACKGROUND: Immune checkpoint inhibitors have recently become widely used for the management of advanced cancer patients. During the development of immune checkpoint inhibitors (ICPIs), it was quickly recognized that they are associated with autoimmune or autoinflammatory side effects. These toxicities are known as immune-related adverse events (irAEs): common endocrine irAEs include hypophysitis and thyroid dysfunction, and uncommon irAEs include type 1 diabetes mellitus (T1DM). CASE PRESENTATION: A 62-year-old Japanese man with metastatic renal cell carcinoma was treated with sunitinib followed by the 10th cycle of treatment with the ICPI nivolumab. He had already had thyroiditis and hypophysitis due to these anti-cancer drugs. On admission, he showed an extremely elevated plasma glucose level (601 mg/dl) and a low C-peptide level, and was diagnosed with acute T1DM. The patient was treated with intravenous fluid infusion and continuous insulin infusion. On the second day, he was switched to multiple daily injections of insulin therapy. Since these treatments, his blood glucose levels have been stable and he has been treated with an additional 10 ICPI treatments for renal cell carcinoma for over a year. CONCLUSIONS: Treatment with ICPIs is expected to increase in the future. There may be cases in which their use for cancer treatment is inevitable despite the side effects. As long as treatment with ICPI continues, multiple side effects can be expected in some cases. It is important to carefully observe the side effects that occur during ICPI treatment and to provide appropriate treatment for each side effect.

Successful Therapy Using Pasireotide Long-acting Release for Cushing's Disease Merged with Biochemical Acromegaly.

It is quite rare that Cushing's disease shows acromegaly, and no pharmacotherapy has yet been discussed. A 21-year-old woman was diagnosed with Cushing's disease and underwent trans-sphenoidal surgery. Five years later, she was diagnosed with recurrent Cushing's disease and biochemical acromegaly because of elevated levels of serum growth hormone (GH), plasma insulin-like growth factor-1, plasma adrenocorticotropic hormone (ACTH), and the 24-hour urinary excretion of free cortisol. After treatment initiation with pasireotide-long-acting release (LAR), both the ACTH and GH declined. Our case is the first to show the efficacy of pasireotide-LAR in controlling both Cushing's disease and acromegaly.

Systemic steroid application for treatment of edematous anastomotic stenosis following delta-shaped anastomosis in laparoscopic distal gastrectomy: a case report.

BACKGROUND: Delta-shaped anastomosis is a common method of intracorporeal gastroduodenostomy in totally laparoscopic distal gastrectomy. One common postoperative complication of this procedure is anastomotic stenosis, and endoscopic balloon dilatation is a major remedy for such complications. Other treatment strategies are necessary to manage unsuccessful endoscopic balloon dilatation. CASE PRESENTATION: We present a case where systemic steroid treatment was applied in sustained anastomotic stenosis after endoscopic balloon dilatation. We performed delta-shaped anastomosis in laparoscopic distal gastrectomy to treat early-stage gastric cancer in a patient. The patient experienced abdominal pain post-surgery; subsequent investigation revealed edematous anastomotic stenosis. The stenosis sustained even after endoscopic balloon dilatation and local steroid injection. Consequently, we applied systemic steroid treatment. CONCLUSION: Systemic steroid treatment improved the stenosis and no recurrence was observed. These results suggest that systemic steroid application could be useful to treat anastomotic stenosis.

Treatment with 2-methoxyestradiol increases endothelial nitric oxide synthase activity via scavenger receptor class BI in human umbilical vein endothelial cells.

Concentrations of 2-methoxyestradiol (2ME2), a principal metabolite of estradiol, are significantly lower in women with severe preeclampsia. Nitric oxide (NO) released by endothelial nitric oxide synthase (eNOS) plays an important role in regulating cardiovascular homeostasis. Importantly, high-density lipoprotein (HDL) stimulates eNOS activity via endothelial human scavenger receptor class B type I (hSR-BI/CLA-1). Here, we aimed to determine the effect of 2ME2 on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). hSR-BI/CLA-1 expression was measured by real-time PCR, western blotting and reporter gene assays; eNOS activity was assessed by the measurement of eNOS phosphorylation. Both the mRNA and protein concentrations of hSR-BI/CLA-1 were significantly increased by 2ME2 in HUVECs. 2ME2 also dose-dependently increased the transcriptional activity of the hSR-BI/CLA-1 promoter. The effect of 2ME2 treatment on the promoter activity of hSR-BI/CLA-1 was abrogated by treatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase, as was the increase in HDL-induced eNOS activation. Notably, constitutively active Akt increased the activity of the hSR-BI/CLA-1 promoter, whereas dominant-negative Akt abolished the effect of 2ME2 treatment on hSR-BI/CLA-1 promoter activity. The nuclear Sp1 protein concentration was significantly increased by exposure to 2ME2 and Sp1 overexpression increased the promoter activity of the hSR-BI/CLA gene. Furthermore, knockdown of Sp1 inhibited the effect of 2ME2 treatment on hSR-BI/CLA-1 protein expression. These results indicate that 2ME2 treatment increases HDL-dependent eNOS phosphorylation by upregulating endothelial hSR-BI/CLA-1 expression, suggesting that 2ME2 has a potential therapeutic value in the treatment of preeclampsia.

Ectopic Cortisol-producing Adrenocortical Adenoma Detected by 131I-6ß-iodomethyl-norcholesterol Scintigraphy.

A 50-year-old man was referred to our department for overt Cushing's syndrome (CS). His plasma cortisol concentrations were 314 µg/L, and his urinary cortisol concentrations were 431 µg/day. The plasma adrenocorticotropic hormone (ACTH) concentration was below the detectable limit. Computed tomography revealed atrophy of both adrenal glands and the presence of a left pararenal tumor. 131I-6ß-iodomethyl-norcholesterol scintigraphy showed an intense uptake by the left pararenal tumor. These findings suggested that the left pararenal tumor was ectopic cortisol-producing adrenocortical adenoma. This case serves as a reminder that 131I-6ß-iodomethyl-norcholesterol scintigraphy is an effective method for diagnosing ACTH-independent CS in which no adrenal tumor has been found.

Multiple gastrointestinal stromal tumors caused by a novel germline KIT gene mutation (Asp820Gly): a case report and literature review.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract; most of them have gain-of-function mutations of the KIT gene. There have been rare cases of families with multiple GISTs, that had autosomal dominant germline KIT mutations. Here, we present a case of multiple GISTs caused by a novel germline KIT mutation. Intraoperatively, the main tumor was present in the body of the stomach, and multiple small nodules were detected mainly in the upper and middle part of the gastric wall; several nodules were also present in the small bowel wall. The main tumor and surrounding nodules were resected. DNA sequencing of the tumor tissue, adjacent normal mucosal tissue, and peripheral blood leukocytes revealed that the patient had germline Asp820Gly mutation in exon 17 of the KIT gene. This is the first case with germline Asp820Gly mutation in exon 17 of the KIT gene.

Role of ATP-binding cassette transporter A1 in suppressing lipid accumulation by glucagon-like peptide-1 agonist in hepatocytes.

OBJECTIVE: Adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) influences hepatic cholesterol transportation. Accumulation of hepatic cholesterol leads to fatty liver disease, which is improved by glucagon-like peptide 1 (GLP-1) in diabetes. Therefore, we analyzed the molecular mechanism in the regulation of hepatic ABCA1 by GLP-1 analogue exendin-4. METHODS: Hepatic ABCA1 expression and transcription were checked by western blotting, real-time polymerase chain reaction (PCR), and luciferase assay in HepG2 cells. Chromatin immunoprecipitation (ChIP) and site-directed mutagenesis were employed to determine transcriptional regulation of the ABCA1 gene. Prolactin regulatory element-binding (PREB)-transgenic mice were generated to access the effect of exendin-4 on improving lipid accumulation caused by a high-fat diet (HFD). RESULTS: Exendin-4 stimulated hepatic ABCA1 expression and transcription via the Ca2+/calmodulin (CaM)-dependent protein kinase kinase/CaM-dependent protein kinase IV (CaMKK/CaMKIV) pathway, whereas GLP-1 receptor antagonist exendin9-39 cancelled this effect. Therefore, exendin-4 decreased hepatic lipid content. ChIP showed that PREB could directly bind to the ABCA1 promoter, which was enhanced by exendin-4. Moreover, PREB stimulated ABCA1 promoter activity, and mutation of PREB-binding site in ABCA1 promoter cancelled exendin-4-enhanced ABCA1 promoter activity. Silencing of PREB attenuated the effect of exendin-4 and induced hepatic cholesterol accumulation. Blockade of CaMKK by STO-609 or siRNA cancelled the upregulation of ABCA1 and PREB induced by exendin-4. In vivo, exendin-4 or overexpression of PREB increased hepatic ABCA1 expression and decreased hepatic lipid accumulation and high plasma cholesterol caused by a HFD. CONCLUSIONS: Our data shows that exendin-4 stimulates hepatic ABCA1 expression and decreases lipid accumulation by the CaMKK/CaMKIV/PREB pathway, suggesting that ABCA1 and PREB might be the therapeutic targets in fatty liver disease.

Changes in oxidative stress levels during two weeks of smoking cessation treatment and their association with nutritional characteristics in Japanese smokers.

Although several experimental studies have reported that oxidative stress levels decrease during smoking cessation, how they change among general smokers has yet to be completely elucidated. In the present study, a total of 23 smokers who underwent smoking cessation treatment were observed for two-week changes in their levels of 8-OHdG and 8-isoprostane. Physical and nutritional characteristics were measured at the initial patient visit, and casual urine samples were collected at the initial visit and at a follow-up visit two weeks later. Oxidative stress was measured by a high performance liquid chromatography electrochemical detector, and the two-week difference in the levels of oxidative stress was assessed according to demographic and nutrient factors. Neither the urinary level of 8-OHdG nor that of 8-isoprostane decreased, although the cotinine level was decreased at two weeks. A Two-way repeated ANOVA revealed a significant interaction for fat intake by time for the change in the 8-OHdG level (P=0.03) and significant interactions for α-tocopherol intake (P=0.03), iron intake, and carbohydrate intake (P=0.03), all of which were time-dependent for the change in the 8-isoprostane level. The 8-OHdG level decreased among smokers with a high fat intake and was increased with a low fat intake. The 8-isoprostane levels were decreased among smokers with a high carbohydrate intake and increased with a low carbohydrate intake, decreased with a low iron intake and increased with a high iron intake and decreased with a low α-tocopherol intake and increased with a high α-tocopherol intake. Although the present study failed to observe a decrease in oxidative stress levels during the two-week smoking cessation period, we hypothesize that the intake levels of specific nutrients when initiating smoking cessation treatment may predict any subsequent changes in the oxidative stress levels.

De-escalated neoadjuvant therapy with nanoparticle albumin-bound paclitaxel and trastuzumab for low-risk pure HER2 breast cancer.

PURPOSE: Neoadjuvant trastuzumab combined with anthracycline and taxane is now considered a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A less toxic, non-anthracycline regimen has been considered as a treatment option for patients with node-negative small tumors. Estrogen receptor-negative and HER2-positive (pure HER2) tumors are more likely to achieve a pathological complete response (pCR). This study evaluates the activity and safety of neoadjuvant nanoparticle albumin-bound paclitaxel (nab-PTX) plus trastuzumab for pure HER2 breast cancer in patients with low risk of relapse. METHODS: We treated patients with tumors measuring ≤ 3 cm, node-negative, pure HER2 breast cancer using neoadjuvant nab-PTX 260 mg/m2 with trastuzumab every 3 weeks for four cycles. The primary endpoint was the pCR rate. The secondary endpoints included the clinical response rate, disease-free survival, pathologic response rate (defined as pCR or minimal residual invasive disease only in the breast), breast-conserving surgery conversion rate, safety, and disease-free survival. Depending on the pathological findings of surgical specimens, the administration of adjuvant anthracycline could be omitted. RESULTS: Eighteen patients were enrolled. No patient required dose delays or reductions; none showed disease progression, and all patients underwent surgery as scheduled. Of the 18 patients, 66.7% achieved pCR, and the adjuvant anthracycline regimen was omitted for all patients. The incidence of severe adverse events was quite low. CONCLUSION: This less toxic, anthracycline-free regimen appears to be a significantly effective neoadjuvant therapy for patients with pure HER2 breast cancer at low relapse risk.

Comparing the Incidences of Occult Contralateral Hernia under Laparo-Endoscopic Techniques and of Contralateral Metachronous Hernia after a Unilateral Groin Hernia Repair in Open Technique.

The aim of this study was to evaluate the utility of immediate repair of a contralateral occult hernia at the same time as incipient hernia repair. A total of 693 patients were diagnosed preoperatively with a unilateral groin hernia from January 2006 to December 2017. The open technique was used for 541 patients, and the laparo-endoscopic technique was used for 152 patients. The incidences of occult contralateral hernia confirmed during surgery under laparo-endoscopic techniques and those of contralateral metachronous hernia after a unilateral groin hernia repair with open technique were compared. Fifty-one (9.4%) of 541 patients underwent a contralateral metachronous hernia repair after unilateral groin hernia repair. Twenty-three (15.1%) of 152 patients had occult contralateral hernias using laparo-endoscopic techniques. There was a significant difference in the incidence of contralateral metachronous hernia and that of occult contralateral hernia (P = 0.02). It is concluded that finding and repairing an occult contralateral hernia at the time of laparo-endoscopic technique has the advantage of avoiding a second operation. However, it has been considered overtreatment to repair all patients with an occult contralateral hernia.

Generation of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats.

Regeneration of human kidneys in animal models would help combat the severe shortage of donors in transplantation therapy. Previously, we demonstrated by interspecific blastocyst complementation between mouse and rats, generation of pluripotent stem cell (PSC)-derived functional pancreas, in apancreatic Pdx1 mutant mice. We, however, were unable to obtain rat PSC-derived kidneys in anephric Sall1 mutant mice, likely due to the poor contribution of rat PSCs to the mouse metanephric mesenchyme, a nephron progenitor. Here, conversely, we show that mouse PSCs can efficiently differentiate into the metanephric mesenchyme in rat, allowing the generation of mouse PSC-derived kidney in anephric Sall1 mutant rat. Glomerular epithelium and renal tubules in the kidneys are entirely composed of mouse PSC-derived cells expressing key functional markers. Importantly, the ureter-bladder junction is normally formed. These data provide proof-of-principle for interspecific blastocyst complementation as a viable approach for kidney generation.

Bilateral Adrenocortical Adenomas along with Virilization and Cushing's Syndrome.

We herein present the case of a 27-year-old woman with clinical and biochemical features of virilism. Imaging studies revealed the presence of a bilateral adrenal tumor. Although the secretion of androgens was remarkable, the autonomous production of cortisol was also evident because of a loss of circadian rhythm and the absence of cortisol suppression by dexamethasone. The surgical excision of both adrenal tumors was performed, and the histological examination showed no malignancy. We also report the successful pregnancy and delivery of the patient who showed evolving adrenocortical insufficiency along with virilization and Cushing's syndrome and who continued to receive glucocorticoid replacement therapy during pregnancy.

An interspecies barrier to tetraploid complementation and chimera formation.

To study development of the conceptus in xenogeneic environments, we assessed interspecies chimera formation as well as tetraploid complementation between mouse and rat. Overall contribution of donor PSC-derived cells was lower in interspecies chimeras than in intraspecies chimeras, and high donor chimerism was associated with anomalies or embryonic death. Organ to organ variation in donor chimerism was greater in interspecies chimeras than in intraspecies chimeras, suggesting species-specific affinity differences among interacting molecules necessary for organogenesis. In interspecies tetraploid complementation, embryo development was near normal until the stage of placental formation, after which no embryos survived.

[A Case of Interstitial Pneumonitis Induced by TAS-102 for Liver and Lung Metastasis of Colorectal Cancer].

A 78-year-old man who developed metastatic liver and lung cancer after undergoing surgery for rectal and sigmoid colon cancer was treated with TAS-102 as fourth-line chemotherapy. He developed high fever and dyspnea and was referred to the emergency room 16 days after receiving the first course of TAS-102. Chest X-ray and computed tomography examinations showed bacterial pneumonia. He was treated with tazobactam/piperacillin, but developed severe dyspnea 4 days later. A diffuse ground-glass appearance was observed in both the lungs on chest X-ray examination, and drug-induced interstitial pneumonitis was suspected. Oxygenation and respiratory support were immediately administered, and steroid pulse therapy with methylprednisolone at 1,000mg/day was initiated. His symptoms and radiographic findings dramatically improved. The TAS102-J003 trial, a double-blind phase 2 trial, showed that interstitial pneumonitis occurs at a rate of only 0.9%, but can lead to severe complications, as observed in the present case. The possibility of interstitial pneumonitis should always be considered when a patient develops a fever and respiratory disorder during treatment containing TAS-102.