COL8A1 enhances the invasion/metastasis in MDA-MB-231 cells via the induction of IL1B and MMP1 expression.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high probability of metastasis and a lack of specific targets and targeted therapeutics. Previously, we have reported that COL8A1, which is highly expressed in the mesenchymal stem-like (MSL) subtype of TNBC, facilitates TNBC growth via FAK/Src activation. Furthermore, we have found that COL8A1 enhances the invasion and metastasis of MDA-MB-231 cells, classified into MSL. However, the mechanism of invasion and metastasis by COL8A1 remains unclear. Here, we investigated the biological function of COL8A1 on the invasion and metastasis of MDA-MB-231 cells. METHODS: The invasion and metastasis of MDA-MB-231 cells were evaluated using three-dimensional (3D) culture methods and xenograft mouse models. DNA microarray analysis examined the gene expression in COL8A1-overexpressing MDA-MB-231 cells and control cells. Gene expression was verified using RT-qPCR. RESULTS: COL8A1-deficient cells showed little or no metastasis, whereas forced expression of COL8A1 in MDA-MB-231 cells, the MSL subtype of TNBC cell lines, significantly promoted distant metastasis after tumor resection. As with in vivo, 3D invasion assay revealed that COL8A1 increased the invasion capacity of MDA-MB-231 and Hs578T cells, classified into the MSL subtype of TNBC. DNA microarray analysis for COL8A1-overexpressing cells indicated that COL8A1 induces interleukin 1B (IL1B) and matrix metalloproteinase-1 (MMP1) expression, both of which are correlated with COL8A1 expression in the mesenchymal subtypes of TNBC, and the Kaplan-Meier plotter provided evidence that the prognosis in the MSL subtype was strongly associated with both gene expressions and COL8A1 expression. Pharmacological inhibitor treatment showed that COL8A1 regulated IL1B and MMP1 expression through a different pathway. Moreover, the knockdown of each gene expression reduced the invasion capacity of COL8A1-overexpressing MDA-MB-231 and Hs578T cells. CONCLUSION: Our findings indicate that COL8A1-induced IL1B and MMP1 enhanced the invasion and metastasis of the MSL subtype of TNBC. Considering our previous findings that COL8A1 promotes tumor growth, COL8A1 may be a prognostic and practical therapeutic target in TNBC.

Development of a novel drug information provision system for Kampo medicine using natural language processing technology.

BACKGROUND: Kampo medicine is widely used in Japan; however, most physicians and pharmacists have insufficient knowledge and experience in it. Although a chatbot-style system using machine learning and natural language processing has been used in some clinical settings and proven useful, the system developed specifically for the Japanese language using this method has not been validated by research. The purpose of this study is to develop a novel drug information provision system for Kampo medicines using a natural language classifier® (NLC®) based on IBM Watson. METHODS: The target Kampo formulas were 33 formulas listed in the 17th revision of the Japanese Pharmacopoeia. The information included in the system comes from the package inserts of Kampo medicines, Manuals for Management of Individual Serious Adverse Drug Reactions, and data on off-label usage. The system developed in this study classifies questions about the drug information of Kampo formulas input by natural language into preset questions and outputs preset answers for the questions. The system uses morphological analysis, synonym conversion by thesaurus, and NLC®. We fine-tuned the information registered into NLC® and increased the thesaurus. To validate the system, 900 validation questions were provided by six pharmacists who were classified into high or low levels of knowledge and experience of Kampo medicines and three pharmacy students. RESULTS: The precision, recall, and F-measure of the system performance were 0.986, 0.915, and 0.949, respectively. The results were stable even with differences in the amount of expertise of the question authors. CONCLUSIONS: We developed a system using natural language classification that can give appropriate answers to most of the validation questions.

COL8A1 facilitates the growth of triple-negative breast cancer via FAK/Src activation.

PURPOSE: Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes, and treatment options are limited because of the lack of signature molecules and heterogeneous properties of cancer. COL8A1 expression is higher in breast cancer than in normal tissues and is strongly correlated with worse overall survival in patients with breast cancer. However, the biological function of COL8A1 on cancer progression is not fully understood. In this study, we investigated the biological function of COL8A1 on TNBC progression. METHODS: COL8A1-deficient cells were generated using the CRISPR-Cas9 system. The tumor growth and metastasis of TNBC cells were evaluated using three-dimensional culture (3D) methods and xenograft mouse models. The activation of focal adhesion kinase (FAK)/Src by COL8A1 in TNBC cells was evaluated by immunoblotting. RESULTS: COL8A1 expression was primarily distributed into TNBC cell lines. Further, relapse-free survival in TNBC patients with the MSL subtype was strongly associated with the COL8A1 expression. MDA-MB-231 and Hs578T cells, classified as the MSL subtype, strongly express COL8A1, and COL8A1 protein expression was induced by hypoxia in both cell lines. Loss of COL8A1 expression inhibited spheroid /tumor growth and metastasis in vitro and in vivo. Further, exogenous COL8A1 promoted TNBC growth via the FAK/Src activation. Finally, the spheroid growth of MDA-MB-231 and Hs578T cells was inhibited by defactinib, a FAK inhibitor, without cytotoxicity. CONCLUSION: These results indicate that COL8A1-mediated FAK/Src activation produces a more aggressive phenotype in TNBC, and its target inhibition may be an efficacious treatment for TNBC.

Comparing incidences of infusion site reactions between brand-name and generic vinorelbine in patients with non-small cell lung cancer.

AIM: This study aimed to compare the incidence of infusion site reactions (ISRs) induced by intravenous administration of brand-name and generic vinorelbine (VNR) for treating non-small cell lung cancer. METHOD: This single-centre retrospective cohort study was conducted by medical chart review of VNR infusions. ISRs were defined as symptoms around the infusion site, including pain, redness and swelling. ISRs requiring treatment were defined as ISRs requiring treatments including steroid ointments, vein repuncture and local steroid injections. RESULTS: In all, 1973 VNR infusions were administered to 340 patients (brand-name 141 patients, generic 199 patients). ISRs and ISRs requiring treatment were observed in 161 and 100 patients, respectively. The ISR incidence per patient and per injection was significantly higher in generic VNR-treated patients than in brand-name VNR-treated patients (53.3% vs 39.0%, P = 0.0112 and 15.0% vs 9.9%, P = 0.0008, respectively). The frequency of ISRs requiring treatment was also significantly higher in the generic group (per patient 36.7% vs 19.2%, P = 0.0005; per injection 11.3% vs 5.5%, P < 0.0001). Multivariate analysis revealed that generic VNR was significantly associated with an increased risk of ISRs (per patient adjusted odds ratio [AOR] 1.775, P = 0.0155; per injection AOR 1.672, P = 0.004) and ISRs requiring treatment (per patient AOR 2.422, P = 0.0012; per injection AOR 2.286, P = 0.001). CONCLUSION: Intravenous infusion of generic VNR was associated with an increased risk of ISRs. Further research is needed to elucidate the mechanism underlying the increased incidence of ISRs with generic VNR.

Relationship between Low Pretreatment Geriatric Nutritional Risk Index and Poor Tolerability of Azacitidine in Patients with Myelodysplastic Syndromes.

BACKGROUND: Predicting tolerability and treatment-related risks associated with azacitidine (AZA) in patients with myelodysplastic syndromes (MDS) before the initiation of therapy is required for appropriate treatment. Thus, in this study, the nutritional status of patients with MDS prior to AZA treatment was evaluated using the geriatric nutritional risk index (GNRI). Tolerability and overall survival (OS) after AZA initiation were also investigated. METHODS: This was a single-center retrospective observational study. A total of 59 patients with MDS treated with AZA were assessed using GNRI, and a comparison of undernourished (GNRI <92, n = 27) and non-undernourished (GNRI ≥92, n = 32) patients was performed. RESULTS: The undernourished group had a significant reduction in the number of patients that successfully completed 4 cycles of AZA treatment compared with the non-undernourished group (undernourished group, 11/27 patients, 40.7% vs. non-undernourished group, 24/32 patients, 75.0%; p = 0.009). Factors associated with the difference included karyotype and GNRI. There was also a significant increase in the rate of infectious complications in the undernourished group compared with the non-undernourished group (undernourished group, 33/60 cycles, 55.0% vs. non-undernourished group, 31/92 cycles, 33.7%; p = 0.012). Lastly, a significant reduction in OS was observed in the undernourished group compared with the non-undernourished group (undernourished group, 11.5 months; 95% CI, 5.2-16.7 vs. non-undernourished group, 21.9 months; 95% CI, 13.8-24.0; p = 0.026). Factors associated with OS included both the revised International Prognostic Scoring System (IPSS-R) and GNRI. CONCLUSIONS: These results indicate that predicting treatment completion and adverse events in patients with MDS prior to AZA treatment is important. This study suggests GNRI may be a valuable nutritional assessment tool for determining tolerability and OS of AZA treatment.

Endocan as a prognostic biomarker of triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) has aggressive characteristics and fewer treatment options than other subtypes. The purpose of this study was to explore prognostic biomarkers for TNBC that can be easily detected from the blood samples. METHODS: MDA-MB-231 and MDA-MB-231BR, a brain metastatic variant of the human TNBC cell line MDA-MB-231, were used as less and more aggressive models of TNBC, respectively. The extent to which the candidate gene/protein identified by RNA sequencing correlated well with aggressiveness of TNBC and how much protein was detected from the blood of tumor-bearing mice were evaluated. RESULTS: Both the in vitro proliferation and in vivo tumor growth of MDA-MB-231BR were more rapid than those of MDA-MB-231. RNA sequencing identified ESM1 as a gene that was expressed significantly more in MDA-MB-231BR than in MDA-MB-231, and qRT-PCR confirmed a significantly higher expression of ESM1 in MDA-MB-231BR xenograft in vivo. Furthermore, Kaplan-Meier analysis of relapse-free survival demonstrated that TNBC patients with high ESM1 expression had clearly worse relapse-free survival than those with low ESM1 expression, which was consistent with our preclinical findings. Endocan, a protein of ESM1 gene product, was successfully detected in both conditioned medium from MDA-MB-231BR and plasma samples from mice bearing MDA-MB-231BR xenograft, which showed a significantly distinct pattern from less aggressive MDA-MB-231. Moreover, bisulfite sequence analysis revealed that overexpression of ESM1 in MDA-MB-231BR might be attributed to DNA demethylation in an upstream region of the ESM1 gene. CONCLUSION: This study indicates that endocan could be used as a blood-based prognostic biomarker in TNBC patients.

Controlled Secretion of the Anticancer Protein MDA-7 from Engineered Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) have been explored as a "live" carrier of cytokines for targeted cancer therapy, but, in earlier reports in the literature, the secretion process of therapeutic cytokines was not regulated. The purpose of this study was to generate MSCs to conditionally secrete the melanoma differentiation-associated gene-7 (MDA-7) tumor-suppressor protein. To control the secretion of MDA-7 from MSCs, a well-established tetracycline-controlled transcriptional activation system was incorporated into MDA-7 plasmid. MDA-7 gene expression was induced in the engineered MSCs only in the presence of doxycycline, as characterized by quantitative reverse transcription (qRT)-PCR. Enzyme-linked immunosorbent assay (ELISA) also revealed that the MDA-7 protein was secreted from the engineered MSCs only after the cells had been exposed to doxycycline. Both recombinant human MDA-7 protein and the conditioned medium from the engineered MSCs in the presence of doxycycline significantly inhibited tube formation of human umbilical vascular endothelial cells (HUVECs), indicating that our system could be used for targeted, antiangiogenic therapy. Overall, this study provides useful information on the potential use of engineered MSCs for the controlled secretion of therapeutic proteins, in this case MDA-7, for targeted cancer therapy.

Mechanisms of cisplatin-induced muscle atrophy.

Fatigue is the most common side effect of chemotherapy. However, the mechanisms of "muscle fatigue" induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue.

Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and the decrease in aquaporins in the colon.

Diarrhea is a common side effect experienced by cancer patients undergoing clinical chemotherapy, such as with 5-fluorouracil (5-FU). However, the precise mechanisms underlying 5-FU-induced diarrhea remain unclear. In the present study, we examined the role of neutrophil in 5-FU-induced diarrhea. Mice were given 5-FU (50mg/kg, i.p.) daily for 4 days. Sivelestat sodium (100 or 300 mg/kg, i.p., neutorophil elastase inhibitor) or SB225002 (3 or 9 mg/kg, i.p., CXCR2 antagonist) was administered before the administration of 5-FU. Gene expression levels of aquaporin (AQP) 4 and 8, CXCL1, CXCL2, CXCL3, neutrophil elastase (Elane) and myeloperoxidase (MPO) in the colon were examined by real-time RT-PCR. The neutrophil (Ly-6G positive cell) number in the mucosa of colon was measured by flow-cytometric analysis. Administration of 5-FU induced diarrhea and decreased the expression levels of AQP 4 and 8 in the colon. Under the present conditions, the expression levels of CXCL1, CXCL2, CXCL3, the neutrophil markers Elane and MPO, as well as Ly-6G-positive neutrophils, in the colon were significantly increased by 5-FU. Neutrophil recruitment with decreased levels of AQP 4 and 8 were dramatically inhibited by either sivelestat sodium or SB225002. Furthermore, these reagents reduced the 5-FU-induced body weight loss and diarrhea. These findings provide evidence that neutrophil recruitment and neutrophil elastase may decrease the levels of AQP 4 and 8 in the colon of mice treated with 5-FU and contribute to the pathophysiology of 5-FU-induced body weight loss and diarrhea.

Distribution of aquaporin genes and selection of individual reference genes for quantitative real-time RT-PCR analysis in multiple tissues of the mouse.

Aquaporins (AQPs) are a family of water-transporting proteins that are selectively expressed in epithelial, endothelial, and many other cell types of various tissues, where they play important physiological functions. However, the accurate distribution of AQP gene expression has not yet been examined in various tissues of the mouse. We first evaluated the tissue distribution of AQP gene expression using tongue, nasal epithelium, bronchus, trachea, lung, esophagus, stomach, ileum, transverse colon, liver, pancreas, whole blood, thigh muscle, spinal cord, brain, thoracic aorta, heart, kidney, thymus, spleen, skin, eye, and testis of the mouse. Furthermore, for a quantitative analysis, we selected appropriate reference genes for normalized qRT-PCR data in various tissues. The stability of the reference genes was assessed using NormFinder. The stably expressed genes identified in the present study were 18s rRNA. When 18s rRNA was used, as the best reference gene in the present study, the genes for AQPs 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, and 12 were notably expressed in the eye, lung, testis, eye, spinal cord, trachea, kidney, testis, testis, testis, testis, and pancreas. These results, regarding the distribution of AQPs, suggest that AQPs may be involved in various physiological and pathophysiological processes.

Single­agent nintedanib suppresses metastatic osteosarcoma growth by inhibiting tumor vascular formation.

New therapeutic approaches are needed for osteosarcoma, which is the most common malignancy of the bone, especially for metastatic cases. Nintedanib is a potent, oral tyrosine kinase inhibitor approved for treating idiopathic pulmonary fibrosis, which blocks a variety of receptor signals, including fibroblast growth factor receptors, vascular endothelial growth factor receptors and platelet-derived growth factor receptors. The present study assessed the effect of nintedanib on previously developed mouse AXT osteosarcoma cells, and on AXT-derived osteosarcoma developed in C57BL/6 mice, which displays lethal tumors with osteoid formation and lung metastatic lesions that mimics human disease. In vitro analysis, including flow cytometry and immunoblotting, revealed that nintedanib inhibited AXT cell proliferation and cell cycle progression, induced apoptosis, and inactivated AKT and ERK1/2. Immunoblot analysis using tumor lysates demonstrated that nintedanib inhibited its target molecules in vivo. As a single agent, nintedanib decreased the size of primary AXT-derived osteosarcoma, and reduced circulating tumor cells and lung metastasis. Immunohistochemical findings indicated that nintedanib exerted antitumor activity mainly by inhibiting the formation of CD31-positive tumor vasculature, while αSMA-positive cells were still enriched in tumors after nintedanib treatment. In addition, nintedanib exhibited an anti-osteosarcoma effect on C57BL/6 severe combined immunodeficient mice in which T- and B-cell function is obsolete, suggesting that the antitumor effect of nintedanib was not attributable to antitumor immunity. Collectively, these findings indicated that nintedanib holds potential for treating osteosarcoma.

Evaluation of the Simple Suspension Method for Oral Anticancer Drugs.

The simple suspension method (SSM) involves administering tablets or capsules using a tube after disintegration and suspension in hot water without crushing or opening the capsule. Particularly, for anticancer drugs, it is an excellent method of administration that reduces the risk of exposure during dispensing. In contrast, information on SSM for individual drugs is insufficient. Anticancer drugs present a therapeutic challenge because their information is limited. We investigated whether SSM is possible with 36 anticancer drugs. Furthermore, we examined the pH of the suspension of these drugs, for which no information on SSM is available. We found that suspension was possible for 24 of the 36 drugs. Furthermore, the pH of the suspension was measured, which provided important information when considering dissolution solutions other than hot water. Little changes in the pH were observed before or after passing through the tube. The results of this study may improve medication adherence in patients with cancer experiencing dysphagia.

Potential risk of driving performance under combined conditions of taking second-generation antihistamines and attending calls using a hands-free function.

OBJECTIVE: Although second-generation antihistamines have reduced sedation-related side effects compared to first-generation antihistamines, sedation may still impair motor vehicle driving performance. Moreover, receiving/making phone calls using a hands-free function can negatively affect driving performance. Therefore, herein, driving performance was evaluated using a driving simulator to gain insights into the hazards of driving by combining second-generation antihistamines and a calling task, i.e., simulated calls using a hands-free function. METHODS: In this study, 20 subjects drove in a driving simulator in the absence or presence of a calling task while taking or not taking second-generation antihistamines. Driving performances for nonemergency and emergency events were determined, and a comparative analysis of intra-individual variability when taking and not taking second-generation antihistamines was conducted. RESULTS: First, when nonemergency and emergency were examined in the absence of a calling task, no significant difference in driving performance was observed between taking and not taking second-generation antihistamines. Next, when the nonemergency event was examined in the presence of a calling task, no significant difference in driving performance was observed between taking and not taking second-generation antihistamines. However, when the emergency event was examined in the presence of a calling task, a significant difference in driving performance was observed between taking and not taking second-generation antihistamines, thus resulting in reduced driving performance. CONCLUSIONS: The new system with added calling tasks allowed the extraction of the potential risks of driving performance of second-generation antihistamines that may have been previously overlooked. This study suggests that pharmacists and other healthcare professionals may need to instruct people taking any second-generation antihistamine to focus on driving and not on subtasks that require cognitive load such as talking while driving.

Increased expression of 5-HT3 and NK 1 receptors in 5-fluorouracil-induced mucositis in mouse jejunum.

BACKGROUND AND OBJECTIVE: Although 5-fluorouracil (5-FU) is a widely used as chemotherapy agent, severe mucositis develops in approximately 80% of patients. 5-FU-induced small intestinal mucositis can cause nausea and vomiting. The current study was designed to investigate peripheral alterations due to the 5-FU-induced mucositis of neuronal and non-neuronal 5-HT3 and NK1 receptor expression by immunohistochemical analysis. METHODS: 5-FU was administered by i.p. injection to C57BL/6 mice. After 4 days, segments of the jejunum were removed. The specimens were analyzed by immunohistochemistry, real-time PCR, and enzyme immunoassay. RESULTS: The numbers of 5-HT3 receptor immunopositive cells and nerve fibers in mucosa were increased by 5-FU treatment. The 5-HT3 receptor immunopositive cell bodies were found only in jejunal submucosa and myenteric plexus in the 5-FU-treated mice. The numbers of NK1 receptor cells in mucosa and immunopositive expression of NK1 receptors in deep muscular plexus were dramatically increased in 5-FU-treated mice. Real-time PCR demonstrated that 5-FU treatment significantly increased mRNA levels of 5-HT3A, 5-HT3B, and NK1 receptors. The amounts of 5-HT and substance P increased after 5-FU treatment. The 5-HT3 or NK1 receptor immunopositive cells colocalized with both 5-HT and substance P. Furthermore, 5-HT3 and NK1 receptors colocalized with CD11b. CONCLUSIONS: The 5-HT3 and NK1 immunopositive macrophages and mucosal mast cells in lamina propria release 5-HT and substance P, which in turn activate their corresponding receptors on mucosal cells in autocrine and paracrine manners. It is assumed to result in the release of 5-HT and substance P in mucosa.

Safety survey on infusion reaction and cardiac dysfunction when switching from reference trastuzumab (HERCEPTIN®) to biosimilar trastuzumab (Trastuzumab­NK) in the treatment of HER2­positive breast cancer.

The present study is a safety survey of patients with human epidermal growth factor receptor type 2-positive, chemotherapy-naive breast cancer treated with trastuzumab plus paclitaxel at the Saitama Cancer Center (Saitama, Japan) between April 2018 and March 2022. The expression of infusion reaction (IR) and the effect on cardiac function were investigated in patients who switched from reference trastuzumab (HERCEPTIN®) to biosimilar trastuzumab (Trastuzumab-NK) and continued treatment (switching group). The two groups (reference vs. biosimilar trastuzumab) had no significant difference in the expression of IR (P>0.999). In the switching group, IR associated with switching did not occur in all nine eligible patients. Left ventricular ejection fraction (LVEF) was used to assess cardiac function, and no patient in either group experienced a significant decrease in LVEF with treatment, meaning that there was no effect of switching on the decrease in LVEF. These results suggested that switching from reference to biosimilar trastuzumab may not have a significant effect on the frequency of IR expression or the occurrence of cardiac dysfunction.

Impact of lenvatinib-induced proteinuria and renal dysfunction in patients with thyroid cancer.

Background: Proteinuria is the most frequent adverse event of lenvatinib use. However, the association between lenvatinib-induced proteinuria and renal dysfunction remains unclear. Methods: We retrospectively reviewed medical records of patients with thyroid cancer without proteinuria treated with lenvatinib as a first-line systemic therapy at the initiation of treatment to assess the association between lenvatinib-induced proteinuria and renal function and the risk factors for the development of ≥3+ proteinuria on a dipstick test. Proteinuria was assessed by the dipstick test throughout the treatment in all cases. Results: Of the 76 patients, 39 developed ≤2+ proteinuria (low proteinuria group) and 37 developed ≥3+ proteinuria (high proteinuria group). There was no significant difference in estimated glomerular filtration rate (eGFR) between high and low proteinuria groups at each time point, but there was a trend toward a significant decrease in eGFR of -9.3 ml/min/1.73 m2 in all patients after 2 years of treatment. The percentage of change in eGFR (ΔeGFR) significantly decreased in the high proteinuria group compared to that in the low proteinuria group (ΔeGFR: -6.8% vs. -17.2%, p=0.04). However, there was no significant difference in development of severe renal dysfunction with eGFR <30 ml/min/1.73 m2 between the two groups. Moreover, no patients permanently discontinued treatment because of renal dysfunction in both groups. Furthermore, renal function after completion of lenvatinib was reversible. Conclusions: There was no association between the degree of lenvatinib-induced proteinuria and renal function. Therefore, treatment should be continued with attention to renal function, regardless of the degree of proteinuria.

Association between baseline blood pressure and the incidence of lenvatinib-induced hypertension in patients with thyroid cancer.

BACKGROUND: Hypertension is the most frequently occurring adverse event of lenvatinib, recognized relatively early in its course. However, the trend in blood pressure after the initiation of lenvatinib and the outcomes with antihypertensive treatment are unclear. This study aimed to clarify the association between baseline blood pressure and the incidence of lenvatinib-induced hypertension in patients with thyroid cancer. METHODS: This retrospective study included 65 patients without hypertension at the time of lenvatinib initiation. Patients were divided into two groups: those who developed hypertension grade ≥3 (HTN group) and those who did not develop hypertension grade ≥3 (non-HTN group). RESULTS: Of the 65 patients, 46 (71%) developed hypertension grade ≥3. In both HTN and non-HTN groups, blood pressure significantly increased the day after lenvatinib initiation. There was no significant difference in the elevated values of both the changes in systolic blood pressure (ΔSBP) and diastolic blood pressure (ΔDBP) between the two groups, with an average increase of 20 mmHg in SBP and 13 mmHg in DBP from baseline. The median (range) time to the onset of hypertension grade ≥3 was 2 days (1-12 days). In the multivariable analysis, patients with normal (SBP 120-129 mmHg and/or DBP 80-84 mmHg) or high-normal baseline blood pressure (SBP 130-139 mmHg and/or DBP 85-89 mmHg) were at higher risk of developing hypertension grade ≥3 than those with optimal baseline blood pressure (SBP <120 mmHg and DBP <80 mmHg) (odds ratio [OR], 5.07; 95% confidential interval [CI] 1.09-23.54 and OR, 7.48; 95% CI, 1.67-33.51, respectively). CONCLUSIONS: Lenvatinib-induced hypertension appears the day after administration, and higher baseline blood pressure is a significant risk factor for developing hypertension grade ≥3. In cases of increased blood pressure with lenvatinib, early initiation of antihypertensives may prevent treatment interruption due to hypertension and maintain the therapeutic intensity of lenvatinib.

＜Editors' Choice＞ Clinical impact of standardized creatinine on dose adjustment of capecitabine.

Although the Cockcroft-Gault equation is still used for the dose adjustment of many drugs that have been approved prior to creatinine standardization, the clinical impact of standardized creatinine in the dose adjustment of capecitabine is poorly understood. We focused on patients with borderline renal function and evaluated the tolerability and safety of capecitabine in patients who received capecitabine plus oxaliplatin (Cape-Ox). We retrospectively identified patients with resected colorectal cancer who had received adjuvant therapy with Cape-Ox regimen. Creatinine clearance (CrCL) was calculated by the Cockcroft-Gault equation with standardized creatinine measured using enzymatic methods, and adjusted CrCL was estimated by adding 0.2 (mg/dL) to the serum creatinine in the equation. We defined patients with "pseudo-normal" renal function as those who had an adjusted CrCL of ≤50 mL/min in patients with normal renal function (CrCL >50 mL/min). We evaluated the tolerability and grade 2 or severer adverse events of capecitabine treatment. One hundred four patients had normal and 10 had impaired renal function (CrCL <50 mL/min). Among the 104 patients with normal renal function, 23 (22.1%) had pseudo-normal renal function. Seventeen patients completed the eight cycles of Cape-Ox therapy without treatment delay or dose reduction, and all of them had truly normal renal function. The patients with pseudo-normal renal function were more likely to have grade 2 or severer thrombocytopenia than those with truly normal renal function. We should recognize correctly the clinical impact of standardized creatinine in the treatment of borderline renal function with Cape-Ox regimen in patients.

Impact of air temperature and drug concentration on liquid emission from elastomeric pumps.

BACKGROUND: Elastomeric pumps (EPs) are devices that allow quantitative and continuous drug administration without the need for electronic control, and they are used by being filled with anticancer agents. Although the package inserts of several manufacturers that provide EPs describe the relationship between the flow rate per unit time and temperature, the solution is only saline solution or 5% glucose solution, and data on anticancer drugs have not been published. In this study, we focused on 5-fluorouracil (5-FU), a drug frequently used in cancer chemotherapy, and examined the effect of changes in standard of EPs and temperature on drug emission. METHODS: We evaluated the EP data of patients treated with Baxter Infusor® LV5 and SV2.5 in terms of emission rate, relationship between 5-FU prescription amount and emission rate, and relationship between emission rate and monthly air temperature in LV5 and SV2.5. The number of EPs sampled in the study was N = 5708 (n = 2988 for LV5 and n = 2720 for SV2.5). RESULTS: In LV5, the emission rate varied from 88 to 97% (median 94.0%), whereas in SV2.5, the emission rate was observed as 97 to 98% (median 97.4%). The 5-FU prescription amount and the emission rate were not correlated in LV5 and SV2.5, respectively (LV5; y = - 0.0015x + 97.305, R2 = 0.0226, SV2.5; y = - 0.001x + 100.25, R2 = 0.0466). LV5 showed a higher emission rate in the months with higher air temperature and a lower emission rate in the month with lower air temperature. In addition, LV5 showed a significant reduction in emission rate compared with SV2.5 in all months (P < 0.001). CONCLUSIONS: In this study, we clarified that air temperature is an important factor that affects the drug emission of EPs. Therefore, it is necessary to examine the conditions for total fluid volume suitable for the air temperature in each region and to provide sufficient information to patients.

CD8+ T cells regulated by CD4+CD25+ regulatory T cells in the early stage exacerbate the development of Dermatophagoides farinae-induced skin lesions via increasing mast cell infiltration in mice.

Atopic dermatitis is a chronic inflammatory skin disease associated with CD4+ Th2 cell-shifted immune responses. Although the infiltration of skin lesions by CD8+ T cells has been recognized, their roles have not been fully defined. In this study, we examined the relationship between CD4+ and CD8+ cells in antigen-induced skin lesions of mice. BALB/c mice were repeatedly challenged with Dermatophagoides farinae (Der f) applied to the right ear nine times. Pre-treatment with anti-CD4 monoclonal antibody (mAb) during the third to sixth challenges, but not the post-treatment during the sixth to ninth challenges, exacerbated the development of Der f-induced ear swelling; pre-treatment with anti-CD25 mAb, which depletes regulatory T cells (Tregs), also exacerbated the lesions. Furthermore, the number of CD8+ T cells in lymph nodes was augmented by these pre-treatments. These findings prompted us to examine the effect of anti-CD8 mAb. Pre-treatment with anti-CD8 mAb, but not post-treatment, strongly inhibited the development of Der f-induced ear swelling; additionally, the epidermal hyperplasia and infiltration of mast cells were inhibited by the pre-treatment. Collectively, we revealed that CD8+ T cells regulated by CD4+CD25+ Tregs in the early stage are key contributors to the development of Der f-induced skin lesions via increasing mast cell infiltration, indicating that CD8+ T and Tregs could be potential therapeutic targets for atopic dermatitis.